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85533BAC69E6E3BBF78B96DE98B9E212

https://www.ema.europa.eu/documents/product-information/litak-epar-product-information_en.pdf

Litak

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT LITAK 2 mg/ml solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each ml of solution contains 2 mg of cladribine (2-CdA). Each vial contains 10 mg of cladribine in 5 ml of solution. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection. Clear, colourless solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications LITAK is indicated for the treatment of hairy cell leukaemia. 4.2 Posology and method of administration Therapy with LITAK should be initiated by a qualified physician with experience in cancer chemotherapy. Posology The recommended posology for hairy cell leukaemia is a single course of LITAK given by subcutaneous bolus injection at a daily dose of 0.14 mg/kg body weight for 5 consecutive days. Deviations from the posology indicated above are not advised. Elderly Experience with patients older than 65 years is limited. Elderly patients should be treated by individual assessment and careful monitoring of the blood counts and of the renal and hepatic function. The risk requires assessment on a case-by-case basis (see section 4.4). Renal and hepatic impairment There are no data on the use of LITAK in patients with renal or hepatic impairment. LITAK is contraindicated in patients with moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) or with moderate to severe hepatic impairment (Child-Pugh score > 6) (see sections 4.3, 4.4 and 5.2). Paediatric population LITAK is contraindicated in patients less than 18 years of age (see section 4.3). Method of administration LITAK is supplied as a ready-to-use solution for injection. The recommended dose is directly withdrawn by a syringe and injected as a subcutaneous bolus injection without dilution. LITAK should be inspected visually for particulate matter and discoloration prior to administration. LITAK should warm up to room temperature prior to administration. 3 Self-administration by the patient LITAK can be self-administered by the patient. Patients should be instructed and trained appropriately. Detailed instructions are contained in the Package Leaflet. 4.3 Contraindications Hypersensitivity to the active substance or any of the excipients listed in section 6.1. Pregnancy and lactation. Patients less than 18 years of age. Moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) or moderate to severe hepatic impairment (Child-Pugh score > 6) (see also section 4.4). Concomitant use of other myelosuppressive medicinal products. 4.4 Special warnings and precautions for use Cladribine is an antineoplastic and immunosuppressive substance that can induce considerable toxic adverse reactions, such as myelo- and immunosuppression, long-lasting lymphocytopenia, and opportunistic infections. Patients undergoing treatment with cladribine should be closely monitored for signs of haematologic and non-haematologic toxicities. Particular caution is advised and risks/benefits should be carefully evaluated if administration of cladribine is considered in patients with increased infection risk, manifested bone marrow failure or infiltration, myelosuppressive pre-treatments, as well as in patients with suspected or manifested renal and hepatic insufficiency. Patients with active infection should be treated for the underlying condition prior to receiving therapy with cladribine. Although anti-infective prophylaxis is not generally recommended, it may be beneficial for patients immunocompromised prior to therapy with cladribine or for patients with a pre-existing agranulocytosis. If severe toxicity occurs, the physician should consider delaying or discontinuing the therapy with the medicinal product until serious complications resolve. In case of infections, antibiotic treatment should be initiated as required. It is recommended that patients receiving cladribine should receive irradiated cellular blood components/products to prevent transfusion-related graft-versus-host disease (Ta-GVHD). Progressive multifocal leukoencephalopathy (PML) Cases of PML, including fatal cases, have been reported with cladribine. PML was reported 6 months to several years after treatment with cladribine. An association with prolonged lymphopenia has been reported in several of these cases. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. Suggested evaluation for PML includes neurology consultation, magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additional follow- up and evaluation may be warranted if no alternative diagnosis can be established. Patients with suspected PML should not receive further treatment with cladribine. 4 Secondary malignancies Like other nucleoside analogues, treatment with cladribine is associated with myelosuppression and profound and prolonged immunosuppression. Treatment with these agents is associated with the occurrence of second malignancies. Secondary malignancies are expected to occur in patients with hairy cell leukaemia. Their frequency varies widely, ranging from 2% to 21%. The peak risk is at 2 years after diagnosis with a median between 40 and 66 months. The cumulative frequencies of second malignancy are 5%, 10-12% and 13-14% following 5, 10 and 15 years respectively after diagnosis of hairy cell leukaemia. Following cladribine, the incidence of second malignancies ranges from 0% to 9.5% after a median observation period of 2.8 to 8.5 years. The frequency of second malignancy following treatment with LITAK was 3.4% in all 232 hairy cell leukaemia patients treated, during a 10-year period. The highest incidence of second malignancy with LITAK was 6.5% after a median follow-up of 8.4 years. Therefore, patients treated with cladribine should be regularly monitored. Haematologic toxicity During the first month following treatment, myelosuppression is most notable and red blood cell or platelet transfusions may be required. Patients with symptoms of bone marrow depression should be treated with caution, since further suppression of bone marrow function should be anticipated. Therapeutic risks and benefits should be carefully evaluated in patients with active or suspected infections. The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment. Dose reduction and regular monitoring of the patient is required in such cases. Pancytopenia is normally reversible and the intensity of bone marrow aplasia is dose-dependent. An increased incidence of opportunistic infections is expected during, and for 6 months following, therapy with cladribine. Careful and regular monitoring of peripheral blood counts is essential during, and for 2 to 4 months following, treatment with cladribine to detect potential adverse reactions and consequent complications (anaemia, neutropenia, thrombocytopenia, infections, haemolysis or bleedings), and to survey haematologic recovery. Fever of unknown origin frequently occurs in patients treated for hairy cell leukaemia and is manifested predominantly during the first 4 weeks of therapy. The origin of febrile events should be investigated by appropriate laboratory and radiologic tests. Less than a third of febrile events are associated with a documented infection. In case of fever related to infections or agranulocytosis, an antibiotic treatment is indicated. Renal and hepatic impairment There are no data on the use of LITAK in patients with renal or hepatic impairment. Clinical experience is very limited and safety of LITAK in these patients is not well established (see sections 4.3 and 5.2). Careful treatment is required in patients with known or suspected renal or hepatic impairment. For all patients treated with LITAK, periodic assessment of renal and hepatic function is advised as clinically indicated. Elderly Elderly patients should be treated by individual assessment and careful monitoring of the blood counts and of the renal and hepatic function. The risk requires assessment on a case-by-case basis (see section 4.2). Prevention of tumour lysis syndrome In patients with a high tumour burden, prophylactic allopurinol therapy to control serum levels of uric acid, together with adequate or increased hydration, should be commenced 24 hours before the start of chemotherapy. A daily oral dose of 100 mg of allopurinol is recommended for a period of 2 weeks. In case of an accumulation of the serum uric acid above the normal range, the dose of allopurinol may be increased to 300 mg/day. Fertility Men being treated with cladribine should be advised not to father a child up to 6 months after treatment and to seek advice of cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with cladribine (see sections 4.6 and 5.3). 5 4.5 Interaction with other medicinal products and other forms of interaction Due to a potential increase of haematological toxicity and bone marrow suppression, cladribine must not be used concomitantly with other myelosuppressive medicinal products. An influence of cladribine on the activity of other antineoplastic agents has not been observed in vitro (e.g. doxorubicin, vincristine, cytarabine, cyclophosphamide) and in vivo. However, an in vitro study revealed cross-resistance between cladribine and nitrogen mustard (chlormethine); for cytarabine, one author has described an in vivo cross-reaction without loss of activity. Due to the similar intracellular metabolism, cross-resistance with other nucleoside analogues, such as fludarabine or 2’-deoxycoformycin may occur. Therefore, simultaneous administration of nucleoside analogues with cladribine is not advisable. Corticosteroids have been shown to enhance the risk for severe infections when used in combination with cladribine and should not be given concomitantly with cladribine. Since interactions with medicinal products undergoing intracellular phosphorylation, such as antiviral agents, or with inhibitors of adenosine uptake may be expected, their concomitant use with cladribine is not recommended. 4.6 Fertility, pregnancy and lactation Pregnancy Cladribine causes serious birth defects when administered during pregnancy. Animal studies and in vitro studies with human cell lines demonstrated the teratogenicity and mutagenicity of cladribine. Cladribine is contraindicated in pregnancy. Women of childbearing potential must use effective contraception during treatment with cladribine and for 6 months after the last cladribine dose. In case of pregnancy during therapy with cladribine, the woman should be informed about the potential hazard to the foetus. Breast-feeding It is unknown whether cladribine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, lactation is contraindicated during treatment with cladribine and for 6 months after the last cladribine dose. Fertility The effects of cladribine on fertility have not been studied in animals. However, a toxicity study conducted with cynomolgus monkeys has shown that cladribine suppresses maturation of rapidly generating cells, including testicular cells. The effect on human fertility is unknown. Antineoplastic agents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on human gametogenesis (see section 5.3). Men being treated with cladribine should be advised not to father a child up to 6 months after treatment and to seek advice of cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with cladribine (see section 4.4). 4.7 Effects on ability to drive and use machines LITAK has a major influence on the ability to drive and use machines. In case certain adverse reactions with a potential impact on performance occur (e.g. dizziness, very common, or drowsiness, which may occur due to anaemia, which is very common), patients should be advised not to drive or use machines. 6 4.8 Undesirable effects Summary of the safety profile Very common adverse reactions observed during the three most relevant clinical trials with cladribine in 279 patients treated for various indications and in 62 patients with hairy cell leukaemia (HCL) were myelosuppression, especially severe neutropenia (41% (113/279), HCL 98% (61/62)), severe thrombocytopenia (21% (58/279), HCL 50% (31/62)) and severe anaemia (14% (21/150), HCL 55% (34/62)), as well as severe immunosuppression/lymphopenia (63% (176/279), HCL 95% (59/62)), infections (39% (110/279), HCL 58% (36/62)) and fever (up to 64%). Culture-negative fever following treatment with cladribine occurs in 10-40% of patients with hairy cell leukaemia and is rarely observed in patients with other neoplastic disorders. Skin rashes (2-31%) are mainly described in patients with other concomitantly administered medicinal products known to cause rash (antibiotics and/or allopurinol). Gastrointestinal adverse reactions like nausea (5-28%), vomiting (1-13%), and diarrhoea (3-12%) as well as fatigue (2-48%), headache (1-23%), and decreased appetite (1-22%) have been reported during treatment with cladribine. Cladribine is unlikely to cause alopecia; mild and transient alopecia for a few days was observed in 4/523 patients during the treatment, but could not clearly be associated with cladribine. Tabulated list of adverse reactions Adverse reactions that have been reported are listed in the table below by frequency category and system organ class. The frequencies are defined as follows: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). For severity, please see text below the table. 7 Infections and infestations Very common: infections * (e.g. pneumonia *, septicaemia *) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common: second malignancies * Rare: tumour lysis syndrome * Blood and lymphatic system disorders Very common: pancytopenia/myelosuppression *, neutropenia, thrombocytopenia, anemia, lymphopenia Uncommon: haemolytic anaemia * Rare: hypereosinophilia Very rare: amyloidosis Immune system disorders Very common: immunosuppression * Rare: graft-versus-host disease * Metabolism and nutrition disorders Very common: decreased appetite Uncommon: cachexia Nervous system disorders Very common: headache, dizziness Common: insomnia, anxiety Uncommon: somnolence, paraesthesia, lethargy, polyneuropathy, confusion, ataxia Rare: apoplexy, neurological disturbances in speech and swallowing Very rare: depression, epileptic seizure Eye disorders Uncommon: conjunctivitis Very rare: blepharitis Cardiac disorders Common: tachycardia, heart murmur, hypotension, epistaxis, myocardial ischemia * Rare: Cardiac failure, atrial fibrillation, cardiac decompensation Vascular disorders Very common: purpura Common: petechiae, haemorrhages * Uncommon: phlebitis Respiratory, thoracic and mediastinal disorders Very common: abnormal breath sounds, abnormal chest sounds, cough Common: shortness of breath, pulmonary interstitial infiltrates mostly due to infectious aetiology, mucositis Uncommon: pharyngitis Very rare: lung embolism Gastrointestinal disorders Very common: nausea, vomiting, constipation, diarrhoea Common: gastrointestinal pain, flatulence Rare: ileus Hepato-biliary disorders Common: reversible, mostly mild increases in bilirubin and transaminases Rare: hepatic failure Very rare: cholecystitis Skin and subcutaneous tissue disorders Very common: rash, localised exanthema, diaphoresis Common: pruritus, skin pain, erythema, urticaria Rare: Stevens-Johnson syndrome/Lyell syndrome Musculoskeletal and connective tissue disorders Common: myalgia, arthralgia, arthritis, bone pain Renal and urinary disorders Rare: renal failure General disorders and administration site conditions Very common: injection site reactions, fever, fatigue, chills, asthenia Common: oedema, malaise, pain * see descriptive section below. 8 Description of selected adverse reactions Non-haematological adverse reactions Non-haematological adverse reactions are generally mild to moderate in severity. Treatment of nausea with antiemetics is usually not necessary. Adverse reactions related to skin and subcutaneous tissue are mostly mild or moderate and transient, usually resolving within a cycle interval of 30 days. Blood counts Since patients with an active hairy cell leukaemia mostly present with low blood counts, especially low neutrophil counts, more than 90% of the cases have transient severe neutropenias (< 1.0 x 109/l). The use of haematopoietic growth factors neither improves the recovery of neutrophil counts nor decreases the incidence of fever. Severe thrombocytopenias (< 50 x 109/l) are observed in about 20% to 30% of all patients. Lymphocytopenia lasting for several months and immunosuppression with an increased risk of infections are expected. The recovery of cytotoxic T-lymphocytes and natural killer cells occurs within 3 to 12 months. A complete recovery of T-helper cells and B-lymphocytes is delayed for up to 2 years. Cladribine induces a severe and prolonged reduction of CD4+ and CD8+ T-lymphocytes. At present there exists no experience on possible long-term consequences of this immunosuppression. Infections Severe long-term lymphocytopenias have been reported rarely which, however, could not be associated with late infectious complications. Very common severe complications, in some cases with fatal outcome, are opportunistic infections (e.g. Pneumocystis carinii, Toxoplasma gondii, listeria, candida, herpes viruses, cytomegalovirus and atypical mycobacteria). Forty percent of the patients who were treated with LITAK at a dose of 0.7 mg/kg body weight per cycle suffered from infections. These were on average more severe than the infections manifested in 27% of all patients receiving a reduced dose of 0.5 mg/kg body weight per cycle. Forty-three percent of patients with hairy cell leukaemia experienced infectious complications at standard dose regimen. One third of these infections have to be considered as severe (e.g. septicaemia, pneumonia). At least 10 cases with acute autoimmune haemolytic anaemia have been reported. All patients were successfully treated with corticosteroids. Rare serious adverse reactions Serious adverse reactions like ileus, severe hepatic failure, renal failure, cardiac failure, atrial fibrillation, cardiac decompensation, apoplexy, neurological disturbances in speech and swallowing, tumour lysis syndrome with acute renal failure, transfusion-related graft-versus-host disease, Stevens-Johnson syndrome/Lyell syndrome (toxic epidermal necrolysis), haemolytic anaemia, hypereosinophilia (with erythematous skin rash, pruritus, and facial oedema) are rare. Fatal outcome The majority of deaths related to the medicinal product are due to infectious complications. Further rare cases with fatal outcome, reported in association with LITAK chemotherapy, were second malignancy, cerebro- and cardiovascular infarctions, graft-versus-host disease caused by multiple transfusions of non-irradiated blood, as well as tumour lysis syndrome with hyperuricaemia, metabolic acidosis, and acute renal failure. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 4.9 Overdose Frequently observed symptoms of overdose are nausea, vomiting, diarrhoea, severe bone marrow depression (including anaemia, thrombocytopenia, leukopenia, and agranulocytosis), acute renal insufficiency, as well as irreversible neurologic toxicity (paraparesis/quadriparesis), Guillain-Barré syndrome, and Brown-Séquard syndrome. Acute, irreversible neuro- and nephrotoxicity have been described in individual patients treated at a dose which was ≥ 4 times higher than the recommended regimen for hairy cell leukaemia. No specific antidote exists. Immediate discontinuation of therapy, careful observation, and initiation of appropriate supportive measures (blood transfusions, dialysis, haemofiltration, anti-infectious therapy, etc.) are the indicated treatment of overdose of cladribine. Patients who have received an overdose of cladribine should be monitored haematologically for at least four weeks. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Purine analogues, ATC code: L01BB04 Cladribine is a purine nucleoside analogue acting as an antimetabolite. The single substitution of hydrogen for chlorine at position 2 distinguishes cladribine from its natural counterpart 2'-deoxyadenosine and renders the molecule resistant to deamination by adenosine deaminase. Mechanism of action Cladribine is a prodrug which is taken up rapidly in cells after parenteral administration, and is phosphorylated intracellularly to the active nucleotide 2-chlorodeoxyadenosine-5'-triphosphate (CdATP) by deoxycytidine kinase (dCK). An accumulation of active CdATP is observed predominantly in cells with a high dCK activity and a low deoxynucleotidase activity, particularly in lymphocytes and in other haematopoietic cells. The cytotoxicity of cladribine is dose-dependent. Non-haematologic tissues seem to be unaffected, explaining the low incidence of non-haematopoietic toxicity of cladribine Unlike other nucleoside analogues, cladribine is toxic in rapidly proliferating cells as well as in resting cells. No cytotoxic effect of cladribine could be observed in cell lines of solid tumours. The mechanism of action of cladribine is attributed to the incorporation of CdATP into DNA strands: the synthesis of new DNA in dividing cells is blocked and the DNA repair mechanism is inhibited, resulting in an accumulation of DNA strand breaks and a decrease of NAD (nicotinamide adenine dinucleotide) and ATP concentration, even in resting cells. Furthermore, CdATP inhibits ribonucleotide reductase, the enzyme responsible for the conversion of ribonucleotides into deoxyribonucleotides. Cell death occurs from energy depletion and apoptosis. Clinical efficacy In the clinical trial using LITAK subcutaneously, 63 patients with hairy cell leukaemia (33 newly diagnosed patients and 30 patients with relapsed or progressive disease) were treated. The overall response rate was 97% with long-lasting remission, with 73% of patients staying in complete remission after four years follow-up time. 5.2 Pharmacokinetic properties Absorption Cladribine shows complete bioavailability after parenteral administration; the mean area under the plasma concentration versus time curve (AUC) is comparable after continuous or intermittent 2-hour intravenous infusion and after subcutaneous injection. 10 Distribution After subcutaneous bolus injection of a 0.14 mg/kg cladribine dose, a Cmax of 91 ng/ml is reached on average after 20 minutes only. In another study using a dose of 0.10 mg/kg body weight/day, the maximum plasma concentration Cmax after continuous intravenous infusion was 5.1 ng/ml (tmax: 12 hours) compared to 51 ng/ml after subcutaneous bolus injection (tmax: 25 minutes). Intracellular concentration of cladribine exceeds its plasma concentration by 128 to 375 times. The mean volume of distribution of cladribine is 9.2 l/kg. Plasma protein binding of cladribine is 25% on average, with a wide interindividual variation (5-50%). Biotransformation The prodrug cladribine is metabolised intracellularly, predominantly by deoxycytidine kinase, to 2-chlorodeoxyadenosine-5'-monophosphate, that is further phosphorylated to the diphosphate by nucleoside monophosphate kinase and to the active metabolite 2-chlorodeoxyadenosine-5'-triphosphate (CdATP) by nucleoside diphosphate kinase. Elimination Pharmacokinetic studies in humans showed that the plasma concentration curve of cladribine fits a 2- or 3-compartment model with - and β-half-lives of on average 35 minutes and 6.7 hours, respectively. The biexponential decline of the serum concentration of cladribine after subcutaneous bolus injection is comparable to elimination parameters after 2-hour intravenous infusion with an initial and terminal half-life of approximately 2 hours and 11 hours, respectively. The intracellular retention time of cladribine nucleotides in vivo is clearly prolonged as compared to the retention time in the plasma: Half-lives t1/2 of initially 15 hours and subsequently more than 30 hours were measured in leukaemic cells. Cladribine is eliminated mainly by the kidneys. The renal excretion of unmetabolised cladribine occurs within 24 hours and accounts for 15% and 18% of the dose after 2-hour intravenous and subcutaneous administration, respectively. The fate of the remainder is unknown. The mean plasma clearance amounts to 794 ml/min after intravenous infusion and to 814 ml/min after subcutaneous bolus injection at a dose of 0.10 mg/kg body weight/day. Special populations Renal and hepatic impairment There are no studies available using cladribine in patients with renal or hepatic impairment (see also section 4.2 and section 4.4). Clinical experience is very limited and safety of LITAK in these patients is not well established. LITAK is contraindicated in patients with moderate to severe renal impairment or with moderate to severe hepatic impairment (see section 4.3). Paediatric use The use of LITAK in children has not been investigated (see section 4.2). Elderly Experience with patients older than 65 years is limited. Elderly patients should be treated by individual assessment and careful monitoring of the blood counts and of the renal and hepatic function. 5.3 Preclinical safety data Cladribine is moderately acutely toxic to mice, with an LD50 of 150 mg/kg by intraperitoneal administration. In 7- to 14-day continuous intravenous infusion studies in cynomolgus monkeys, the target organs were the immune system ( 0.3 mg/kg/day), bone marrow, skin, mucous membranes, nervous system and testes ( 0.6 mg/kg/day) and kidneys ( 1 mg/kg/day). Unless fatal, indications were that most or all of these effects would be slowly reversible upon cessation of exposure. 11 Cladribine is teratogenic in mice (at doses of 1.5-3.0 mg/kg/day, given on gestation days 6-15). Effects on sternal ossification were seen at 1.5 and 3.0 mg/kg/day. Increased resorptions, reduced live litter sizes, reduced foetal weights and increased foetal malformations of the head, trunk and appendages were seen at 3.0 mg/kg/day. In rabbits, cladribine is teratogenic at doses of 3.0 mg/kg/day (given on gestation days 7-19). At this dose, severe limb anomalies were seen as well as a significant decrease in the mean foetal weight. Reduced ossification was observed at 1.0 mg/kg/day. Carcinogenesis/mutagenesis Long-term studies in animals to evaluate the carcinogenic potential of cladribine have not been conducted. On the basis of available data, no evaluation can be made of the carcinogenic risk of cladribine to humans. Cladribine is a cytotoxic medicinal product, which is mutagenic to cultured mammalian cells. Cladribine is incorporated into DNA strands and inhibits DNA synthesis and repair. Exposure to cladribine induces DNA fragmentation and cell death in various normal and leukaemic cells and cell lines at concentrations of 5 nM to 20 µM. Fertility The effects of cladribine on fertility have not been studied in animals. However, a toxicity study conducted with cynomolgus monkeys has shown that cladribine suppresses maturation of rapidly generating cells, including testicular cells. The effect on human fertility is unknown. Antineoplastic agents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on human gametogenesis (see sections 4.4 and 4.6). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Water for injections 6.2 Incompatibilities LITAK must not be mixed with other medicinal products. 6.3 Shelf life 4 years. From a microbiological point of view, unless the opening precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. 6.4 Special precautions for storage Store in a refrigerator (2°C-8°C). Do not freeze. 6.5 Nature and contents of container 10 ml type I glass vial with rubber stopper (bromobutyl) and flip-off aluminium cap. Packs contain 1 or 5 vials, each with 5 ml of solution. Not all pack-sizes may be marketed. 12 6.6 Special precautions for disposal and other handling Procedures for proper handling and disposal of antineoplastic medicinal products should be used. Cytotoxic medicinal products should be handled with caution. Avoid contact by pregnant women. The use of disposable gloves and protective garments is recommended when handling and administering LITAK. If LITAK contacts the skin or mucous membranes, rinse the area immediately with copious amounts of water. Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration. The vials are for single use only. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Lipomed GmbH Hegenheimer Strasse 2 D-79576 Weil/Rhein Germany 8. MARKETING AUTHORISATION NUMBER(S) EU/1/04/275/001 EU/1/04/275/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 14/04/2004 Date of last renewal: 27/03/2009 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 13 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 14 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Lipomed GmbH Hegenheimer Strasse 2 D-79576 Weil/Rhein Germany B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION The holder of this marketing authorisation must inform the European Commission about the marketing plans for the medicinal product authorised by this decision. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Not applicable. 15 ANNEX III LABELLING AND PACKAGE LEAFLET 16 A. LABELLING 17 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON (1-VIAL PACK) 1. NAME OF THE MEDICINAL PRODUCT LITAK 2 mg/ml solution for injection cladribine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml solution contains 2 mg cladribine. 10 mg/5 ml 3. LIST OF EXCIPIENTS Contains sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment) and water for injections 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial containing 5 ml solution for injection 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic. Special handling precautions (see package leaflet) For single use only 8. EXPIRY DATE EXP 18 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator Do not freeze 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Lipomed GmbH Hegenheimer Strasse 2 D-79576 Weil/Rhein Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/04/275/001 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON (5-VIAL PACK) 1. NAME OF THE MEDICINAL PRODUCT LITAK 2 mg/ml solution for injection cladribine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml solution contains 2 mg cladribine. 10 mg/5 ml 3. LIST OF EXCIPIENTS Contains sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment) and water for injections 4. PHARMACEUTICAL FORM AND CONTENTS 5 vials each containing 5 ml solution for injection 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic. Special handling precautions (see package leaflet) For single use only 8. EXPIRY DATE EXP 20 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator Do not freeze 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Lipomed GmbH Hegenheimer Strasse 2 D-79576 Weil/Rhein Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/04/275/002 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 21 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION LITAK 2 mg/ml solution for injection cladribine Subcutaneous use 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Batch 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10 mg/5 ml 6. OTHER Cytotoxic 22 B. PACKAGE LEAFLET 23 PACKAGE LEAFLET: INFORMATION FOR THE USER LITAK 2 mg/ml solution for injection cladribine Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What LITAK is and what it is used for 2. What you need to know before you use LITAK 3. How to use LITAK 4. Possible side effects 5. How to store LITAK 6. Contents of the pack and other information 1. What LITAK is and what it is used for LITAK contains the active substance cladribine. Cladribine is a cytostatic agent. It affects the growth of malignant (cancerous) white blood cells which play a role in hairy cell leukaemia. LITAK is used to treat this disease. 2. What you need to know before you use LITAK Do not use LITAK - if you are allergic to cladribine or any of the other ingredients of LITAK (listed in section 6) - if you are pregnant or breast-feeding - if you are less than 18 years of age - if you have moderate to severe kidney or liver impairment - if you are using other medicines which affect the production of blood cells in the bone marrow (myelosuppression). Warnings and precautions Talk to your doctor or pharmacist before using LITAK. At any time during or after your treatment, tell your doctor or nurse immediately if you: experience blurred, loss of or double vision, difficulty speaking, weakness in an arm or a leg, a change in the way you walk or problems with your balance, persistent numbness, decreased sensation or loss of sensation, memory loss or confusion. These may all be symptoms of a serious and potentially fatal brain condition known as progressive multifocal leukoencephalopathy (PML). If you had these symptoms prior to treatment with cladribine, tell your doctor about any change in these symptoms. 24 Tell your doctor if you have or have had: - liver or kidney problems - infections  if you suffer from an infection, this will be treated before you start using LITAK.  if you notice any signs of infections (such as flu-like symptoms or fever) during or after treatment with LITAK, inform your doctor immediately. - fever Before and during treatment with LITAK, you will have regular blood tests to check whether it is safe for you to continue with your treatment. Your doctor may decide that you should receive blood transfusions to improve your level of blood cells. In addition, the proper function of your liver and your kidneys will be checked. If you want to father a child, please tell your doctor before treatment with LITAK is started. You should not father a child during treatment and up to 6 months after treatment with LITAK. Your doctor may advise you about the possibility to store deep-frozen sperm (cryoconservation). Other medicines and LITAK Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. In particular, tell your doctor if you are using any medicines containing: - corticosteroids, commonly used to treat inflammation - antiviral agents, used to treat viral infections You must not use LITAK with other medicines that affect the production of blood cells in the bone marrow (myelosuppression). Pregnancy and breast-feeding Your must not use LITAK if you are pregnant. You must take adequate contraceptive precautions during therapy and for at least six months after your last LITAK dose. If pregnancy occurs during your treatment, you must immediately inform your doctor. You must not breast-feed while you are treated with LITAK and for at least six months after your last LITAK dose. Driving and using machines LITAK has a major effect on the ability to drive and use machines. If you feel drowsy, which may occur due to a low number of red blood cells caused by LITAK treatment, or dizzy, you should not drive or use machines. 3. How to use LITAK Always use LITAK as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Your doctor will calculate your dose according to your body weight and explain the treatment schedule in detail. The recommended daily dose is 0.14 mg per kg body weight for five consecutive days (single treatment course). LITAK has to be injected under your skin (subcutaneous injection), at about the same time each day. If you are injecting LITAK yourself, first you must receive adequate training by your doctor or nurse. You will find detailed instructions for injection at the end of this leaflet. You may also receive an additional medicine containing the active substance allopurinol in order to reduce excess of uric acid. 25 If you use more LITAK than you should In case you inject an incorrect dose, tell your doctor immediately. If you forget to use LITAK Do not inject a double dose to make up for a forgotten dose. In case you miss an injection of a dose, tell your doctor immediately. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, LITAK can cause side effects, although not everybody gets them. Tell your doctor immediately if you have any of the following during or after treatment with LITAK: - any signs of infections (such as flu-like symptoms) - fever Repeated occurrence of malignant (cancerous) disease cannot be excluded. This means that the risk that you develop a malignant disease in the future is slightly higher than for healthy people. This slightly increased risk can be due to hairy cell leukaemia or to therapies used to treat the disease including LITAK. The following side effects may occur: Very common side effects (may affect more than 1 in 10 people)  Infections.  Fever.  Low numbers of certain white blood cells (neutrophils and lymphocytes) and platelets in blood tests.  Low number of red blood cells, which may result in anaemia, with symptoms such as tiredness and drowsiness.  Reduced function of your body’s immune system.  Headache, dizziness.  Abnormal breath sounds, abnormal chest sounds, cough.  Feeling sick, vomiting, constipation and diarrhoea.  Skin eruption (rash), swelling, redness as well as soreness around the site of injection, sweating. Skin reactions are mostly mild to moderate and usually resolve within a few days.  Tiredness, chills, decreased appetite.  Weakness. Common side effects (may affect up to 1 in 10 people)  Repeated occurrence of malignant (cancerous) disease.  Low number of platelets, which can cause unusual bleeding (for example nose or skin bleeds).  Sleeplessness, anxiety.  Increased heart rate, abnormal heart sound, low blood pressure, decreased blood supply to the heart muscle.  Shortness of breath, swelling in lung tissue due to infection, inflammation of mouth and tongue.  Abdominal pain and presence of excessive amount of gas in the stomach or bowels, mostly mild increases in liver laboratory values (bilirubin, transaminases) which will return to normal values once treatment is over.  Itching, itching skin eruption (urticaria), redness of the skin and skin pain.  Swelling in tissues (oedema), not feeling well, pain (muscle pain, joint pain, and bone pain). 26 Uncommon side effects (may affect up to 1 in 100 people)  Anaemia caused by destruction of red blood cells.  Sleepiness, numbness and tingling of the skin, feebleness, inactivity, disorder of peripheral nerves, confusion, impaired ability to coordinate movements.  Eye inflammation.  Sore throat.  Inflammation of a vein.  Severe weight loss. Rare side effects (may affect up to 1 in 1.000 people)  Reduced liver function.  Reduced kidney function.  Complications caused by cancer treatment due to break-down of cancer cells.  Rejection response to blood transfusions.  Increased number of certain white blood cells (eosinophils).  Stroke.  Disturbances in speech and swallowing.  Heart failure.  Abnormal heart rhythm.  Inability of the heart to maintain adequate blood circulation.  Obstruction of the bowels.  Serious allergic skin reaction (Stevens-Johnson syndrome or Lyell syndrome). Very rare side effects (may affect up to 1 in 10.000 people)  Depression, epileptic attack.  Swelling of the eyelid.  Blood clot in the lung.  Inflammation of the gallbladder.  Reduced function of organs due to high amounts of a specific substance produced by the body (a glycoprotein). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store LITAK Keep out of the sight and reach of children. Store in a refrigerator (2C-8C). Do not freeze. Do not use LITAK after the expiry date which is stated on the vial label and the outer carton after EXP. The expiry date refers to the last day of that month. From a microbiological point of view, unless the opening precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Do not use LITAK if you notice that the vial is damaged or that the solution is not clear or contains any particles. Any unused product or waste material should be disposed of in accordance with local requirements. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 27 6. Contents of the pack and other information What LITAK contains - The active substance is cladribine. Each ml solution contains 2 mg cladribine. Each vial contains 10 mg cladribine in 5 ml solution. - The other ingredients are sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment) and water for injections. What LITAK looks like and contents of the pack LITAK is available in glass vials containing 5 ml of clear, colourless solution for injection. Pack size of 1 or 5 vials. Not all pack-sizes may be marketed. Marketing Authorisation Holder and Manufacturer Lipomed GmbH Hegenheimer Strasse 2 D-79576 Weil/Rhein Germany For any information about this medicine, please contact the Marketing Authorisation Holder. This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu. INSTRUCTIONS FOR INJECTION This section contains information on how to give an injection of LITAK. It is important that you do not try to give yourself the injection unless you have been instructed by your doctor or nurse. Your doctor will tell you how much LITAK you need and how often and when you have to inject yourself. LITAK should be injected into the tissue just under the skin (subcutaneous injection). If you have any question with regard to giving the injection, please ask your doctor or nurse for help. LITAK is a cytotoxic and should therefore be handled with caution. When LITAK is not self-administered by the patient, the use of disposable gloves and protective garments is recommended when handling and administering LITAK. If LITAK contacts the skin or eyes, rinse the involved surface immediately with copious amounts of water. Pregnant women must avoid contact with LITAK. What do I need for the injection? To give yourself a subcutaneous injection, you will need: - one vial of LITAK (or two vials if you need to inject more than 5 ml). Do not use vials which are damaged, or if the solution is not clear or if it contains any particles. - one sterile syringe (e.g. 10 ml LUER syringe), - one sterile injection needle (e.g. 0.5 x 19 mm, 25 G x ¾’’), - alcohol wipes, - a puncture-proof container for safe disposal of the used syringe. 28 What should I do before I give myself a subcutaneous injection of LITAK? 1. Before injection, allow LITAK to warm up to room temperature. 2. Wash your hands thoroughly. 3. Find a comfortable, well-lit place and put everything you need where you can reach it. How do I prepare the injection? Before you inject LITAK, you must do the following: 1. Remove the red protective cap from the LITAK vial. Do not remove the rubber stopper of the vial. Clean the rubber top of the vial with an alcohol wipe. Remove the syringe from the wrapping without touching the tip of the syringe. Remove the injection needle from the wrapping and place it firmly on the tip of the syringe. Remove the needle guard without touching the needle. 2. Push the needle through the rubber stopper of the vial and turn the vial and the syringe upside down. Be sure that the tip of the needle is in the solution. 3. Draw the correct volume of LITAK into the syringe by pulling back the plunger (your doctor will inform you how many ml of LITAK you need to inject). 4. Pull the needle out of the vial. 5. Make sure there is no air left in the syringe: point the needle upwards and push the air out. 6. Check you have the right volume. 7. Inject straight away. Where should I give my injection? The most suitable places to inject yourself are shown here: the top of your thighs and the abdomen, except for the area around the navel. If someone else is injecting you, they can also use the outer surface of the upper arms or the buttocks. 29 How do I give my injection? 3. Pull slightly on the plunger to check that no blood vessel has been punctured. If you see blood in the syringe, remove the needle and re-insert it in another place. 4. Inject the liquid slowly and evenly for approximately one minute, always keeping the skin pinched. 5. After injecting the liquid, remove the needle. 6. Put the used syringe in the puncture-proof container. Use a new syringe and injection needle for each injection. The vials are for single use only. Return any portion of the contents remaining after use to your doctor or pharmacist for proper disposal. Disposing of used syringes Put used syringes into a puncture-proof container and keep it out of the reach and sight of children. Dispose the puncture-proof container as instructed by your doctor, nurse or pharmacist. Do not put used syringes into the normal household garbage bin. 1. Disinfect your skin by using an alcohol wipe, wait for the area to dry and pinch the skin between your thumb and forefinger, without squeezing it. 2. Put the needle fully into the skin at an angle of about 45°, as shown in the picture. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to use litak', 'Section_Content': 'always use litak as your doctor has told you. you should check with your doctor or pharmacist if you are not sure. your doctor will calculate your dose according to your body weight and explain the treatment schedule in detail. the recommended daily dose is 0.14 mg per kg body weight for five consecutive days (single treatment course). litak has to be injected under your skin (subcutaneous injection), at about the same time each day. if you are injecting litak yourself, first you must receive adequate training by your doctor or nurse. you will find detailed instructions for injection at the end of this leaflet. you may also receive an additional medicine containing the active substance allopurinol in order to reduce excess of uric acid. if you use more litak than you should in case you inject an incorrect dose, tell your doctor immediately. if you forget to use litak do not inject a double dose to make up for a forgotten dose. in case you miss an injection of a dose, tell your doctor immediately. if you have any further questions on the use of this product, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'litak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the treatment schedule', 'Type': 'TREATMENT', 'BeginOffset': 194, 'EndOffset': 216}, {'Text': '0.14', 'Type': 'NUMBER', 'BeginOffset': 258, 'EndOffset': 262}, {'Text': 'single treatment course', 'Type': 'TREATMENT', 'BeginOffset': 312, 'EndOffset': 335}, {'Text': 'your skin (subcutaneous injection', 'Type': 'TREATMENT', 'BeginOffset': 369, 'EndOffset': 402}, {'Id': 3, 'BeginOffset': 498, 'EndOffset': 515, 'Score': 0.3967585861682892, 'Text': 'adequate training', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 581, 'EndOffset': 590, 'Score': 0.5343340635299683, 'Text': 'injection', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Text': 'an additional medicine', 'Type': 'TREATMENT', 'BeginOffset': 640, 'EndOffset': 662}, {'Text': 'the active substance allopurinol', 'Type': 'TREATMENT', 'BeginOffset': 674, 'EndOffset': 706}, {'Text': 'excess of uric acid', 'Type': 'PROBLEM', 'BeginOffset': 726, 'EndOffset': 745}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 894, 'EndOffset': 907}]}

{'Title': '4. possible side effects', 'Section_Content': "like all medicines, litak can cause side effects, although not everybody gets them. tell your doctor immediately if you have any of the following during or after treatment with litak: - any signs of infections (such as flu-like symptoms) - fever repeated occurrence of malignant (cancerous) disease cannot be excluded. this means that the risk that you develop a malignant disease in the future is slightly higher than for healthy people. this slightly increased risk can be due to hairy cell leukaemia or to therapies used to treat the disease including litak. the following side effects may occur: very common side effects (may affect more than 1 in 10 people) infections. fever. low numbers of certain white blood cells (neutrophils and lymphocytes) and platelets in blood tests. low number of red blood cells, which may result in anaemia, with symptoms such as tiredness and drowsiness. reduced function of your body's immune system. headache, dizziness. abnormal breath sounds, abnormal chest sounds, cough. feeling sick, vomiting, constipation and diarrhoea. skin eruption (rash), swelling, redness as well as soreness around the site of injection, sweating. skin reactions are mostly mild to moderate and usually resolve within a few days. tiredness, chills, decreased appetite. weakness. common side effects (may affect up to 1 in 10 people) repeated occurrence of malignant (cancerous) disease. low number of platelets, which can cause unusual bleeding (for example nose or skin bleeds). sleeplessness, anxiety. increased heart rate, abnormal heart sound, low blood pressure, decreased blood supply to the heart muscle. shortness of breath, swelling in lung tissue due to infection, inflammation of mouth and tongue. abdominal pain and presence of excessive amount of gas in the stomach or bowels, mostly mild increases in liver laboratory values (bilirubin, transaminases) which will return to normal values once treatment is over. itching, itching skin eruption (urticaria), redness of the skin and skin pain. swelling in tissues (oedema), not feeling well, pain (muscle pain, joint pain, and bone pain). uncommon side effects (may affect up to 1 in 100 people) anaemia caused by destruction of red blood cells. sleepiness, numbness and tingling of the skin, feebleness, inactivity, disorder of peripheral nerves, confusion, impaired ability to coordinate movements. eye inflammation. sore throat. inflammation of a vein. severe weight loss. rare side effects (may affect up to 1 in 1.000 people) reduced liver function. reduced kidney function. complications caused by cancer treatment due to break-down of cancer cells. rejection response to blood transfusions. increased number of certain white blood cells (eosinophils). stroke. disturbances in speech and swallowing. heart failure. abnormal heart rhythm. inability of the heart to maintain adequate blood circulation. obstruction of the bowels. serious allergic skin reaction (stevens-johnson syndrome or lyell syndrome). very rare side effects (may affect up to 1 in 10.000 people) depression, epileptic attack. swelling of the eyelid. blood clot in the lung. inflammation of the gallbladder. reduced function of organs due to high amounts of a specific substance produced by the body (a glycoprotein). reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'litak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Id': 20, 'BeginOffset': 36, 'EndOffset': 48, 'Score': 0.9534839987754822, 'Text': 'side effects', 'Category': 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clot in the lung', 'Type': 'PROBLEM', 'BeginOffset': 3103, 'EndOffset': 3125}, {'Text': 'inflammation of the gallbladder', 'Type': 'PROBLEM', 'BeginOffset': 3127, 'EndOffset': 3158}, {'Text': 'reduced function of organs', 'Type': 'PROBLEM', 'BeginOffset': 3160, 'EndOffset': 3186}, {'Id': 155, 'BeginOffset': 3283, 'EndOffset': 3295, 'Score': 0.8872284889221191, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.579041600227356}]}, {'Id': 156, 'BeginOffset': 3311, 'EndOffset': 3323, 'Score': 0.909881591796875, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6648083329200745}]}, {'Id': 157, 'BeginOffset': 3387, 'EndOffset': 3399, 'Score': 0.953612744808197, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.574166476726532}, {'Name': 'DIAGNOSIS', 'Score': 0.4319167137145996}]}, {'Id': 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{'Title': '5. how to store litak', 'Section_Content': 'keep out of the sight and reach of children. store in a refrigerator (2c-8c). do not freeze. do not use litak after the expiry date which is stated on the vial label and the outer carton after exp. the expiry date refers to the last day of that month. from a microbiological point of view, unless the opening precludes the risk of microbiological contamination, the product should be used immediately. if not used immediately, in-use storage times and conditions are the responsibility of the user. do not use litak if you notice that the vial is damaged or that the solution is not clear or contains any particles. any unused product or waste material should be disposed of in accordance with local requirements.', 'Entity_Recognition': [{'Text': 'litak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'microbiological contamination', 'Type': 'PROBLEM', 'BeginOffset': 331, 'EndOffset': 360}, {'Text': 'waste material', 'Type': 'PROBLEM', 'BeginOffset': 638, 'EndOffset': 652}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what litak contains - the active substance is cladribine. each ml solution contains 2 mg cladribine. each vial contains 10 mg cladribine in 5 ml solution. - the other ingredients are sodium chloride, sodium hydroxide (for ph adjustment), hydrochloric acid (for ph adjustment) and water for injections. what litak looks like and contents of the pack litak is available in glass vials containing 5 ml of clear, colourless solution for injection. pack size of 1 or 5 vials. not all pack-sizes may be marketed.', 'Entity_Recognition': [{'Text': 'litak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 46, 'EndOffset': 56, 'Score': 0.996428906917572, 'Text': 'cladribine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8710398077964783, 'RelationshipScore': 0.9999896287918091, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 66, 'EndOffset': 74, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each ml solution', 'Type': 'TREATMENT', 'BeginOffset': 58, 'EndOffset': 74}, {'Text': '2 mg cladribine', 'Type': 'TREATMENT', 'BeginOffset': 84, 'EndOffset': 99}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 120, 'EndOffset': 122}, {'Id': 5, 'BeginOffset': 126, 'EndOffset': 136, 'Score': 0.986882746219635, 'Text': 'cladribine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9813644289970398, 'RelationshipScore': 0.9999998807907104, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 120, 'EndOffset': 125, 'Text': '10 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.810003399848938, 'RelationshipScore': 0.9934298396110535, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 140, 'EndOffset': 144, 'Text': '5 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9373220801353455, 'RelationshipScore': 0.9935559630393982, 'RelationshipType': 'FORM', 'Id': 7, 'BeginOffset': 145, 'EndOffset': 153, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 140, 'EndOffset': 141}, {'Id': 8, 'BeginOffset': 183, 'EndOffset': 198, 'Score': 0.998327910900116, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9813644289970398, 'RelationshipScore': 0.7062814831733704, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 120, 'EndOffset': 125, 'Text': '10 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.810003399848938, 'RelationshipScore': 0.6051064133644104, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 140, 'EndOffset': 144, 'Text': '5 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9373220801353455, 'RelationshipScore': 0.9292004704475403, 'RelationshipType': 'FORM', 'Id': 7, 'BeginOffset': 145, 'EndOffset': 153, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 9, 'BeginOffset': 200, 'EndOffset': 216, 'Score': 0.9989892840385437, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ph adjustment', 'Type': 'TREATMENT', 'BeginOffset': 222, 'EndOffset': 235}, {'Id': 10, 'BeginOffset': 238, 'EndOffset': 255, 'Score': 0.9914857745170593, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.3560119867324829, 'RelationshipScore': 0.6378856897354126, 'RelationshipType': 'DOSAGE', 'Id': 11, 'BeginOffset': 394, 'EndOffset': 398, 'Text': '5 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'ph adjustment)', 'Type': 'TREATMENT', 'BeginOffset': 261, 'EndOffset': 275}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 290, 'EndOffset': 300}, {'Text': 'the pack litak', 'Type': 'TREATMENT', 'BeginOffset': 340, 'EndOffset': 354}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 394, 'EndOffset': 395}, {'Text': 'clear, colourless solution', 'Type': 'TREATMENT', 'BeginOffset': 402, 'EndOffset': 428}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 457, 'EndOffset': 458}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 462, 'EndOffset': 463}]}

D0CC9635D229DB1D224636A7078CA5D9

https://www.ema.europa.eu/documents/product-information/ribavirin-teva-pharma-bv-epar-product-information_en.pdf

Ribavirin Teva Pharma B.V.

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Ribavirin Teva Pharma B.V. 200 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each Ribavirin Teva Pharma B.V. tablet contains 200 mg of ribavirin For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Light pink to pink, (debossed with “93” on one side and “7232” on the other). 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Ribavirin Teva Pharma B.V. is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults, children 3-years of age or older and adolescents and must only be used as part of a combination regimen with interferon alfa-2b. Ribavirin monotherapy must not be used. There is no safety or efficacy information on the use of ribavirin with other forms of interferon (i.e. not alfa-2b). Naïve patients Adult patients: Ribavirin Teva Pharma B.V. is indicated, in combination with interferon alfa-2b, for the treatment of adult patients with all types of chronic hepatitis C except genotype 1, not previously treated, without liver decompensation, with elevated alanine aminotransferase (ALT), who are positive for hepatitis C viral ribonucleic acid HCV-RNA (see section 4.4). Paediatric patients (children 3 years of age and older and adolescents: Ribavirin Teva Pharma B.V. is indicated in a combination regimen with interferon alfa2b, for the treatment of children and adolescents 3 years of age and older, who have all types of chronic hepatitis C except genotype 1, not previously treated, without liver decompensation, and who are positive for HCV-RNA. When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition, that may be irreversible in some patients. The decision to treat should be made on a case by case basis (see section 4.4). Previous treatment failure patients Adult patients: Ribavirin Teva Pharma B.V. is indicated, in combination with interferon alfa-2b, for the treatment of adult patients with chronic hepatitis C who have previously responded (with normalisation of ALT at the end of treatment) to interferon alpha monotherapy but who have subsequently relapsed (see section 5.1). 4.2 Posology and method of administration Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C. Posology 3 Ribavirin Teva Pharma B.V. must be used in combination therapy as described in section 4.1. Please refer to the corresponding Summary of Product Characteristics (SmPC) of medicinal products used in combination with Ribavirin Teva Pharma B.V. for prescribing information particular to that product and for further dosage recommendations on co-administration with Ribavirin Teva Pharma B.V.. Ribavirin Teva Pharma B.V. tablets are to be administered orally each day in two divided doses (morning and evening) with food. Adults: The recommended dose and duration of Ribavirin Teva Pharma B.V. depends on patient’s weight and on the medicinal product that is used in combination. Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirin Teva Pharma B.V.. In the cases in which no specific dose recommendation is made, the following dose should be used: Patient weight: < 75 kg =1,000 mg and > 75 kg = 1,200 mg. Paediatric population: No data are available in children below 3 years of age. Note: For patients who weigh < 47 kg, or are unable to swallow tablets, ribavirin oral solution is available and should be used if appropriate. Dosing of ribavirin for children and adolescent patients is determined by the patient body weight. For example, the body weight dosing used in conjunction with interferon alfa-2b is shown in Table 1. Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin as some combination regimens do not adhere to the ribavirin dosing guidance provided in Table 1. Table 1 Ribavirin Teva Pharma B.V. dose based on body weight when used in combination with interferon alfa-2b in paediatric patients Patient weight (kg) Daily ribavirin dose Number of 200 mg tablets 47-49 600 mg 3 x 200 mg tabletsa 50-65 800 mg 4 x 200 mg tabletsb > 65 Refer to adult dose recommendation a: 1 morning, 2 evening b: 2 morning, 2 evening Dose modification for adverse reactions Dose modification for adults Dose reduction of ribavirin depends on the initial ribavirin posology which depends on the medicinal product that is used in combination with ribavirin. If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration, cardiac status and indirect bilirubin concentration. 4 Table 2 Management of Adverse Reactions Laboratory values Reduce ribavirin dose* if: Discontinue ribavirin if: Haemoglobin in patients with No Cardiac Disease < 10 g/dL < 8.5 g/dL Haemoglobin: Patients with History of Stable Cardiac Disease  2 g/dL decrease in haemoglobin during any 4 week period during treatment (permanent dose reduction) < 12 g/dL despite 4 weeks at reduced dose Bilirubin – Indirect > 5 mg/dL > 4 mg/dL (adults) * For patients receiving a 1,000 mg (< 75 kg) or 1,200 mg (> 75 kg) dose, ribavirin dose should be reduced to 600 mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets in the evening). If the abnormality is reversed, ribavirin may be restarted at 600 mg daily, and further increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended. For patients receiving a 800 mg (< 65 kg) - 1,000 mg (65-80 kg) - 1,200 mg (81-105 kg) or 1,400 mg (> 105 kg) dose, 1st dose reduction of Ribavirin Teva Pharma B.V. is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Ribavirin Teva Pharma B.V. is by an additional 200 mg/day. Patients whose dose of Ribavirin Teva Pharma B.V. is reduced to 600 mg daily receive one 200 mg tablet in the morning and two 200 mg tablets in the evening. In case of serious adverse reaction potentially related to medicinal products used in combination with ribavirin, refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the ribavirin dose modification and/or discontinuation guidelines as described in Table 2. Dose modification for paediatric patients Dose reduction in paediatric patients without cardiac disease follows the same guidelines as adult patients without cardiac disease regarding haemoglobin levels (Table 2). There are no data for paediatric patients with cardiac disease (see section 4.4). Table 3 provides guidelines for discontinuation based on the patient’s indirect bilirubin concentration. Table 3 Management of Adverse Reactions Laboratory values Discontinue ribavirin if: Bilirubin – Indirect > 5 mg/dL (for > 4 weeks) (children and adolescents treated with interferon alfa-2b), or > 4 mg/dL (for > 4 weeks) (children and adolescents treated with peginterferon alfa-2b) Special populations Elderly ( 65 years of age) There does not appear to be a significant age-related effect on the pharmacokinetics of ribavirin. However, as in younger patients, renal function must be determined prior to administration of ribavirin (see section 5.2). Paediatric patients (children 3 years of age and older and adolescents) Ribavirin may be used in combination with interferon alfa-2b (see section 4.4). The selection of ribavirin formulation is based on individual characteristics of the patient. 5 The safety and efficacy of ribavirin used together with direct-acting-anti-virals in these patients has not been established. No data are available. Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin for further dosage recommendations on co-administration. Renal impairment The pharmacokinetics of ribavirin is altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2). Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of ribavirin. Adult patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance of < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered ribavirin 200 mg/day. Table 4 provides guidelines for dose modification for patients with renal dysfunction. Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. No data are available regarding dose modification for paediatric patients with renal impairment. Table 4 Dosage Modification for Renal Impairment in Adult Patients Creatinine Clearance Ribavirin Dose (daily) 30 to 50 mL/min Alternating doses, 200 mg and 400 mg every other day Less than 30 mL/min 200 mg daily Haemodialysis (ESRD) 200 mg daily Hepatic impairment No pharmacokinetic interaction appears between ribavirin and hepatic function (see section 5.2). For use in patients with decompensated cirrhosis, see the corresponding SmPC of the medicinal products used in combination with ribavirin. Method of administration Ribavirin Teva Pharma B.V. tablets should be administered orally with food. 4.3 Contraindications - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Pregnancy (see sections 4.4, 4.6 and 5.3). In females of childbearing potential, Ribavirin Teva Pharma B.V. must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. - Breast-feeding - History of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months (see section 4.4). - Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia). Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirin Teva Pharma B.V. for contraindications specific to these products. 4.4 Special warnings and precautions for use Ribavirin must be used in combination with other medicinal products (see section 5.1). Please refer to the SmPC of (peg)interferon alfa for details on the recommendations of monitoring and management regarding the adverse reactions listed below before initiating therapy and other precautions associated with (peg)interferon alfa. There are several serious adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa. These include: 6 - Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behaviour, etc.) - Growth inhibition in children and adolescents that may be irreversible in some patients - Increased thyroid stimulating hormone (TSH) in children and adolescents - Severe ocular disorders - Dental and periodontal disorders. Paediatric population When deciding not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to consider that this combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case. Haemolysis A decrease in haemoglobin levels to < 10 g/dL was observed in up to 14 % of adult patients and 7 % of children and adolescents treated with ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although ribavirin has no direct cardiovascular effects, anaemia associated with ribavirin may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, ribavirin must be administered with caution to patients with pre-existing cardiac disease (see section 4.3). Cardiac status must be assessed before start of therapy and monitored clinically during therapy; if any deterioration occurs, therapy must be stopped (see section 4.2). Cardiovascular Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders must be closely monitored. It is recommended that those patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of therapy. There are no data in children or adolescents with a history of cardiac disease. Teratogenic risk Prior to initiation of treatment with ribavirin the physician must comprehensively inform both male and female patients of the teratogenic risk of ribavirin, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during or following treatment with ribavirin (see section 4.6). For laboratory monitoring of pregnancy, please refer to Laboratory tests. Acute hypersensitivity If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ribavirin Teva Pharma B.V. must be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment. Liver function Any patient developing significant liver function abnormalities during treatment must be monitored closely. Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirin Teva Pharma B.V. for discontinuation or dose modification recommendations. Renal impairment The pharmacokinetics of ribavirin is altered in patients with renal dysfunction due to reduction of apparent clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of ribavirin. Due to substantial increases in ribavirin plasma concentrations in patients with moderate and severe renal impairment, ribavirin dose adjustments are recommended in adult patients with creatinine clearance < 50 mL/minute. No data are available regarding dose modification for paediatric patients with renal impairment (see sections 4.2 and 5.2). Haemoglobin concentrations should be monitored closely during treatment and corrective action taken as necessary (see section 4.2). 7 Potential to exacerbate immunosuppression Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see section 4.5). HCV/HIV Co-infection Mitochondrial toxicity and lactic acidosis: Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon alfa-2b/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial toxicity and lactic acidosis when ribavirin is administered. For additional details see section 4.5. Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis: Co-infected patients with advanced cirrhosis receiving combined anti-retroviral therapy (cART) may be at increased risk of hepatic decompensation and death. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentrations. Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin for discontinuation or dose modification recommendations. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed. Haematological abnormalities in HCV/HIV co-infected patients: HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and cART may be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed by dose reduction, close monitoring of haematological parameters should be undertaken in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8). Patients treated with ribavirin and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of ribavirin with zidovudine is not recommended (see section 4.5). Patients with low CD4 counts: In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in subjects with CD4 counts less than 200 cells/µL. Caution is therefore warranted in the treatment of patients with low CD4 counts. Please refer to the corresponding SmPC of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ribavirin. Laboratory tests Standard haematologic tests, blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) and pregnancy tests must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of ribavirin therapy: Haemoglobin Adult: ≥ 12 g/dL (females); ≥ 13 g/dL (males) Children and adolescents: ≥ 11 g/dL (females); ≥ 12 g/dL (males) Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2). 8 Uric acid may increase with ribavirin due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients. 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults. Results of in vitro studies using both human and rat liver microsome preparations indicated no cytochrome P450 enzyme mediated metabolism of ribavirin. Ribavirin does not inhibit cytochrome P450 enzymes. There is no evidence from toxicity studies that ribavirin induces liver enzymes. Therefore, there is a minimal potential for P450 enzyme-based interactions. Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. The use of pegylated alpha interferons and ribavirin concomitantly with azathioprine should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these medicines should be stopped (see section 4.4). No interaction studies have been conducted with ribavirin and other medicinal products, except for peginterferon alfa-2b, interferon alfa-2b and antacids. No pharmacokinetic interactions were noted between ribavirin and peginterferon alfa-2b or interferon alfa-2b in a multiple-dose pharmacokinetic study. Antacid The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid containing magnesium aluminium and simethicone; AUCtf decreased 14 %. It is possible that the decreased bioavailability in this study was due to delayed transit of ribavirin or modified pH. This interaction is not considered to be clinically relevant. Nucleoside analogues Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see section 4.4). The exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4).Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia. Any potential for interactions may persist for up to two months (five half-lives for ribavirin) after cessation of ribavirin therapy due to the long half-life (see section 5.2). There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors or protease inhibitors. Conflicting findings are reported in literature on co-administration between abacavir and ribavirin. Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at 9 risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised when both medicines are co-administered. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/contraception in males and females Female patients Ribavirin Teva Pharma B.V. must not be used by females who are pregnant (see sections 4.3, 4.4 and 5.3). Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Ribavirin therapy must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Females of childbearing potential must use an effective contraceptive during treatment and for four months after treatment has been concluded; routine monthly pregnancy tests must be performed during this time (see section 4.4). If pregnancy does occur during treatment or within four months from stopping treatment, the patient must be advised of the significant teratogenic risk of ribavirin to the foetus (see section 4.4). Male patients and their female partners Extreme care must be taken to avoid pregnancy in partners of male patients taking Ribavirin Teva Pharma B.V. (see sections 4.3, 4.4 and 5.3). Ribavirin accumulates intracellularly and is cleared from the body very slowly. It is unknown whether the ribavirin that is contained in sperm will exert its potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on approximately 300 prospectively followed pregnancies with paternal exposure to ribavirin have not shown an increased risk of malformation compared to the general population, nor any specific pattern of malformation, either male patients or their female partners of childbearing age must be advised to use an effective contraceptive during treatment with ribavirin and for seven months after treatment. Routine monthly pregnancy tests must be performed during this time. Men whose partners are pregnant must be instructed to use a condom to minimise delivery of ribavirin to the partner. Pregnancy The use of Ribavirin Teva Pharma B.V. is contraindicated during pregnancy. Ribavirin has been shown in preclinical studies to be teratogenic and genotoxic (see section 4.4 and 5.3). Breast-feeding It is not known whether ribavirin is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment. Fertility Preclinical data: - Fertility: In animal studies, ribavirin produced reversible effects on spermatogenesis (see section 5.3). - Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted, occurring at doses as low as one twentieth of the recommended human dose (see section 5.3). - Genotoxicity: Ribavirin induces genotoxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Ribavirin Teva Pharma B.V. has no or negligible influence on the ability to drive and use machines; however, other medicinal products used in combination may have an effect. Thus, patients who develop fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or operating machinery. 4.8 Undesirable effects 10 Summary of the safety profile The salient safety issue of ribavirin is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with ribavirin therapy may result in deterioration of cardiac function and/or worsening of pre-existing cardiac disease. An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients. The adverse reactions listed in this section are primarily derived from clinical trials and/or as adverse drug reactions from spontaneous reports when ribavirin was used in combination with interferon alfa-2b or peginterferon alfa-2b. Please refer to the corresponding SmPC of medicinal products that are used in combination with ribavirin for additional undesirable effects reported with these products. Adults The safety of ribavirin is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied ribavirin in combination with interferon alfa-2b, two trials studied ribavirin in combination with peginterferon alfa-2b. Patients who are treated with interferon alfa-2b and ribavirin after previous relapse from interferon therapy or who are treated for a shorter period are likely to have an improved safety profile than that described below. Tabulated list of adverse reactions for adults The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naïve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with ribavirin) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b SPCs for adverse reactions that may be attributable to interferon monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 5 Adverse reactions reported during clinical trials or following the marketing use of ribavirin with pegylated interferon alfa-2b or interferon alfa-2b System Organ Class Adverse Reactions Infections and infestations Very common: Viral infection, pharyngitis Common: Bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infection Uncommon Lower respiratory tract infection Rare: Pneumonia* Neoplasms benign, malignant and unspecified (including cysts and polyps) Common: Neoplasm unspecified Blood and lymphatic system disorders Very common: Anaemia, neutropenia Common: Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia Very rare: Aplastic anaemia* Not known: Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura Immune system disorders 11 Uncommon: Drug hypersensitivity Rare: Sarcoidosis*, rheumatoid arthritis (new or aggravated) Not known: Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis Endocrine disorders Common: Hypothyroidism, hyperthyroidism Metabolism and nutrition disorders Very common: Anorexia Common: Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite Uncommon: Diabetes mellitus, hypertriglyceridemia* Psychiatric disorders Very common: Depression, anxiety, emotional lability, insomnia Common: Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, anger, mood altered, abnormal behaviour nervousness, sleep disorder, decreased libido, apathy, abnormal dreams, crying. Uncommon: Suicide attempts, panic attack, hallucination Rare: Bipolar disorder* Very rare: Suicide* Not known: Homicidal ideation*, mania*, mental status change Nervous system disorders Very common: Headache, dizziness, dry mouth, concentration impaired Common: Amnesia, memory impairment, syncope, migraine, ataxia, paraesthaesia, dysphonia, taste loss, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia Uncommon: Neuropathy, peripheral neuropathy Rare: Seizure (convulsion)* Very rare: Cerebrovascular haemorrhage*, cerebrovascular ischaemia*, encephalopathy*, polyneuropathy* Not known: Facial palsy, mononeuropathies Eye disorders Common: Visual disturbance, blurred vision, conjunctivitis, eye irritation, eye pain, abnormal vision, lacrimal gland disorder, dry eye Rare: Retinal haemorrhages*, retinopathies (including macular oedema)*, retinal artery occlusion*, retinal vein occlusion*, optic neuritis*, papilloedema*, loss of visual acuity or visual field*, retinal exudates* Ear and labyrinth disorders Common: Vertigo, hearing impaired/loss, tinnitus, ear pain Cardiac disorders Common: Palpitation, tachycardia Uncommon: Myocardial infarction Rare: Cardiomyopathy*, arrhythmia* Very rare: Cardiac ischaemia* Not known: Pericardial effusion*, pericarditis* Vascular disorders Common: Hypotension, hypertension, flushing Rare: Vasculitis Very rare: Peripheral ischaemia* 12 Respiratory, thoracic and mediastinal disorders Very common: Dyspnoea, coughing Common: Epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain, nonproductive cough Very rare: Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis* Gastro-intestinal disorders Very common: Diarrhoea, vomiting, nausea, abdominal pain Common: Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia, gastroesophageal reflux*, glossitis, cheilitis, abdominal distension, gingival bleeding, gingivitis, loose stools, tooth disorder, constipation, flatulence Uncommon: Pancreatitis, oral pain Rare: Ischaemic colitis Very rare: Ulcerative colitis* Not Known: Periodontal disorder, dental disorder, tongue pigmentation Hepatobiliary disorders Common: Hepatomegaly, jaundice, hyperbilirubinemia* Very rare: Hepatotoxicity (including fatalities)* Skin and subcutaneous tissue disorders Very common: Alopecia, pruritus, skin dry, rash Common: Psoriasis, aggravated psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema, urticaria, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder* Rare: Cutaneous sarcoidosis Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme* Musculoskeletal and connective tissue disorders Very common: Arthralgia, myalgia, musculoskeletal pain Common: Arthritis, back pain, muscle spasms, pain in extremity Uncommon: Bone pain, muscle weakness Rare: Rhabdomyolysis*, myositis* Renal and urinary disorders Common: Micturition frequency, polyuria, urine abnormality Rare: Renal failure, renal insufficiency* Very rare: Nephrotic syndrome* Reproductive system and breast disorders Common: Female: amenorrhea, menorrhagia, menstrual disorder, dysmenorrhea, breast pain, ovarian disorder, vaginal disorder. Male: impotence, prostatitis, erectile dysfunction, Sexual dysfunction (not specified)* General disorders and administration site conditions Very common: Fatigue, rigors, pyrexia, influenza like illness, asthenia, irritability Common: Chest pain, chest discomfort, peripheral oedema, malaise, feeling abnormal, thirst 13 Uncommon: Face oedema Investigations Very common: Weight decrease Common: Cardiac murmur * Since ribavirin has always been prescribed with an alpha interferon product, and the listed adverse drug reactions included reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from clinical trials using ribavirin in combination with interferon alfa-2b (pegylated or nonpegylated). Description of selected adverse reactions A reduction in haemoglobin concentrations by > 4 g/dL was observed in 30 % of patients treated with ribavirin and peginterferon alfa-2b and 37 % of patients treated with ribavirin and interferon alfa-2b. Haemoglobin levels dropped below 10 g/dL in up to 14 % of adult patients and 7 % of children and adolescents treated with ribavirin in combination with either peginterferon alfa-2b or interferon alfa-2b. Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with Ribavirin Teva Pharma B.V. in combination with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]); WHO grade 3 leukopenia was also reported in 7 % of this treatment group. An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some patients treated with Ribavirin Teva Pharma B.V. used in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of therapy. Among those patients with elevated uric acid levels, very few patients treated with the combination developed clinical gout, none of which required treatment modification or discontinuation from the clinical trials. HCV/HIV co-infected patients For HCV/HIV co-infected patients receiving ribavirin in combination with peginterferon alfa-2b, other adverse reactions (that were not reported in mono-infected patients) which have been reported in the studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %). Mitochondrial toxicity Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated-ribavirin for co-HCV infection (see section 4.4). Laboratory values for HCV/HIV co-infected patients Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving ribavirin in combination with peginterferon alfa-2b when compared to patients receiving ribavirin in combination with interferon alfa-2b. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving ribavirin in combination with peginterferon alfa-2b. Anaemia a (haemoglobin < 9.4 g/dL) was reported in 12 % (23/194) of patients treated with ribavirin in combination with peginterferon alfa-2b. CD4 lymphocytes decrease Treatment with ribavirin in combination with peginterferon alfa-2b was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of 14 ribavirin in combination with peginterferon alfa-2b had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-infected patients with CD4+ cell counts < 200/µL (see section 4.4). Please refer to the corresponding Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with Ribavirin Teva Pharma B.V in combination with other medicinal products. Paediatric population: In combination with peginterferon alfa-2b In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of peginterferon alfa-2b and ribavirin, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with pegylated interferon alfa-2b and ribavirin, growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and in height percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients). At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety four of 107 children enrolled in the 5 year long-term follow up trial. The effects on growth were less in those children treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow up among children treated for 24 or 48 weeks, height for age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 48 weeks had a > 15 percentile height for age decrease from pre-treatment to the end of 5 year long term follow up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline > 30 height for age percentiles to the end of the 5 year long term follow-up. For weight, pre-treatment to end of long term follow up, weight for age percentiles decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow up, BMI for age percentiles decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4). In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH. In combination with interferon alfa-2b In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy of interferon alfa-2b and ribavirin 6 % discontinued therapy due to adverse events. In general, the 15 adverse event profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as decrease in height percentile (mean percentile decrease of growth velocity of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with interferon alfa- 2b and ribavirin, growth inhibition was observed that resulted in reduced final adult height in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children (see section 4.4). Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for anaemia and neutropenia. Tabulated list of adverse reactions in paediatric population Reported adverse reactions listed in Table 6 are based on experience from the two multicentre children and adolescents clinical trials using ribavirin with interferon alfa-2b or peginterferon alfa-2b. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10), and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with ribavirin in combination with interferon alfa-2b or peginterferon alfa-2b System Organ Class Adverse Reactions Infections and infestations Very common: Viral infection, pharyngitis Common: Fungal infection, bacterial infection, pulmonary infection, nasopharyngitis, pharyngitis streptococcal, otitis media, sinusitis, tooth abscess, influenza, oral herpes, herpes simplex, urinary tract infection, vaginitis, gastroenteritis Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis Neoplasms benign, malignant and unspecified (including cysts and polyps) Common: Neoplasm unspecified Blood and lymphatic system disorders Very common: Anaemia, neutropenia Common: Thrombocytopenia, lymphadenopathy Endocrine disorders Very common: Hypothyroidism Common: Hyperthyroidism, virilism Metabolism and nutrition disorders Very common: Anorexia, increased appetite, decreased appetite Common: Hypertriglyceridemia, hyperuricemia Psychiatric disorders Very common: Depression, insomnia, emotional liability 16 Common: Suicidal ideation, aggression, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy Uncommon: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare Nervous system disorders Very common: Headache, dizziness Common: Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep Uncommon: Neuralgia, lethargy, psychomotor hyperactivity Eye disorders Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia Ear and labyrinth disorders Common: Vertigo Cardiac disorders Common: Tachycardia, palpitations Vascular disorders Common: Pallor, flushing Uncommon: Hypotension Respiratory, thoracic and mediastinal disorders Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal pain Uncommon: Wheezing, nasal discomfort Gastro-intestinal disorders Very common: Abdominal pain, abdominal pain upper, vomiting , diarrhoea, nausea Common: Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder, stomach discomfort, oral pain Uncommon: Gingivitis Hepatobiliary disorders Common: Hepatic function abnormal Uncommon: Hepatomegaly Skin and subcutaneous tissue disorders Very common: Alopecia, rash Common: Pruritus, photosensitivity reaction, maculopapular rash, hyperhidrosis, eczema, acne, skin disorder, nail disorder, skin discolouration, dry skin, erythema, bruise Uncommon: Pigmentation disorder, dermatitis atopic, skin exfoliation Musculoskeletal and connective tissue disorders Very common: Arthralgia, myalgia, musculoskeletal pain Common: Pain in extremity, back pain, muscle contracture Renal and urinary disorders Common: Enuresis, micturition disorder, urinary incontinence, proteinuria Reproductive system and breast disorders 17 Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal disorder, Male: testicular pain Uncommon: Female: dysmenorrhoea General disorders and administration site conditions Very common: Fatigue, rigors, pyrexia, influenza-like illness, asthenia, malaise, irritability Common: Chest pain, oedema, pain, feeling cold Uncommon: Chest discomfort, facial pain Investigations Very common: Growth rate decrease (height and/or weight decrease for age) Common: Blood thyroid stimulating hormone increased, thyroglobulin increased Uncommon: Anti-thyroid antibody positive Injury, poisoning and procedural complications Common: Skin laceration Uncommon: Contusion Most of the changes in laboratory values in the ribavirin/peginterferon alfa-2b clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with ribavirin used in combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V 4.9 Overdose In clinical trials with ribavirin used in combination with peginterferon alfa-2b or interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of ribavirin (50 x 200 mg capsules) and 39 MIU of interferon alfa-2b (13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at suicide. The patient was observed for two days in the emergency room, during which time no adverse reaction from the overdose was noted. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antivirals for systemic use, nucleosides and nucleotides excl.reverse transcriptase inhibitors, ATC code: J05AB04. Mechanism of action Ribavirin is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which ribavirin in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of ribavirin monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that ribavirin monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 18 Clinical efficacy and safety The use of ribavirin in combination treatment with interferon alfa-2b was evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/mL), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT. Naïve patients Three trials examined the use of interferon in naïve patients, two with ribavirin + interferon alfa-2b (C95-132 and I95-143) and one with ribavirin + peginterferon alfa-2b (C/I98-580). In all cases the treatment was for one year with a follow-up of six months. The sustained response at the end of follow-up was significantly increased by the addition of ribavirin to interferon alfa-2b (41 % vs 16 %, p < 0.001). In clinical trials C95-132 and I95-143, ribavirin + interferon alfa-2b combination therapy proved to be significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained response). Combination therapy also decreased the relapse rate. This was true for all HCV genotypes. In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following combination regimens:  Ribavirin (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).  Ribavirin (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) (n = 514).  Ribavirin (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505). In this trial, the combination of ribavirin and peginterferon alfa-2b (1.5 micrograms/kg/week) was significantly more effective than the combination of ribavirin and interferon alfa-2b, particularly in patients infected with Genotype 1. Sustained response was assessed by the response rate six months after the cessation of treatment. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of ribavirin administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that received > 10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received ≤ 10.6 mg/kg ribavirin (Table 7), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher. Table 7 Sustained response rates with ribavirin + peginterferon alfa-2b (by ribavirin dose [mg/kg], genotype and viral load) HCV Genotype Ribavirin dose (mg/kg) P 1.5/R P 0.5/R I/R All Genotypes All ≤ 10.6 > 10.6 54 % 50 % 61 % 47 % 41 % 48 % 47 % 27 % 47 % Genotype 1 All ≤ 10.6 > 10.6 42 % 38 % 48 % 34 % 25 % 34 % 33 % 20 % 34 % Genotype 1 ≤ 600,000 IU/mL All ≤ 10.6 > 10.6 73 % 74 % 71 % 51 % 25 % 52 % 45 % 33 % 45 % Genotype 1 > 600,000 IU/mL All ≤ 10.6 > 10.6 30 % 27 % 37 % 27 % 25 % 27 % 29 % 17 % 29 % 19 Genotype 2/3 All ≤ 10.6 > 10.6 82 % 79 % 88 % 80 % 73 % 80 % 79 % 50 % 80 % P1.5/R Ribavirin (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg) P0.5/R Ribavirin (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg) I/R Ribavirin (1,000/1,200 mg) + interferon alfa-2b (3 MIU) HCV/HIV Co-infected patients Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 8. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either ribavirin (800 mg/day) plus peginterferon alfa-2b (1.5 µg/kg/week) or ribavirin (800 mg/day) plus interferon alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co- infected with HIV. Patients were randomized to receive either ribavirin (800-1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or ribavirin (800 -1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL (Amplicor) who were treated for 24 weeks with a 6 month follow-up period. Table 8 Sustained virological response based on genotype after ribavirin in combination with peginterferon alfa-2b in HCV/HIV co-infected patients Study 11 Study 22 Ribavirin (800 mg/day) + peginterferon alfa-2b (1.5 µg /kg/ week) Ribavirin (800 mg/day) + interferon alfa- 2b (3 MIU TIW) p valuea Ribavirin (800- 1,200 mg/day) d + peginterferon alfa-2b (100 or 150c µg/week) Ribavirin (800- 1,200 mg/day) d + interferon alfa-2b (3 MIU TIW) p valueb All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017 Genotype 1, 4 17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007 Genotype 2, 3 44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730 MIU = million international units; TIW = three times a week. a: p value based on Cochran-Mantel Haenszel Chi square test. b: p value based on chi-square test. c: subjects < 75 kg received 100 µg/week peginterferon alfa-2b and subjects ≥ 75 kg received 150 µg/week peginterferon alfa-2b . d: Ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg. 1 Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848. 2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36. Histological response Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with ribavirin in combination with peginterferon alfa-2b. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3. 20 Retreatment of relapse patients with Ribavirin and interferon alfa-2b combination treatment Two trials examined the use of ribavirin and interferon alfa-2b combination treatment in relapse patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up. Combination therapy with ribavirin and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and histological staging. Long-term efficacy data - Adults Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with nonpegylated interferon alfa-2b (with or without ribavirin) and pegylated interferon alfa- 2b (with or without ribavirin), respectively. The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies. The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-99 %) for patients receiving nonpegylated interferon alfa-2b (with or without ribavirin), and is 99 % (95 % CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without ribavirin). SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and nonpegylated, with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma). Paediatric population Clinical efficacy and safety Ribavirin in combination with interferon alfa-2b Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received ribavirin 15 mg/kg per day plus interferon alfa-2b 3 MIU/m2 3 times a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % ≤ 12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 9. Table 9. Sustained virological response in previously untreated children and adolescents Ribavirin 15 mg/kg/day + interferon alfa-2b 3 MIU/m2 3 times a week Overall Responsea (n=118) 54 (46 %)* Genotype 1 (n=92) 33 (36 %)* Genotype 2/3/4 (n=26) 21 (81 %)* * Number (%) of patients 21 a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period Long-term efficacy data Ribavirin in combination with peginterferon alfa-2b A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR relapsed during the 5 years of follow-up. Ribavirin in combination with interferon alfa-2b A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit. SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma). 5.2 Pharmacokinetic properties Absorption Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax=1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins. Distribution Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the high volume of distribution of ribavirin. The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes. Biotransformation Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally. 22 Ribavirin has been shown to produce high inter and intra subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30 % for both AUC and Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment. Elimination Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr. Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/mL. Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments. Transfer into seminal fluid Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin. Food effect The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat meal (AUCtf and Cmax both increased by 70 %). It is possible that the increased bioavailability in this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take ribavirin with food to achieve the maximal plasma concentration of ribavirin. Renal function Based on published data, single-dose ribavirin pharmacokinetics was altered (increased AUCtf and Cmax) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 mL/minute). The mean AUCtf was threefold greater in subjects with creatinine clearance between 10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and 50 mL/min, AUCtf was twofold greater compared with control subjects. This appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged by haemodialysis. Hepatic function Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) is similar to those of normal controls. Older people (≥ 65 years of age) Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is the determining factor. Population pharmacokinetic analysis was performed using sparsely sampled serum concentration values from four controlled clinical trials. The clearance model developed showed that body weight, gender, age, and serum creatinine were the main covariates. For males, clearance was approximately 20 % higher than for females. Clearance increased as a function of body weight and was reduced at ages greater than 40 years. Effects of these covariates on ribavirin clearance appear to be of limited clinical significance due to the substantial residual variability not accounted for by the model. Paediatric population Ribavirin in combination with interferon alfa-2b Multiple-dose pharmacokinetic properties for ribavirin and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 10. The 23 pharmacokinetics of ribavirin and interferon alfa-2b (dose-normalized) is similar in adults and children or adolescents. Table 10. Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and ribavirin when administered to paediatric patients with chronic hepatitis C Parameter Ribavirin 15 mg/kg/day as 2 divided doses (n = 17) Interferon alfa-2b 3 MIU/m2 3 times a week (n = 54) Tmax (hr) 1.9 (83) 5.9 (36) Cmax (ng/mL) 3,275 (25) 51 (48) AUC* 29,774 (26) 622 (48) Apparent clearance L/hr/kg 0.27 (27) Not done *AUC12 (ng.hr/mL) for Ribavirin; AUC0-24 (IU.hr/mL) for interferon alfa-2b 5.3 Preclinical safety data Ribavirin Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was reduced. In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls. No histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose. Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment. In 3- and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles (see section 4.6). Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was active in the Balb/3T3 in vitro transformation assay. Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. Conventional carcinogenicity rodent studies with low exposures compared to human exposure under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential of ribavirin in humans is unlikely. Ribavirin plus interferon 24 When used in combination with peginterferon alfa-2b or interferon alfa-2b, ribavirin did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Calcium hydrogen phosphate anhydrous Croscarmellose sodium Povidone Magnesium stearate Tablet coating Polyvinyl alcohol – partly hydrolysed Macrogol / Polyethylene glycol 3350 Titanium dioxide (E171) Talc Iron oxide red Iron oxide yellow Iron oxide black 6.2 Incompatibilities Not applicable 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Ribavirin Teva Pharma B.V. tablets are packaged in aluminium blisters consisting of polyvinyl chloride (PVC)/polyethylene (PE)/polyvinyl Acetate (PVAc) Packs of 14, 28, 42, 56, 84, 112, 140 and 168 tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Teva B.V. Swensweg 5 25 2031GA Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/09/527/001 - 14 tablets EU/1/09/527/002 - 28 tablets EU/1/09/527/003 - 42 tablets EU/1/09/527/004 - 56 tablets EU/1/09/527/005 - 84 tablets EU/1/09/527/006 - 112 tablets EU/1/09/527/007 - 140 tablets EU/1/09/527/008 - 168 tablets 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation : 01 July 2009 Date of latest renewal : 16 January 2014 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. http://www.emea.europa.eu/� 26 1. NAME OF THE MEDICINAL PRODUCT Ribavirin Teva Pharma B.V. 400 mg film coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each Ribavirin Teva Pharma B.V. tablet contains 400 mg of ribavirin For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Light pink to pink, (debossed with “R” on one side and “400” on the other). 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Ribavirin Teva Pharma B.V. is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults, children 3-years of age or older and adolescents and must only be used as part of a combination regimen with interferon alfa-2b. Ribavirin monotherapy must not be used. There is no safety or efficacy information on the use of ribavirin with other forms of interferon (i.e. not alfa-2b). Naïve patients  Adult patients: Ribavirin Teva Pharma B.V. is indicated, in combination with interferon alfa-2b, for the treatment of adult patients with all types of chronic hepatitis C except genotype 1 , not previously treated, without liver decompensation, with elevated alanine aminotransferase (ALT), who are positive for hepatitis C viral ribonucleic acid HCV-RNA (see section 4.4). Paediatric patients (children 3 years of age and older and adolescents: Ribavirin Teva Pharma B.V. is indicated, in a combination regimen with interferon alfa-2b, for the treatment of children and adolescents 3 years of age and older, who have all types of chronic hepatitis C except genotype 1, not previously treated, without liver decompensation, and who are positive for serum HCV-RNA. When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case basis (see section 4.4). Previous treatment failure patients  Adult patients: Ribavirin Teva Pharma B.V. is indicated, in combination with interferon alfa-2b, for the treatment of adult patients with chronic hepatitis C who have previously responded (with normalisation of ALT at the end of treatment) to interferon alpha monotherapy but who have subsequently relapsed.(see section 5.1). 4.2 Posology and method of administration Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C. Posology 27 Ribavirin Teva Pharma B.V. must be used in combination therapy as described in section 4.1. Please refer to the corresponding Summary of Product Characteristics (SmPC) of medicinal products used in combination with Ribavirin Teva Pharma B.V. for prescribing information particular to that product and for further dosage recommendations on co-administration with Ribavirin Teva Pharma B.V.. Ribavirin Teva Pharma B.V. tablets are to be administered orally each day in two divided doses (morning and evening) with food. Adults: The recommended dose and duration of Ribavirin Teva Pharma B.V. depends on patient’s weight and on the medicinal product that is used in combination. Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirin Teva Pharma B.V.. In the cases in which no specific dose recommendation is made, the following dose should be used: Patient weight: < 75 kg =1,000 mg and > 75 kg = 1,200 mg. Paediatric population: No data are available in children below 3 years of age. Note: For patients who weigh <47 kg, or are unable to swallow tablets, ribavirin oral solution is available and should be used if appropriate. Dosing of ribavirin for children and adolescent patients is determined by the patient body weight. For example, the body weight dosing used in conjunction with interferon alfa-2b is shown in Table 1. Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin as some combination regimens do not adhere to the ribavirin dosing guidance provided in Table 1. Table 1 Ribavirin Teva Pharma B.V. dose based on body weight when used in combination with interferon alfa-2b in paediatric patients Patient weight (kg) Daily ribavirin dose Number of 200 mg tablets* 47-49 600 mg 3 x 200 mg tabletsa 50-65 800 mg 4 x 200 mg tabletsb > 65 Refer to adult dose recommendation a: 1 morning, 2 evening b: 2 morning, 2 evening Ribavirin Teva Pharma B.V. 400 mg Tablets *Nb: for 800 mg daily dose, 2 x 200 mg tablets can be substituted for 1 x 400 mg tablet. Dose modification for adverse reactions Dose modification for adults Dose reduction of ribavirin depends on the initial ribavirin posology which depends on the medicinal product that is used in combination with ribavirin. If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration, cardiac status and indirect bilirubin concentration. 28 Table 2 Management of Adverse Reactions Laboratory values Reduce ribavirin dose* if: Discontinue ribavirin if: Haemoglobin in patients with No Cardiac Disease < 10 g/dL < 8.5 g/dL Haemoglobin: Patients with History of Stable Cardiac Disease  2 g/dL decrease in haemoglobin during any 4 week period during treatment (permanent dose reduction) < 12 g/dL despite 4 weeks at reduced dose Bilirubin – Indirect > 5 mg/dL > 4 mg/dL (adults) * For patients receiving a 1,000 mg (< 75 kg) or 1,200 mg (> 75 kg) dose, ribavirin dose should be reduced to 600 mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets in the evening). If the abnormality is reversed, ribavirin may be restarted at 600 mg daily, and further increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended. For patients receiving a 800 mg (< 65 kg) - 1,000 mg (65-80 kg) - 1,200 mg (81-105 kg) or 1,400 mg (> 105 kg) dose, 1st dose reduction of Ribavirin Teva Pharma B.V. is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Ribavirin Teva Pharma B.V. is by an additional 200 mg/day. Patients whose dose of Ribavirin Teva Pharma B.V. is reduced to 600 mg daily receive one 200 mg tablet in the morning and two 200 mg tablets in the evening. In case of serious adverse reaction potentially related to medicinal products used in combination with ribavirin, refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the ribavirin dose modification and/or discontinuation guidelines as described in Table 2. Dose modification for paediatric patients Dose reduction in paediatric patients without cardiac disease follows the same guidelines as adult patients without cardiac disease regarding haemoglobin levels (Table 2). There are no data for paediatric patients with cardiac disease (see section 4.4). Table 3 provides guidelines for discontinuation based on the patient’s indirect bilirubin concentration. Table 3 Management of Adverse Reactions Laboratory values Discontinue ribavirin if: Bilirubin – Indirect > 5 mg/dL (for > 4 weeks) (children and adolescents treated with interferon alfa-2b), or > 4 mg/dL (for > 4 weeks) (children and adolescents treated with peginterferon alfa-2b) Special populations Elderly ( 65 years of age) There does not appear to be a significant age-related effect on the pharmacokinetics of ribavirin. However, as in younger patients, renal function must be determined prior to administration of ribavirin (see section 5.2). Paediatric patients (children 3 years of age and older and adolescents) Ribavirin may be used in combination with interferon alfa-2b (see section 4.4). The selection of ribavirin formulation is based on individual characteristics of the patient. The safety and efficacy of ribavirin used together with direct-acting-anti-virals in these patients has not been established. No data are available. 29 Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin for further dosage recommendations on co-administration. Renal impairment The pharmacokinetics of ribavirin is altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2). Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of ribavirin. Adult patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance of < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered ribavirin 200 mg/day. Table 4 provides guidelines for dose modification for patients with renal dysfunction. Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. No data are available regarding dose modification for paediatric patients with renal impairment. Table 4 Dosage Modification for Renal Impairment in Adult Patients Creatinine Clearance Ribavirin Dose (daily) 30 to 50 mL/min Alternating doses, 200 mg and 400 mg every other day Less than 30 mL/min 200 mg daily Haemodialysis (ESRD) 200 mg daily Hepatic impairment No pharmacokinetic interaction appears between ribavirin and hepatic function (see section 5.2). For use in patients with decompensated cirrhosis, see the corresponding SmPC of the medicinal products used in combination with ribavirin. Method of administration Ribavirin Teva Pharma B.V. tablets should be administered orally with food. 4.3 Contraindications - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Pregnancy (see sections 4.4, 4.6 and 5.3). In females of childbearing potential, Ribavirin Teva Pharma B.V. must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. - Breast-feeding - History of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months (see section 4.4). - Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia). Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirin Teva Pharma B.V. for contraindications specific to these products. 4.4 Special warnings and precautions for use Ribavirin must be used in combination with other medicinal products (see section 5.1). Please refer to the SmPC of (peg)interferon alfa for details on the recommendations of monitoring and management regarding the adverse reactions listed below before initiating therapy and other precautions associated with (peg)interferon alfa. There are several serious adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa. These include: - Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behaviour, etc.) - Growth inhibition in children and adolescents that may be irreversible in some patients 30 - Increased thyroid stimulating hormone (TSH) in children and adolescents - Severe ocular disorders - Dental and periodontal disorders. Paediatric population When deciding not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to consider that this combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case. Haemolysis A decrease in haemoglobin levels to < 10 g/dL was observed in up to 14 % of adult patients and 7 % of children and adolescents treated with ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although ribavirin has no direct cardiovascular effects, anaemia associated with ribavirin may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, ribavirin must be administered with caution to patients with pre-existing cardiac disease (see section 4.3). Cardiac status must be assessed before start of therapy and monitored clinically during therapy; if any deterioration occurs, therapy must be stopped (see section 4.2). Cardiovascular Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders must be closely monitored. It is recommended that those patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of therapy. There are no data in children or adolescents with a history of cardiac disease. Teratogenic risk Prior to initiation of treatment with ribavirin the physician must comprehensively inform both male and female patients of the teratogenic risk of ribavirin, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during or following treatment with ribavirin (see section 4.6). For laboratory monitoring of pregnancy, please refer to Laboratory tests. Acute hypersensitivity If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ribavirin Teva Pharma B.V. must be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment. Liver function Any patient developing significant liver function abnormalities during treatment must be monitored closely. Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirin Teva Pharma B.V. for discontinuation or dose modification recommendations. Renal impairment The pharmacokinetics of ribavirin is altered in patients with renal dysfunction due to reduction of apparent clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of ribavirin. Due to substantial increases in ribavirin plasma concentrations in patients with moderate and severe renal impairment, ribavirin dose adjustments are recommended in adult patients with creatinine clearance < 50 mL/minute. No data are available regarding dose modification for paediatric patients with renal impairment (see sections 4.2 and 5.2). Haemoglobin concentrations should be monitored closely during treatment and corrective action taken as necessary (see section 4.2). Potential to exacerbate immunosuppression 31 Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see section 4.5). HCV/HIV Co-infection Mitochondrial toxicity and lactic acidosis: Caution should be taken in HIV-positive subjects co- infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon alfa-2b/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial toxicity and lactic acidosis when ribavirin is administered. For additional details see section 4.5. Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis: Co-infected patients with advanced cirrhosis receiving combined anti-retroviral therapy (cART) may be at increased risk of hepatic decompensation and death. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentrations. Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin for discontinuation or dose modification recommendations. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed. Haematological abnormalities in HCV/HIV co-infected patients: HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and cART may be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed by dose reduction, close monitoring of haematological parameters should be undertaken in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8). Patients treated with ribavirin and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of ribavirin with zidovudine is not recommended (see section 4.5). Patients with low CD4 counts: In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in subjects with CD4 counts less than 200 cells/µL. Caution is therefore warranted in the treatment of patients with low CD4 counts. Please refer to the corresponding SmPC of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ribavirin. Laboratory tests Standard haematologic tests, blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) and pregnancy tests must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of ribavirin therapy: Haemoglobin Adult: ≥ 12 g/dL (females); ≥ 13 g/dL (males) Children and adolescents: ≥ 11 g/dL (females); ≥ 12 g/dL (males) Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2). 32 Uric acid may increase with ribavirin due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients. 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults. Results of in vitro studies using both human and rat liver microsome preparations indicated no cytochrome P450 enzyme mediated metabolism of ribavirin. Ribavirin does not inhibit cytochrome P450 enzymes. There is no evidence from toxicity studies that ribavirin induces liver enzymes. Therefore, there is a minimal potential for P450 enzyme-based interactions. Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. The use of pegylated alpha interferons and ribavirin concomitantly with azathioprine should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these medicines should be stopped (see section 4.4). No interaction studies have been conducted with ribavirin and other medicinal products, except for peginterferon alfa-2b, interferon alfa-2b and antacids. No pharmacokinetic interactions were noted between ribavirin and peginterferon alfa-2b or interferon alfa-2b in a multiple-dose pharmacokinetic study. Antacid The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid containing magnesium aluminium and simethicone; AUCtf decreased 14 %. It is possible that the decreased bioavailability in this study was due to delayed transit of ribavirin or modified pH. This interaction is not considered to be clinically relevant. Nucleoside analogues Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see section 4.4). The exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4).Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia. Any potential for interactions may persist for up to two months (five half-lives for ribavirin) after cessation of ribavirin therapy due to the long half-life (see section 5.2). There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors or protease inhibitors. Conflicting findings are reported in literature on co-administration between abacavir and ribavirin. Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at 33 risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised when both medicines are co-administered. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/contraception in males and females Female patients Ribavirin Teva Pharma B.V. must not be used by females who are pregnant (see sections 4.3, 4.4 and 5.3). Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Ribavirin therapy must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Females of childbearing potential must use an effective contraceptive during treatment and for four months after treatment has been concluded; routine monthly pregnancy tests must be performed during this time (see section 4.4). If pregnancy does occur during treatment or within four months from stopping treatment, the patient must be advised of the significant teratogenic risk of ribavirin to the foetus (see section 4.4). Male patients and their female partners Extreme care must be taken to avoid pregnancy in partners of male patients taking Ribavirin Teva Pharma B.V. (see sections 4.3, 4.4 and 5.3). Ribavirin accumulates intracellularly and is cleared from the body very slowly. It is unknown whether the ribavirin that is contained in sperm will exert its potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on approximately 300 prospectively followed pregnancies with paternal exposure to ribavirin have not shown an increased risk of malformation compared to the general population, nor any specific pattern of malformation, either male patients or their female partners of childbearing age must be advised to use an effective contraceptive during treatment with ribavirin and for seven months after treatment. Routine monthly pregnancy tests must be performed during this time. Men whose partners are pregnant must be instructed to use a condom to minimise delivery of ribavirin to the partner. Pregnancy The use of Ribavirin Teva Pharma B.V. is contraindicated during pregnancy. Ribavirin has been shown in preclinical studies to be teratogenic and genotoxic (see section 4.4 and 5.3). Breast-feeding It is not known whether ribavirin is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment. Fertility Preclinical data: - Fertility: In animal studies, ribavirin produced reversible effects on spermatogenesis (see section 5.3). - Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted, occurring at doses as low as one twentieth of the recommended human dose (see section 5.3). - Genotoxicity: Ribavirin induces genotoxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Ribavirin Teva Pharma B.V. has no or negligible influence on the ability to drive and use machines; however, other medicinal products used in combination may have an effect. Thus, patients who develop fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or operating machinery. 4.8 Undesirable effects 34 Summary of the safety profile The salient safety issue of ribavirin is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with ribavirin therapy may result in deterioration of cardiac function and/or worsening of pre-existing cardiac disease. An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients. The adverse reactions listed in this section are primarily derived from clinical trials and/or as adverse drug reactions from spontaneous reports when ribavirin was used in combination with interferon alfa-2b or peginterferon alfa-2b. Please refer to the corresponding SmPC of medicinal products that are used in combination with ribavirin for additional undesirable effects reported with these products. Adults The safety of ribavirin is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied ribavirin in combination with interferon alfa-2b, two trials studied ribavirin in combination with peginterferon alfa-2b. Patients who are treated with interferon alfa-2b and ribavirin after previous relapse from interferon therapy or who are treated for a shorter period are likely to have an improved safety profile than that described below. Tabulated list of adverse reactions for adults The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naïve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with ribavirin) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b SPCs for adverse reactions that may be attributable to interferon monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 5 Adverse reactions reported during clinical trials or following the marketing use of ribavirin with pegylated interferon alfa-2b or interferon alfa-2b System Organ Class Adverse Reactions Infections and infestations Very common: Viral infection, pharyngitis Common: Bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infection Uncommon Lower respiratory tract infection Rare: Pneumonia* Neoplasms benign, malignant and unspecified (including cysts and polyps) Common: Neoplasm unspecified Blood and lymphatic system disorders Very common: Anaemia, neutropenia Common: Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia Very rare: Aplastic anaemia* Not known: Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura Immune system disorders 35 Uncommon: Drug hypersensitivity Rare: Sarcoidosis*, rheumatoid arthritis (new or aggravated) Not known: Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis Endocrine disorders Common: Hypothyroidism, hyperthyroidism Metabolism and nutrition disorders Very common: Anorexia Common: Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite Uncommon: Diabetes mellitus, hypertriglyceridemia* Psychiatric disorders Very common: Depression, anxiety, emotional lability, insomnia Common: Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, anger, mood altered, abnormal behaviour nervousness, sleep disorder, decreased libido, apathy, abnormal dreams, crying, Uncommon: Suicide attempts, panic attack, hallucination Rare: Bipolar disorder* Very rare: Suicide* Not known: Homicidal ideation*, mania*, mental status change Nervous system disorders Very common: Headache, dizziness, dry mouth, concentration impaired Common: Amnesia, memory impairment, syncope, migraine, ataxia,, paraesthaesia, dysphonia, taste loss, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia Uncommon: Neuropathy, peripheral neuropathy Rare: Seizure (convulsion)* Very rare: Cerebrovascular haemorrhage*, cerebrovascular ischaemia*, encephalopathy*, polyneuropathy* Not known: Facial palsy, mononeuropathies Eye disorders Common: Visual disturbance, blurred vision, conjunctivitis, eye irritation, eye pain, abnormal vision, lacrimal gland disorder, dry eye Rare: Retinal haemorrhages*, retinopathies (including macular oedema)*, retinal artery occlusion*, retinal vein occlusion*, optic neuritis*, papilloedema*, loss of visual acuity or visual field*, retinal exudates* Ear and labyrinth disorders Common: Vertigo, hearing impaired/loss, tinnitus, ear pain Cardiac disorders Common: Palpitation, tachycardia Uncommon: Myocardial infarction Rare: Cardiomyopathy*, arrhythmia* Very rare: Cardiac ischaemia* Not known: Pericardial effusion*, pericarditis* Vascular disorders Common: Hypotension, hypertension, flushing Rare: Vasculitis Very rare: Peripheral ischaemia* 36 Respiratory, thoracic and mediastinal disorders Very common: Dyspnoea, coughing Common: Epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain, nonproductive cough Very rare: Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis* Gastro-intestinal disorders Very common: Diarrhoea, vomiting, nausea, abdominal pain Common: Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia, gastroesophageal reflux*, glossitis, cheilitis, abdominal distension, gingival bleeding, gingivitis, loose stools, tooth disorder, constipation, flatulence Uncommon: Pancreatitis, oral pain Rare: Ischaemic colitis Very rare: Ulcerative colitis* Not Known: Periodontal disorder, dental disorder, tongue pigmentation Hepatobiliary disorders Common: Hepatomegaly, jaundice, hyperbilirubinemia* Very rare: Hepatotoxicity (including fatalities)* Skin and subcutaneous tissue disorders Very common: Alopecia, pruritus, skin dry, rash Common: Psoriasis, aggravated psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema, urticaria, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder* Rare: Cutaneous sarcoidosis Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme* Musculoskeletal and connective tissue disorders Very common: Arthralgia, myalgia, musculoskeletal pain Common: Arthritis, back pain, muscle spasms, pain in extremity Uncommon: Bone pain, muscle weakness Rare: Rhabdomyolysis*, myositis* Renal and urinary disorders Common: Micturition frequency, polyuria, urine abnormality Rare: Renal failure*, renal insufficiency* Very rare: Nephrotic syndrome* Reproductive system and breast disorders Common: Female: amenorrhea, menorrhagia, menstrual disorder, dysmenorrhea, breast pain, ovarian disorder, vaginal disorder. Male: impotence, prostatitis, erectile dysfunction, Sexual dysfunction (not specified)* General disorders and administration site conditions Very common: Fatigue, rigors, pyrexia, influenza like illness, asthenia, irritability Common: Chest pain, chest discomfort, peripheral oedema, malaise, feeling abnormal, thirst 37 Uncommon: Face oedema Investigations Very common: Weight decrease Common: Cardiac murmur * Since ribavirin has always been prescribed with an alpha interferon product, and the listed adverse drug reactions included reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from clinical trials using ribavirin in combination with interferon alfa-2b (pegylated or nonpegylated). Description of selected adverse reactions A reduction in haemoglobin concentrations by > 4 g/dL was observed in 30 % of patients treated with ribavirin and peginterferon alfa-2b and 37 % of patients treated with ribavirin and interferon alfa-2b. Haemoglobin levels dropped below 10 g/dL in up to 14 % of adult patients and 7 % of children and adolescents treated with ribavirin in combination with either peginterferon alfa-2b or interferon alfa- 2b. Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with Ribavirin Teva Pharma B.V. in combination with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]); WHO grade 3 leukopenia was also reported in 7 % of this treatment group. An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some patients treated with Ribavirin Teva Pharma B.V. used in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of therapy. Among those patients with elevated uric acid levels, very few patients treated with the combination developed clinical gout, none of which required treatment modification or discontinuation from the clinical trials. HCV/HIV co-infected patients For HCV/HIV co-infected patients receiving ribavirin in combination with peginterferon alfa-2b, other adverse reactions (that were not reported in mono-infected patients) which have been reported in the studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %). Mitochondrial toxicity Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated-ribavirin for co-HCV infection (see section 4.4). Laboratory values for HCV/HIV co-infected patients Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving ribavirin in combination with peginterferon alfa- 2b when compared to patients receiving ribavirin in combination with interferon alfa-2b. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving ribavirin in combination with peginterferon alfa-2b. Anaemia a (haemoglobin < 9.4 g/dL) was reported in 12 % (23/194) of patients treated with ribavirin in combination with peginterferon alfa-2b. CD4 lymphocytes decrease Treatment with ribavirin in combination with peginterferon alfa-2b was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of 38 ribavirin in combination with peginterferon alfa-2b had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-infected patients with CD4+ cell counts < 200/µL (see section 4.4). Please refer to the corresponding Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with Ribavirin Teva Pharma B.V in combination with other medicinal products. Paediatric population: In combination with peginterferon alfa-2b In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of peginterferon alfa-2b and ribavirin, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with pegylated interferon alfa-2b and ribavirin, growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and in height percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients). At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety four of 107 children enrolled in the 5 year long-term follow up trial. The effects on growth were less in those children treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow up among children treated for 24 or 48 weeks, height for age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 48 weeks had a > 15 percentile height for age decrease from pre-treatment to the end of 5 year long term follow up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline > 30 height for age percentiles to the end of the 5 year long term follow-up. For weight, pre-treatment to end of long term follow up, weight for age percentiles decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow up, BMI for age percentiles decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4). In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH. In combination with interferon alfa-2b In clinical trials of 118 children and adolescents 3 to 16 years of age, treated with combination therapy of interferon alfa-2b and ribavirin, 6 % discontinued therapy due to adverse events. In general, the 39 adverse event profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as decrease in height percentile (mean percentile decrease of growth velocity of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with interferon alfa- 2b and ribavirin, growth inhibition was observed that resulted in reduced final adult height in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children (see section 4.4). Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for anaemia and neutropenia. Tabulated list of adverse reactions in paediatric population Reported adverse reactions listed in Table 6 are based on experience from the two multicentre children and adolescents clinical trials using ribavirin with interferon alfa-2b or peginterferon alfa-2b. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10), and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with ribavirin in combination with interferon alfa-2b or peginterferon alfa-2b System Organ Class Adverse Reactions Infections and infestations Very common: Viral infection, pharyngitis Common: Fungal infection, bacterial infection, pulmonary infection, nasopharyngitis, pharyngitis streptococcal, otitis media, sinusitis, tooth abscess, influenza, oral herpes, herpes simplex, urinary tract infection, vaginitis, gastroenteritis Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis Neoplasms benign, malignant and unspecified (including cysts and polyps) Common: Neoplasm unspecified Blood and lymphatic system disorders Very common: Anaemia, neutropenia Common: Thrombocytopenia, lymphadenopathy Endocrine disorders Very common: Hypothyroidism Common: Hyperthyroidism, virilism Metabolism and nutrition disorders Very common: Anorexia, increased appetite, decreased appetite Common: Hypertriglyceridemia, hyperuricemia Psychiatric disorders Very common: Depression, insomnia, emotional liability 40 Common: Suicidal ideation, aggression, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy Uncommon: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare Nervous system disorders Very common: Headache, dizziness Common: Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep Uncommon: Neuralgia, lethargy, psychomotor hyperactivity Eye disorders Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia Ear and labyrinth disorders Common: Vertigo Cardiac disorders Common: Tachycardia, palpitations Vascular disorders Common: Pallor, flushing Uncommon: Hypotension Respiratory, thoracic and mediastinal disorders Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal pain. Uncommon: Wheezing, nasal discomfort Gastro-intestinal disorders Very common: Abdominal pain, abdominal pain upper, vomiting , diarrhoea, nausea Common: Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder, stomach discomfort, oral pain Uncommon: Gingivitis Hepatobiliary disorders Common: Hepatic function abnormal Uncommon: Hepatomegaly Skin and subcutaneous tissue disorders Very common: Alopecia, rash Common: Pruritus, photosensitivity reaction, maculopapular rash, hyperhidrosis, eczema, acne, skin disorder, nail disorder, skin discolouration, dry skin, erythema, bruise Uncommon: Pigmentation disorder, dermatitis atopic, skin exfoliation Musculoskeletal and connective tissue disorders Very common: Arthralgia, myalgia, musculoskeletal pain Common: Pain in extremity, back pain, muscle contracture Renal and urinary disorders Common: Enuresis, micturition disorder, urinary incontinence, proteinuria Reproductive system and breast disorders 41 Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal disorder, Male: testicular pain Uncommon: Female: dysmenorrhoea General disorders and administration site conditions Very common: Fatigue, rigors, pyrexia, influenza-like illness, asthenia, malaise, irritability Common: Chest pain, oedema, pain, feeling cold Uncommon: Chest discomfort, facial pain Investigations Very common: Growth rate decrease (height and/or weight decrease for age) Common: Blood thyroid stimulating hormone increased, thyroglobulin increased Uncommon: Anti-thyroid antibody positive Injury, poisoning and procedural complications Common: Skin laceration Uncommon: Contusion Most of the changes in laboratory values in the ribavirin/peginterferon alfa-2b clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with ribavirin used in combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In clinical trials with ribavirin used in combination with peginterferon alfa-2b or interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of ribavirin (50 x 200 mg capsules) and 39 MIU of interferon alfa-2b (13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at suicide. The patient was observed for two days in the emergency room, during which time no adverse reaction from the overdose was noted. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antivirals for systemic use, nucleosides and nucleotides excl.reverse transcriptase inhibitors, ATC code: J05AB04. Mechanism of action Ribavirin is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which ribavirin in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of ribavirin monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that ribavirin monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 42 Clinical efficacy and safety The use of ribavirin in combination treatment with interferon alfa-2b was evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV- RNA polymerase chain reaction assay (PCR) (> 30 IU/mL), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT. Naïve patients Three trials examined the use of interferon in naïve patients, two with ribavirin + interferon alfa-2b (C95-132 and I95-143) and one with ribavirin + peginterferon alfa-2b (C/I98-580). In all cases the treatment was for one year with a follow-up of six months. The sustained response at the end of follow-up was significantly increased by the addition of ribavirin to interferon alfa-2b (41 % vs 16 %, p < 0.001). In clinical trials C95-132 and I95-143, ribavirin + interferon alfa-2b combination therapy proved to be significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained response). Combination therapy also decreased the relapse rate. This was true for all HCV genotypes. In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following combination regimens:  Ribavirin (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).  Ribavirin (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) (n = 514).  Ribavirin (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505). In this trial, the combination of ribavirin and peginterferon alfa-2b (1.5 micrograms/kg/week) was significantly more effective than the combination of ribavirin and interferon alfa-2b, particularly in patients infected with Genotype 1. Sustained response was assessed by the response rate six months after the cessation of treatment. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of ribavirin administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that received > 10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received ≤ 10.6 mg/kg ribavirin (Table 7), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher. Table 7 Sustained response rates with ribavirin + peginterferon alfa-2b (by ribavirin dose [mg/kg], genotype and viral load) HCV Genotype Ribavirin dose (mg/kg) P 1.5/R P 0.5/R I/R All Genotypes All ≤ 10.6 > 10.6 54 % 50 % 61 % 47 % 41 % 48 % 47 % 27 % 47 % Genotype 1 All ≤ 10.6 > 10.6 42 % 38 % 48 % 34 % 25 % 34 % 33 % 20 % 34 % Genotype 1 ≤ 600,000 IU/mL All ≤ 10.6 > 10.6 73 % 74 % 71 % 51 % 25 % 52 % 45 % 33 % 45 % Genotype 1 > 600,000 IU/mL All ≤ 10.6 > 10.6 30 % 27 % 37 % 27 % 25 % 27 % 29 % 17 % 29 % 43 Genotype 2/3 All ≤ 10.6 > 10.6 82 % 79 % 88 % 80 % 73 % 80 % 79 % 50 % 80 % P1.5/R Ribavirin (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg) P0.5/R Ribavirin (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg) I/R Ribavirin (1,000/1,200 mg) + interferon alfa-2b (3 MIU) HCV/HIV Co-infected patients Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 8. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either ribavirin (800 mg/day) plus peginterferon alfa-2b (1.5 µg/kg/week) or ribavirin (800 mg/day) plus interferon alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co- infected with HIV. Patients were randomized to receive either ribavirin (800-1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or ribavirin (800 - 1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL (Amplicor) who were treated for 24 weeks with a 6 month follow-up period. Table 8 Sustained virological response based on genotype after ribavirin in combination with peginterferon alfa-2b in HCV/HIV co-infected patients Study 11 Study 22 Ribavirin (800 mg/day) + peginterferon alfa-2b (1.5 µg /kg/ week) Ribavirin (800 mg/day) + interferon alfa- 2b (3 MIU TIW) p valuea Ribavirin (800- 1,200 mg/day) d + peginterferon alfa-2b (100 or 150c µg/week) Ribavirin (800- 1,200 mg/day) d + interferon alfa-2b (3 MIU TIW) p valueb All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017 Genotype 1, 4 17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007 Genotype 2, 3 44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730 MIU = million international units; TIW = three times a week. a: p value based on Cochran-Mantel Haenszel Chi square test. b: p value based on chi-square test. c: subjects < 75 kg received 100 µg/week peginterferon alfa-2b and subjects ≥ 75 kg received 150 µg/week peginterferon alfa-2b . d: Ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg. 1 Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848. 2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36. Histological response Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with ribavirin in combination with peginterferon alfa-2b. This decline was significant among responders (- 0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3. 44 Retreatment of relapse patients with Ribavirin and interferon alfa-2b combination treatment Two trials examined the use of ribavirin and interferon alfa-2b combination treatment in relapse patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up. Combination therapy with ribavirin and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and histological staging. Long-term efficacy data - Adults Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with nonpegylated interferon alfa-2b (with or without ribavirin) and pegylated interferon alfa- 2b (with or without ribavirin), respectively. The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies. The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-99 %) for patients receiving nonpegylated interferon alfa-2b (with or without ribavirin), and is 99 % (95 % CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without ribavirin). SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and nonpegylated, with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma). Paediatric population Clinical efficacy and safety Ribavirin in combination with interferon alfa-2b Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received ribavirin 15 mg/kg per day plus interferon alfa-2b 3 MIU/m2 3 times a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % ≤ 12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 9. Table 9. Sustained virological response in previously untreated children and adolescents Ribavirin 15 mg/kg/day + interferon alfa-2b 3 MIU/m2 3 times a week Overall Responsea (n=118) 54 (46 %)* Genotype 1 (n=92) 33 (36 %)* Genotype 2/3/4 (n=26) 21 (81 %)* * Number (%) of patients 45 a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period Long-term efficacy data Ribavirin in combination with peginterferon alfa-2b A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR relapsed during the 5 years of follow-up. Ribavirin in combination with interferon alfa-2b A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit. SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma). 5.2 Pharmacokinetic properties Absorption Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax=1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins. Distribution Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the high volume of distribution of ribavirin. The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes. Biotransformation Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally. 46 Ribavirin has been shown to produce high inter and intra subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30 % for both AUC and Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment. Elimination Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr. Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/mL. Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments. Transfer into seminal fluid Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin. Food effect The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat meal (AUCtf and Cmax both increased by 70 %). It is possible that the increased bioavailability in this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take ribavirin with food to achieve the maximal plasma concentration of ribavirin. Renal function Based on published data, single-dose ribavirin pharmacokinetics was altered (increased AUCtf and Cmax) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 mL/minute). The mean AUCtf was threefold greater in subjects with creatinine clearance between 10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and 50 mL/min, AUCtf was twofold greater compared with control subjects. This appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged by haemodialysis. Hepatic function Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) is similar to those of normal controls. Older people (≥ 65 years of age) Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is the determining factor. Population pharmacokinetic analysis was performed using sparsely sampled serum concentration values from four controlled clinical trials. The clearance model developed showed that body weight, gender, age, and serum creatinine were the main covariates. For males, clearance was approximately 20 % higher than for females. Clearance increased as a function of body weight and was reduced at ages greater than 40 years. Effects of these covariates on ribavirin clearance appear to be of limited clinical significance due to the substantial residual variability not accounted for by the model. Paediatric population Ribavirin in combination with interferon alfa-2b Multiple-dose pharmacokinetic properties for ribavirin and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 10. The 47 pharmacokinetics of ribavirin and interferon alfa-2b (dose-normalized) is similar in adults and children or adolescents. Table 10. Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and ribavirin when administered to paediatric patients with chronic hepatitis C Parameter Ribavirin 15 mg/kg/day as 2 divided doses (n = 17) Interferon alfa-2b 3 MIU/m2 3 times a week (n = 54) Tmax (hr) 1.9 (83) 5.9 (36) Cmax (ng/mL) 3,275 (25) 51 (48) AUC* 29,774 (26) 622 (48) Apparent clearance L/hr/kg 0.27 (27) Not done *AUC12 (ng.hr/mL) for Ribavirin; AUC0-24 (IU.hr/mL) for interferon alfa-2b 5.3 Preclinical safety data Ribavirin Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was reduced. In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls. No histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose. Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment. In 3- and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles (see section 4.6). Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was active in the Balb/3T3 in vitro transformation assay. Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. Conventional carcinogenicity rodent studies with low exposures compared to human exposure under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential of ribavirin in humans is unlikely. Ribavirin plus interferon 48 When used in combination with peginterferon alfa-2b or interferon alfa-2b, ribavirin did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Calcium hydrogen phosphate anhydrous Croscarmellose sodium Povidone Magnesium stearate Tablet coating Polyvinyl alcohol – partly hydrolysed Macrogol / Polyethylene glycol 3350 Titanium dioxide (E171) Talc Iron oxide red Iron oxide yellow Iron oxide black 6.2 Incompatibilities Not applicable 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Ribavirin Teva Pharma B.V. tablets are packaged in aluminium blisters consisting of polyvinyl chloride (PVC)/polyethylene (PE)/polyvinyl Acetate (PVAc) Packs of 14, 28, 42, 56, 84, 112, 140 and 168 tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Teva B.V. Swensweg 5 49 2031GA Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/09/527/009 - 14 tablets EU/1/09/527/010 - 28 tablets EU/1/09/527/011 - 42 tablets EU/1/09/527/012 - 56 tablets EU/1/09/527/013 - 84 tablets EU/1/09/527/014 - 112 tablets EU/1/09/527/015 - 140 tablets EU/1/09/527/016 - 168 tablets 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation : 01 July 2009 Date of latest renewal : 16 January 2014 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. http://www.emea.europa.eu/� 50 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 51 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Teva Pharmaceutical Works Private Limited Company Pallagi Street 13 H-4042 Debrecen Hungary Teva UK Ltd. Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG United Kingdom Pharmachemie BV Swensweg 5 2031 GA Haarlem The Netherlands Teva Pharma SLU C/ C, n° 4, Polígono Industrial Malpica, 50016 Zaragoza Spain The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, Section 4.2) C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) Not applicable. 52 ANNEX III LABELLING AND PACKAGE LEAFLET 53 A. LABELLING 54 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Outer Carton for 14, 28, 42, 56, 84, 112, 140 and 168 film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT Ribavirin Teva Pharma B.V. 200 mg film-coated tablets ribavirin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 200 mg of ribavirin 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 film-coated tablets 28 film-coated tablets 42 film-coated tablets 56 film-coated tablets 84 film-coated tablets 112 film-coated tablets 140 film-coated tablets 168 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 55 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Teva B.V. Swensweg 5 2031GA Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/527/001 (14 tablets) EU/1/09/527/002 (28 tablets) EU/1/09/527/003 (42 tablets) EU/1/09/527/004 (56 tablets) EU/1/09/527/005 (84 tablets) EU/1/09/527/006 (112 tablets) EU/1/09/527/007 (140 tablets) EU/1/09/527/008 (168 tablets) 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Ribavirin Teva Pharma B.V. 200mg film-coated tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 56 PC: SN: NN: 57 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Immediate packaging (blister foil) 1. NAME OF THE MEDICINAL PRODUCT Ribavirin Teva Pharma B.V. 200 mg film-coated tablets ribavirin 2. NAME OF THE MARKETING AUTHORISATION HOLDER Teva B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER BN 5. OTHER 58 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Outer Carton for 14, 28, 42, 56, 84, 112, 140 and 168 film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT Ribavirin Teva Pharma B.V. 400 mg film-coated tablets ribavirin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 400 mg of ribavirin 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 film-coated tablets 28 film-coated tablets 42 film-coated tablets 56 film-coated tablets 84 film-coated tablets 112 film-coated tablets 140 film-coated tablets 168 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 59 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Teva B.V. Swensweg 5 2031GA Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/527/009 (14 tablets) EU/1/09/527/010 (28 tablets) EU/1/09/527/011 (42 tablets) EU/1/09/527/012 (56 tablets) EU/1/09/527/013 (84 tablets) EU/1/09/527/014 (112 tablets) EU/1/09/527/015 (140 tablets) EU/1/09/527/016 (168 tablets) 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Ribavirin Teva Pharma B.V. 400mg film-coated tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 60 PC: SN: NN: 61 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Immediate packaging (blister foil) 1. NAME OF THE MEDICINAL PRODUCT Ribavirin Teva Pharma B.V. 400 mg film-coated tablets ribavirin 2. NAME OF THE MARKETING AUTHORISATION HOLDER Teva B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER BN 5. OTHER 62 B. PACKAGE LEAFLET 63 Package leaflet: Information for the user Ribavirin Teva Pharma B.V. 200 mg film-coated tablets ribavirin Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illsness are the same as yours. - If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What Ribavirin Teva Pharma B.V. is and what it is used for 2. What you need to know before you use Ribavirin Teva Pharma B.V. 3. How to use Ribavirin Teva Pharma B.V. 4. Possible side effects 5. How to store Ribavirin Teva Pharma B.V. 6. Contents of the pack and other information 1. What Ribavirin Teva Pharma B.V. is and what it is used for Ribavirin Teva Pharma B.V. contains the active substance ribavirin. This medicine stops the multiplication of many types of viruses, including hepatitis C virus. This medicine must not be used without interferon alfa-2b, i.e. Ribavirin Teva Pharma B.V. must not be used alone. Previously untreated patients: The combination of Ribavirin Teva Pharma B.V. with interferon alfa-2b is used to treat patients 3 years of age and older who have chronic hepatitis C (HCV) infection. For paediatric patients (children and adolescents) weighing less than 47 kg a solution formulation is available. Previously treated adult patients: The combination of Ribavirin Teva Pharma B.V. with interferon alfa-2b is used to treat adult patients with chronic hepatitis C, who have previously responded to treatment with an alpha interferon alone, but whose condition has recurred. There is no safety or efficacy information on the use of ribavirin with pegylated or other forms of interferon (i.e., not alfa-2b). If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 2. What you need to know before you use Ribavirin Teva Pharma B.V. Do not take Ribavirin Teva Pharma B.V. Do not take Ribavirin Teva Pharma B.V. if any of the following apply to you or the child you are caring for. If you are not sure, talk to your doctor or pharmacist before taking Ribavirin Teva Pharma B.V. if you: - are allergic to ribavirin or any of the other ingredients of this medicine (listed in section 6). - are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”). - are breast-feeding - had a serious heart problem during the past 6 months 64 - have any blood disorder such as anaemia (low blood count), thalassemia or sickle-cell anaemia Reminder: Please read the “Do not take” section of the Package leaflet for the other medicines used in combination before you begin combination treatment with this medicine. Warnings and precautions There are several serious adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa. These include:  Psychiatric and central nervous system effects (such as depression, suicidal thoughts, attempted suicide and aggressive behaviour, etc.). Be sure to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or change in your behaviour. You may want to consider asking a family member or close friend to help you stay alert to signs of depression or changes in your behaviour  Severe eye disorders  Dental and periodontal disorders: Dental and gum disorders have been reported in patients receiving ribavirin in combination with (peg)interferon alfa-2b. You should brush your teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth thoroughly afterwards  Inability to achieve full adult height may occur in some children and adolescents  Increased hormone related to your thyroid (TSH) in children and adolescents Paediatric population If you are caring for a child and your doctor decides not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to understand that this combination therapy induces a growth inhibition that may be irreversible in some patients. In addition these events have occurred in patients taking Ribavirin Teva Pharma B.V.: Haemolysis: Ribavirin Teva Pharma B.V. can cause a break down in red blood cells causing anaemia which may impair your heart function or worsen symptoms of heart disease. Pancytopenia: Ribavirin Teva Pharma B.V. can cause a decrease in your platelet and red and white blood cell count when used in combination with peginterferon. Standard blood tests will be taken to check your blood, kidney and liver function. - Blood tests will be done regularly to help your doctor to know if this treatment is working. - Depending upon the results of these tests, your doctor may change/adjust the number of tablets you or the child you are caring for take, prescribe a different pack size of this medicine, and/or change the length of time to take this treatment. - If you have or develop severe kidney or liver problems, this treatment will be stopped. Seek medical help immediately if you develop symptoms of a severe allergic reaction (such as difficulty in breathing, wheezing or hives) while taking this treatment. Talk to your doctor if you or your child you are caring for:  are a woman of childbearing age (see section “Pregnancy and breast-feeding”).  are a male and your female partner is of childbearing age (see section “Pregnancy and breast- feeding”).  had a previous heart condition or have heart disease.  have another liver problem in addition to hepatitis C infection.  have problems with your kidneys.  have HIV (human immunodeficiency virus) or have ever had any other problems with your immune system. Please refer to the Package Leaflet of (peg)interferon alfa for more detailed information on these safety issues. 65 Reminder: Please read the “Warnings and precautions” section of the Package Leaflet for the other medicines used in combination with Ribavirin Teva Pharma B.V. before you begin combination treatment. Use in children and adolescents If the child is weighing less than 47 kg or unable to swallow tablets an oral solution of ribavirin should be used. Other medicines and Ribavirin Teva Pharma B.V. Tell your doctor or pharmacist if you or the child you are caring for, are taking, have recently taken or might take: - azathioprine is a medicine that suppresses your immune system, using this medicine in combination with ribavirin may increase your risk of developing severe blood disorders. - anti-Human Immunodeficiency Virus (HIV) medicines – [nucleoside reverse transcriptase inhibitor (NRTI), and/or combined anti-retroviral therapy (cART)]: - Taking this medicine in combination with an alpha interferon and an anti-HIV medicine may increase the risk of lactic acidosis, liver failure, and blood abnormalities development (reduction in number of red blood cells which carry oxygen, certain white blood cells that fight infection, and blood clotting cells called platelets). - With zidovudine or stavudine, it is not certain if this medicine will change the way these medicines work. Therefore, your blood will be checked regularly to be sure that the HIV infection is not getting worse. If it gets worse, your doctor will decide whether or not your Ribavirin Teva Pharma B.V. treatment needs to be changed. Additionally, patients receiving zidovudine with ribavirin in combination with alpha interferons could be at increased risk of developing anaemia (low number of red blood cells). Therefore the use of zidovudine and ribavirin in combination with alpha interferons is not recommended. - Due to the risk of lactic acidosis (a build-up of lactic acid in the body) and pancreatitis, the use of ribavirin and didanosine is not recommended and the use of ribavirin and stavudine should be avoided. - Co-infected patients with advanced liver disease receiving cART may be at increased risk of worsening liver function. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. Reminder: Please read the “Other medicines” section of the Package Leaflet for the other medicines used in combination with Ribavirin Teva Pharma B.V. before you begin combination treatment with this medicine. Pregnancy and breast-feeding If you are pregnant you must not take this medicine. This medicine can be very damaging to your unborn baby (embryo). Both female and male patients must take special precautions in their sexual activity if there is any possibility for pregnancy to occur: • Girl or woman of childbearing age: You must have a negative pregnancy test before treatment, each month during treatment, and for the 4 months after treatment is stopped. This should be discussed with your doctor. • Men Do not have sex with a pregnant woman unless you use a condom. This will lessen the possibility for ribavirin to be left in the woman’s body. If your female partner is not pregnant now but is of childbearing age, she must be tested for pregnancy each month during treatment and for the 7 months after treatment has stopped. You or your female partner must use an effective contraceptive during the time you are taking this medicine and for 7 months after stopping treatment. This should be discussed with your doctor (see “Do not take Ribavirin Teva Pharma B.V.”). 66 If you are a woman who is breast-feeding, you must not take this medicine. Discontinue breast- feeding before starting to take this medicine. Driving and using machines This medicine does not effect your ability to drive or use machines; however, other medicines used in combination with Ribavirin Teva Pharma B.V. may cause sleepiness, tiredness or confusion. Do not drive or use any tools or machines if you feel tired or sleepy, or are confused. 3. How to use Ribavirin Teva Pharma B.V. General information about taking this medicine: Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Do not take more than the recommended dosage and take the medicine for as long as prescribed. Your doctor has determined the correct dose of this medicine based on how much you or the child you are caring for weighs. Adults The recommended dose and duration of Ribavirin Teva Pharma B.V. depends on how much the patient weighs and the medicines that are used in combination. Use in children and adolescents Dosing for children above 3 years of age and adolescents depends on how much the person weighs and the medicines that are used in combination. The recommended dose of Ribavirin Teva Pharma B.V. combined with interferon alfa-2b, is shown in the below table. Ribavirin Teva Pharma B.V. dose based on body weight when used in combination with interferon alfa-2b or peginterferon alfa-2b in children above 3 years of age and adolescents If the child/adolescent weighs (kg) Usual daily Ribavirin Teva Pharma B.V. dose Number of 200 mg tablets 47 - 49 600 mg 1 tablet in the morning and 2 tablets in the evening 50 - 65 800 mg 2 tablets in the morning and 2 tablets in the evening > 65 See adult dose Take your prescribed dose by mouth with water and during your meal. Do not chew the film-coated tablets. For children or adolescents who cannot swallow a film-coated tablet, an oral solution of ribavirin is available. Reminder: This medicine is only to be used in combination with other medicines for hepatitis C virus infection. For complete information be sure to read the “How to use” section of the Package Leaflet for the other medicines used in combination with Ribavirin Teva Pharma B.V.. If you take more Ribavirin Teva Pharma B.V. than you should Tell your doctor or pharmacist as soon as possible. If you forget to take Ribavirin Teva Pharma B.V. Take/administer the missed dose as soon as possible during the same day. If an entire day has gone by, check with your doctor. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this product, ask your doctor or pharmacist. 67 4. Possible side effects Please read the “Possible side effects” section of the Package Leaflet for the other medicines used in combination with Ribavirin Teva Pharma B.V.. Like all medicines, this medicine used in combination with other medicines can cause side effects, although not everybody gets them. Although not all of these unwanted effects may occur, they may need medical attention if they do occur. Contact your doctor immediately if you notice any of the following side effects occuring during combination treatment with other medicines: - chest pain or persistent cough; changes in the way your heart beats; fainting, - confusion, feeling depressed; suicidal thoughts or aggressive behaviour, attempt suicide, thoughts about threatening the life of others, - feelings of numbness or tingling, - trouble sleeping, thinking or concentrating, - severe stomach pain; black or tar-like stools; blood in stool or urine; lower back or side pain, - painful or difficult urination, - severe bleeding from your nose, - fever or chills beginning after a few weeks of treatment, - problems with your eyesight or hearing, - severe skin rash or redness. The following side effects have been reported with the combination of ribavirin and an alpha interferon product in adults: Very commonly reported side effects (may affect more than 1 in 10 people):  decreases in the number of red blood cells (that may cause fatigue, shortness of breath, dizziness), decrease in neutrophils(that make you more susceptible to different infections),  difficulty concentrating, feeling anxious or nervous, mood swings, feeling depressed or irritable, tired feeling, trouble falling asleep or staying asleep,  cough, dry mouth, pharyngitis (sore throat),  diarrhoea, dizziness, fever, flu-like symptoms, headache, nausea, shaking chills, virus infection, vomiting, weakness,  loss of appetite, loss of weight, stomach pain,  dry skin, irritation, hair loss, itching, muscle pain, muscle aches, pain in joints and muscles, rash. Commonly reported side effects (may affect up to 1 in 10 people):  decrease in blood clotting cells called platelets that may result in easy bruising and spontaneous bleeding, decrease in certain white blood cells called lymphocytes that help fight infection, decrease in thyroid gland activity (which may make you feel tired, depressed, increase your sensitivity to cold and other symptoms), excess of sugar or uric acid (as in gout) in the blood, low calcium level in the blood, severe anaemia,  fungal or bacterial infections, crying, agitation, amnesia, memory impaired, nervousness, abnormal behaviour, aggressive behaviour, anger, feeling confused, lack of interest, mental disorder, mood changes, unusual dreams, wanting to harm yourself, feeling sleepy, trouble sleeping, lack of interest in sex or inability to perform, vertigo (spinning feeling),  blurred or abnormal vision, eye irritation or pain or infection, dry or teary eyes, changes in your hearing or voice, ringing in ears, ear infection, earache, cold sores (herpes simplex), change in taste, taste loss, bleeding gums or sores in mouth, burning sensation on tongue, sore tongue, inflamed gums, tooth problem, migraine, respiratory infections, sinusitis, nose bleed, nonproductive cough, rapid or difficult breathing, stuffy or runny nose, thirst, tooth disorder, 68  cardiac murmur (abnormal heart beat sounds), chest pain or discomfort, feeling faint, feeling unwell, flushing, increased sweating, heat intolerance and excessive sweating, low or high blood pressure, palpitations (pounding heart beat), rapid heart rate,  bloating, constipation, indigestion, intestinal gas (flatus), increased appetite, irritated colon, irritation of prostate gland, jaundice (yellow skin), loose stools, pain on the right side around your ribs, enlarged liver, stomach upset, frequent need to urinate, passing more urine than usual, urinary tract infection, abnormal urine,  difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, painful menstruation, disorder of ovary or vagina, breast pain, erectile problem,  abnormal hair texture, acne, arthritis, bruising, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), hives, increased or decreased sensitivity to touch, nail disorder, muscle spasms, numbness or tingling feeling, limb pain, pain in joints, shaky hands, psoriasis, puffy or swollen hands and ankles, sensitivity to sunlight, rash with raised spotted lesions, redness of skin or skin disorder, swollen face, swollen glands (swollen lymph nodes), tense muscles, tumour (unspecified), unsteady when walking, water impairment. Uncommonly reported side effects (may affect up to 1 in 100 people):  hearing or seeing images that are not present,  heart attack, panic attack,  hypersensitivity reaction to the medication  inflammation of pancreas, pain in bone, diabetes mellitus,  muscle weakness, Rarely reported side effects (may affect up to 1 in 1,000 people):  seizure (convulsions)  pneumonia,  rheumatoid arthritis, kidney problems,  dark or bloody stools, intense abdominal pain  sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands),  vasculitis. Very rarely reported side effects (may affect up to 1 in 10,000 people):  suicide,  stroke (cerebrovascular events). Not known side effects (frequency cannot be estimated from the available data):  thoughts about threatening the life of others,  mania (excessive or unreasonable enthusiasm),  pericarditis (inflammation of the lining of the heart), pericardial effusion [a fluid collection that develops between the pericardium (the lining of the heart) and the heart itself],  change in colour of the tongue. Side effects in children and adolescents The following side effects have been reported with the combination of ribavirin and an interferon alfa- 2b product in children and adolescents: Very commonly reported side effects (may affect more than 1 in 10 people):  decreases in the number of red blood cells (that may cause fatigue, shortness of breath, dizziness), decrease in neutrophils (that make you more susceptible to different infections),  decrease in thyroid gland activity (which may make you feel tired, depressed, increase your sensitivity to cold and other symptoms),  feeling depressed or irritable, feeling sick to stomach, feeling unwell, mood swings, tired feeling, trouble falling asleep or staying asleep, virus infection, weakness, 69  diarrhoea, dizziness, fever, flu-like symptoms, headache, loss of or increase in appetite, loss of weight, decrease in the rate of growth (height and weight), pain on right side of ribs, pharyngitis (sore throat), shaking chills, stomach pain, vomiting,  dry skin, hair loss, irritation, itching, muscle pain, muscle aches, pain in joints and muscles, rash. Commonly reported side effects (may affect up to 1 in 10 people):  decrease in blood clotting cells called platelets (that may result in easy bruising and spontaneous bleeding),  excess of triglycerides in the blood, excess of uric acid (as in gout) in the blood, increase in thyroid gland activity (which may cause nervousness, heat intolerance and excessive sweating, weight loss, palpitation, tremors),  agitation, anger, aggressive behaviour, behaviour disorder, difficulty concentrating, emotional instability, fainting, feeling anxious or nervous, feeling cold, feeling confused, feeling of restlessness, feeling sleepy, lack of interest or attention, mood changes, pain, poor quality sleep, sleepwalking, suicide attempt, trouble sleeping, unusual dreams, wanting to harm yourself,  bacterial infections, common cold, fungal infections, abnormal vision, dry or teary eyes, ear infection, eye irritation or pain or infection, change in taste, changes in your voice, cold sores, coughing, inflamed gums, nose bleed, nose irritation, oral pain, pharyngitis (sore throat), rapid breathing, respiratory infections, scaling lips and clefts in the corners of the mouth, shortness of breath, sinusitis, sneezing, sores in mouth, sore tongue, stuffy or runny nose, throat pain, toothache, tooth abscess, tooth disorder, vertigo (spinning feeling), weakness,  chest pain, flushing, palpitations (pounding heart beat), rapid heart rate,  abnormal liver function,  acid reflux, back pain, bedwetting, constipation, gastroesophageal or rectal disorder, incontinence, increased appetite, inflammation of the membrane of the stomach and intestine, stomach upset, loose stools,  urination disorders, urinary tract infection,  difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, disorder of vagina, inflammation of the vagina, testis pain, development of male body traits,  acne, bruising, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), increased or decreased sensitivity to touch, increased sweating, increase in muscle movement, tense muscle, limb pain, nail disorder, numbness or tingling feeling, pale skin, rash with raised spotted lesions, shaky hands, redness of skin or skin disorder, skin discolouration, skin sensitive to sunlight, skin wound, swelling due to a build-up of excess water, swollen glands (swollen lymph nodes), tremor, tumour (unspecified). Uncommonly reported side effects (may affect up to 1 in 100 people):  abnormal behaviour, emotional disorder, fear, nightmare,  bleeding of the mucous membrane that lines the inner surface of the eyelids, blurred vision, drowsiness, intolerance to light, itchy eyes, facial pain, inflamed gums,  chest discomfort, difficult breathing, lung infection, nasal discomfort, pneumonia,wheezing,  low blood pressure,  enlarged liver,  painful menstruation,  itchy anal area (pinworms or ascarids), blistering rash (shingles), decreased sensitivity to touch, muscle twitching, pain in skin, paleness, peeling of skin, redness, swelling. The attempt to self-harm has also been reported in adults, children, and adolescents. This medicine in combination with an alpha interferon product may also cause:  aplastic anaemia, pure red cell aplasia (a condition where the body stopped or reduced the production of red blood cells); this causes severe anaemia, symptoms of which would include unusual tiredness and a lack of energy,  delusions, upper and lower respiratory tract infection,  inflammation of the pancreas, 70  severe rashes which may be associated with blisters in the mouth, nose, eyes and other mucosal membranes (erythema multiforme, Stevens Johnson syndrome), toxic epidermal necrolysis (blistering and peeling of the top layer of skin). The following other side effects have also been reported with the combination of this medicine and an alpha interferon product:  abnormal thoughts, hearing or seeing images that are not present, altered mental status, disorientation,  angioedema (swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in swallowing or breathing), stroke (cerebrovascular events),  Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, skin and the membranes of the ears, brain and spinal cord),  bronchoconstriction and anaphylaxis (a severe, whole-body allergic reaction), constant cough,  eye problems including damage to the retina, obstruction of the retinal artery, inflammation of the optic nerve, swelling of the eye and cotton wool spots (white deposits on the retina),  enlarged abdominal area, heartburn, trouble having bowel movement or painful bowel movement,  acute hypersensitivity reactions including urticaria (hives), bruises, intense pain in a limb, leg or thigh pain, loss of range of motion, stiffness, sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands). This medicine in combination with peginterferon alfa-2b or interferon alfa-2b may also cause:  dark, cloudy or abnormally coloured urine,  difficulty breathing, changes in the way your heart beats, chest pain, pain down left arm, jaw pain,  loss of consciousness,  loss of use, drooping or loss of power of facial muscles, loss of feeling sensation,  loss of vision. You or your caregiver should call your doctor immediately if you have any of these side effects. If you are a HCV/HIV co-infected adult patient receiving anti-HIV treatment, the addition of this medicine and peginterferon alfa-2b may increase your risk of worsening liver function combined anti- retroviral therapy (cART) and increase your risk of lactic acidosis, liver failure, and blood abnormalities development (reduction in number of red blood cells which carry oxygen, certain white blood cells that fight infection, and blood clotting cells called platelets) (NRTI). In HCV/HIV co-infected patients receiving cART, the following other side effects have occurred with the combination of ribavirin and peginterferon alfa-2b (not listed above in adults side effects):  appetite decreased,  back pain,  CD4 lymphocytes decreased,  defective metabolism of fat,  hepatitis,  limb pain,  oral candidiasis (oral thrush),  various laboratory blood values abnormalities. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Ribavirin Teva Pharma B.V. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 71 Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the outer packaging. The expiry date refers to the last day of that month. This medicinal product requires no special storage conditions. Do not use this medicine if you notice any change in the appearance of the tablets. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Ribavirin Teva Pharma B.V. contains The active substance is Ribavirin. Each film-coated tablet contains 200 mg of ribavirin. The other ingredients are Tablet core; Calcium hydrogen phosphate anhydrous, croscarmellose sodium, povidone, magnesium stearate. Film coating, composed of : polyvinyl alcohol – partly hydrolysed, macrogol / polyethylene glycol 3350, titanium dioxide (E171), talc, iron oxide red, iron oxide yellow, iron oxide black. What Ribavirin Teva Pharma B.V. looks like and contents of the pack Ribavirin Teva Pharma B.V. 200 mg film-coated tablets are light-pink to pink, (debossed with “93” on one side and “7232” on the other). Ribavirin Teva Pharma B.V. is available in different pack sizes containing 14, 28, 42, 56, 84, 112, 140 or 168 tablets. Not all pack sizes may be marketed. Your physician will prescribe the pack size which is best for you. Marketing Authorisation Holder Teva B.V. Swensweg 5 2031GA Haarlem The Netherlands Manufacturer Teva Pharmaceutical Works Private Limited Company Pallagi út 13 Debrecen H-4042 Hungary TEVA UK Ltd Brampton Road Hampden Park Eastbourne, East Sussex BN22 9AG UK 72 Pharmachemie B.V. Swensweg 5 2031 GA Haarlem The Netherlands Teva Pharma SLU C/ C, n° 4, Polígono Industrial Malpica, 50016 Zaragoza Spain For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Teva Pharma Belgium N.V./S.A./AG Tel/Tél: +32 3 820 73 73 Lietuva UAB “Sicor Biotech” Tel: +370 5 266 02 03 България Тева Фармасютикълс България ЕООД Teл: +359 2 489 95 82 Luxembourg/Luxemburg Teva Pharma Belgium N.V./S.A./AG Belgien/ Belgique Tél/Tel: +32 3 820 73 73 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251 007 111 Magyarország Teva Gyógyszergyár Zrt. Tel: (36) 1 288 6400 Danmark Teva Denmark A/S Tlf: +45 44 98 55 11 Malta Teva Pharmaceuticals Ireland Tel: +353 51 321740 L-Irlanda Deutschland TEVA GmbH Tel: +49 731 402 08 Nederland Teva Nederland B.V. Tel: +31 (0) 800 0228400 Eesti Teva Eesti esindus UAB Sicor Biotech Eesti filiaal Tel: +372 661 0801 Norge Teva Norway AS Tlf: +47 66 77 55 90 Ελλάδα Teva Ελλάς Α.Ε. Τηλ: +30 210 72 79 099 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 (0)1 97007 0 España Teva Pharma, S.L.U Tél: +(34) 91 387 32 80 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel.: +(48) 22 345 93 00 France Teva Santé Tél: +(33) 1 55 91 7800 Portugal Teva Pharma - Produtos Farmacêuticos Lda Tel: +351 21 476 75 50 73 Hrvatska Pliva Hrvatska d.o.o. Tel:+ 385 1 37 20 000 România Teva Pharmaceuticals S.R.L Tel: +4021 230 65 24 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)51 321 740 Slovenija Pliva Ljubljana d.o.o. Tel: +386 1 58 90 390 Ísland ratiopharm Oy Finnland Sími: +358 20 180 5900 Slovenská republika Teva Pharmaceuticals Slovakia s.r.o. Tel: +(421) 2 5726 7911 Italia Teva Italia S.r.l. Tel: +39 028917981 Suomi/Finland ratiopharm Oy Puh/Tel: +358 20 180 5900 Κύπρος Teva Ελλάς Α.Ε. Ελλάδα Τηλ: +30 210 72 79 099 Sverige Teva Sweden AB Tel: +(46) 42 12 11 00 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 673 23 666 United Kingdom Teva UK Limited Tel: +44 1977628500 This leaflet was last revised in {MM/YYYY}. Other sources of information Detailed information on this medicine is available on the website of the European Medicines Agency http://www.ema.europa.eu This leaflet is available in all EU/EEA languages on the European Medicines Agency website. http://www.ema.europa.eu/� 74 Package leaflet: Information for the user Ribavirin Teva Pharma B.V. 400 mg film-coated tablets ribavirin Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illsness are the same as yours. - If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What Ribavirin Teva Pharma B.V. is and what it is used for 2. What you need to know before you use Ribavirin Teva Pharma B.V. 3. How to use Ribavirin Teva Pharma B.V. 4. Possible side effects 5. How to store Ribavirin Teva Pharma B.V. 6. Contents of the pack and other information 1. What Ribavirin Teva Pharma B.V. is and what it is used for Ribavirin Teva Pharma B.V. contains the active substance ribavirin. This medicine stops the multiplication of many types of viruses, including hepatitis C virus. This medicine must not be used without interferon alfa-2b, i.e. Ribavirin Teva Pharma B.V. must not be used alone. Previously untreated patients: The combination of Ribavirin Teva Pharma B.V. with interferon alfa-2b is used to treat patients 3 years of age and older who have chronic hepatitis C (HCV) infection. For paediatric patients (children and adolescents) weighing less than 47 kg a solution formulation is available. Previously treated adult patients: The combination of Ribavirin Teva Pharma B.V. with interferon alfa-2b is used to treat adult patients with chronic hepatitis C, who have previously responded to treatment with an alpha interferon alone, but whose condition has recurred. There is no safety or efficacy information on the use of ribavirin with pegylated or other forms of interferon (i.e., not alfa-2b). If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 2. What you need to know before you use Ribavirin Teva Pharma B.V. Do not take Ribavirin Teva Pharma B.V. Do not take Ribavirin Teva Pharma B.V. if any of the following apply to you or the child you are caring for. If you are not sure, talk to your doctor or pharmacist before taking Ribavirin Teva Pharma B.V. if you: - are allergic to ribavirin or any of the other ingredients of this medicine (listed in section 6). - are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”). - are breast-feeding - had a serious heart problem during the past 6 months 75 - have any blood disorder, such as anaemia (low blood count), thalassemia or sickle-cell anaemia Reminder: Please read the “Do not take” section of the Package leaflet for the other medicines used in combination before you begin combination treatment with this medicine. Warnings and precautions There are several serious adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa. These include:  Psychiatric and central nervous system effects (such as depression, suicidal thoughts, attempted suicide and aggressive behaviour, etc.). Be sure to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or change in your behaviour. You may want to consider asking a family member or close friend to help you stay alert to signs of depression or changes in your behaviour  Severe eye disorders  Dental and periodontal disorders: Dental and gum disorders have been reported in patients receiving ribavirin in combination with (peg)interferon alfa-2b. You should brush your teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth thoroughly afterwards  Inability to achieve full adult height may occur in some children and adolescents  Increased hormone related to your thyroid (TSH) in children and adolescents Paediatric population If you are caring for a child and your doctor decides not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to understand that this combination therapy induces a growth inhibition that may be irreversible in some patients. In addition these events have occurred in patients taking Ribavirin Teva Pharma B.V.: Haemolysis: Ribavirin Teva Pharma B.V. can cause a break down in red blood cells causing anaemia which may impair your heart function or worsen symptoms of heart disease. Pancytopenia: Ribavirin Teva Pharma B.V. can cause a decrease in your platelet and red and white blood cell count when used in combination with peginterferon. Standard blood tests will be taken to check your blood, kidney and liver function. - Blood tests will be done regularly to help your doctor to know if this treatment is working. - Depending upon the results of these tests, your doctor may change/adjust the number of tablets you or the child you are caring for take, prescribe a different pack size of this medicine, and/or change the length of time to take this treatment. - If you have or develop severe kidney or liver problems, this treatment will be stopped. Seek medical help immediately if you develop symptoms of a severe allergic reaction (such as difficulty in breathing, wheezing or hives) while taking this treatment. Talk to your doctor if you or your child you are caring for:  are a woman of childbearing age (see section “Pregnancy and breast-feeding”).  are a male and your female partner is of childbearing age (see section “Pregnancy and breast- feeding”).  had a previous heart condition or have heart disease.  have another liver problem in addition to hepatitis C infection.  have problems with your kidneys.  have HIV (human immunodeficiency virus) or have ever had any other problems with your immune system. 76 Please refer to the Package Leaflet of (peg)interferon alfa for more detailed information on these safety issues. Reminder: Please read the “Warnings and precautions” section of the Package Leaflet for the other medicines used in combination with Ribavirin Teva Pharma B.V. before you begin combination treatment. Use in children and adolescents If the child is weighing less than 47 kg or unable to swallow tablets an oral solution of ribavirin should be used. Other medicines and Ribavirin Teva Pharma B.V. Tell your doctor or pharmacist if you or the child you are caring for, are taking, have recently taken or might take: - azathioprine is a medicine that suppresses your immune system, using this medicine in combination with ribavirin may increase your risk of developing severe blood disorders. - anti-Human Immunodeficiency Virus (HIV) medicines – [nucleoside reverse transcriptase inhibitor (NRTI), and/or combined anti-retroviral therapy (cART)]: - Taking this medicine in combination with an alpha interferon and an anti-HIV medicine may increase the risk of lactic acidosis, liver failure, and blood abnormalities development (reduction in number of red blood cells which carry oxygen, certain white blood cells that fight infection, and blood clotting cells called platelets). - With zidovudine or stavudine, it is not certain if this medicine will change the way these medicines work. Therefore, your blood will be checked regularly to be sure that the HIV infection is not getting worse. If it gets worse, your doctor will decide whether or not your Ribavirin Teva Pharma B.V. treatment needs to be changed. Additionally, patients receiving zidovudine with ribavirin in combination with alpha interferons could be at increased risk of developing anaemia (low number of red blood cells). Therefore the use of zidovudine and ribavirin in combination with alpha interferons is not recommended. - Due to the risk of lactic acidosis (a build-up of lactic acid in the body) and pancreatitis, the use of ribavirin and didanosine is not recommended and the use of ribavirin and stavudine should be avoided. - Co-infected patients with advanced liver disease receiving cART may be at increased risk of worsening liver function. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. Reminder: Please read the “Other medicines” section of the Package Leaflet for the other medicines used in combination with Ribavirin Teva Pharma B.V. before you begin combination treatment with this medicine. Pregnancy and breast-feeding If you are pregnant you must not take this medicine. This medicine can be very damaging to your unborn baby (embryo). Both female and male patients must take special precautions in their sexual activity if there is any possibility for pregnancy to occur: • Girl or woman of childbearing age: You must have a negative pregnancy test before treatment, each month during treatment, and for the 4 months after treatment is stopped. This should be discussed with your doctor. • Men Do not have sex with a pregnant woman unless you use a condom. This will lessen the possibility for ribavirin to be left in the woman’s body. If your female partner is not pregnant now but is of childbearing age, she must be tested for pregnancy each month during treatment and for the 7 months after treatment has stopped. You or your female partner must use an effective contraceptive during the time you are taking this medicine and for 77 7 months after stopping treatment. This should be discussed with your doctor (see “Do not take Ribavirin Teva Pharma B.V.”). If you are a woman who is breast-feeding, you must not take this medicine. Discontinue breast-feeding before starting to take this medicine. Driving and using machines This medicine does not effect your ability to drive or use machines; However, other medicines used in combination with Ribavirin Teva Pharma B.V. may cause sleepiness, tiredness or confusion. Do not drive or use any tools or machines if you feel tired or sleepy, or are confused. 3. How to use Ribavirin Teva Pharma B.V. General information about taking this medicine: Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Do not take more than the recommended dosage and take the medicine for as long as prescribed. Your doctor has determined the correct dose of this medicine based on how much you or the child you are caring for weighs. Adults The recommended dose and duration of Ribavirin Teva Pharma B.V. depends on how much the patient weighs and the medicines that are used in combination. Use in children and adolescents Dosing for children above 3 years of age and adolescents depends on how much the person weighs and the medicines that are used in combination. The recommended dose of Ribavirin Teva Pharma B.V. combined with interferon alfa-2b, is shown in the below table. Ribavirin Teva Pharma B.V. dose based on body weight when used in combination with interferon alfa-2b or peginterferon alfa-2b in children above 3 years of age and adolescents If the child/adolescent weighs (kg) Usual daily Ribavirin Teva Pharma B.V. dose Number of 200 mg tablets 47 - 49 600 mg 1 tablet in the morning and 2 tablets in the evening 50 - 65 800 mg 2 tablets in the morning and 2 tablets in the evening or 1 (400 mg) tablet in the morning and 1 (400 mg) tablet in the evening > 65 See adult dose Take your prescribed dose by mouth with water and during your meal. Do not chew the film-coated tablets. For children or adolescents who cannot swallow a film-coated tablet, an oral solution of ribavirin is available. Reminder: This medicine is only to be used in combination with other medicines for hepatitis C virus infection. For complete information be sure to read the “How to use” section of the Package Leaflet for the other medicines used in combination with Ribavirin Teva Pharma B.V.. If you take more Ribavirin Teva Pharma B.V. than you should Tell your doctor or pharmacist as soon as possible. If you forget to take Ribavirin Teva Pharma B.V. 78 Take/administer the missed dose as soon as possible during the same day. If an entire day has gone by, check with your doctor. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. Possible side effects Please read the “Possible side effects” section of the Package Leaflet for the other medicines used in combination with Ribavirin Teva Pharma B.V.. Like all medicines, this medicine used in combination with other medicines can cause side effects, although not everybody gets them. Although not all of these unwanted effects may occur, they may need medical attention if they do occur. Contact your doctor immediately if you notice any of the following side effects occuring during combination treatment with other medicines: - chest pain or persistent cough; changes in the way your heart beats; fainting - confusion, feeling depressed; suicidal thoughts or aggressive behaviour, attempt suicide, thoughts about threatening the life of others - feelings of numbness or tingling - trouble sleeping, thinking or concentrating - severe stomach pain; black or tar-like stools; blood in stool or urine; lower back or side pain, painful or difficult urination - severe bleeding from your nose - fever or chills beginning after a few weeks of treatment - problems with your eyesight or hearing - severe skin rash or redness. The following side effects have been reported with the combination of ribavirin and an alpha interferon product in adults: Very commonly reported side effects (may affect more than 1 in 10 people):  decreases in the number of red blood cells (that may cause fatigue, shortness of breath, dizziness), decrease in neutrophils(that make you more susceptible to different infections),  difficulty concentrating, feeling anxious or nervous, mood swings, feeling depressed or irritable, tired feeling, trouble falling asleep or staying asleep,  cough, dry mouth, pharyngitis (sore throat),  diarrhoea, dizziness, fever, flu-like symptoms, headache, nausea, shaking chills, virus infection, vomiting, weakness,  loss of appetite, loss of weight, stomach pain,  dry skin, irritation, hair loss, itching, muscle pain, muscle aches, pain in joints and muscles, rash. Commonly reported side effects (may affect up to 1 in 10 people):  decrease in blood clotting cells called platelets that may result in easy bruising and spontaneous bleeding, decrease in certain white blood cells called lymphocytes that help fight infection, decrease in thyroid gland activity (which may make you feel tired, depressed, increase your sensitivity to cold and other symptoms), excess of sugar or uric acid (as in gout) in the blood, low calcium level in the blood, severe anaemia,  fungal or bacterial infections, crying, agitation, amnesia, memory impaired, nervousness, abnormal behaviour, aggressive behaviour, anger, feeling confused, lack of interest, mental disorder, mood changes, unusual dreams, wanting to harm yourself, feeling sleepy, trouble sleeping, lack of interest in sex or inability to perform, vertigo (spinning feeling),  blurred or abnormal vision, eye irritation or pain or infection, dry or teary eyes, changes in your hearing or voice, ringing in ears, ear infection, earache, cold sores (herpes simplex), change in taste, 79 taste loss, bleeding gums or sores in mouth, burning sensation on tongue, sore tongue, inflamed gums, tooth problem, migraine, respiratory infections, sinusitis, nose bleed, nonproductive cough, rapid or difficult breathing, stuffy or runny nose, thirst, tooth disorder,  cardiac murmur (abnormal heart beat sounds), chest pain or discomfort, feeling faint, feeling unwell, flushing, increased sweating, heat intolerance and excessive sweating, low or high blood pressure, palpitations (pounding heart beat), rapid heart rate,  bloating, constipation, indigestion, intestinal gas (flatus), increased appetite, irritated colon, irritation of prostate gland, jaundice (yellow skin), loose stools, pain on the right side around your ribs, enlarged liver, stomach upset, frequent need to urinate, passing more urine than usual, urinary tract infection, abnormal urine,  difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, painful menstruation, disorder of ovary or vagina, breast pain, erectile problem,  abnormal hair texture, acne, arthritis, bruising, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), hives, increased or decreased sensitivity to touch, nail disorder, muscle spasms, numbness or tingling feeling, limb pain, pain in joints, shaky hands, psoriasis, puffy or swollen hands and ankles, sensitivity to sunlight, rash with raised spotted lesions, redness of skin or skin disorder, swollen face, swollen glands (swollen lymph nodes), tense muscles, tumour (unspecified), unsteady when walking, water impairment. Uncommonly reported side effects (may affect up to 1 in 100 people):  hearing or seeing images that are not present,  heart attack, panic attack,  hypersensitivity reaction to the medication  inflammation of pancreas, pain in bone, diabetes mellitus,  muscle weakness, Rarely reported side effects (may affect up to 1 in 1,000 people):  seizure (convulsions)  pneumonia,  rheumatoid arthritis, kidney problems,  dark or bloody stools, intense abdominal pain  sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands),  vasculitis. Very rarely reported side effects (may affect up to 1 in 10,000 people):  suicide,  stroke (cerebrovascular events). Not known side effects (frequency cannot be estimated from the available data):  thoughts about threatening the life of others,  mania (excessive or unreasonable enthusiasm),  pericarditis (inflammation of the lining of the heart), pericardial effusion [a fluid collection that develops between the pericardium (the lining of the heart) and the heart itself],  change in colour of the tongue. Side effects in children and adolescents The following side effects have been reported with the combination of ribavirin and an interferon alfa- 2b product in children and adolescents: Very commonly reported side effects (may affect more than 1 in 10 people):  decreases in the number of red blood cells (that may cause fatigue, shortness of breath, dizziness), decrease in neutrophils (that make you more susceptible to different infections),  decrease in thyroid gland activity (which may make you feel tired, depressed, increase your sensitivity to cold and other symptoms), 80  feeling depressed or irritable, feeling sick to stomach, feeling unwell, mood swings, tired feeling, trouble falling asleep or staying asleep, virus infection, weakness,  diarrhoea, dizziness, fever, flu-like symptoms, headache, loss of or increase in appetite, loss of weight, decrease in the rate of growth (height and weight), pain on right side of ribs, pharyngitis (sore throat), shaking chills, stomach pain, vomiting,  dry skin, hair loss, irritation, itching, muscle pain, muscle aches, pain in joints and muscles, rash. Commonly reported side effects (may affect up to 1 in 10 people):  decrease in blood clotting cells called platelets (that may result in easy bruising and spontaneous bleeding),  excess of triglycerides in the blood, excess of uric acid (as in gout) in the blood, increase in thyroid gland activity (which may cause nervousness, heat intolerance and excessive sweating, weight loss, palpitation, tremors),  agitation, anger, aggressive behaviour, behaviour disorder, difficulty concentrating, emotional instability, fainting, feeling anxious or nervous, feeling cold, feeling confused, feeling of restlessness, feeling sleepy, lack of interest or attention, mood changes, pain, poor quality sleep, sleepwalking, suicide attempt, trouble sleeping, unusual dreams, wanting to harm yourself,  bacterial infections, common cold, fungal infections, abnormal vision, dry or teary eyes, ear infection, eye irritation or pain or infection, change in taste, changes in your voice, cold sores, coughing, inflamed gums, nose bleed, nose irritation, oral pain, pharyngitis (sore throat), rapid breathing, respiratory infections, scaling lips and clefts in the corners of the mouth, shortness of breath, sinusitis, sneezing, sores in mouth, sore tongue, stuffy or runny nose, throat pain, toothache, tooth abscess, tooth disorder, vertigo (spinning feeling), weakness,  chest pain, flushing, palpitations (pounding heart beat), rapid heart rate,  abnormal liver function,  acid reflux, back pain, bedwetting, constipation, gastroesophageal or rectal disorder, incontinence, increased appetite, inflammation of the membrane of the stomach and intestine, stomach upset, loose stools,  urination disorders, urinary tract infection,  difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, disorder of vagina, inflammation of the vagina, testis pain, development of male body traits,  acne, bruising, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), increased or decreased sensitivity to touch, increased sweating, increase in muscle movement, tense muscle, limb pain, nail disorder, numbness or tingling feeling, pale skin, rash with raised spotted lesions, shaky hands, redness of skin or skin disorder, skin discolouration, skin sensitive to sunlight, skin wound, swelling due to a build-up of excess water, swollen glands (swollen lymph nodes), tremor, tumour (unspecified). Uncommonly reported side effects (may affect up to 1 in 100 people):  abnormal behaviour, emotional disorder, fear, nightmare,  bleeding of the mucous membrane that lines the inner surface of the eyelids, blurred vision, drowsiness, intolerance to light, itchy eyes, facial pain, inflamed gums,  chest discomfort, difficult breathing, lung infection, nasal discomfort, pneumonia,wheezing,  low blood pressure,  enlarged liver,  painful menstruation,  itchy anal area (pinworms or ascarids), blistering rash (shingles), decreased sensitivity to touch, muscle twitching, pain in skin, paleness, peeling of skin, redness, swelling. The attempt to self-harm has also been reported in adults, children, and adolescents. This medicine in combination with an alpha interferon product may also cause:  aplastic anaemia, pure red cell aplasia (a condition where the body stopped or reduced the production of red blood cells); this causes severe anaemia, symptoms of which would include unusual tiredness and a lack of energy, 81  delusions, upper and lower respiratory tract infection,  inflammation of the pancreas,  severe rashes which may be associated with blisters in the mouth, nose, eyes and other mucosal membranes (erythema multiforme, Stevens Johnson syndrome), toxic epidermal necrolysis (blistering and peeling of the top layer of skin). The following other side effects have also been reported with the combination of this medicine and an alpha interferon product:  abnormal thoughts, hearing or seeing images that are not present, altered mental status, disorientation,  angioedema (swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in swallowing or breathing), stroke (cerebrovascular events),  Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, skin and the membranes of the ears, brain and spinal cord),  bronchoconstriction and anaphylaxis (a severe, whole-body allergic reaction), constant cough,  eye problems including damage to the retina, obstruction of the retinal artery, inflammation of the optic nerve, swelling of the eye and cotton wool spots (white deposits on the retina),  enlarged abdominal area, heartburn, trouble having bowel movement or painful bowel movement,  acute hypersensitivity reactions including urticaria (hives), bruises, intense pain in a limb, leg or thigh pain, loss of range of motion, stiffness, sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands). This medicine in combination with peginterferon alfa-2b or interferon alfa-2b may also cause:  dark, cloudy or abnormally coloured urine,  difficulty breathing, changes in the way your heart beats, chest pain, pain down left arm, jaw pain,  loss of consciousness,  loss of use, drooping or loss of power of facial muscles, loss of feeling sensation,  loss of vision. You or your caregiver should call your doctor immediately if you have any of these side effects. If you are a HCV/HIV co-infected adult patient receiving anti-HIV treatment, the addition of this medicine and peginterferon alfa-2b may increase your risk of worsening liver function combined anti- retroviral therapy (cART) and increase your risk of lactic acidosis, liver failure, and blood abnormalities development (reduction in number of red blood cells which carry oxygen, certain white blood cells that fight infection, and blood clotting cells called platelets) (NRTI). In HCV/HIV co-infected patients receiving cART, the following other side effects have occurred with the combination of ribavirin and peginterferon alfa-2b (not listed above in adults side effects):  appetite decreased,  back pain,  CD4 lymphocytes decreased,  defective metabolism of fat,  hepatitis,  limb pain,  oral candidiasis (oral thrush),  various laboratory blood values abnormalities. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 82 5. How to store Ribavirin Teva Pharma B.V. Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the outer packaging. The expiry date refers to the last day of that month. This medicinal product requires no special storage conditions. Do not use this medicine if you notice any change in the appearance of the tablets. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Ribavirin Teva Pharma B.V. contains The active substance is Ribavirin. Each film-coated tablet contains 400 mg of ribavirin. The other ingredients are Tablet core; Calcium hydrogen phosphate anhydrous, croscarmellose sodium, povidone, magnesium stearate. Film coating, composed of : polyvinyl alcohol – partly hydrolysed, macrogol / polyethylene glycol 3350, titanium dioxide (E171), talc, iron oxide red, iron oxide yellow, iron oxide black. What Ribavirin Teva Pharma B.V. looks like and contents of the pack Ribavirin Teva Pharma B.V. 400 mg film-coated tablets are light-pink to pink, (debossed with “R” on one side and “400” on the other). Ribavirin Teva Pharma B.V. is available in different pack sizes containing 14, 28, 42, 56, 84, 112, 140 or 168 tablets. Not all pack sizes may be marketed. Your physician will prescribe the pack size which is best for you. Marketing Authorisation Holder Teva B.V. Swensweg 5 2031GA Haarlem The Netherlands Manufacturer Teva Pharmaceutical Works Private Limited Company Pallagi út 13 Debrecen H-4042 Hungary TEVA UK Ltd Brampton Road 83 Hampden Park Eastbourne, East Sussex BN22 9AG UK Pharmachemie B.V. Swensweg 5 2031 GA Haarlem The Netherlands Teva Pharma SLU C/ C, n° 4, Polígono Industrial Malpica, 50016 Zaragoza Spain For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Teva Pharma Belgium N.V./S.A./AG Tel/Tél: +32 3 820 73 73 Lietuva UAB “Sicor Biotech” Tel: +370 5 266 02 03 България Тева Фармасютикълс България ЕООД Teл: +359 2 489 95 82 Luxembourg/Luxemburg Teva Pharma Belgium N.V./S.A./AG Belgien/ Belgique Tél/Tel: +32 3 820 73 73 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251 007 111 Magyarország Teva Gyógyszergyár Zrt. Tel: (36) 1 288 6400 Danmark Teva Denmark A/S Tlf: +45 44 98 55 11 Malta Teva Pharmaceuticals Ireland Tel: +353 51 321740 L-Irlanda Deutschland TEVA GmbH Tel: +49 731 402 08 Nederland Teva Nederland B.V. Tel: +31 (0) 800 0228400 Eesti Teva Eesti esindus UAB Sicor Biotech Eesti filiaal Tel: +372 661 0801 Norge Teva Norway AS Tlf: +47 66 77 55 90 Ελλάδα Teva Ελλάς Α.Ε. Τηλ: +30 210 72 79 099 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 (0)1 97007 0 España Teva Pharma, S.L.U Tél: +(34) 91 387 32 80 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel.: +(48) 22 345 93 00 84 France Teva Santé Tél: +(33) 1 55 91 7800 Portugal Teva Pharma - Produtos Farmacêuticos Lda Tel: +351 21 476 75 50 Hrvatska Pliva Hrvatska d.o.o. Tel:+ 385 1 37 20 000 România Teva Pharmaceuticals S.R.L Tel: +4021 230 65 24 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)51 321 740 Slovenija Pliva Ljubljana d.o.o. Tel: +386 1 58 90 390 Ísland ratiopharm Oy Finnland Sími: +358 20 180 5900 Slovenská republika Teva Pharmaceuticals Slovakia s.r.o. Tel: +(421) 2 5726 7911 Italia Teva Italia S.r.l. Tel: +39 028917981 Suomi/Finland ratiopharm Oy Puh/Tel: +358 20 180 5900 Κύπρος Teva Ελλάς Α.Ε. Ελλάδα Τηλ: +30 210 72 79 099 Sverige Teva Sweden AB Tel: +(46) 42 12 11 00 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 673 23 666 United Kingdom Teva UK Limited Tel: +44 1977628500 This leaflet was last revised in {MM/YYYY}. Other sources of information Detailed information on this medicine is available on the website of the European Medicines Agency http://www.ema.europa.eu This leaflet is available in all EU/EEA languages on the European Medicines Agency website. http://www.ema.europa.eu/� SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what ribavirin teva pharma b.v. is and what it is used for', 'Section_Content': 'ribavirin teva pharma b.v. contains the active substance ribavirin. this medicine stops the multiplication of many types of viruses, including hepatitis c virus. this medicine must not be used without interferon alfa-2b, i.e. ribavirin teva pharma b.v. must not be used alone. previously untreated patients: the combination of ribavirin teva pharma b.v. with interferon alfa-2b is used to treat patients 3 years of age and older who have chronic hepatitis c (hcv) infection. for paediatric patients (children and adolescents) weighing less than 47 kg a solution formulation is available. previously treated adult patients: the combination of ribavirin teva pharma b.v. with interferon alfa-2b is used to treat adult patients with chronic hepatitis c, who have previously responded to treatment with an alpha interferon alone, but whose condition has recurred. there is no safety or efficacy information on the use of ribavirin with pegylated or other forms of interferon (i.e., not alfa-2b). if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'ribavirin teva pharma b.v.', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 21}, {'Text': 'the active substance ribavirin', 'Type': 'TREATMENT', 'BeginOffset': 36, 'EndOffset': 66}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 68, 'EndOffset': 81}, {'Text': 'viruses', 'Type': 'PROBLEM', 'BeginOffset': 124, 'EndOffset': 131}, {'Id': 17, 'BeginOffset': 143, 'EndOffset': 160, 'Score': 0.9264360666275024, 'Text': 'hepatitis c virus', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.96271151304245}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 162, 'EndOffset': 175}, {'Id': 4, 'BeginOffset': 201, 'EndOffset': 219, 'Score': 0.9448727965354919, 'Text': 'interferon alfa-2b', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 226, 'EndOffset': 247}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 327, 'EndOffset': 348}, {'Id': 7, 'BeginOffset': 359, 'EndOffset': 374, 'Score': 0.8929995894432068, 'Text': 'interferon alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 404, 'EndOffset': 405}, {'Text': 'chronic hepatitis c (hcv) infection', 'Type': 'PROBLEM', 'BeginOffset': 438, 'EndOffset': 473}, {'Text': '47', 'Type': 'NUMBER', 'BeginOffset': 545, 'EndOffset': 547}, {'Text': 'a solution formulation', 'Type': 'TREATMENT', 'BeginOffset': 551, 'EndOffset': 573}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 642, 'EndOffset': 663}, {'Id': 11, 'BeginOffset': 674, 'EndOffset': 689, 'Score': 0.9509330987930298, 'Text': 'interferon alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'chronic hepatitis c', 'Type': 'PROBLEM', 'BeginOffset': 730, 'EndOffset': 749}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 784, 'EndOffset': 793}, {'Text': 'an alpha interferon', 'Type': 'TREATMENT', 'BeginOffset': 799, 'EndOffset': 818}, {'Id': 13, 'BeginOffset': 917, 'EndOffset': 926, 'Score': 0.9507077932357788, 'Text': 'ribavirin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 932, 'EndOffset': 941, 'Score': 0.7014036774635315, 'Text': 'pegylated', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 960, 'EndOffset': 970, 'Score': 0.8278757929801941, 'Text': 'interferon', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 982, 'EndOffset': 986, 'Score': 0.3812326490879059, 'Text': 'alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1040, 'EndOffset': 1053}]}

{'Title': '2. what you need to know before you use ribavirin teva pharma b.v.', 'Section_Content': 'do not take ribavirin teva pharma b.v. do not take ribavirin teva pharma b.v. if any of the following apply to you or the child you are caring for. if you are not sure, talk to your doctor or pharmacist before taking ribavirin teva pharma b.v. if you: - are allergic to ribavirin or any of the other ingredients of this medicine (listed in section 6). - are pregnant or planning to become pregnant (see section "pregnancy and breast-feeding"). - are breast-feeding - had a serious heart problem during the past 6 months 64 - have any blood disorder such as anaemia (low blood count), thalassemia or sickle-cell anaemia reminder: please read the "do not take" section of the package leaflet for the other medicines used in combination before you begin combination treatment with this medicine. warnings and precautions there are several serious adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa. these include: psychiatric and central nervous system effects (such as depression, suicidal thoughts, attempted suicide and aggressive behaviour, etc.). be sure to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or change in your behaviour. you may want to consider asking a family member or close friend to help you stay alert to signs of depression or changes in your behaviour severe eye disorders dental and periodontal disorders: dental and gum disorders have been reported in patients receiving ribavirin in combination with (peg)interferon alfa-2b. you should brush your teeth thoroughly twice daily and have regular dental examinations. in addition some patients may experience vomiting. if you have this reaction, be sure to rinse your mouth thoroughly afterwards inability to achieve full adult height may occur in some children and adolescents increased hormone related to your thyroid (tsh) in children and adolescents paediatric population if you are caring for a child and your doctor decides not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to understand that this combination therapy induces a growth inhibition that may be irreversible in some patients. in addition these events have occurred in patients taking ribavirin teva pharma b.v.: haemolysis: ribavirin teva pharma b.v. can cause a break down in red blood cells causing anaemia which may impair your heart function or worsen symptoms of heart disease. pancytopenia: ribavirin teva pharma b.v. can cause a decrease in your platelet and red and white blood cell count when used in combination with peginterferon. standard blood tests will be taken to check your blood, kidney and liver function. - blood tests will be done regularly to help your doctor to know if this treatment is working. - depending upon the results of these tests, your doctor may change/adjust the number of tablets you or the child you are caring for take, prescribe a different pack size of this medicine, and/or change the length of time to take this treatment. - if you have or develop severe kidney or liver problems, this treatment will be stopped. seek medical help immediately if you develop symptoms of a severe allergic reaction (such as difficulty in breathing, wheezing or hives) while taking this treatment. talk to your doctor if you or your child you are caring for: are a woman of childbearing age (see section "pregnancy and breast-feeding"). are a male and your female partner is of childbearing age (see section "pregnancy and breast- feeding"). had a previous heart condition or have heart disease. have another liver problem in addition to hepatitis c infection. have problems with your kidneys. have hiv (human immunodeficiency virus) or have ever had any other problems with your immune system. please refer to the package leaflet of (peg)interferon alfa for more detailed information on these safety issues. reminder: please read the "warnings and precautions" section of the package leaflet for the other medicines used in combination with ribavirin teva pharma b.v. before you begin combination treatment. use in children and adolescents if the child is weighing less than 47 kg or unable to swallow tablets an oral solution of ribavirin should be used. other medicines and ribavirin teva pharma b.v. tell your doctor or pharmacist if you or the child you are caring for, are taking, have recently taken or might take: - azathioprine is a medicine that suppresses your immune system, using this medicine in combination with ribavirin may increase your risk of developing severe blood disorders. - anti-human immunodeficiency virus (hiv) medicines [nucleoside reverse transcriptase inhibitor (nrti), and/or combined anti-retroviral therapy (cart)]: - taking this medicine in combination with an alpha interferon and an anti-hiv medicine may increase the risk of lactic acidosis, liver failure, and blood abnormalities development (reduction in number of red blood cells which carry oxygen, certain white blood cells that fight infection, and blood clotting cells called platelets). - with zidovudine or stavudine, it is not certain if this medicine will change the way these medicines work. therefore, your blood will be checked regularly to be sure that the hiv infection is not getting worse. if it gets worse, your doctor will decide whether or not your ribavirin teva pharma b.v. treatment needs to be changed. additionally, patients receiving zidovudine with ribavirin in combination with alpha interferons could be at increased risk of developing anaemia (low number of red blood cells). therefore the use of zidovudine and ribavirin in combination with alpha interferons is not recommended. - due to the risk of lactic acidosis (a build-up of lactic acid in the body) and pancreatitis, the use of ribavirin and didanosine is not recommended and the use of ribavirin and stavudine should be avoided. - co-infected patients with advanced liver disease receiving cart may be at increased risk of worsening liver function. adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. reminder: please read the "other medicines" section of the package leaflet for the other medicines used in combination with ribavirin teva pharma b.v. before you begin combination treatment with this medicine. pregnancy and breast-feeding if you are pregnant you must not take this medicine. this medicine can be very damaging to your unborn baby (embryo). both female and male patients must take special precautions in their sexual activity if there is any possibility for pregnancy to occur: girl or woman of childbearing age: you must have a negative pregnancy test before treatment, each month during treatment, and for the 4 months after treatment is stopped. this should be discussed with your doctor. men do not have sex with a pregnant woman unless you use a condom. this will lessen the possibility for ribavirin to be left in the woman\'s body. if your female partner is not pregnant now but is of childbearing age, she must be tested for pregnancy each month during treatment and for the 7 months after treatment has stopped. you or your female partner must use an effective contraceptive during the time you are taking this medicine and for 7 months after stopping treatment. this should be discussed with your doctor (see "do not take ribavirin teva pharma b.v."). if you are a woman who is breast-feeding, you must not take this medicine. discontinue breast- feeding before starting to take this medicine. driving and using machines this medicine does not effect your ability to drive or use machines; however, other medicines used in combination with ribavirin teva pharma b.v. may cause sleepiness, tiredness or confusion. do not drive or use any tools or machines if you feel tired 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{'Title': '3. how to use ribavirin teva pharma b.v.', 'Section_Content': 'general information about taking this medicine: always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. do not take more than the recommended dosage and take the medicine for as long as prescribed. your doctor has determined the correct dose of this medicine based on how much you or the child you are caring for weighs. adults the recommended dose and duration of ribavirin teva pharma b.v. depends on how much the patient weighs and the medicines that are used in combination. use in children and adolescents dosing for children above 3 years of age and adolescents depends on how much the person weighs and the medicines that are used in combination. the recommended dose of ribavirin teva pharma b.v. combined with interferon alfa-2b, is shown in the below table. ribavirin teva pharma b.v. dose based on body weight when used in combination with interferon alfa-2b or peginterferon alfa-2b in children above 3 years of age and adolescents if the child/adolescent weighs (kg) usual daily ribavirin teva pharma b.v. dose number of 200 mg tablets 47 - 49 600 mg 1 tablet in the morning and 2 tablets in the evening 50 - 65 800 mg 2 tablets in the morning and 2 tablets in the evening > 65 see adult dose take your prescribed dose by mouth with water and during your meal. do not chew the film-coated tablets. for children or adolescents who cannot swallow a film-coated tablet, an oral solution of ribavirin is available. reminder: this medicine is only to be used in combination with other medicines for hepatitis c virus infection. for complete information be sure to read the "how to use" section of the package leaflet for the other medicines used in combination with ribavirin teva pharma b.v.. if you take more ribavirin teva pharma b.v. than you should tell your doctor or pharmacist as soon as possible. if you forget to take ribavirin teva pharma b.v. take/administer the missed dose as soon as possible during the same day. if an entire day has gone by, check with your doctor. do not take a double dose to make up for a forgotten dose. if you have any further questions on the use of this product, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'ribavirin teva pharma b.v.', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 33, 'EndOffset': 46}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 223, 'EndOffset': 235}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 310, 'EndOffset': 323}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 430, 'EndOffset': 451}, {'Text': 'the medicines', 'Type': 'TREATMENT', 'BeginOffset': 500, 'EndOffset': 513}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 602, 'EndOffset': 603}, {'Text': 'the medicines', 'Type': 'TREATMENT', 'BeginOffset': 675, 'EndOffset': 688}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 743, 'EndOffset': 764}, {'Id': 4, 'BeginOffset': 784, 'EndOffset': 799, 'Score': 0.9645336270332336, 'Text': 'interferon alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 833, 'EndOffset': 854}, {'Id': 6, 'BeginOffset': 916, 'EndOffset': 934, 'Score': 0.949459433555603, 'Text': 'interferon alfa-2b', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 938, 'EndOffset': 956, 'Score': 0.9035574197769165, 'Text': 'peginterferon alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 978, 'EndOffset': 979}, {'Text': 'the child/adolescent weighs (kg)', 'Type': 'TREATMENT', 'BeginOffset': 1012, 'EndOffset': 1044}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 1057, 'EndOffset': 1078}, {'Text': '200', 'Type': 'NUMBER', 'BeginOffset': 1099, 'EndOffset': 1102}, {'Text': '47', 'Type': 'NUMBER', 'BeginOffset': 1114, 'EndOffset': 1116}, {'Text': '49', 'Type': 'NUMBER', 'BeginOffset': 1119, 'EndOffset': 1121}, {'Text': '600', 'Type': 'NUMBER', 'BeginOffset': 1122, 'EndOffset': 1125}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1129, 'EndOffset': 1130}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 1157, 'EndOffset': 1158}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 1182, 'EndOffset': 1184}, {'Text': '65', 'Type': 'NUMBER', 'BeginOffset': 1187, 'EndOffset': 1189}, {'Text': '800', 'Type': 'NUMBER', 'BeginOffset': 1190, 'EndOffset': 1193}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 1197, 'EndOffset': 1198}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 1226, 'EndOffset': 1227}, {'Text': '65', 'Type': 'NUMBER', 'BeginOffset': 1253, 'EndOffset': 1255}, {'Text': 'the film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 1351, 'EndOffset': 1374}, {'Text': 'a film-coated tablet', 'Type': 'TREATMENT', 'BeginOffset': 1423, 'EndOffset': 1443}, {'Text': 'an oral solution of ribavirin', 'Type': 'TREATMENT', 'BeginOffset': 1445, 'EndOffset': 1474}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1499, 'EndOffset': 1512}, {'Text': 'other medicines', 'Type': 'TREATMENT', 'BeginOffset': 1552, 'EndOffset': 1567}, {'Id': 34, 'BeginOffset': 1572, 'EndOffset': 1599, 'Score': 0.8739393949508667, 'Text': 'hepatitis c virus infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9808277487754822}]}, {'Text': 'the package leaflet', 'Type': 'TREATMENT', 'BeginOffset': 1670, 'EndOffset': 1689}, {'Text': 'the other medicines', 'Type': 'TREATMENT', 'BeginOffset': 1694, 'EndOffset': 1713}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 1739, 'EndOffset': 1760}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 1784, 'EndOffset': 1805}, {'Text': 'ribavirin teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 1901, 'EndOffset': 1922}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 2067, 'EndOffset': 2080}]}

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{'Title': '5. how to store ribavirin teva pharma b.v.', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer packaging. the expiry date refers to the last day of that month. this medicinal product requires no special storage conditions. do not use this medicine if you notice any change in the appearance of the tablets. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what ribavirin teva pharma b.v. contains the active substance is ribavirin. each film-coated tablet contains 200 mg of ribavirin. the other ingredients are tablet core; calcium hydrogen phosphate anhydrous, croscarmellose sodium, povidone, magnesium stearate. film coating, composed of : polyvinyl alcohol partly hydrolysed, macrogol / polyethylene glycol 3350, titanium dioxide (e171), talc, iron oxide red, iron oxide yellow, iron oxide black. what ribavirin teva pharma b.v. looks like and contents of the pack ribavirin teva pharma b.v. 200 mg film-coated tablets are light-pink to pink, (debossed with "93" on one side and "7232" on the other). ribavirin teva pharma b.v. is available in different pack sizes containing 14, 28, 42, 56, 84, 112, 140 or 168 tablets. not all pack sizes may be marketed. your physician will prescribe the pack size which is best for you.', 'Entity_Recognition': [{'Text': 'ribavirin 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D3495F6E62BF7176BF1803F4DB89AC41

https://www.ema.europa.eu/documents/product-information/velphoro-epar-product-information_en.pdf

Velphoro

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Velphoro 500 mg chewable tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide also known as a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. The active ingredient sucroferric oxyhydroxide contains 750 mg sucrose and 700 mg starches (potato starch and pregelatinised maize starch) per tablet. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Chewable tablet. Brown, circular tablets embossed with PA500 on one side. Tablets have a 20 mm diameter and a thickness of 6.5 mm. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Velphoro is indicated for the control of serum phosphorus levels in adult chronic kidney disease (CKD) patients on haemodialysis (HD) or peritoneal dialysis (PD). Velphoro should be used within the context of a multiple therapeutic approach, which could include calcium supplement, 1,25-dihydroxy vitamin D3 or one of its analogues, or calcimimetics to control the development of renal bone disease. 4.2 Posology and method of administration Posology Starting dose The recommended starting dose of Velphoro is 1,500 mg iron (3 tablets) per day, divided across the meals of the day. Velphoro is for oral administration only and must be taken with meals. Patients receiving Velphoro should adhere to their prescribed diets. Titration and maintenance Serum phosphorus levels must be monitored and the dose of Velphoro up or down titrated in increments of 500 mg iron (1 tablet) per day every 2 – 4 weeks until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. In clinical practice, treatment will be based on the need to control serum phosphorus levels, though patients who respond to Velphoro therapy usually achieve optimal serum phosphorus levels at doses of 1,500 – 2,000 mg iron per day (3 to 4 tablets). If one or more doses are missed, the normal dose of the medicinal product should be resumed with the next meal. 3 Maximum tolerated daily dose The maximum recommended dose is 3,000 mg iron (6 tablets) per day. Paediatric population The safety and efficacy of Velphoro in children and adolescents below the age of 18 years has not yet been established. No data are available. Elderly population (≥65 years of age) Velphoro has been administered to over 248 seniors (≥65 years of age) according to the approved dosing regimen. Of the total number of subjects in clinical studies of Velphoro, 29.7% were aged 65 and over, while 8.7% were aged 75 and over. No special dose and administration guidelines were applied to seniors in these studies and the dosing schedules were not associated with any significant concerns. Renal impairment Velphoro is indicated for the control of serum phosphorus levels in adult CKD patients on HD or PD. There is no clinical data available with Velphoro in patients with earlier stages of renal impairment. Hepatic impairment Patients with severe hepatic impairment were excluded from participating in clinical studies with Velphoro. However, no evidence of hepatic impairment or significant alteration of hepatic enzymes were observed in the clinical studies with Velphoro. See further information in section 4.4. Method of administration Oral use. Velphoro is a chewable tablet that must be taken with meals. In order to maximise the adsorption of dietary phosphate, the total daily dose should be divided across the meals of the day. Patients are not required to drink more fluid than they normally would. Tablets must be chewed or crushed; tablets must not be swallowed whole. 4.3 Contraindications • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Haemochromatosis and any other iron accumulation disorders. 4.4 Special warnings and precautions for use Peritonitis, gastric and hepatic disorders and gastrointestinal surgery Patients with a recent history of peritonitis (within the last 3 months), significant gastric or hepatic disorders and patients with major gastrointestinal surgery have not been included in clinical studies with Velphoro. Velphoro should only be used in these patients following careful assessment of benefit/risk. Information about sucrose and starches (carbohydrates) Velphoro contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. It may be harmful to the teeth. 4 Velphoro contains potato starch and pregelatinised maize starch. Patients with diabetes should take notice that one tablet of Velphoro is equivalent to approximately 1.4 g of carbohydrates (equivalent to 0.116 bread units). Discoloured stool Velphoro can cause discoloured (black) stool. Discoloured (black) stool may visually mask gastrointestinal bleeding (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction Velphoro is almost not absorbed from the gastrointestinal tract. Although the potential for interactions with medicinal products seems low, for concomitant treatment with medicinal products with a narrow therapeutic window, the clinical effect and adverse events should be monitored, on initiation or dose- adjustment of either Velphoro or the concomitant medicinal product, or the physician should consider measuring blood levels. When administering any medicinal product that is already known to interact with iron (like alendronate and doxycycline) or has the potential to interact with Velphoro based only on in vitro studies like levothyroxine, the medicinal product should be administered at least one hour before or two hours after Velphoro. In vitro studies with the following active substances did not show any relevant interaction: acetylsalicylic acid, cephalexin, cinacalcet, ciprofloxacin, clopidogrel, enalapril, hydrochlorothiazide, metformin, metoprolol, nifedipine, pioglitazone and quinidine. Drug-drug interaction studies have only been performed in healthy volunteers. They have been conducted in healthy human male and female subjects with losartan, furosemide, digoxin, warfarin, and omeprazole. Concomitant administration of Velphoro did not affect the bioavailability of these medicinal products as measured by the area under the curve (AUC). Data from clinical studies have shown that Velphoro does not affect the lipid lowering effects of HMG-CoA reductase inhibitors (e.g., atorvastatin and simvastatin). In addition, post-hoc analyses from clinical studies demonstrated no impact of Velphoro on iPTH lowering effect of oral Vitamin D analogues. Vitamin D and 1,25-dihydroxy Vitamin D levels remained unchanged. Velphoro does not affect guaiac based (Haemoccult) or immunological based (iColo Rectal and Hexagon Obti) faecal occult blood tests. 4.6 Fertility, pregnancy and lactation Pregnancy There are no available clinical data from the use of sucroferric oxyhydroxide on exposed human pregnancies. Reproductive and developmental toxicity studies in animals revealed no risk with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3). Velphoro should only be used by pregnant women if clearly needed following careful assessment of benefit/risk. Breast-feeding There are no available clinical data from the use of Velphoro in breast-feeding women. Since absorption of iron from Velphoro is minimal (see section 5.2), excretion of iron from Velphoro in breast milk is unlikely. A decision on whether to continue breast-feeding or to continue therapy with Velphoro should be made taking into account the benefit of breast-feeding to the child and the benefit of Velphoro therapy to the mother. 5 Fertility There are no data on the effect of Velphoro on fertility in humans. In animal studies, there were no adverse effects on mating performance, fertility, and litter parameters following treatment with Velphoro (see section 5.3). 4.7 Effects on ability to drive and use machines Velphoro has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The current safety profile of Velphoro is based on a total of 778 patients on haemodialysis and 57 patients on peritoneal dialysis, who received Velphoro treatment of up to 55 weeks. In these clinical trials, approximately 43% of patients experienced at least one adverse reaction during Velphoro treatment, which were reported as serious adverse reactions in 0.36%. The majority of the adverse reactions reported from trials were gastrointestinal disorders, with the most frequently reported adverse reactions being diarrhoea and discoloured faeces (very common). The vast majority of these gastrointestinal disorders occurred early during treatment and abated with time with continued dosing. No dose-dependent trends were observed in the adverse reaction profile of Velphoro. Tabulated list of adverse reactions Adverse reactions reported from the use of Velphoro at doses from 250 mg iron/day to 3,000 mg iron/day in these patients (n=835) are listed in Table 1. The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100). Table 1 Adverse reactions detected in clinical trials System Organ Class Very common Common Uncommon Metabolism and nutrition disorders Hypercalcaemia Hypocalcaemia Nervous system disorders Headache Respiratory, thoracic and mediastinal disorders Dyspnoea Gastrointestinal disorders Diarrhoea* Faeces discoloured Nausea Constipation Vomiting Dyspepsia Abdominal pain Flatulence Tooth discolouration Abdominal distension Gastritis Abdominal discomfort Dysphagia Gastro-oesophageal reflux disease (GORD) Tongue discolouration Skin and subcutaneous tissue disorders Pruritus Rash General disorders and administration site conditions Product taste abnormal Fatigue 6 Description of selected adverse reactions *Diarrhoea Diarrhoea occurred in 11.6% of patients in clinical trials. In the 55 weeks long term studies, the majority of these diarrhoea adverse reactions were transient, occurred early during treatment initiation and led to treatment discontinuation in 3.1% of the patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Any instances of overdose of Velphoro (e.g. hypophosphataemia) should be treated by standard clinical practice. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia; ATC code: V03AE05 Mechanism of action Velphoro contains a mixture of polynuclear iron(III)-oxyhydroxide (pn-FeOOH), sucrose and starches. Phosphate binding takes place by ligand exchange between hydroxyl groups and/or water and the phosphate ions throughout the physiological pH range of the gastrointestinal tract. Serum phosphorus levels are reduced as a consequence of the reduced dietary phosphate absorption. Clinical efficacy One phase 3 clinical study has been performed in patients with CKD on dialysis to investigate the efficacy and safety of Velphoro in this population. This study was an open-label, randomised, active- controlled (sevelamer carbonate), parallel group study for up to 55 weeks. Adult patients with hyperphosphataemia (serum phosphorus levels ≥1.94 mmol/L) were treated with Velphoro at a starting dose of 1,000 mg iron/day followed by an 8-week dose titration period. Non-inferiority to sevelamer carbonate was determined at week 12. Subjects were continued on their study medication from week 12 to week 55. From week 12 to 24, dose titrations were allowed for both tolerability and efficacy reasons. Treatment of patient sub-populations from week 24 to week 27 with maintenance dose of Velphoro (1,000 to 3,000 mg iron/day) or low dose (250 mg iron/day) of Velphoro demonstrated superiority of the maintenance dose. In Study-05A, 1,055 patients on hemodialysis (N=968) or peritoneal dialysis (N=87) with serum phosphorus ≥1.94 mmol/L following a 2 – 4-week phosphate binder washout period, were randomized and treated with either Velphoro, at a starting dose of 1,000 mg iron/day (N=707), or active-control (sevelamer carbonate, N=348) for 24 weeks. At the end of week 24, 93 patients on hemodialysis whose serum phosphorus levels were controlled (<1.78 mmol/L) with Velphoro in the first part of the study, were re-randomized to continue treatment with either their week 24 maintenance dose (N=44 or a non-effective low dose control 250 mg iron/day, N=49) of Velphoro for a further 3 weeks. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 7 Following completion of Study-05A, 658 patients (597 on hemodialysis and 61 on peritoneal dialysis) were treated in the 28-week extension study (Study-05B) with either Velphoro (N=391) or sevelamer carbonate (N=267) according to their original randomization. Mean serum phosphorus levels were 2.5 mmol/L at baseline and 1.8 mmol/L at week 12 for Velphoro (reduction by 0.7 mmol/L). Corresponding levels for sevelamer carbonate at baseline were 2.4 mmol/L and 1.7 mmol/L at week 12 (reduction by 0.7 mmol/L), respectively. The serum phosphorus reduction was maintained over 55 weeks. Serum phosphorus levels and calcium-phosphorus product levels were reduced as a consequence of the reduced dietary phosphate absorption. The response rates, defined as the proportion of subjects achieving serum phosphorus levels within the KDOQI (Kidney Disease Outcomes Quality Initiative) recommended range were 45.3% and 59.1% at week 12 and 51.9% and 55.2% at week 52, for Velphoro and sevelamer carbonate, respectively. The mean daily dose of Velphoro over 55 weeks of treatment was 1,650 mg iron and the mean daily dose of sevelamer carbonate was 6,960 mg. Post-authorization data A prospective, non-interventional, post-authorisation safety study (VERIFIE) has been conducted, evaluating the short- and long-term (up to 36 months) safety and effectiveness of Velphoro in adult patients on haemodialysis (n=1,198) or peritoneal dialysis (n=160), who were followed in routine clinical practice for 12 to 36 months (safety analysis set, N=1,365). During the study, 45% (n=618) of these patients were concomitantly treated with phosphate binder(s) other than Velphoro. In the safety analysis set, the most common ADRs were diarrhoea and discoloured faeces, reported by 14% (n=194) and 9% (n=128) of patients, respectively. The incidence of diarrhoea was highest in the first week and decreased with duration of use. Diarrhoea was of mild to moderate intensity in most patients and resolved in the majority of patients within 2 weeks. Discoloured (black) faeces is expected for an oral iron-based compound, and may visually mask gastrointestinal bleeding. For 4 of the 40 documented concomitant gastrointestinal bleeding events, Velphoro-related stool discolouration was reported as causing an insignificant delay in diagnosis of gastrointestinal bleeding, without affecting patient health. In the remaining cases, no delay in diagnosis of gastrointestinal bleeding has been reported. The results from this study showed that the effectiveness of Velphoro in a real-life setting (including concomitant use of other phosphate binders in 45% of patients), was in line with that observed in the phase 3 clinical study. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Velphoro in one or more subsets of the paediatric population in the treatment of hyperphosphataemia (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Velphoro works by binding phosphate in the gastrointestinal tract and thus the serum concentration is not relevant for its efficacy. Due to the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out, e.g., determination of the distribution volume, area under the curve, mean residence time, etc. In 2 Phase 1 studies, it was concluded that the potential for iron overload is minimal and no dose dependent effects were observed in healthy volunteers. 8 Absorption The active moiety of Velphoro, pn-FeOOH, is practically insoluble and therefore not absorbed. Its degradation product, mononuclear iron species, can however be released from the surface of pn- FeOOH and be absorbed. The absolute absorption studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that systemic absorption was very low (≤1% of the administered dose). The iron uptake from radiolabelled Velphoro drug substance, 2,000 mg iron in 1 day was investigated in 16 CKD patients (8 pre-dialysis and 8 haemodialysis patients) and 8 healthy volunteers with low iron stores (serum ferritin <100 mcg/L). In healthy subjects, the median uptake of radiolabelled iron in the blood was estimated to be 0.43% (range 0.16 – 1.25%) on Day 21, in pre-dialysis patients 0.06% (range 0.008 – 0.44%) and in haemodialysis patients 0.02% (range 0 – 0.04%). Blood levels of radiolabelled iron were very low and confined to the erythrocytes. Distribution The distribution studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that pn-FeOOH is distributed from the plasma to the liver, spleen and bone marrow, and utilized by incorporation into red blood cells. In patients, absorbed iron is expected to be also distributed to the target organs, i.e. liver, spleen and bone marrow, and utilized by incorporation into red blood cells. Biotransformation The active moiety of Velphoro, pn-FeOOH, is not metabolised. However, the degradation product of Velphoro, mononuclear iron species, can be released from the surface of polynuclear iron(III)- oxyhydroxide and be absorbed. Clinical studies have demonstrated that the systemic absorption of iron from Velphoro is low. In vitro data suggest that the sucrose and starch components of the drug substance can be digested to glucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in the blood. Elimination In animal studies with rats and dogs administered 59Fe-Velphoro drug substance orally, radiolabelled iron was recovered in the faeces but not the urine. 5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Effects seen in the rabbit embryo-foetal development toxicity study (skeletal variations and incomplete ossificaton) are related to exaggerated pharmacology, and likely not relevant for patients. Other reproduction toxicity studies showed no adverse effects. Carcinogenicity studies were performed in mice and rats. There was no clear evidence of a carcinogenic effect in mice. Mucosal hyperplasia, with diverticulum/cyst formation was observed in the colon and caecum of mice after 2-years treatment, but this was considered a species-specific effect with no diverticula/cysts seen in long term studies in rats or dogs. In rats, there was a slightly increased incidence of benign C-cell adenoma in the thyroid of male rats given the highest dose of sucroferric oxyhydroxide. This is thought to be most likely an adaptive response to the pharmacological effect of the drug, and not clinically relevant. 9 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Woodberry flavour Neohesperidin-dihydrochalcone Magnesium stearate Colloidal anhydrous silica 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years Shelf life after first opening of the bottle: 90 days 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container High density polyethylene (HDPE) bottle with child-resistant polypropylene closure and foil induction seal, containing a molecular sieve desiccant and cotton. Pack sizes of 30 or 90 chewable tablets. Child-resistant aluminium/aluminium perforated unit-dose blister, each blister containing 6 chewable tablets. Pack sizes of 30 × 1 or multipack of 90 (3 packs of 30 × 1) chewable tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Vifor Fresenius Medical Care Renal Pharma France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex France 8. MARKETING AUTHORISATION NUMBER(S) EU/1/14/943/001 EU/1/14/943/002 EU/1/14/943/003 EU/1/14/943/004 10 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 26 August 2014 Date of latest renewal: 25 March 2019 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 11 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 12 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Vifor France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex FRANCE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 13 ANNEX III LABELLING AND PACKAGE LEAFLET 14 A. LABELLING 15 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON – BOTTLE OF 30 AND 90 CHEWABLE TABLETS 1. NAME OF THE MEDICINAL PRODUCT Velphoro 500 mg chewable tablets iron as sucroferric oxyhydroxide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide. 3. LIST OF EXCIPIENTS Contains sucrose, potato starch and pregelatinised maize starch. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 30 chewable tablets 90 chewable tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Tablets must be chewed or crushed and taken with meals. Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: Shelf-life after first opening the bottle: 90 days Opening date: 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 16 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Vifor Fresenius Medical Care Renal Pharma France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/943/001 30 chewable tablets EU/1/14/943/002 90 chewable tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE velphoro 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 17 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING LABEL – BOTTLE OF 30 AND 90 CHEWABLE TABLETS 1. NAME OF THE MEDICINAL PRODUCT Velphoro 500 mg chewable tablets iron as sucroferric oxyhydroxide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide. 3. LIST OF EXCIPIENTS Contains sucrose, potato starch and pregelatinised maize starch. Read the package leaflet before use. 4. PHARMACEUTICAL FORM AND CONTENTS 30 chewable tablets 90 chewable tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Tablets must be chewed or crushed and taken with meals. Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: Shelf-life after first opening the bottle: 90 days Opening date: 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 18 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Vifor Fresenius Medical Care Renal Pharma France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/943/001 30 chewable tablets EU/1/14/943/002 90 chewable tablets 13. BATCH NUMBER Lot: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON –30 CHEWABLE TABLETS (5 BLISTERS OF 6 CHEWABLE TABLETS) 1. NAME OF THE MEDICINAL PRODUCT Velphoro 500 mg chewable tablets iron as sucroferric oxyhydroxide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide. 3. LIST OF EXCIPIENTS Contains sucrose, potato starch and pregelatinised maize starch. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 30 × 1 chewable tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Tablets must be chewed or crushed and taken with meals. Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 20 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Vifor Fresenius Medical Care Renal Pharma France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/943/003 13. BATCH NUMBER Lot: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE velphoro 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON – 30 CHEWABLE TABLETS (5 BLISTERS OF 6 CHEWABLE TABLETS), PART OF MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Velphoro 500 mg chewable tablets iron as sucroferric oxyhydroxide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide. 3. LIST OF EXCIPIENTS Contains sucrose, potato starch and pregelatinised maize starch. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 30 × 1 chewable tablets. Component of a multipack. Can’t be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Tablets must be chewed or crushed and taken with meals. Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 22 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Vifor Fresenius Medical Care Renal Pharma France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/943/003 13. BATCH NUMBER Lot: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE velphoro 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 23 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON (MULTIPACK) – 90 (3 PACKS OF 30) CHEWABLE TABLETS 1. NAME OF THE MEDICINAL PRODUCT Velphoro 500 mg chewable tablets iron as sucroferric oxyhydroxide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide. 3. LIST OF EXCIPIENTS Contains sucrose, potato starch and pregelatinised maize starch. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Multipack: 90 (3 packs of 30) chewable tablets. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Tablets must be chewed or crushed and taken with meals. Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 24 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Vifor Fresenius Medical Care Renal Pharma France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/943/004 13. BATCH NUMBER Lot: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE velphoro 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 25 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER OF 6 CHEWABLE TABLETS 1. NAME OF THE MEDICINAL PRODUCT Velphoro 500 mg chewable tablets iron as sucroferric oxyhydroxide 2. NAME OF THE MARKETING AUTHORISATION HOLDER Vifor Fresenius Medical Care Renal Pharma France 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 26 B. PACKAGE LEAFLET 27 Package leaflet: Information for the patient Velphoro 500 mg chewable tablets iron as sucroferric oxyhydroxide Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. – Keep this leaflet. You may need to read it again. – If you have any further questions, ask your doctor or pharmacist – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. – If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Velphoro is and what it is used for 2. What you need to know before you take Velphoro 3. How to take Velphoro 4. Possible side effects 5. How to store Velphoro 6. Contents of the pack and other information 1. What Velphoro is and what it is used for Velphoro is a medicine that contains the active substance sucroferric oxyhydroxide, which is made up from iron, sugar (sucrose) and starches. Velphoro is for use by adult patients who undergo haemodialysis or peritoneal dialysis (procedures to eliminate toxic substances from the blood) because of chronic kidney disease; it is used in order to help control the phosphorus level in their blood when it is too high (hyperphosphataemia). Too much phosphorus in the blood can lead to calcium being deposited in tissues (calcification). This can result in stiffening of the blood vessels, making it harder for the blood to be pumped around the body. It may also lead to calcium deposits in soft tissues and bone causing effects such as red eyes, itchy skin and bone pain. Velphoro works by binding phosphorus from food in your digestive tract (stomach and intestines). This reduces the amount of phosphorus that can be absorbed into the bloodstream and thus lowers phosphorus levels in your blood. 2. What you need to know before you take Velphoro Do not take Velphoro: – if you are allergic to sucroferric oxyhydroxide or any of the other ingredients of this medicine (listed in section 6) – if you have a history of abnormal iron build-up in your organs (haemochromatosis) – if you have any other disorder associated with too much iron. If you are not sure, talk to your doctor before taking this medicine. 28 Warnings and precautions Talk to your doctor or pharmacist before taking Velphoro: – if you have had peritonitis, an inflammation of the peritoneum (the thin tissue that lines the inner wall of the abdomen) within the last 3 months, – if you have significant stomach and/or liver problems, – if you have had major surgery on your stomach and/or intestines. If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking this medicine. Velphoro can cause black stools. Any potential bleeding from your digestive tract (stomach and gut) may be hidden by these black stools. If you have black stools and also have symptoms like increasing tiredness and breathlessness contact your doctor immediately (see section 4). Children and adolescents The safety and efficacy of Velphoro in children and adolescents below the age of 18 years has not yet been established. Therefore Velphoro is not recommended for use in children and adolescents. Other medicines and Velphoro Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. If you are taking any other medicine that is known to be affected by iron (for example medicines containing the active substance alendronate (used to treat certain bone disorders) or doxycycline (an antibiotic)) or has the potential to be affected by iron (for example medicines containing the active substance levothyroxine (used to treat thyroid function disorder)), make sure that you take this medicine at least one hour before taking Velphoro or at least two hours after taking Velphoro. Ask your doctor if you are not sure. Pregnancy and breastfeeding There is no information on the effects of this medicine if taken during pregnancy or breastfeeding. If you are pregnant or breastfeeding, or you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Your doctor will advise you whether Velphoro should be used during pregnancy, based on benefit and risk assessment for use during pregnancy. If you are breastfeeding, your doctor will discuss with you whether to continue breastfeeding or to continue therapy with Velphoro, taking into account the benefit of Velphoro therapy to you and the benefit of breastfeeding to your child. It is unlikely that this medicine would pass into the mother’s milk. Driving and using machines This medicine has no significant effect on your ability to drive or to use tools or machines. Velphoro contains sucrose and starches (carbohydrates) If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Velphoro may be harmful to the teeth. 29 Velphoro contains starches. If you have diabetes you should take notice that one tablet of Velphoro is equivalent to approximately 1.4 g of carbohydrates (equivalent to 0.116 bread units). 3. How to take Velphoro Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The usual recommended starting dose is the equivalent of 1,500 mg iron per day (3 tablets). The maximum recommended dose is 3,000 mg iron (6 tablets) per day. Your doctor may adjust the dose during the treatment course depending on the phosphorus level in your blood. Method of administration – Velphoro should only be taken by mouth. – Take the tablet during a meal and chew it (if necessary, the tablet may be crushed to make this easier for you). DO NOT swallow it whole. – The amount of tablets taken per day should be divided across the meals of the day. – When taking Velphoro you should adhere to your recommended diet and treatments prescribed by your doctor such as calcium supplements, vitamin D3 or calcimimetics. Only for the blister packs: – Separate the blister pack at perforations. – Peel back the paper foil at the corner. – Push the tablet through the aluminium foil. If you take more Velphoro than you should If you have accidentally taken too many tablets, do not take any more and talk to your doctor or pharmacist immediately. If you forget to take Velphoro If you have missed a dose, just take the next dose at the usual time with a meal. Do not take a double dose to make up for a forgotten dose. If you stop taking Velphoro Do not stop taking the medicine before talking to your doctor or pharmacist as the phosphorus level in your blood may increase (see section 1). 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Black stools may occur very commonly in patients taking Velphoro. If you also have symptoms like increasing tiredness and breathlessness contact your doctor immediately (see section 2 “Warnings”). The following side effects have also been reported in patients taking this medicine: Very common (may affect more than 1 in 10 people): diarrhoea (generally occurring early on in the treatment, and improving over time). 30 Common (may affect up to 1 in 10 people): feeling sick (nausea), constipation, vomiting, indigestion, pain in stomach and gut, gas, tooth discolouration, change in taste. Uncommon (may affect up to 1 in 100 people): bloating (abdominal distension), inflammation of the stomach, abdominal discomfort, difficulty swallowing, acid coming back up from the stomach (gastro- oesophageal reflux disease), tongue discolouration, low or high calcium levels in the blood seen in tests, tiredness, itch, rash, headache, shortness of breath. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Velphoro Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date stated on the carton, bottle or blister after “EXP”. The expiry date refers to the last day of that month. After first opening of the bottle the chewable tablets can be used for 90 days. Store in the original package in order to protect from moisture. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Velphoro contains – The active substance is iron as sucroferric oxyhydroxide also known as a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide. Each tablet also contains 750 mg sucrose and 700 mg starches. See section 2 for further information on sucrose and starches. – The other ingredients are woodberry flavour, neohesperidin-dihydrochalcone, magnesium stearate, colloidal anhydrous silica. What Velphoro looks like and contents of the pack The chewable tablets are brown, circular, and embossed with PA500 on one side. The tablets have a 20 mm diameter and a thickness of 6.5 mm. The tablets are packed in high density polyethylene bottles with a child resistant polypropylene closure and a foil induction seal, or in child resistant aluminium blister. Velphoro is available in packs containing 30 or 90 chewable tablets. Multipacks are available for the blister packs with 90 chewable tablets (containing 3 individual packs of 30 × 1 chewable tablets each). Not all pack sizes may be marketed. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 31 Marketing Authorisation Holder Vifor Fresenius Medical Care Renal Pharma France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex France Manufacturer Vifor France 100–101 Terrasse Boieldieu Tour Franklin La Défense 8 92042 Paris la Défense Cedex France For any information about this medicine, please contact the Marketing Authorisation Holder. This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to take velphoro', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the usual recommended starting dose is the equivalent of 1,500 mg iron per day (3 tablets). the maximum recommended dose is 3,000 mg iron (6 tablets) per day. your doctor may adjust the dose during the treatment course depending on the phosphorus level in your blood. method of administration velphoro should only be taken by mouth. take the tablet during a meal and chew it (if necessary, the tablet may be crushed to make this easier for you). do not swallow it whole. the amount of tablets taken per day should be divided across the meals of the day. when taking velphoro you should adhere to your recommended diet and treatments prescribed by your doctor such as calcium supplements, vitamin d3 or calcimimetics. only for the blister packs: separate the blister pack at perforations. peel back the paper foil at the corner. push the tablet through the aluminium foil. if you take more velphoro than you should if you have accidentally taken too many tablets, do not take any more and talk to your doctor or pharmacist immediately. if you forget to take velphoro if you have missed a dose, just take the next dose at the usual time with a meal. do not take a double dose to make up for a forgotten dose. if you stop taking velphoro do not stop taking the medicine before talking to your doctor or pharmacist as the phosphorus level in your blood may increase (see section 1).', 'Entity_Recognition': [{'Text': 'velphoro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': '1,500', 'Type': 'NUMBER', 'BeginOffset': 192, 'EndOffset': 197}, {'Id': 2, 'BeginOffset': 201, 'EndOffset': 205, 'Score': 0.9713308811187744, 'Text': 'iron', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. black stools may occur very commonly in patients taking velphoro. if you also have symptoms like increasing tiredness and breathlessness contact your doctor immediately (see section 2 "warnings"). the following side effects have also been reported in patients taking this medicine: very common (may affect more than 1 in 10 people): diarrhoea (generally occurring early on in the treatment, and improving over time). common (may affect up to 1 in 10 people): feeling sick (nausea), constipation, vomiting, indigestion, pain in stomach and gut, gas, tooth discolouration, change in taste. uncommon (may affect up to 1 in 100 people): bloating (abdominal distension), inflammation of the stomach, abdominal discomfort, difficulty swallowing, acid coming back up from the stomach (gastro- oesophageal reflux disease), tongue discolouration, low or high calcium levels in the blood seen in tests, tiredness, itch, rash, headache, shortness of breath. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'velphoro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 9, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9652749300003052, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7289592623710632}]}, {'Id': 10, 'BeginOffset': 92, 'EndOffset': 104, 'Score': 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'BeginOffset': 694, 'EndOffset': 722, 'Score': 0.2013242244720459, 'Text': 'affect up to 1 in 100 people', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 707, 'EndOffset': 708}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 712, 'EndOffset': 715}, {'Text': 'bloating (abdominal distension', 'Type': 'PROBLEM', 'BeginOffset': 725, 'EndOffset': 755}, {'Text': 'inflammation of the stomach', 'Type': 'PROBLEM', 'BeginOffset': 758, 'EndOffset': 785}, {'Id': 29, 'BeginOffset': 787, 'EndOffset': 807, 'Score': 0.9165917038917542, 'Text': 'abdominal discomfort', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9712663292884827}]}, {'Id': 30, 'BeginOffset': 809, 'EndOffset': 830, 'Score': 0.9887329339981079, 'Text': 'difficulty swallowing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9487640261650085}]}, {'Text': 'acid', 'Type': 'TEST', 'BeginOffset': 832, 'EndOffset': 836}, {'Id': 4, 'BeginOffset': 861, 'EndOffset': 868, 'Score': 0.9905732274055481, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'gastro- oesophageal reflux disease', 'Type': 'PROBLEM', 'BeginOffset': 870, 'EndOffset': 904}, {'Id': 32, 'BeginOffset': 907, 'EndOffset': 928, 'Score': 0.47698327898979187, 'Text': 'tongue discolouration', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6858677268028259}]}, {'Text': 'low or high calcium levels', 'Type': 'PROBLEM', 'BeginOffset': 930, 'EndOffset': 956}, {'Text': 'the blood', 'Type': 'TEST', 'BeginOffset': 960, 'EndOffset': 969}, {'Text': 'tests', 'Type': 'TEST', 'BeginOffset': 978, 'EndOffset': 983}, {'Id': 34, 'BeginOffset': 985, 'EndOffset': 994, 'Score': 0.9422650337219238, 'Text': 'tiredness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.907649576663971}]}, {'Id': 35, 'BeginOffset': 996, 'EndOffset': 1000, 'Score': 0.9993075132369995, 'Text': 'itch', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9746338129043579}]}, {'Id': 36, 'BeginOffset': 1002, 'EndOffset': 1006, 'Score': 0.9996347427368164, 'Text': 'rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9758123755455017}]}, {'Id': 37, 'BeginOffset': 1008, 'EndOffset': 1016, 'Score': 0.9995803236961365, 'Text': 'headache', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9778775572776794}]}, {'Id': 38, 'BeginOffset': 1018, 'EndOffset': 1037, 'Score': 0.9977583885192871, 'Text': 'shortness of breath', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.935815691947937}]}, {'Id': 39, 'BeginOffset': 1052, 'EndOffset': 1064, 'Score': 0.947027325630188, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8268043398857117}]}, {'Id': 40, 'BeginOffset': 1080, 'EndOffset': 1092, 'Score': 0.91413414478302, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7737213969230652}]}, {'Id': 41, 'BeginOffset': 1156, 'EndOffset': 1168, 'Score': 0.950439453125, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6880674958229065}]}, {'Id': 42, 'BeginOffset': 1217, 'EndOffset': 1229, 'Score': 0.8484674692153931, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7002816796302795}]}, {'Id': 7, 'BeginOffset': 1283, 'EndOffset': 1291, 'Score': 0.47275006771087646, 'Text': 'appendix', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 43, 'BeginOffset': 1308, 'EndOffset': 1320, 'Score': 0.759097695350647, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7328263521194458}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1376, 'EndOffset': 1389}]}

{'Title': '5. how to store velphoro', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date stated on the carton, bottle or blister after "exp". the expiry date refers to the last day of that month. after first opening of the bottle the chewable tablets can be used for 90 days. store in the original package in order to protect from moisture. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'velphoro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'blister', 'Type': 'PROBLEM', 'BeginOffset': 138, 'EndOffset': 145}, {'Text': 'the bottle the chewable tablets', 'Type': 'TREATMENT', 'BeginOffset': 236, 'EndOffset': 267}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 284, 'EndOffset': 286}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what velphoro contains the active substance is iron as sucroferric oxyhydroxide also known as a mixture of polynuclear iron(iii)-oxyhydroxide, sucrose, and starches. each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide. each tablet also contains 750 mg sucrose and 700 mg starches. see section 2 for further information on sucrose and starches. the other ingredients are woodberry flavour, neohesperidin-dihydrochalcone, magnesium stearate, colloidal anhydrous silica. what velphoro looks like and contents of the pack the chewable tablets are brown, circular, and embossed with pa500 on one side. the tablets have a 20 mm diameter and a thickness of 6.5 mm. the tablets are packed in high density polyethylene bottles with a child resistant polypropylene closure and a foil induction seal, or in child resistant aluminium blister. velphoro is available in packs containing 30 or 90 chewable tablets. multipacks are available for the blister packs with 90 chewable tablets (containing 3 individual packs of 30 × 1 chewable tablets each). not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'velphoro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 13, 'Score': 0.3120555579662323, 'Text': 'velphoro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 47, 'EndOffset': 51, 'Score': 0.8150963187217712, 'Text': 'iron', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 55, 'EndOffset': 79, 'Score': 0.9653513431549072, 'Text': 'sucroferric oxyhydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'polynuclear iron(iii)', 'Type': 'TREATMENT', 'BeginOffset': 107, 'EndOffset': 128}, {'Id': 4, 'BeginOffset': 129, 'EndOffset': 141, 'Score': 0.9428072571754456, 'Text': 'oxyhydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.25667843222618103, 'RelationshipScore': 0.7942814230918884, 'RelationshipType': 'FORM', 'Id': 6, 'BeginOffset': 171, 'EndOffset': 186, 'Text': 'chewable tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 143, 'EndOffset': 150, 'Score': 0.5312530398368835, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.25667843222618103, 'RelationshipScore': 0.9905897378921509, 'RelationshipType': 'FORM', 'Id': 6, 'BeginOffset': 171, 'EndOffset': 186, 'Text': 'chewable tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9678069353103638, 'RelationshipScore': 0.7652649879455566, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 196, 'EndOffset': 202, 'Text': '500 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7818684577941895, 'RelationshipScore': 0.9746211171150208, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 242, 'EndOffset': 248, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'starches', 'Type': 'TREATMENT', 'BeginOffset': 156, 'EndOffset': 164}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 196, 'EndOffset': 199}, {'Id': 8, 'BeginOffset': 203, 'EndOffset': 207, 'Score': 0.7727231979370117, 'Text': 'iron', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.25667843222618103, 'RelationshipScore': 0.7595678567886353, 'RelationshipType': 'FORM', 'Id': 6, 'BeginOffset': 171, 'EndOffset': 186, 'Text': 'chewable tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9678069353103638, 'RelationshipScore': 0.9983628392219543, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 196, 'EndOffset': 202, 'Text': '500 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7818684577941895, 'RelationshipScore': 0.9972297549247742, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 242, 'EndOffset': 248, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 9, 'BeginOffset': 211, 'EndOffset': 235, 'Score': 0.9836878776550293, 'Text': 'sucroferric oxyhydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9678069353103638, 'RelationshipScore': 0.7641745209693909, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 196, 'EndOffset': 202, 'Text': '500 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7818684577941895, 'RelationshipScore': 0.9999988079071045, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 242, 'EndOffset': 248, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.995807409286499, 'RelationshipScore': 0.9466602206230164, 'RelationshipType': 'DOSAGE', 'Id': 11, 'BeginOffset': 263, 'EndOffset': 269, 'Text': '750 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.7680658102035522, 'RelationshipScore': 0.9527841806411743, 'RelationshipType': 'DOSAGE', 'Id': 13, 'BeginOffset': 282, 'EndOffset': 288, 'Text': '700 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '750', 'Type': 'NUMBER', 'BeginOffset': 263, 'EndOffset': 266}, {'Id': 12, 'BeginOffset': 270, 'EndOffset': 277, 'Score': 0.8441392183303833, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.7818684577941895, 'RelationshipScore': 0.9986635446548462, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 242, 'EndOffset': 248, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.995807409286499, 'RelationshipScore': 0.9999986886978149, 'RelationshipType': 'DOSAGE', 'Id': 11, 'BeginOffset': 263, 'EndOffset': 269, 'Text': '750 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.7680658102035522, 'RelationshipScore': 0.9933735132217407, 'RelationshipType': 'DOSAGE', 'Id': 13, 'BeginOffset': 282, 'EndOffset': 288, 'Text': '700 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '700', 'Type': 'NUMBER', 'BeginOffset': 282, 'EndOffset': 285}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 311, 'EndOffset': 312}, {'Text': 'sucrose and starches', 'Type': 'TREATMENT', 'BeginOffset': 340, 'EndOffset': 360}, {'Text': 'woodberry flavour', 'Type': 'TREATMENT', 'BeginOffset': 388, 'EndOffset': 405}, {'Id': 14, 'BeginOffset': 407, 'EndOffset': 436, 'Score': 0.8976523876190186, 'Text': 'neohesperidin-dihydrochalcone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 438, 'EndOffset': 456, 'Score': 0.9945100545883179, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 458, 'EndOffset': 484, 'Score': 0.9665205478668213, 'Text': 'colloidal anhydrous silica', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 491, 'EndOffset': 499, 'Score': 0.4306926131248474, 'Text': 'velphoro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 634, 'EndOffset': 636}, {'Text': '6.5', 'Type': 'NUMBER', 'BeginOffset': 668, 'EndOffset': 671}, {'Text': 'the tablets', 'Type': 'TREATMENT', 'BeginOffset': 676, 'EndOffset': 687}, {'Text': 'high density polyethylene bottles', 'Type': 'TREATMENT', 'BeginOffset': 702, 'EndOffset': 735}, {'Text': 'a child resistant polypropylene closure', 'Type': 'TREATMENT', 'BeginOffset': 741, 'EndOffset': 780}, {'Text': 'a foil induction seal', 'Type': 'TREATMENT', 'BeginOffset': 785, 'EndOffset': 806}, {'Text': 'child resistant aluminium blister', 'Type': 'PROBLEM', 'BeginOffset': 814, 'EndOffset': 847}, {'Id': 18, 'BeginOffset': 849, 'EndOffset': 857, 'Score': 0.7452182173728943, 'Text': 'velphoro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.4316171705722809, 'RelationshipScore': 0.999841570854187, 'RelationshipType': 'FORM', 'Id': 19, 'BeginOffset': 909, 'EndOffset': 916, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 891, 'EndOffset': 893}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 897, 'EndOffset': 899}, {'Id': 20, 'BeginOffset': 918, 'EndOffset': 928, 'Score': 0.38372671604156494, 'Text': 'multipacks', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.4316171705722809, 'RelationshipScore': 0.996185839176178, 'RelationshipType': 'FORM', 'Id': 19, 'BeginOffset': 909, 'EndOffset': 916, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the blister packs', 'Type': 'TREATMENT', 'BeginOffset': 947, 'EndOffset': 964}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 970, 'EndOffset': 972}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 1002, 'EndOffset': 1003}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 1024, 'EndOffset': 1026}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1029, 'EndOffset': 1030}]}

92375E51FA395F8F8CBDC47C7D2FFD9B

https://www.ema.europa.eu/documents/product-information/aprovel-epar-product-information_en.pdf

Aprovel

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Aprovel 75 mg tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 75 mg of irbesartan. Excipient with known effect: 15.37 mg of lactose monohydrate per tablet. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablet. White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2771 engraved on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aprovel is indicated in adults for the treatment of essential hypertension. It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 and 5.1). 4.2 Posology and method of administration Posology The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel (see section 4.5). In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). Special Populations Renal impairment 3 No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). Hepatic impairment No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment. Older people Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for older people. Paediatric population The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. Method of Administration For oral use. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Second and third trimesters of pregnancy (see sections 4.4 and 4.6). The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). 4.4 Special warnings and precautions for use Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor antagonists. Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel in patients with a recent kidney transplantation. Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 4 aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see section 4.5). Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Primary aldosteronism: patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended. General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke. As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1). Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2). Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Diuretics and other antihypertensive agents: other antihypertensive agents may increase the hypotensive effects of irbesartan; however Aprovel has been safely administered with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Aprovel (see section 4.4). Aliskiren-containing products or ACE-inhibitors: clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, 5 angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4). Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter. Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan. 4.6 Fertility, pregnancy and lactation Pregnancy The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 6 Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4). Breast-feeding Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. It is unknown whether irbesartan or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk (for details see 5.3). Fertility Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment. 4.8 Undesirable effects In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment. In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in excess of placebo. The following table presents the adverse drug reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions additionally reported from post-marketing experience are also listed. These adverse reactions are derived from spontaneous reports. 7 Blood and lymphatic system disorders Not known: thrombocytopenia Immune system disorders Not known: hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, anaphylactic shock Metabolism and nutrition disorders Not known: hyperkalaemia Nervous system disorders Common: dizziness, orthostatic dizziness* Not known: vertigo, headache Ear and labyrinth disorder Not known: tinnitus Cardiac disorders Uncommon: tachycardia Vascular disorders Common: orthostatic hypotension* Uncommon: flushing Respiratory, thoracic and mediastinal disorders Uncommon: cough Gastrointestinal disorders Common: nausea/vomiting Uncommon: diarrhoea, dyspepsia/heartburn Not known: dysgeusia Hepatobiliary disorders Uncommon: jaundice Not known: hepatitis, abnormal liver function Skin and subcutaneous tissue disorders Not known: leukocytoclastic vasculitis Musculoskeletal and connective tissue disorders Common: musculoskeletal pain* Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps 8 Renal and urinary disorders Not known: impaired renal function including cases of renal failure in patients at risk (see section 4.4) Reproductive system and breast disorders Uncommon: sexual dysfunction General disorders and administration site conditions Common: fatigue Uncommon: chest pain Investigations Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group and 26.3% of the patients in the placebo group. Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects. None of these increases were associated with identifiable clinical musculoskeletal events. In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been observed. Paediatric population In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdose with Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 9 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Angiotensin-II antagonists, plain. ATC code: C09C A04. Mechanism of action Irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity. Clinical efficacy Hypertension Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice daily dosing on the same total dose. The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed. The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic). The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients. There is no clinically important effect on serum uric acid or urinary uric acid secretion. Paediatric population Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the 10 three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2). Hypertension and type 2 diabetes with renal disease The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all- cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed. Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo- based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified. The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of 11 treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group. 5.2 Pharmacokinetic properties Absorption After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan. Distribution Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53-93 litres. Biotransformation Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Linearity/non-linearity Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157- 12 176 and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18-40 years). However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people. Elimination Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Paediatric population The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing. Renal impairment In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. Hepatic impairment In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment. 5.3 Preclinical safety data There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. There was no evidence of mutagenicity, clastogenicity or carcinogenicity. Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live 13 foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. Irbesartan is excreted in the milk of lactating rats. Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline cellulose Croscarmellose sodium Lactose monohydrate Magnesium stearate Colloidal hydrated silica Pregelatinised maize starch Poloxamer 188 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container Cartons of 14 tablets in PVC/PVDC/Aluminium blisters. Cartons of 28 tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 tablets in PVC/PVDC/Aluminium blisters. Cartons of 98 tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 x 1 tablet in PVC/PVDC/Aluminium perforated unit dose blisters. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 14 8. MARKETING AUTHORISATION NUMBERS EU/1/97/046/001-003 EU/1/97/046/010 EU/1/97/046/013 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 27 August 1997 Date of latest renewal: 27 August 2007 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 15 1. NAME OF THE MEDICINAL PRODUCT Aprovel 150 mg tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 150 mg of irbesartan. Excipient with known effect: 30.75 mg of lactose monohydrate per tablet. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablet. White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2772 engraved on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aprovel is indicated in adults for the treatment of essential hypertension. It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 and 5.1). 4.2 Posology and method of administration Posology The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel (see section 4.5). In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). Special Populations Renal impairment 16 No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). Hepatic impairment No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment. Older people Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for older people. Paediatric population The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. Method of Administration For oral use. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Second and third trimesters of pregnancy (see sections 4.4 and 4.6). The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). 4.4 Special warnings and precautions for use Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor antagonists. Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel in patients with a recent kidney transplantation. Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 17 blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see section 4.5). Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Primary aldosteronism: patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended. General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke. As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1). Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2). Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Diuretics and other antihypertensive agents: other antihypertensive agents may increase the hypotensive effects of irbesartan; however Aprovel has been safely administered with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Aprovel (see section 4.4). 18 Aliskiren-containing products or ACE-inhibitors: clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4). Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter. Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan. 4.6 Fertility, pregnancy and lactation Pregnancy The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started. 19 Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4). Breast-feeding Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. It is unknown whether irbesartan or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk (for details see 5.3). Fertility Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment. 4.8 Undesirable effects In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment. In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in excess of placebo. The following table presents the adverse drug reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions additionally reported from post-marketing experience are also listed. These adverse reactions are derived from spontaneous reports. 20 Blood and lymphatic system disorders Not known: thrombocytopenia Immune system disorders Not known: hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, anaphylactic shock Metabolism and nutrition disorders Not known: hyperkalaemia Nervous system disorders Common: dizziness, orthostatic dizziness* Not known: vertigo, headache Ear and labyrinth disorder Not known: tinnitus Cardiac disorders Uncommon: tachycardia Vascular disorders Common: orthostatic hypotension* Uncommon: flushing Respiratory, thoracic and mediastinal disorders Uncommon: cough Gastrointestinal disorders Common: nausea/vomiting Uncommon: diarrhoea, dyspepsia/heartburn Not known: dysgeusia Hepatobiliary disorders Uncommon: jaundice Not known: hepatitis, abnormal liver function Skin and subcutaneous tissue disorders Not known: leukocytoclastic vasculitis Musculoskeletal and connective tissue disorders Common: musculoskeletal pain* Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps 21 Renal and urinary disorders Not known: impaired renal function including cases of renal failure in patients at risk (see section 4.4) Reproductive system and breast disorders Uncommon: sexual dysfunction General disorders and administration site conditions Common: fatigue Uncommon: chest pain Investigations Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group and 26.3% of the patients in the placebo group. Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects. None of these increases were associated with identifiable clinical musculoskeletal events. In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been observed. Paediatric population In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdose with Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 22 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Angiotensin-II antagonists, plain. ATC code: C09C A04. Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity. Clinical efficacy Hypertension Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice daily dosing on the same total dose. The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed. The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic). The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients. There is no clinically important effect on serum uric acid or urinary uric acid secretion. Paediatric population Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough 23 seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2). Hypertension and type 2 diabetes with renal disease The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all- cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed. Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo- based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified. The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 24 Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group. 5.2 Pharmacokinetic properties Absorption After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan. Distribution Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53-93 litres. Biotransformation Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Linearity/non-linearity Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157- 176 and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily 25 dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18-40 years). However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people. Elimination Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Paediatric population The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing. Renal impairment In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. Hepatic impairment In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment. 5.3 Preclinical safety data There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. There was no evidence of mutagenicity, clastogenicity or carcinogenicity. Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. Irbesartan is excreted in the milk of lactating rats. 26 Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline cellulose Croscarmellose sodium Lactose monohydrate Magnesium stearate Colloidal hydrated silica Pregelatinised maize starch Poloxamer 188 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container Cartons of 14 tablets in PVC/PVDC/Aluminium blisters. Cartons of 28 tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 tablets in PVC/PVDC/Aluminium blisters. Cartons of 98 tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 x 1 tablet in PVC/PVDC/Aluminium perforated unit dose blisters. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 27 8. MARKETING AUTHORISATION NUMBERS EU/1/97/046/004-006 EU/1/97/046/011 EU/1/97/046/014 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 27 August 1997 Date of latest renewal: 27 August 2007 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 28 1. NAME OF THE MEDICINAL PRODUCT Aprovel 300 mg tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 300 mg of irbesartan. Excipient with known effect: 61.50 mg of lactose monohydrate per tablet. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablet. White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2773 engraved on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aprovel is indicated in adults for the treatment of essential hypertension. It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 and 5.1). 4.2 Posology and method of administration Posology The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel (see section 4.5). In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). Special Populations Renal impairment 29 No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). Hepatic impairment No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment. Older people Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for older people. Paediatric population The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. Method of Administration For oral use. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Second and third trimesters of pregnancy (see sections 4.4 and 4.6). The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). 4.4 Special warnings and precautions for use Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor antagonists. Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel in patients with a recent kidney transplantation. Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is 30 considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see section 4.5). Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Primary aldosteronism: patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended. General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke. As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1). Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2). Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Diuretics and other antihypertensive agents: other antihypertensive agents may increase the hypotensive effects of irbesartan; however Aprovel has been safely administered with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Aprovel (see section 4.4). Aliskiren-containing products or ACE-inhibitors: clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events 31 such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4). Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter. Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan. 4.6 Fertility, pregnancy and lactation Pregnancy The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 32 Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4). Breast-feeding Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. It is unknown whether irbesartan or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk (for details see 5.3). Fertility Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment. 4.8 Undesirable effects In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment. In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in excess of placebo. The following table presents the adverse drug reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions additionally reported from post-marketing experience are also listed. These adverse reactions are derived from spontaneous reports. 33 Blood and lymphatic system disorders Not known: thrombocytopenia Immune system disorders Not known: hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, anaphylactic shock Metabolism and nutrition disorders Not known: hyperkalaemia Nervous system disorders Common: dizziness, orthostatic dizziness* Not known: vertigo, headache Ear and labyrinth disorder Not known: tinnitus Cardiac disorders Uncommon: tachycardia Vascular disorders Common: orthostatic hypotension* Uncommon: flushing Respiratory, thoracic and mediastinal disorders Uncommon: cough Gastrointestinal disorders Common: nausea/vomiting Uncommon: diarrhoea, dyspepsia/heartburn Not known: dysgeusia Hepatobiliary disorders: Uncommon: jaundice Not known: hepatitis, abnormal liver function Skin and subcutaneous tissue disorders Not known: leukocytoclastic vasculitis Musculoskeletal and connective tissue disorders Common: musculoskeletal pain* Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps 34 Renal and urinary disorders Not known: impaired renal function including cases of renal failure in patients at risk (see section 4.4) Reproductive system and breast disorders Uncommon: sexual dysfunction General disorders and administration site conditions Common: fatigue Uncommon: chest pain Investigations Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group and 26.3% of the patients in the placebo group. Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects. None of these increases were associated with identifiable clinical musculoskeletal events. In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been observed. Paediatric population In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdose with Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 35 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Angiotensin-II antagonists, plain. ATC code: C09C A04. Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity. Clinical efficacy Hypertension Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice daily dosing on the same total dose. The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed. The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic). The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients. There is no clinically important effect on serum uric acid or urinary uric acid secretion. Paediatric population Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough 36 seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2). Hypertension and type 2 diabetes with renal disease The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all- cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed. Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo- based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified. The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 37 Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group. 5.2 Pharmacokinetic properties Absorption After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan. Distribution Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53-93 litres. Biotransformation Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Linearity/non-linearity Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157- 176 and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. 38 Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18-40 years). However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people. Elimination Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Paediatric population The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing. Renal impairment In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. Hepatic impairment In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment. 5.3 Preclinical safety data There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. There was no evidence of mutagenicity, clastogenicity or carcinogenicity. Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 39 Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. Irbesartan is excreted in the milk of lactating rats. Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline cellulose Croscarmellose sodium Lactose monohydrate Magnesium stearate Colloidal hydrated silica Pregelatinised maize starch Poloxamer 188 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container Cartons of 14 tablets in PVC/PVDC/Aluminium blisters. Cartons of 28 tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 tablets in PVC/PVDC/Aluminium blisters. Cartons of 98 tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 x 1 tablet in PVC/PVDC/Aluminium perforated unit dose blisters. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 40 8. MARKETING AUTHORISATION NUMBERS EU/1/97/046/007-009 EU/1/97/046/012 EU/1/97/046/015 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 27 August 1997 Date of latest renewal: 27 August 2007 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 41 1. NAME OF THE MEDICINAL PRODUCT Aprovel 75 mg film-coated tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 75 mg of irbesartan. Excipient with known effect: 25.50 mg of lactose monohydrate per film-coated tablet. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2871 engraved on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aprovel is indicated in adults for the treatment of essential hypertension. It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 and 5.1). 4.2 Posology and method of administration Posology The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel (see section 4.5). In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). Special Populations Renal impairment 42 No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). Hepatic impairment No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment. Older people Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for older people. Paediatric population The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made. Method of Administration For oral use. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Second and third trimesters of pregnancy (see sections 4.4 and 4.6). The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). 4.4 Special warnings and precautions for use Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor antagonists. Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel in patients with a recent kidney transplantation. Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 43 aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see section 4.5). Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Primary aldosteronism: patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended. General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke. As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1). Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2). Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Diuretics and other antihypertensive agents: other antihypertensive agents may increase the hypotensive effects of irbesartan; however Aprovel has been safely administered with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Aprovel (see section 4.4). Aliskiren-containing products and ACE-inhibitors: clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events 44 such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4). Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter. Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan. 4.6 Fertility, pregnancy and lactation Pregnancy The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 45 Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4). Breast-feeding Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. It is unknown whether irbesartan or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk (for details see 5.3). Fertility Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment. 4.8 Undesirable effects In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment. In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in excess of placebo. The following table presents the adverse drug reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions additionally reported from post-marketing experience are also listed. These adverse reactions are derived from spontaneous reports. 46 Blood and lymphatic system disorders Not known: thrombocytopenia Immune system disorders Not known: hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, anaphylactic shock Metabolism and nutrition disorders Not known: hyperkalaemia Nervous system disorders Common: dizziness, orthostatic dizziness* Not known: vertigo, headache Ear and labyrinth disorder Not known: tinnitus Cardiac disorders: Uncommon: tachycardia Vascular disorders Common: orthostatic hypotension* Uncommon: flushing Respiratory, thoracic and mediastinal disorders Uncommon: cough Gastrointestinal disorders Common: nausea/vomiting Uncommon: diarrhoea, dyspepsia/heartburn Not known: dysgeusia Hepatobiliary disorders Uncommon: jaundice Not known: hepatitis, abnormal liver function Skin and subcutaneous tissue disorders Not known: leukocytoclastic vasculitis Musculoskeletal and connective tissue disorders Common: musculoskeletal pain* Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps 47 Renal and urinary disorders Not known: impaired renal function including cases of renal failure in patients at risk (see section 4.4) Reproductive system and breast disorders Uncommon: sexual dysfunction General disorders and administration site conditions Common: fatigue Uncommon: chest pain Investigations Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group and 26.3% of the patients in the placebo group. Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects. None of these increases were associated with identifiable clinical musculoskeletal events. In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been observed. Paediatric population In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdose with Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 48 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Angiotensin-II antagonists, plain. ATC code: C09C A04. Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity. Clinical efficacy Hypertension Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice daily dosing on the same total dose. The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed. The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic). The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients. There is no clinically important effect on serum uric acid or urinary uric acid secretion. Paediatric population Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough 49 seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2). Hypertension and type 2 diabetes with renal disease The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all- cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed. Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo- based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified. The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 50 Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group. 5.2 Pharmacokinetic properties Absorption After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan. Distribution Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53 - 93 litres. Biotransformatin Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Linearity/non-linearity Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5 - 2 hours after oral administration. The total body and renal clearance are 157 - 176 and 3 - 3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11 - 15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing 51 regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18 - 40 years). However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people. Elimination Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Paediatric population The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing. Renal impairment In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. Hepatic impairment In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment. 5.3 Preclinical safety data There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. There was no evidence of mutagenicity, clastogenicity or carcinogenicity. Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 52 Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. Irbesartan is excreted in the milk of lactating rats. Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Lactose monohydrate Microcrystalline cellulose Croscarmellose sodium Hypromellose Silicon dioxide Magnesium stearate. Film-coating: Lactose monohydrate Hypromellose Titanium dioxide Macrogol 3000 Carnauba wax. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 x 1 film-coated tablet in PVC/PVDC/Aluminium perforated unit dose blisters. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 53 7. MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 8. MARKETING AUTHORISATION NUMBERS EU/1/97/046/016-020 EU/1/97/046/031 EU/1/97/046/034 EU/1/97/046/037 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 27 August 1997 Date of latest renewal: 27 August 2007 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 54 1. NAME OF THE MEDICINAL PRODUCT Aprovel 150 mg film-coated tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 150 mg of irbesartan. Excipient with known effect: 51.00 mg of lactose monohydrate per film-coated tablet. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2872 engraved on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aprovel is indicated in adults for the treatment of essential hypertension. It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 and 5.1). 4.2 Posology and method of administration Posology The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel (see section 4.5). In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). Special Populations Renal impairment 55 No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). Hepatic impairment No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment. Older people Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for older people. Paediatric population The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made. Method of Administration For oral use. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Second and third trimesters of pregnancy (see sections 4.4 and 4.6). The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). 4.4 Special warnings and precautions for use Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor antagonists. Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel in patients with a recent kidney transplantation. Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 56 blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see section 4.5). Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Primary aldosteronism: patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended. General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke. As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1). Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2). Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine 4.5 Interaction with other medicinal products and other forms of interaction Diuretics and other antihypertensive agents: other antihypertensive agents may increase the hypotensive effects of irbesartan; however Aprovel has been safely administered with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Aprovel (see section 4.4). 57 Aliskiren-containing products and ACE-inhibitors: clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4). Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter. Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan. 4.6 Fertility, pregnancy and lactation Pregnancy The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started. 58 Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4). Breast-feeding Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. It is unknown whether irbesartan or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk (for details see 5.3). Fertility Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment. 4.8 Undesirable effects In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment. In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in excess of placebo. The following table presents the adverse drug reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions additionally reported from post-marketing experience are also listed. These adverse reactions are derived from spontaneous reports. 59 Blood and lymphatic system disorders Not known: thrombocytopenia Immune system disorders Not known: hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, anaphylactic shock Metabolism and nutrition disorders Not known: hyperkalaemia Nervous system disorders Common: dizziness, orthostatic dizziness* Not known: vertigo, headache Ear and labyrinth disorder Not known: tinnitus Cardiac disorders Uncommon: tachycardia Vascular disorders Common: orthostatic hypotension* Uncommon: flushing Respiratory, thoracic and mediastinal disorders Uncommon: cough Gastrointestinal disorders Common: nausea/vomiting Uncommon: diarrhoea, dyspepsia/heartburn Not known: dysgeusia Hepatobiliary disorders Uncommon: jaundice Not known: hepatitis, abnormal liver function Skin and subcutaneous tissue disorders Not known: leukocytoclastic vasculitis Musculoskeletal and connective tissue disorders Common: musculoskeletal pain* Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps 60 Renal and urinary disorders Not known: impaired renal function including cases of renal failure in patients at risk (see section 4.4) Reproductive system and breast disorders Uncommon: sexual dysfunction General disorders and administration site conditions Common: fatigue Uncommon: chest pain Investigations Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group and 26.3% of the patients in the placebo group. Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects. None of these increases were associated with identifiable clinical musculoskeletal events. In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been observed. Paediatric population In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdose with Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 61 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Angiotensin-II antagonists, plain. ATC code: C09C A04. Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity. Clinical efficacy Hypertension Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice daily dosing on the same total dose. The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed. The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic). The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients. There is no clinically important effect on serum uric acid or urinary uric acid secretion. Paediatric population Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough 62 seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2). Hypertension and type 2 diabetes with renal disease The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all- cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed. Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo- based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified. The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 63 Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group. 5.2 Pharmacokinetic properties Absorption After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan. Distribution Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53 - 93 litres. Biotransformation Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Linearity/non-linearity Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5 - 2 hours after oral administration. The total body and renal clearance are 157 - 176 and 3 - 3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11 - 15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily 64 dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18 - 40 years). However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people. Elimination Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Paediatric population The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing. Renal impairment In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. Hepatic impairment In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment. 5.3 Preclinical safety data There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. There was no evidence of mutagenicity, clastogenicity or carcinogenicity. Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. Irbesartan is excreted in the milk of lactating rats. 65 Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Lactose monohydrate Microcrystalline cellulose Croscarmellose sodium Hypromellose Silicon dioxide Magnesium stearate. Film-coating: Lactose monohydrate Hypromellose Titanium dioxide Macrogol 3000 Carnauba wax. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 x 1 film-coated tablet in PVC/PVDC/Aluminium perforated unit dose blisters. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 66 7. MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 8. MARKETING AUTHORISATION NUMBERS EU/1/97/046/021-025 EU/1/97/046/032 EU/1/97/046/035 EU/1/97/046/038 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 27 August 1997 Date of latest renewal: 27 August 2007 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 67 1. NAME OF THE MEDICINAL PRODUCT Aprovel 300 mg film-coated tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 300 mg of irbesartan. Excipient with known effect: 102.00 mg of lactose monohydrate per film-coated tablet. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2873 engraved on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aprovel is indicated in adults for the treatment of essential hypertension. It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 and 5.1). 4.2 Posology and method of administration Posology The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel (see section 4.5). In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). Special Populations Renal impairment No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). 68 Hepatic impairment No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment. Older people Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for older people. Paediatric population The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made. Method of Administration For oral use. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Second and third trimesters of pregnancy (see sections 4.4 and 4.6). The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). 4.4 Special warnings and precautions for use Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor antagonists. Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel in patients with a recent kidney transplantation. Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to 69 frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see section 4.5). Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Primary aldosteronism: patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended. General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke. As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1). Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2). Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine 4.5 Interaction with other medicinal products and other forms of interaction Diuretics and other antihypertensive agents: other antihypertensive agents may increase the hypotensive effects of irbesartan; however Aprovel has been safely administered with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Aprovel (see section 4.4). Aliskiren-containing products and ACE-inhibitors: clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events 70 such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4). Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter. Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan. 4.6 Fertility, pregnancy and lactation Pregnancy The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 71 Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4). Breast-feeding Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. It is unknown whether irbesartan or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk (for details see 5.3). Fertility Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment. 4.8 Undesirable effects In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment. In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in excess of placebo. The following table presents the adverse drug reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions additionally reported from post–marketing experience are also listed. These adverse reactions are derived from spontaneous reports. 72 Blood and lymphatic system disorders Not known: thrombocytopenia Immune system disorders Not known: hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, anaphylactic shock Metabolism and nutrition disorders Not known: hyperkalaemia Nervous system disorders Common: dizziness, orthostatic dizziness* Not known: vertigo, headache Ear and labyrinth disorder Not known: tinnitus Cardiac disorders Uncommon: tachycardia Vascular disorders Common: orthostatic hypotension* Uncommon: flushing Respiratory, thoracic and mediastinal disorders Uncommon: cough Gastrointestinal disorders Common: nausea/vomiting Uncommon: diarrhoea, dyspepsia/heartburn Not known: dysgeusia Hepatobiliary disorders Uncommon: jaundice Not known: hepatitis, abnormal liver function Skin and subcutaneous tissue disorders Not known: leukocytoclastic vasculitis Musculoskeletal and connective tissue disorders Common: musculoskeletal pain* Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps 73 Renal and urinary disorders Not known: impaired renal function including cases of renal failure in patients at risk (see section 4.4) Reproductive system and breast disorders Uncommon: sexual dysfunction General disorders and administration site conditions Common: fatigue Uncommon: chest pain Investigations Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group and 26.3% of the patients in the placebo group. Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects. None of these increases were associated with identifiable clinical musculoskeletal events. In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been observed. Paediatric population In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdose with Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 74 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Angiotensin-II antagonists, plain. ATC code: C09C A04. Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity. Clinical efficacy Hypertension Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice daily dosing on the same total dose. The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed. The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic). The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients. There is no clinically important effect on serum uric acid or urinary uric acid secretion. Paediatric population Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high 75 dose). No significant difference was apparent between these doses. Adjusted mean change of trough seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2). Hypertension and type 2 diabetes with renal disease The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all- cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed. Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo- based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified. The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of treatment. The slowing in the progression to clinical proteinuria was evident as early as three months 76 and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group. 5.2 Pharmacokinetic properties AbsorptionAfter oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan. Distribution Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53 - 93 litres. Biotransformation Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Linearity/non-linearity Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5 - 2 hours after oral administration. The total body and renal clearance are 157 - 176 and 3 - 3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11 - 15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing 77 regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18 - 40 years). However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people. Elimination Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Paediatric population The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing. Renal impairment In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. Hepatic impairment In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment. 5.3 Preclinical safety data There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. There was no evidence of mutagenicity, clastogenicity or carcinogenicity. Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 78 Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. Irbesartan is excreted in the milk of lactating rats. Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Lactose monohydrate Microcrystalline cellulose Croscarmellose sodium Hypromellose Silicon dioxide Magnesium stearate. Film-coating: Lactose monohydrate Hypromellose Titanium dioxide Macrogol 3000 Carnauba wax. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. Cartons of 56 x 1 film-coated tablet in PVC/PVDC/Aluminium perforated unit dose blisters. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 79 7. MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 8. MARKETING AUTHORISATION NUMBERS EU/1/97/046/026-030 EU/1/97/046/033 EU/1/97/046/036 EU/1/97/046/039 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 27 August 1997 Date of latest renewal: 27 August 2007 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 80 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 81 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Sanofi Winthrop Industrie 1 rue de la Vierge Ambarès & Lagrave F-33565 Carbon Blanc Cedex France Sanofi Winthrop Industrie 30-36 Avenue Gustave Eiffel, BP 7166 F-37071 Tours Cedex 2 France Chinoin Private Co. Ltd. Lévai u.5. 2112 Veresegyhaz Hungary SANOFI-AVENTIS, S.A. Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 17404 Riells i Viabrea (Girona) - Spain The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) Not applicable. 82 ANNEX III LABELLING AND PACKAGE LEAFLET 83 A. LABELLING 84 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aprovel 75 mg tablets irbesartan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains: irbesartan 75 mg 3. LIST OF EXCIPIENTS Excipients: also contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 14 tablets 28 tablets 56 tablets 56 x 1 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 85 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/97/046/010 - 14 tablets EU/1/97/046/001 - 28 tablets EU/1/97/046/002 - 56 tablets EU/1/97/046/013 - 56 x 1 tablets EU/1/97/046/003 - 98 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aprovel 75 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 86 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT Aprovel 75 mg tablets irbesartan 2. NAME OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 14 - 28 - 56 - 98 tablets: Mon Tue Wed Thu Fri Sat Sun 56 x 1 tablets: 87 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aprovel 150 mg tablets irbesartan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains: irbesartan 150 mg 3. LIST OF EXCIPIENTS Excipients: also contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 14 tablets 28 tablets 56 tablets 56 x 1 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 88 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/97/046/011 - 14 tablets EU/1/97/046/004 - 28 tablets EU/1/97/046/005 - 56 tablets EU/1/97/046/014 - 56 x 1 tablets EU/1/97/046/006 - 98 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aprovel 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 89 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT Aprovel 150 mg tablets irbesartan 2. NAME OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 14 - 28 - 56 - 98 tablets: Mon Tue Wed Thu Fri Sat Sun 56 x 1 tablets: 90 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aprovel 300 mg tablets irbesartan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains: irbesartan 300 mg 3. LIST OF EXCIPIENTS Excipients: also contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 14 tablets 28 tablets 56 tablets 56 x 1 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 91 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/97/046/012 - 14 tablets EU/1/97/046/007 - 28 tablets EU/1/97/046/008 - 56 tablets EU/1/97/046/015 - 56 x 1 tablets EU/1/97/046/009 - 98 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aprovel 300 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 92 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT Aprovel 300 mg tablets irbesartan 2. NAME OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 14 - 28 - 56 - 98 tablets: Mon Tue Wed Thu Fri Sat Sun 56 x 1 tablets: 93 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aprovel 75 mg film-coated tablets irbesartan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains: irbesartan 75 mg 3. LIST OF EXCIPIENTS Excipients: also contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 14 tablets 28 tablets 30 tablets 56 tablets 56 x 1 tablets 84 tablets 90 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 94 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/97/046/016 - 14 tablets EU/1/97/046/017 - 28 tablets EU/1/97/046/034 - 30 tablets EU/1/97/046/018 - 56 tablets EU/1/97/046/019 - 56 x 1 tablets EU/1/97/046/031 - 84 tablets EU/1/97/046/037 - 90 tablets EU/1/97/046/020 - 98 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aprovel 75 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 95 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT Aprovel 75 mg tablets irbesartan 2. NAME OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 14 - 28 - 56 - 84 - 98 tablets: Mon Tue Wed Thu Fri Sat Sun 30 - 56 x 1 - 90 tablets: 96 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aprovel 150 mg film-coated tablets irbesartan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains: irbesartan 150 mg 3. LIST OF EXCIPIENTS Excipients: also contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 14 tablets 28 tablets 30 tablets 56 tablets 56 x 1 tablets 84 tablets 90 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 97 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/97/046/021 - 14 tablets EU/1/97/046/022 - 28 tablets EU/1/97/046/035 - 30 tablets EU/1/97/046/023 - 56 tablets EU/1/97/046/024 - 56 x 1 tablets EU/1/97/046/032 - 84 tablets EU/1/97/046/038 - 90 tablets EU/1/97/046/025 - 98 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aprovel 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 98 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT Aprovel 150 mg tablets irbesartan 2. NAME OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 14 - 28 - 56 - 84 - 98 tablets: Mon Tue Wed Thu Fri Sat Sun 30 - 56 x 1 - 90 tablets: 99 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aprovel 300 mg film-coated tablets irbesartan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains: irbesartan 300 mg 3. LIST OF EXCIPIENTS Excipients: also contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 14 tablets 28 tablets 30 tablets 56 tablets 56 x 1 tablets 84 tablets 90 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 100 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/97/046/026 - 14 tablets EU/1/97/046/027 - 28 tablets EU/1/97/046/036 - 30 tablets EU/1/97/046/028 - 56 tablets EU/1/97/046/029 - 56 x 1 tablets EU/1/97/046/033 - 84 tablets EU/1/97/046/039 - 90 tablets EU/1/97/046/030 - 98 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aprovel 300 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: 101 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT Aprovel 300 mg tablets irbesartan 2. NAME OF THE MARKETING AUTHORISATION HOLDER sanofi-aventis groupe 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 14 - 28 - 56 - 84 - 98 tablets: Mon Tue Wed Thu Fri Sat Sun 30 - 56 x 1 - 90 tablets: 102 B. PACKAGE LEAFLET 103 Package leaflet: Information for the user Aprovel 75 mg tablets irbesartan Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor or pharmacist.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aprovel is and what it is used for 2. What you need to know before you take Aprovel 3. How to take Aprovel 4. Possible side effects 5. How to store Aprovel 6. Contents of the pack and other information 1. What Aprovel is and what it is used for Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the decrease of kidney function in patients with high blood pressure and type 2 diabetes. Aprovel is used in adult patients  to treat high blood pressure (essential hypertension)  to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory evidence of impaired kidney function. 2. What you need to know before you take Aprovel Do not take Aprovel  if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6)  if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy – see pregnancy section)  if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warning and precautions Talk to your doctor before taking Aprovel and if any of the following apply to you:  if you get excessive vomiting or diarrhoea  if you suffer from kidney problems  if you suffer from heart problems  if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform regular blood tests, especially for measuring blood potassium levels in case of poor kidney function  if you are going to have an operation (surgery) or be given anaesthetics  if you are taking any of the following medicines used to treat high blood pressure: 104 o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-related kidney problems. o aliskiren. Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading “Do not take Aprovel”. You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section). Children and adolescents This medicinal product should not be used in children and adolescents because the safety and efficacy have not yet been fully established. Other medicines and Aprovel Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Aprovel” and “Warnings and precautions”). You may need to have blood checks if you take:  potassium supplements  salt substitutes containing potassium  potassium-sparing medicines (such as certain diuretics)  medicines containing lithium If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan may be reduced. Aprovel with food and drink Aprovel can be taken with or without food. Pregnancy and breast-feeding Pregnancy You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Aprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy. Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely. Driving and using machines Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If you experience these, talk to your doctor before attempting to drive or use machines. Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal product. 105 3. How to take Aprovel Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Method of administration Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). You can take Aprovel with or without food. Try to take your daily dose at about the same time each day. It is important that you continue to take Aprovel until your doctor tells you otherwise.  Patients with high blood pressure The usual dose is 150 mg once a day (two tablets a day). The dose may later be increased to 300 mg (four tablets a day) once daily depending on blood pressure response.  Patients with high blood pressure and type 2 diabetes with kidney disease In patients with high blood pressure and type 2 diabetes, 300 mg (four tablets a day) once daily is the preferred maintenance dose for the treatment of associated kidney disease. The doctor may advise a lower dose, especially when starting treatment in certain patients such as those on haemodialysis, or those over the age of 75 years. The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. Use in children and adolescents Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, contact your doctor immediately. If you take more Aprovel than you should If you accidentally take too many tablets, contact your doctor immediately. If you forget to take Aprovel If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these effects may be serious and may require medical attention. As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any of these symptoms or get short of breath, stop taking Aprovel and contact your doctor immediately. The frequency of the side effects listed below is defined using the following convention: Very common: may affect more than 1 in 10 people Common: may affect up to 1 in 10 people Uncommon: may affect up to 1 in 100 people Side effects reported in clinical studies for patients treated with Aprovel were:  Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 106  Common (may affect up to 1 in 10 people): dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from a lying or sitting position, low blood pressure when getting up from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin) were also reported.  Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, increased blood potassium levels, impaired kidney function, inflammation of small blood vessels mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of the eyes) have also been reported. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aprovel Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. The expiry date refers to the last day of that month. Do not store above 30°C. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aprovel contains  The active substance is irbesartan. Each tablet of Aprovel 75 mg contains 75 mg irbesartan.  The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, and poloxamer 188. Please see section 2 “Aprovel contains lactose”. What Aprovel looks like and contents of the pack Aprovel 75 mg tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2771 engraved on the other side. Aprovel 75 mg tablets are supplied in blister packs of 14, 28, 56 or 98 tablets. Unidose blister packs of 56 x 1 tablet for delivery in hospitals are also available. Not all pack sizes may be marketed. 107 Marketing Authorisation Holder: sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France Manufacturer: SANOFI WINTHROP INDUSTRIE 1, rue de la Vierge Ambarès & Lagrave F-33565 Carbon Blanc Cedex - France SANOFI WINTHROP INDUSTRIE 30-36 Avenue Gustave Eiffel, BP 7166 F-37071 Tours Cedex 2 – France For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 Lietuva UAB sanofi-aventis Lietuva Tel: +370 5 2755224 България Sanofi Bulgaria EOOD Тел.: +359 (0)2 970 53 00 Luxembourg/Luxemburg Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) Česká republika sanofi-aventis, s.r.o. Tel: +420 233 086 111 Magyarország SANOFI-AVENTIS Zrt. Tel.: +36 1 505 0050 Danmark Sanofi A/S Tlf: +45 45 16 70 00 Malta Sanofi S.p.A. Tel: +39 02 39394275 Deutschland Sanofi-Aventis Deutschland GmbH Tel: 0800 52 52 010 Tel. aus dem Ausland: +49 69 305 21 131 Nederland sanofi-aventis Netherlands B.V. Tel: +31 20 245 4000 Eesti sanofi-aventis Estonia OÜ Tel: +372 627 34 88 Norge sanofi-aventis Norge AS Tlf: +47 67 10 71 00 Ελλάδα sanofi-aventis AEBE Τηλ: +30 210 900 16 00 Österreich sanofi-aventis GmbH Tel: +43 1 80 185 – 0 España sanofi-aventis, S.A. Tel: +34 93 485 94 00 Polska sanofi-aventis Sp. z o.o. Tel.: +48 22 280 00 00 France sanofi-aventis France Tél: 0 800 222 555 Appel depuis l’étranger: +33 1 57 63 23 23 Portugal Sanofi - Produtos Farmacêuticos, Lda Tel: +351 21 35 89 400 108 Hrvatska sanofi-aventis Croatia d.o.o. Tel: +385 1 600 34 00 România Sanofi Romania SRL Tel: +40 (0) 21 317 31 36 Ireland sanofi-aventis Ireland Ltd. T/A SANOFI Tel: +353 (0) 1 403 56 00 Slovenija sanofi-aventis d.o.o. Tel: +386 1 560 48 00 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. Tel: +421 2 33 100 100 Italia Sanofi S.p.A. Tel: 800 536389 Suomi/Finland Sanofi Oy Puh/Tel: +358 (0) 201 200 300 Κύπρος sanofi-aventis Cyprus Ltd. Τηλ: +357 22 871600 Sverige Sanofi AB Tel: +46 (0)8 634 50 00 Latvija sanofi-aventis Latvia SIA Tel: +371 67 33 24 51 United Kingdom Sanofi Tel: +44 (0) 845 372 7101 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/ 109 Package leaflet: Information for the user Aprovel 150 mg tablets irbesartan Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor or pharmacist.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aprovel is and what it is used for 2. What you need to know before you take Aprovel 3. How to take Aprovel 4. Possible side effects 5. How to store Aprovel 6. Contents of the pack and other information 1. What Aprovel is and what it is used for Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the decrease of kidney function in patients with high blood pressure and type 2 diabetes. Aprovel is used in adult patients  to treat high blood pressure (essential hypertension)  to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory evidence of impaired kidney function. 2. What you need to know before you take Aprovel Do not take Aprovel  if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6)  if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy – see pregnancy section)  if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warning and precautions Talk to your doctor before taking Aprovel and if any of the following apply to you:  if you get excessive vomiting or diarrhoea  if you suffer from kidney problems  if you suffer from heart problems  if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform regular blood tests, especially for measuring blood potassium levels in case of poor kidney function  if you are going to have an operation (surgery) or be given anaesthetics  if you are taking any of the following medicines used to treat high blood pressure: 110 o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-related kidney problems. o aliskiren Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading “Do not take Aprovel”. You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section). Children and adolescents This medicinal product should not be used in children and adolescents because the safety and efficacy have not yet been fully established. Other medicines and Aprovel Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Aprovel” and “Warnings and precautions”). You may need to have blood checks if you take:  potassium supplements  salt substitutes containing potassium  potassium-sparing medicines (such as certain diuretics)  medicines containing lithium If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan may be reduced. Aprovel with food and drink Aprovel can be taken with or without food. Pregnancy and breast-feeding Pregnancy You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Aprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy. Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely. Driving and using machines Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If you experience these, talk to your doctor before attempting to drive or use machines. Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal product. 111 3. How to take Aprovel Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Method of administration Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). You can take Aprovel with or without food. Try to take your daily dose at about the same time each day. It is important that you continue to take Aprovel until your doctor tells you otherwise.  Patients with high blood pressure The usual dose is 150 mg once a day. The dose may later be increased to 300 mg (two tablets a day) once daily depending on blood pressure response.  Patients with high blood pressure and type 2 diabetes with kidney disease In patients with high blood pressure and type 2 diabetes, 300 mg (two tablets a day) once daily is the preferred maintenance dose for the treatment of associated kidney disease. The doctor may advise a lower dose, especially when starting treatment in certain patients such as those on haemodialysis, or those over the age of 75 years. The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. Use in children and adolescents Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, contact your doctor immediately. If you take more Aprovel than you should If you accidentally take too many tablets, contact your doctor immediately. If you forget to take Aprovel If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these effects may be serious and may require medical attention. As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any of these symptoms or get short of breath, stop taking Aprovel and contact your doctor immediately. The frequency of the side effects listed below is defined using the following convention: Very common: may affect more than 1 in 10 people Common: may affect up to 1 in 10 people Uncommon: may affect up to 1 in 100 people Side effects reported in clinical studies for patients treated with Aprovel were:  Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 112  Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from a lying or sitting position, low blood pressure when getting up from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin) were also reported.  Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, increased blood potassium levels, impaired kidney function, inflammation of small blood vessels mainly affecting the skin (a condition known as leukocytoclastic vasculitis),and severe allergic reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of the eyes) have also been reported. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aprovel Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. The expiry date refers to the last day of that month. Do not store above 30°C. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away of medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aprovel contains  The active substance is irbesartan. Each tablet of Aprovel 150 mg contains 150 mg irbesartan.  The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, and poloxamer 188. Please see section 2 “Aprovel contains lactose”. What Aprovel looks like and contents of the pack Aprovel 150 mg tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2772 engraved on the other side. Aprovel 150 mg tablets are supplied in blister packs of 14, 28, 56 or 98 tablets. Unidose blister packs of 56 x 1 tablet for delivery in hospitals are also available. Not all pack sizes may be marketed. 113 Marketing Authorisation Holder: sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France Manufacturer: SANOFI WINTHROP INDUSTRIE 1, rue de la Vierge Ambarès & Lagrave F-33565 Carbon Blanc Cedex - France SANOFI WINTHROP INDUSTRIE 30-36 Avenue Gustave Eiffel, BP 7166 F-37071 Tours Cedex 2 - France CHINOIN PRIVATE CO. LTD. Lévai u.5. 2112 Veresegyház - Hungary For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 Lietuva UAB sanofi-aventis Lietuva Tel: +370 5 2755224 България Sanofi Bulgaria EOOD Тел.: +359 (0)2 970 53 00 Luxembourg/Luxemburg Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) Česká republika sanofi-aventis, s.r.o. Tel: +420 233 086 111 Magyarország SANOFI-AVENTIS Zrt. Tel.: +36 1 505 0050 Danmark Sanofi A/S Tlf: +45 45 16 70 00 Malta Sanofi S.p.A. Tel: +39 02 39394275 Deutschland Sanofi-Aventis Deutschland GmbH Tel: 0800 52 52 010 Tel. aus dem Ausland: +49 69 305 21 131 Nederland sanofi-aventis Netherlands B.V. Tel: +31 20 245 4000 Eesti sanofi-aventis Estonia OÜ Tel: +372 627 34 88 Norge sanofi-aventis Norge AS Tlf: +47 67 10 71 00 Ελλάδα sanofi-aventis AEBE Τηλ: +30 210 900 16 00 Österreich sanofi-aventis GmbH Tel: +43 1 80 185 – 0 España sanofi-aventis, S.A. Tel: +34 93 485 94 00 Polska sanofi-aventis Sp. z o.o. Tel.: +48 22 280 00 00 114 France sanofi-aventis France Tél: 0 800 222 555 Appel depuis l’étranger: +33 1 57 63 23 23 Portugal Sanofi - Produtos Farmacêuticos, Lda Tel: +351 21 35 89 400 Hrvatska sanofi-aventis Croatia d.o.o. Tel: +385 1 600 34 00 România Sanofi Romania SRL Tel: +40 (0) 21 317 31 36 Ireland sanofi-aventis Ireland Ltd. T/A SANOFI Tel: +353 (0) 1 403 56 00 Slovenija sanofi-aventis d.o.o. Tel: +386 1 560 48 00 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. Tel: +421 2 33 100 100 Italia Sanofi S.p.A. Tel: 800 536389 Suomi/Finland Sanofi Oy Puh/Tel: +358 (0) 201 200 300 Κύπρος sanofi-aventis Cyprus Ltd. Τηλ: +357 22 871600 Sverige Sanofi AB Tel: +46 (0)8 634 50 00 Latvija sanofi-aventis Latvia SIA Tel: +371 67 33 24 51 United Kingdom Sanofi- Tel: +44 (0) 845 372 7101 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/ 115 Package leaflet: Information for the user Aprovel 300 mg tablets irbesartan Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor or pharmacist.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aprovel is and what it is used for 2. What you need to know before you take Aprovel 3. How to take Aprovel 4. Possible side effects 5. How to store Aprovel 6. Contents of the pack and other information 1. What Aprovel is and what it is used for Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the decrease of kidney function in patients with high blood pressure and type 2 diabetes. Aprovel is used in adult patients  to treat high blood pressure (essential hypertension)  to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory evidence of impaired kidney function. 2. What you need to know before you take Aprovel Do not take Aprovel  if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6)  if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy – see pregnancy section)  if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warning and precautions Talk to your doctor before taking Aprovel and if any of the following apply to you:  if you get excessive vomiting or diarrhoea  if you suffer from kidney problems  if you suffer from heart problems  if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform regular blood tests, especially for measuring blood potassium levels in case of poor kidney function  if you are going to have an operation (surgery) or be given anaesthetics  if you are taking any of the following medicines used to treat high blood pressure: 116 o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-related kidney problems. o aliskiren Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading “Do not take Aprovel”. You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section). Children and adolescents This medicinal product should not be used in children and adolescents because the safety and efficacy have not yet been fully established. Other medicines and Aprovel Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Aprovel” and “Warnings and precautions”). You may need to have blood checks if you take:  potassium supplements  salt substitutes containing potassium  potassium-sparing medicines (such as certain diuretics)  medicines containing lithium If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan may be reduced. Aprovel with food and drink Aprovel can be taken with or without food. Pregnancy and breast-feeding Pregnancy You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Aprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy. Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely. Driving and using machines Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If you experience these, talk to your doctor before attempting to drive or use machines. Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal product. 117 3. How to take Aprovel Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Method of administration Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). You can take Aprovel with or without food. Try to take your daily dose at about the same time each day. It is important that you continue to take Aprovel until your doctor tells you otherwise.  Patients with high blood pressure The usual dose is 150 mg once a day. The dose may later be increased to 300 mg once daily depending on blood pressure response.  Patients with high blood pressure and type 2 diabetes with kidney disease In patients with high blood pressure and type 2 diabetes, 300 mg once daily is the preferred maintenance dose for the treatment of associated kidney disease. The doctor may advise a lower dose, especially when starting treatment in certain patients such as those on haemodialysis, or those over the age of 75 years. The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. Use in children and adolescents Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, contact your doctor immediately. If you take more Aprovel than you should If you accidentally take too many tablets, contact your doctor immediately. If you forget to take Aprovel If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these effects may be serious and may require medical attention. As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any of these symptoms or get short of breath, stop taking Aprovel and contact your doctor immediately. The frequency of the side effects listed below is defined using the following convention: Very common: may affect more than 1 in 10 people Common: may affect up to 1 in 10 people Uncommon: may affect up to 1 in 100 people Side effects reported in clinical studies for patients treated with Aprovel were:  Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 118  Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from a lying or sitting position, low blood pressure when getting up from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin) were also reported.  Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, increased blood potassium levels, impaired kidney function, inflammation of small blood vessels mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of the eyes) have also been reported. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aprovel Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. The expiry date refers to the last day of that month. Do not store above 30°C. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away of medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aprovel contains  The active substance is irbesartan. Each tablet of Aprovel 300 mg contains 300 mg irbesartan.  The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, and poloxamer 188. Please see section 2 “Aprovel contains lactose”. What Aprovel looks like and contents of the pack Aprovel 300 mg tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2773 engraved on the other side. Aprovel 300 mg tablets are supplied in blister packs of 14, 28, 56 or 98 tablets. Unidose blister packs of 56 x 1 tablet for delivery in hospitals are also available. Not all pack sizes may be marketed. 119 Marketing Authorisation Holder: sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France Manufacturer: SANOFI WINTHROP INDUSTRIE 1, rue de la Vierge Ambarès & Lagrave F-33565 Carbon Blanc Cedex - France SANOFI WINTHROP INDUSTRIE 30-36 Avenue Gustave Eiffel, BP 7166 F-37071 Tours Cedex 2 - France CHINOIN PRIVATE CO. LTD. Lévai u.5. 2112 Veresegyház - Hungary For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 Lietuva UAB sanofi-aventis Lietuva Tel: +370 5 2755224 България Sanofi Bulgaria EOOD Тел.: +359 (0)2 970 53 00 Luxembourg/Luxemburg Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) Česká republika sanofi-aventis, s.r.o. Tel: +420 233 086 111 Magyarország SANOFI-AVENTIS Zrt. Tel.: +36 1 505 0050 Danmark Sanofi A/S Tlf: +45 45 16 70 00 Malta Sanofi S.p.A. Tel: +39 02 39394275 Deutschland Sanofi-Aventis Deutschland GmbH Tel: 0800 52 52 010 Tel. aus dem Ausland: +49 69 305 21 131 Nederland sanofi-aventis Netherlands B.V. Tel: +31 20 245 4000 Eesti sanofi-aventis Estonia OÜ Tel: +372 627 34 88 Norge sanofi-aventis Norge AS Tlf: +47 67 10 71 00 Ελλάδα sanofi-aventis AEBE Τηλ: +30 210 900 16 00 Österreich sanofi-aventis GmbH Tel: +43 1 80 185 – 0 España sanofi-aventis, S.A. Tel: +34 93 485 94 00 Polska sanofi-aventis Sp. z o.o. Tel.: +48 22 280 00 00 120 France sanofi-aventis France Tél: 0 800 222 555 Appel depuis l’étranger: +33 1 57 63 23 23 Portugal Sanofi - Produtos Farmacêuticos, Lda Tel: +351 21 35 89 400 Hrvatska sanofi-aventis Croatia d.o.o. Tel: +385 1 600 34 00 România Sanofi Romania SRL Tel: +40 (0) 21 317 31 36 Ireland sanofi-aventis Ireland Ltd. T/A SANOFI Tel: +353 (0) 1 403 56 00 Slovenija sanofi-aventis d.o.o. Tel: +386 1 560 48 00 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. Tel: +421 2 33 100 100 Italia Sanofi S.p.A. Tel: 800 536389 Suomi/Finland Sanofi Oy Puh/Tel: +358 (0) 201 200 300 Κύπρος sanofi-aventis Cyprus Ltd. Τηλ: +357 22 871600 Sverige Sanofi AB Tel: +46 (0)8 634 50 00 Latvija sanofi-aventis Latvia SIA Tel: +371 67 33 24 51 United Kingdom Sanofi Tel: +44 (0) 845 372 7101 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/ 121 Package leaflet: Information for the user Aprovel 75 mg film-coated tablets irbesartan Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor or pharmacist.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aprovel is and what it is used for 2. What you need to know before you take Aprovel 3. How to take Aprovel 4. Possible side effects 5. How to store Aprovel 6. Contents of the pack and other information 1. What Aprovel is and what it is used for Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the decrease of kidney function in patients with high blood pressure and type 2 diabetes. Aprovel is used in adult patients  to treat high blood pressure (essential hypertension)  to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory evidence of impaired kidney function. 2. What you need to know before you take Aprovel Do not take Aprovel  if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6)  if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy – see pregnancy section)  if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warnings and precautions Talk to your doctor before taking Aprovel and if any of the following apply to you:  if you get excessive vomiting or diarrhoea  if you suffer from kidney problems  if you suffer from heart problems  if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform regular blood tests, especially for measuring blood potassium levels in case of poor kidney function  if you are going to have an operation (surgery) or be given anaesthetics  if you are taking any of the following medicines used to treat high blood pressure: 122 o an ACE-inhibitor ( for example enalapril, lisinopril, ramipril) in particular if you have diabetes-related kidney problems. o aliskiren Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading “Do not take Aprovel”. You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section). Children and adolescents This medicinal product should not be used in children and adolescents because the safety and efficacy have not yet been fully established. Other medicines and Aprovel Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Aprovel” and “Warnings and precautions”). You may need to have blood checks if you take:  potassium supplements  salt substitutes containing potassium  potassium-sparing medicines (such as certain diuretics)  medicines containing lithium If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan may be reduced. Aprovel with food and drink Aprovel can be taken with or without food. Pregnancy and breast-feeding Pregnancy You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Aprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy. Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely. Driving and using machines Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If you experience these, talk to your doctor before attempting to drive or use machines. Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal product. 123 3. How to take Aprovel Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Method of administration Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). You can take Aprovel with or without food. Try to take your daily dose at about the same time each day. It is important that you continue to take Aprovel until your doctor tells you otherwise.  Patients with high blood pressure The usual dose is 150 mg once a day (two tablets a day). The dose may later be increased to 300 mg (four tablets a day) once daily depending on blood pressure response.  Patients with high blood pressure and type 2 diabetes with kidney disease In patients with high blood pressure and type 2 diabetes, 300 mg (four tablets a day) once daily is the preferred maintenance dose for the treatment of associated kidney disease. The doctor may advise a lower dose, especially when starting treatment in certain patients such as those on haemodialysis, or those over the age of 75 years. The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. Use in children and adolescents Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, contact your doctor immediately. If you take more Aprovel than you should: If you accidentally take too many tablets, contact your doctor immediately. If you forget to take Aprovel: If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these effects may be serious and may require medical attention. As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any of these symptoms or get short of breath, stop taking Aprovel and contact your doctor immediately. The frequency of the side effects listed below is defined using the following convention: Very common: may affect more than 1 in 10 people Common: may affect up to 1 in 10 people Uncommon: may affect up to 1 in 100 people Side effects reported in clinical studies for patients treated with Aprovel were:  Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 124  Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from a lying or sitting position, low blood pressure when getting up from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin) were also reported.  Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, increased blood potassium levels, impaired kidney function, inflammation of small blood vessels mainly affecting the skin (a condition known as leukocytoclastic vasculitis),and severe allergic reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of the eyes) have also been reported. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aprovel Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. The expiry date refers to the last day of that month. Do not store above 30°C. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aprovel contains  The active substance is irbesartan. Each tablet of Aprovel 75 mg contains 75 mg irbesartan.  The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000, carnauba wax. Please see section 2 “Aprovel contains lactose”. What Aprovel looks like and contents of the pack Aprovel 75 mg film-coated tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2871 engraved on the other side. Aprovel 75 mg film-coated tablets are supplied in blister packs of 14, 28, 30, 56, 84, 90 or 98 film- coated tablets. Unidose blister packs of 56 x 1 film-coated tablet for delivery in hospitals are also available. Not all pack sizes may be marketed. 125 Marketing Authorisation Holder: sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France Manufacturer: SANOFI WINTHROP INDUSTRIE 1, rue de la Vierge Ambarès & Lagrave F-33565 Carbon Blanc Cedex - France SANOFI WINTHROP INDUSTRIE 30-36 Avenue Gustave Eiffel, BP 7166 F-37071 Tours Cedex 2 - France For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 Lietuva UAB sanofi-aventis Lietuva Tel: +370 5 2755224 България Sanofi Bulgaria EOOD Тел.: +359 (0)2 970 53 00 Luxembourg/Luxemburg Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) Česká republika sanofi-aventis, s.r.o. Tel: +420 233 086 111 Magyarország SANOFI-AVENTIS Zrt. Tel.: +36 1 505 0050 Danmark Sanofi A/S Tlf: +45 45 16 70 00 Malta Sanofi S.p.A. Tel: +39 02 39394275 Deutschland Sanofi-Aventis Deutschland GmbH Tel: 0800 52 52 010 Tel. aus dem Ausland: +49 69 305 21 131 Nederland sanofi-aventis Netherlands B.V. Tel: +31 20 245 4000 Eesti sanofi-aventis Estonia OÜ Tel: +372 627 34 88 Norge sanofi-aventis Norge AS Tlf: +47 67 10 71 00 Ελλάδα sanofi-aventis AEBE Τηλ: +30 210 900 16 00 Österreich sanofi-aventis GmbH Tel: +43 1 80 185 – 0 España sanofi-aventis, S.A. Tel: +34 93 485 94 00 Polska sanofi-aventis Sp. z o.o. Tel.: +48 22 280 00 00 France sanofi-aventis France Tél: 0 800 222 555 Appel depuis l’étranger: +33 1 57 63 23 23 Portugal Sanofi - Produtos Farmacêuticos, Lda Tel: +351 21 35 89 400 126 Hrvatska sanofi-aventis Croatia d.o.o. Tel: +385 1 600 34 00 România Sanofi Romania SRL Tel: +40 (0) 21 317 31 36 Ireland sanofi-aventis Ireland Ltd. T/A SANOFI Tel: +353 (0) 1 403 56 00 Slovenija sanofi-aventis d.o.o. Tel: +386 1 560 48 00 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. Tel: +421 2 33 100 100 Italia Sanofi S.p.A. Tel: 800 536389 Suomi/Finland Sanofi Oy Puh/Tel: +358 (0) 201 200 300 Κύπρος sanofi-aventis Cyprus Ltd. Τηλ: +357 22 871600 Sverige Sanofi AB Tel: +46 (0)8 634 50 00 Latvija sanofi-aventis Latvia SIA Tel: +371 67 33 24 51 United Kingdom Sanofi Tel: +44 (0) 845 372 7101 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/ 127 Package leaflet: Information for the user Aprovel 150 mg film-coated tablets irbesartan Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor or pharmacist.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aprovel is and what it is used for 2. What you need to know before you take Aprovel 3. How to take Aprovel 4. Possible side effects 5. How to store Aprovel 6. Contents of the pack and other information 1. What Aprovel is and what it is used for Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the decrease of kidney function in patients with high blood pressure and type 2 diabetes. Aprovel is used in adult patients  to treat high blood pressure (essential hypertension)  to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory evidence of impaired kidney function. 2. What you need to know before you take Aprovel Do not take Aprovel  if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6)  if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy – see pregnancy section)  if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warnings and precautions Talk to your doctor before taking Aprovel and if any of the following apply to you:  if you get excessive vomiting or diarrhoea  if you suffer from kidney problems  if you suffer from heart problems  if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform regular blood tests, especially for measuring blood potassium levels in case of poor kidney function  if you are going to have an operation (surgery) or be given anaesthetics  if you are taking any of the following medicines used to treat high blood pressure: 128 o an ACE-inhibitor ( for example enalapril, lisinopril, ramipril) in particular if you have diabetes-related kidney problems. o aliskiren Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading “Do not take Aprovel”. You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section). Children and adolescents This medicinal product should not be used in children and adolescents because the safety and efficacy have not yet been fully established. Other medicines and Aprovel Tell your doctor or pharmacist if you are taking,have recently taken or might take any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Aprovel” and “Warnings and precautions”). You may need to have blood checks if you take:  potassium supplements  salt substitutes containing potassium  potassium-sparing medicines (such as certain diuretics)  medicines containing lithium If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan may be reduced. Aprovel with food and drink Aprovel can be taken with or without food. Pregnancy and breast-feeding Pregnancy You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Aprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy. Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely. Driving and using machines Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If you experience these, talk to your doctor before attempting to drive or use machines. Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal product. 129 3. How to take Aprovel Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Method of administration Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). You can take Aprovel with or without food. Try to take your daily dose at about the same time each day. It is important that you continue to take Aprovel until your doctor tells you otherwise.  Patients with high blood pressure The usual dose is 150 mg once a day. The dose may later be increased to 300 mg (two tablets a day) once daily depending on blood pressure response.  Patients with high blood pressure and type 2 diabetes with kidney disease In patients with high blood pressure and type 2 diabetes, 300 mg (two tablets a day) once daily is the preferred maintenance dose for the treatment of associated kidney disease. The doctor may advise a lower dose, especially when starting treatment in certain patients such as those on haemodialysis, or those over the age of 75 years. The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. Use in children and adolescents Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, contact your doctor immediately. If you take more Aprovel than you should: If you accidentally take too many tablets, contact your doctor immediately. If you forget to take Aprovel: If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these effects may be serious and may require medical attention. As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any of these symptoms or get short of breath, stop taking Aprovel and contact your doctor immediately. The frequency of the side effects listed below is defined using the following convention: Very common: may affect more than 1 in 10 people Common: may affect up to 1 in 10 people Uncommon: may affect up to 1 in 100 people Side effects reported in clinical studies for patients treated with Aprovel were:  Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 130  Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from a lying or sitting position, low blood pressure when getting up from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin) were also reported.  Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, increased blood potassium levels, impaired kidney function, inflammation of small blood vessels mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of the eyes) have also been reported. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aprovel Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. The expiry date refers to the last day of that month. Do not store above 30°C. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aprovel contains  The active substance is irbesartan. Each tablet of Aprovel 150 mg contains 150 mg irbesartan.  The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000, carnauba wax. Please see section 2 “Aprovel contains lactose”. What Aprovel looks like and contents of the pack Aprovel 150 mg film-coated tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2872 engraved on the other side. Aprovel 150 mg film-coated tablets are supplied in blister packs of 14, 28, 30, 56, 84, 90 or 98 film- coated tablets. Unidose blister packs of 56 x 1 film-coated tablet for delivery in hospitals are also available. Not all pack sizes may be marketed. 131 Marketing Authorisation Holder: sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France Manufacturer: SANOFI WINTHROP INDUSTRIE 1, rue de la Vierge Ambarès & Lagrave F-33565 Carbon Blanc Cedex - France SANOFI WINTHROP INDUSTRIE 30-36 Avenue Gustave Eiffel, BP 7166 F-37071 Tours Cedex 2 - France CHINOIN PRIVATE CO. LTD. Lévai u.5. 2112 Veresegyház – Hungary SANOFI-AVENTIS, S.A. Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 17404 Riells i Viabrea (Girona) - Spain For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 Lietuva UAB sanofi-aventis Lietuva Tel: +370 5 2755224 България Sanofi Bulgaria EOOD Тел.: +359 (0)2 970 53 00 Luxembourg/Luxemburg Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) Česká republika sanofi-aventis, s.r.o. Tel: +420 233 086 111 Magyarország SANOFI-AVENTIS Zrt. Tel.: +36 1 505 0050 Danmark Sanofi A/S Tlf: +45 45 16 70 00 Malta Sanofi S.p.A. Tel: +39 02 39394275 Deutschland Sanofi-Aventis Deutschland GmbH Tel: 0800 52 52 010 Tel. aus dem Ausland: +49 69 305 21 131 Nederland sanofi-aventis Netherlands B.V. Tel: +31 20 245 4000 Eesti sanofi-aventis Estonia OÜ Tel: +372 627 34 88 Norge sanofi-aventis Norge AS Tlf: +47 67 10 71 00 Ελλάδα sanofi-aventis AEBE Τηλ: +30 210 900 16 00 Österreich sanofi-aventis GmbH Tel: +43 1 80 185 – 0 132 España sanofi-aventis, S.A. Tel: +34 93 485 94 00 Polska sanofi-aventis Sp. z o.o. Tel.: +48 22 280 00 00 France sanofi-aventis France Tél: 0 800 222 555 Appel depuis l’étranger: +33 1 57 63 23 23 Portugal Sanofi - Produtos Farmacêuticos, Lda Tel: +351 21 35 89 400 Hrvatska sanofi-aventis Croatia d.o.o. Tel: +385 1 600 34 00 România Sanofi Romania SRL Tel: +40 (0) 21 317 31 36 Ireland sanofi-aventis Ireland Ltd. T/A SANOFI Tel: +353 (0) 1 403 56 00 Slovenija sanofi-aventis d.o.o. Tel: +386 1 560 48 00 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. Tel: +421 2 33 100 100 Italia Sanofi S.p.A. Tel: 800 536389 Suomi/Finland Sanofi Oy Puh/Tel: +358 (0) 201 200 300 Κύπρος sanofi-aventis Cyprus Ltd. Τηλ: +357 22 871600 Sverige Sanofi AB Tel: +46 (0)8 634 50 00 Latvija sanofi-aventis Latvia SIA Tel: +371 67 33 24 51 United Kingdom Sanofi Tel: +44 (0) 845 372 7101 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/ 133 Package leaflet: Information for the user Aprovel 300 mg film-coated tablets irbesartan Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor or pharmacist.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aprovel is and what it is used for 2. What you need to know before you take Aprovel 3. How to take Aprovel 4. Possible side effects 5. How to store Aprovel 6. Contents of the pack and other information 1. What Aprovel is and what it is used for Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the decrease of kidney function in patients with high blood pressure and type 2 diabetes. Aprovel is used in adult patients  to treat high blood pressure (essential hypertension)  to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory evidence of impaired kidney function. 2. What you need to know before you take Aprovel Do not take Aprovel  if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6)  if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy – see pregnancy section)  if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warnings and precautions Talk to your doctor before taking Aprovel and if any of the following apply to you:  if you get excessive vomiting or diarrhoea  if you suffer from kidney problems  if you suffer from heart problems  if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform regular blood tests, especially for measuring blood potassium levels in case of poor kidney function  if you are going to have an operation (surgery) or be given anaesthetics  if you are taking any of the following medicines used to treat high blood pressure: o an ACE-inhibitor ( for example enalapril, lisinopril, ramipril) in particular if you have diabetes-related kidney problems. 134 o aliskiren Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading “Do not take Aprovel”. You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section). Children and adolescents This medicinal product should not be used in children and adolescents because the safety and efficacy have not yet been fully established. Other medicines and Aprovel Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Aprovel” and “Warnings and precautions”). You may need to have blood checks if you take:  potassium supplements  salt substitutes containing potassium  potassium-sparing medicines (such as certain diuretics)  medicines containing lithium If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan may be reduced. Aprovel with food and drink Aprovel can be taken with or without food. Pregnancy and breast-feeding Pregnancy You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Aprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy. Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely. Driving and using machines Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If you experience these, talk to your doctor before attempting to drive or use machines. Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal product. 135 3. How to take Aprovel Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Method of administration Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). You can take Aprovel with or without food. Try to take your daily dose at about the same time each day. It is important that you continue to take Aprovel until your doctor tells you otherwise.  Patients with high blood pressure The usual dose is 150 mg once a day. The dose may later be increased to 300 mg once daily depending on blood pressure response.  Patients with high blood pressure and type 2 diabetes with kidney disease In patients with high blood pressure and type 2 diabetes, 300 mg once daily is the preferred maintenance dose for the treatment of associated kidney disease. The doctor may advise a lower dose, especially when starting treatment in certain patients such as those on haemodialysis, or those over the age of 75 years. The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. Use in children and adolescents Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, contact your doctor immediately. If you take more Aprovel than you should: If you accidentally take too many tablets, contact your doctor immediately. If you forget to take Aprovel: If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these effects may be serious and may require medical attention. As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any of these symptoms or get short of breath, stop taking Aprovel and contact your doctor immediately. The frequency of the side effects listed below is defined using the following convention: Very common: may affect more than 1 in 10 people Common: may affect up to 1 in 10 people Uncommon: may affect up to 1 in 100 people Side effects reported in clinical studies for patients treated with Aprovel were:  Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 136  Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from a lying or sitting position, low blood pressure when getting up from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin) were also reported.  Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, increased blood potassium levels, impaired kidney function, inflammation of small blood vessels mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of the eyes) have also been reported. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aprovel Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. The expiry date refers to the last day of that month. Do not store above 30°C. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aprovel contains  The active substance is irbesartan. Each tablet of Aprovel 300 mg contains 300 mg irbesartan.  The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000, carnauba wax. Please see section 2 “Aprovel contains lactose”. What Aprovel looks like and contents of the pack Aprovel 300 mg film-coated tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2873 engraved on the other side. Aprovel 300 mg film-coated tablets are supplied in blister packs of 14, 28, 30, 56, 84, 90 or 98 film- coated tablets. Unidose blister packs of 56 x 1 film-coated tablet for delivery in hospitals are also available. Not all pack sizes may be marketed. 137 Marketing Authorisation Holder: sanofi-aventis groupe 54, rue La Boétie F-75008 Paris - France Manufacturer: SANOFI WINTHROP INDUSTRIE 1, rue de la Vierge Ambarès & Lagrave F-33565 Carbon Blanc Cedex - France SANOFI WINTHROP INDUSTRIE 30-36 Avenue Gustave Eiffel, BP 7166 F-37071 Tours Cedex 2 - France CHINOIN PRIVATE CO. LTD. Lévai u.5. 2112 Veresegyház - Hungary SANOFI-AVENTIS, S.A. Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 17404 Riells i Viabrea (Girona) - Spain For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 Lietuva UAB sanofi-aventis Lietuva Tel: +370 5 2755224 България Sanofi Bulgaria EOOD Тел.: +359 (0)2 970 53 00 Luxembourg/Luxemburg Sanofi Belgium Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) Česká republika sanofi-aventis, s.r.o. Tel: +420 233 086 111 Magyarország SANOFI-AVENTIS Zrt. Tel.: +36 1 505 0050 Danmark Sanofi A/S Tlf: +45 45 16 70 00 Malta Sanofi S.p.A. Tel: +39 02 39394275 Deutschland Sanofi-Aventis Deutschland GmbH Tel: 0800 52 52 010 Tel. aus dem Ausland: +49 69 305 21 131 Nederland sanofi-aventis Netherlands B.V. Tel: +31 20 245 4000 Eesti sanofi-aventis Estonia OÜ Tel: +372 627 34 88 Norge sanofi-aventis Norge AS Tlf: +47 67 10 71 00 Ελλάδα sanofi-aventis AEBE Τηλ: +30 210 900 16 00 Österreich sanofi-aventis GmbH Tel: +43 1 80 185 – 0 138 España sanofi-aventis, S.A. Tel: +34 93 485 94 00 Polska sanofi-aventis Sp. z o.o. Tel.: +48 22 280 00 00 France sanofi-aventis France Tél: 0 800 222 555 Appel depuis l’étranger: +33 1 57 63 23 23 Portugal Sanofi - Produtos Farmacêuticos, Lda Tel: +351 21 35 89 400 Hrvatska sanofi-aventis Croatia d.o.o. Tel: +385 1 600 34 00 România Sanofi Romania SRL Tel: +40 (0) 21 317 31 36 Ireland sanofi-aventis Ireland Ltd. T/A SANOFI Tel: +353 (0) 1 403 56 00 Slovenija sanofi-aventis d.o.o. Tel: +386 1 560 48 00 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. Tel: +421 2 33 100 100 Italia Sanofi S.p.A. Tel: 800.536389 Suomi/Finland Sanofi Oy Puh/Tel: +358 (0) 201 200 300 Κύπρος sanofi-aventis Cyprus Ltd. Τηλ: +357 22 871600 Sverige Sanofi AB Tel: +46 (0)8 634 50 00 Latvija sanofi-aventis Latvia SIA Tel: +371 67 33 24 51 United Kingdom Sanofi Tel: +44 (0) 845 372 7101 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what aprovel is and what it is used for', 'Section_Content': 'aprovel belongs to a group of medicines known as angiotensin-ii receptor antagonists. angiotensin-ii is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. this results in an increase in blood pressure. aprovel prevents the binding of angiotensin-ii to these receptors, causing the blood vessels to relax and the blood pressure to lower. aprovel slows the decrease of kidney function in patients with high blood pressure and type 2 diabetes. aprovel is used in adult patients to treat high blood pressure (essential hypertension) to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory evidence of impaired kidney function.', 'Entity_Recognition': [{'Text': 'aprovel', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 30, 'EndOffset': 39}, {'Text': 'angiotensin', 'Type': 'TREATMENT', 'BeginOffset': 49, 'EndOffset': 60}, {'Text': 'ii receptor antagonists', 'Type': 'TREATMENT', 'BeginOffset': 61, 'EndOffset': 84}, {'Text': 'angiotensin', 'Type': 'TREATMENT', 'BeginOffset': 86, 'EndOffset': 97}, {'Text': 'blood pressure', 'Type': 'TEST', 'BeginOffset': 235, 'EndOffset': 249}, {'Text': 'the blood vessels', 'Type': 'PROBLEM', 'BeginOffset': 326, 'EndOffset': 343}, {'Text': 'the blood pressure', 'Type': 'TEST', 'BeginOffset': 357, 'EndOffset': 375}, {'Text': 'the decrease of kidney function', 'Type': 'PROBLEM', 'BeginOffset': 400, 'EndOffset': 431}, {'Id': 5, 'BeginOffset': 449, 'EndOffset': 468, 'Score': 0.8106280565261841, 'Text': 'high blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.594490647315979}]}, {'Id': 6, 'BeginOffset': 473, 'EndOffset': 488, 'Score': 0.4479144215583801, 'Text': 'type 2 diabetes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9337968230247498}]}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 478, 'EndOffset': 479}, {'Id': 7, 'BeginOffset': 533, 'EndOffset': 552, 'Score': 0.9358248710632324, 'Text': 'high blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8947483897209167}]}, {'Text': 'essential hypertension', 'Type': 'PROBLEM', 'BeginOffset': 554, 'EndOffset': 576}, {'Id': 2, 'BeginOffset': 593, 'EndOffset': 599, 'Score': 0.9661362171173096, 'Text': 'kidney', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 9, 'BeginOffset': 617, 'EndOffset': 636, 'Score': 0.842628538608551, 'Text': 'high blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7814926505088806}]}, {'Id': 10, 'BeginOffset': 638, 'EndOffset': 653, 'Score': 0.6329423189163208, 'Text': 'type 2 diabetes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.917797327041626}]}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 643, 'EndOffset': 644}, {'Id': 11, 'BeginOffset': 681, 'EndOffset': 705, 'Score': 0.8724459409713745, 'Text': 'impaired kidney function', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SIGN', 'Score': 0.5001691579818726}, {'Name': 'DIAGNOSIS', 'Score': 0.49060532450675964}]}, {'Id': 3, 'BeginOffset': 690, 'EndOffset': 696, 'Score': 0.9793689846992493, 'Text': 'kidney', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}]}

{'Title': '2. what you need to know before you take aprovel', 'Section_Content': 'do not take aprovel if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6) if you are more than 3 months pregnant. (it is also better to avoid aprovel in early pregnancy see pregnancy section) if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren warning and precautions talk to your doctor before taking aprovel and if any of the following apply to you: if you get excessive vomiting or diarrhoea if you suffer from kidney problems if you suffer from heart problems if you receive aprovel for diabetic kidney disease. in this case your doctor may perform regular blood tests, especially for measuring blood potassium levels in case of poor kidney function if you are going to have an operation (surgery) or be given anaesthetics if you are taking any of the following medicines used to treat high blood pressure: 104 o an ace-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-related kidney problems. o aliskiren. your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. see also information under the heading "do not take aprovel". you must tell your doctor if you think you are (or might become) pregnant. aprovel is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section). children and adolescents this medicinal product should not be used in children and adolescents because the safety and efficacy have not yet been fully established. other medicines and aprovel tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. your doctor may need to change your dose and/or to take other precautions: if you are taking an ace-inhibitor or aliskiren (see also information under the headings "do not take aprovel" and "warnings and precautions"). you may need to have blood checks if you take: potassium supplements salt substitutes containing potassium potassium-sparing medicines (such as certain diuretics) medicines containing lithium if you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan may be reduced. aprovel with food and drink aprovel can be taken with or without food. pregnancy and breast-feeding pregnancy you must tell your doctor if you think you are (or might become) pregnant. your doctor will normally advise you to stop taking aprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of aprovel. aprovel is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy. breast-feeding tell your doctor if you are breast-feeding or about to start breast-feeding. aprovel is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely. driving and using machines aprovel is unlikely to affect your ability to drive or use machines. however, occasionally dizziness or weariness may occur during treatment of high blood pressure. if you experience these, talk to your doctor before attempting to drive or use machines. aprovel contains lactose. if you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicinal product.', 'Entity_Recognition': [{'Text': 'aprovel', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 31, 'EndOffset': 39}, {'Id': 7, 'BeginOffset': 43, 'EndOffset': 53, 'Score': 0.9848644733428955, 'Text': 'irbesartan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 82, 'EndOffset': 95}, 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{'Title': '3. how to take aprovel', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. method of administration aprovel is for oral use. swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). you can take aprovel with or without food. try to take your daily dose at about the same time each day. it is important that you continue to take aprovel until your doctor tells you otherwise. patients with high blood pressure the usual dose is 150 mg once a day (two tablets a day). the dose may later be increased to 300 mg (four tablets a day) once daily depending on blood pressure response. patients with high blood pressure and type 2 diabetes with kidney disease in patients with high blood pressure and type 2 diabetes, 300 mg (four tablets a day) once daily is the preferred maintenance dose for the treatment of associated kidney disease. the doctor may advise a lower dose, especially when starting treatment in certain patients such as those on haemodialysis, or those over the age of 75 years. the maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. use in children and adolescents aprovel should not be given to children under 18 years of age. if a child swallows some tablets, contact your doctor immediately. if you take more aprovel than you should if you accidentally take too many tablets, contact your doctor immediately. if you forget to take aprovel if you accidentally miss a daily dose, just take the next dose as normal. do not take a double dose to make up for a forgotten dose. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'aprovel', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 'method of administration aprovel', 'Type': 'TREATMENT', 'BeginOffset': 121, 'EndOffset': 153}, {'Text': 'swallow', 'Type': 'TREATMENT', 'BeginOffset': 171, 'EndOffset': 178}, {'Id': 2, 'BeginOffset': 219, 'EndOffset': 224, 'Score': 0.3868787884712219, 'Text': 'fluid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'high blood pressure', 'Type': 'TREATMENT', 'BeginOffset': 459, 'EndOffset': 478}, {'Text': '150', 'Type': 'NUMBER', 'BeginOffset': 497, 'EndOffset': 500}, {'Text': '300', 'Type': 'NUMBER', 'BeginOffset': 571, 'EndOffset': 574}, {'Text': 'blood pressure response', 'Type': 'TEST', 'BeginOffset': 623, 'EndOffset': 646}, {'Id': 15, 'BeginOffset': 662, 'EndOffset': 681, 'Score': 0.8034780621528625, 'Text': 'high blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7830564379692078}]}, {'Id': 16, 'BeginOffset': 686, 'EndOffset': 701, 'Score': 0.5567436218261719, 'Text': 'type 2 diabetes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9514649510383606}]}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 691, 'EndOffset': 692}, {'Id': 17, 'BeginOffset': 707, 'EndOffset': 721, 'Score': 0.9460458159446716, 'Text': 'kidney disease', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9718682765960693}]}, {'Id': 18, 'BeginOffset': 739, 'EndOffset': 758, 'Score': 0.7474012970924377, 'Text': 'high blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7153428792953491}]}, {'Text': 'type 2 diabetes', 'Type': 'PROBLEM', 'BeginOffset': 763, 'EndOffset': 778}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 768, 'EndOffset': 769}, {'Text': '300', 'Type': 'NUMBER', 'BeginOffset': 780, 'EndOffset': 783}, {'Text': 'associated kidney disease', 'Type': 'PROBLEM', 'BeginOffset': 874, 'EndOffset': 899}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 962, 'EndOffset': 971}, {'Id': 22, 'BeginOffset': 1009, 'EndOffset': 1022, 'Score': 0.5710193514823914, 'Text': 'haemodialysis', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 21, 'BeginOffset': 1049, 'EndOffset': 1051, 'Score': 0.9676322340965271, 'Text': '75', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'AGE', 'Traits': []}, {'Text': 'the maximal blood pressure', 'Type': 'TEST', 'BeginOffset': 1059, 'EndOffset': 1085}, {'Text': '18', 'Type': 'NUMBER', 'BeginOffset': 1235, 'EndOffset': 1237}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 1552, 'EndOffset': 1565}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1647, 'EndOffset': 1660}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some of these effects may be serious and may require medical attention. as with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. if you get any of these symptoms or get short of breath, stop taking aprovel and contact your doctor immediately. the frequency of the side effects listed below is defined using the following convention: very common: may affect more than 1 in 10 people common: may affect up to 1 in 10 people uncommon: may affect up to 1 in 100 people side effects reported in clinical studies for patients treated with aprovel were: very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. common (may affect up to 1 in 10 people): dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an enzyme that measures the muscle and heart function (creatine kinase enzyme). in patients with high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from a lying or sitting position, low blood pressure when getting up from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin) were also reported. uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. some undesirable effects have been reported since marketing of aprovel. undesirable effects where the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, increased blood potassium levels, impaired kidney function, inflammation of small blood vessels mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic reactions (anaphylactic shock). uncommon cases of jaundice (yellowing of the skin and/or whites of the eyes) have also been reported. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'aprovel', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 18, 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0.9390524625778198}]}, {'Id': 84, 'BeginOffset': 2220, 'EndOffset': 2228, 'Score': 0.9879905581474304, 'Text': 'jaundice', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5560007691383362}]}, {'Id': 85, 'BeginOffset': 2230, 'EndOffset': 2251, 'Score': 0.4917501211166382, 'Text': 'yellowing of the skin', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5615812540054321}]}, {'Id': 76, 'BeginOffset': 2273, 'EndOffset': 2277, 'Score': 0.9929053783416748, 'Text': 'eyes', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 86, 'BeginOffset': 2317, 'EndOffset': 2329, 'Score': 0.9517619609832764, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7711443901062012}]}, {'Id': 87, 'BeginOffset': 2345, 'EndOffset': 2357, 'Score': 0.9231062531471252, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7278584837913513}]}, {'Id': 88, 'BeginOffset': 2421, 'EndOffset': 2433, 'Score': 0.9598897695541382, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6251223683357239}, {'Name': 'DIAGNOSIS', 'Score': 0.40546515583992004}]}, {'Id': 89, 'BeginOffset': 2482, 'EndOffset': 2494, 'Score': 0.874529242515564, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7053490877151489}]}, {'Id': 90, 'BeginOffset': 2548, 'EndOffset': 2559, 'Score': 0.39523938298225403, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5926774144172668}, {'Name': 'DIAGNOSIS', 'Score': 0.4042018949985504}]}, {'Id': 91, 'BeginOffset': 2573, 'EndOffset': 2585, 'Score': 0.867557942867279, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7242248058319092}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2641, 'EndOffset': 2654}]}

{'Title': '5. how to store aprovel', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and on the blister after exp. the expiry date refers to the last day of that month. do not store above 30. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what aprovel contains the active substance is irbesartan. each tablet of aprovel 75 mg contains 75 mg irbesartan. the other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, and poloxamer 188. please see section 2 "aprovel contains lactose". what aprovel looks like and contents of the pack aprovel 75 mg tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2771 engraved on the other side. aprovel 75 mg tablets are supplied in blister packs of 14, 28, 56 or 98 tablets. unidose blister packs of 56 x 1 tablet for delivery in hospitals are also available. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'aprovel', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 46, 'EndOffset': 56, 'Score': 0.9919748902320862, 'Text': 'irbesartan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.17298145592212677, 'RelationshipScore': 0.7252709865570068, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 58, 'EndOffset': 69, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8229377865791321, 'RelationshipScore': 0.9645026922225952, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 81, 'EndOffset': 86, 'Text': '75 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 3, 'BeginOffset': 73, 'EndOffset': 80, 'Score': 0.9412809014320374, 'Text': 'aprovel', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.17298145592212677, 'RelationshipScore': 0.9908730983734131, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 58, 'EndOffset': 69, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8229377865791321, 'RelationshipScore': 0.9853971600532532, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 81, 'EndOffset': 86, 'Text': '75 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 81, 'EndOffset': 83}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 96, 'EndOffset': 98}, {'Id': 6, 'BeginOffset': 102, 'EndOffset': 112, 'Score': 0.9973401427268982, 'Text': 'irbesartan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.17298145592212677, 'RelationshipScore': 0.951008677482605, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 58, 'EndOffset': 69, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9347754716873169, 'RelationshipScore': 0.9998490810394287, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 96, 'EndOffset': 101, 'Text': '75 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 7, 'BeginOffset': 140, 'EndOffset': 166, 'Score': 0.9905279874801636, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 168, 'EndOffset': 189, 'Score': 0.9891863465309143, 'Text': 'croscarmellose sodium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 191, 'EndOffset': 210, 'Score': 0.9568353295326233, 'Text': 'lactose monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 212, 'EndOffset': 230, 'Score': 0.9918801188468933, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 232, 'EndOffset': 257, 'Score': 0.9393035173416138, 'Text': 'colloidal hydrated silica', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 259, 'EndOffset': 286, 'Score': 0.42586418986320496, 'Text': 'pregelatinised maize starch', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 292, 'EndOffset': 301, 'Score': 0.7806322574615479, 'Text': 'poloxamer', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '188.', 'Type': 'NUMBER', 'BeginOffset': 302, 'EndOffset': 306}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 326, 'EndOffset': 327}, {'Text': 'the pack aprovel', 'Type': 'TREATMENT', 'BeginOffset': 396, 'EndOffset': 412}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 413, 'EndOffset': 415}, {'Id': 0, 'BeginOffset': 484, 'EndOffset': 489, 'Score': 0.919411838054657, 'Text': 'heart', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '2771', 'Type': 'NUMBER', 'BeginOffset': 526, 'EndOffset': 530}, {'Text': 'aprovel', 'Type': 'TREATMENT', 'BeginOffset': 559, 'EndOffset': 566}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 567, 'EndOffset': 569}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 614, 'EndOffset': 616}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 618, 'EndOffset': 620}, {'Text': '56', 'Type': 'NUMBER', 'BeginOffset': 622, 'EndOffset': 624}, {'Text': '98', 'Type': 'NUMBER', 'BeginOffset': 628, 'EndOffset': 630}, {'Text': 'unidose blister packs', 'Type': 'TREATMENT', 'BeginOffset': 640, 'EndOffset': 661}, {'Text': '56', 'Type': 'NUMBER', 'BeginOffset': 665, 'EndOffset': 667}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 670, 'EndOffset': 671}, {'Text': 'delivery', 'Type': 'TREATMENT', 'BeginOffset': 683, 'EndOffset': 691}]}

872F0A92D7E5CA03CBF88E6EC8A5FDE6

https://www.ema.europa.eu/documents/product-information/kiovig-epar-product-information_en.pdf

Kiovig

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT KIOVIG 100 mg/ml solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Human normal immunoglobulin (IVIg) One ml contains: Human normal immunoglobulin ……………100 mg (purity of at least 98% IgG) Each vial of 10 ml contains: 1 g of human normal immunoglobulin Each vial of 25 ml contains: 2.5 g of human normal immunoglobulin Each vial of 50 ml contains: 5 g of human normal immunoglobulin Each vial of 100 ml contains: 10 g of human normal immunoglobulin Each vial of 200 ml contains: 20 g of human normal immunoglobulin Each vial of 300 ml contains: 30 g of human normal immunoglobulin Distribution of IgG subclasses (approx. values): IgG1 ≥56.9% IgG2 ≥26.6% IgG3 ≥3.4% IgG4 ≥1.7% The maximum IgA content is 140 micrograms/ml. Produced from the plasma of human donors. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for infusion The solution is clear or slightly opalescent and colourless or pale yellow. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Replacement therapy in adults, and children and adolescents (0-18 years) in:  Primary immunodeficiency syndromes (PID) with impaired antibody production (see section 4.4).  Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or serum IgG level of <4 g/l. *PSAF = failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines 3 Immunomodulation in adults, and children and adolescents (0-18 years) in:  Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.  Guillain Barré syndrome.  Kawasaki disease (in conjunction with acetylsalicylic acid; see 4.2).  Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).  Multifocal Motor Neuropathy (MMN). 4.2 Posology and method of administration Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency. Posology The dose and dose regimen is dependent on the indication. In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. Dose based on bodyweight may require adjustment in underweight or overweight patients. The following dose regimens are given as a guideline. Replacement therapy in primary immunodeficiency syndromes The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/L. Three to six months are required after the initiation of therapy for equilibration (steady-state IgG levels) to occur. The recommended starting dose is 0.4-0.8 g/kg given once, followed by at least 0.2 g/kg given every three to four weeks. The dose required to achieve a trough level of 5-6 g/L is of the order of 0.2-0.8 g/kg/month. The dose interval when steady state has been reached varies from 3-4 weeks. IgG trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of bacterial infection, it may be necessary to increase the dose and aim for higher trough levels. Secondary immunodeficiencies (as defined in 4.1.) The recommended dose is 0.2-0.4 g/kg every three to four weeks. IgG trough levels should be measured and assessed in conjunction with the incidence of infection. Dose should be adjusted as necessary to achieve optimal protection against infections, an increase may be necessary in patients with persisting infection; a dose decrease can be considered when the patient remains infection free. Primary immune thrombocytopenia There are two alternative treatment schedules:  0.8-1g/kg given on day one; this dose may be repeated once within 3 days  0.4 g/kg given daily for two to five days. The treatment can be repeated if relapse occurs. 4 Guillain Barré syndrome 0.4 g/kg/day over 5 days (possible repeat of dosing in case of relapse). Kawasaki Disease 2 g/kg should be administered as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid. Chronic inflammatory demyelinating polyneuropathy (CIDP) Starting dose: 2 g/kg divided over 2 -5 consecutive days Maintenance doses: 1 g/kg over 1-2 consecutive days every 3 weeks. The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months, the treatment should be discontinued. If the treatment is effective long term treatment should be subject to the physicians discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease. Multifocal Motor Neuropathy (MMN) Starting dose: 2 g/kg given over 2-5 consecutive days. Maintenance dose: 1 g/kg every 2 to 4 weeks or 2 g/kg every 4 to 8 weeks over 2-5 days. The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months, the treatment should be discontinued. If the treatment is effective long term treatment should be subject to the physicians discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease. The dose recommendations are summarised in the following table: Indication Dose Frequency of injections Replacement therapy in primary immunodeficiency starting dose: 0.4-0.8 g/kg maintenance dose: 0.2-0.8 g/kg every 3-4 weeks to obtain IgG trough level of at least 5-6 g/l Replacement therapy in secondary immunodeficiency 0.2-0.4 g/kg every 3-4 weeks to obtain IgG trough level of at least 5-6 g/l Immunomodulation: Primary immune thrombocytopenia 0.8-1 g/kg or 0.4 g/kg/d on day 1, possibly repeated once within 3 days for 2-5 days Guillain Barré syndrome 0.4 g/kg/d for 5 days Kawasaki disease 2 g/kg in one dose in association with acetylsalicylic acid 5 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) starting dose 2g/kg maintenance dose: 1g/kg In divided doses over 2-5 days every 3 weeks over 1-2 days Multifocal Motor Neuropathy (MMN) starting dose: 2 g/kg maintenance dose: 1 g/kg or 2 g/kg given over 2-5 days every 2-4 weeks or every 4-8 weeks over 2-5 days Paediatric population The posology in children and adolescents (0-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned conditions. Hepatic impairment No evidence is available to require a dose adjustment. Renal impairment No dose adjustment unless clinically warranted, see section 4.4. Elderly No dose adjustment unless clinically warranted, see section 4.4. Method of administration For intravenous use. Human normal immunoglobulin should be infused intravenously at an initial rate of 0.5 ml/kg BW/hr for 30 minutes. If well tolerated (see section 4.4), the rate of administration may gradually be increased to a maximum of 6 ml/kg BW/hr. Clinical data obtained from a limited number of patients also indicate that adult PID patients may tolerate an infusion rate of up to 8 ml/kg BW/hr. For further precautions for use see section 4.4. If dilution prior to infusion is required, KIOVIG may be diluted with 5% glucose solution to a final concentration of 50 mg/ml (5% immunoglobulin). For instructions on dilution of the medicinal product before administration, see section 6.6. Any infusion-related adverse events should be treated by lowering infusion rates or by stopping the infusion. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA. 6 Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA containing product can result in anaphylaxis. 4.4 Special warnings and precautions for use Infusion reaction Certain severe adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension) may be related to the rate of infusion. The recommended infusion rate given under section 4.2 must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Certain adverse reactions may occur more frequently  in case of high rate of infusion  in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion.  in patients with an untreated infection or underlying chronic inflammation. Precautions for use Potential complications can often be avoided by ensuring that patients: - are not sensitive to human normal immunoglobulin by initially injecting the product slowly (0.5 ml/kg BW/hr); - are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored at the hospital during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration. In all patients, IVIg administration requires:  adequate hydration prior to the initiation of the infusion of IVIg  monitoring of urine output  monitoring of serum creatinine levels  monitoring for signs and symptoms of thrombosis  assessment of blood viscosity in patients at risk for hyperviscosity  avoidance of concomitant use of loop diuretics (see 4.5). In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction. If dilution of KIOVIG to lower concentrations is required for patients suffering from diabetes mellitus, the use of 5% glucose solution for dilution may have to be reconsidered. Hypersensitivity Hypersensitivity reactions are rare. Anaphylaxis can develop in patients  with undetectable IgA who have anti-IgA antibodies  who had tolerated previous treatment with human normal immunoglobulin In case of shock, standard medical treatment for shock should be implemented. 7 Thromboembolism There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusion of IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypertension, use of estrogens, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, hypercoagulable disorders, patients with prolonged periods of immobilisation, severely hypovolaemic patients, patients with diseases which increase blood viscosity, patients with indwelling vascular catheters and patients with high dose and rapid infusion). Hyperproteinemia, increased serum viscosity and subsequent relative pseudohyponatremia may occur in patients receiving IVIg therapy. This should be taken into account by physicians, since initiation of treatment for true hyponatremia (i.e. decreasing serum free water) in these patients may lead to a further increase in serum viscosity and a possible predisposition to thromboembolic events. In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable. Acute renal failure Cases of acute renal failure have been reported in patients receiving IVIg therapy. These include acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolaemia, overweight, concomitant nephrotoxic medicinal products, age over 65, sepsis, hyperviscosity or paraproteinemia. Renal parameters should be assessed prior to infusion of IVIg, particularly in patients judged to have a potential increased risk for developing acute renal failure, and again at appropriate intervals. In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable. In case of renal impairment, IVIg discontinuation should be considered. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain these excipients may be considered. KIOVIG does not contain sucrose, maltose or glucose. Transfusion Related Acute Lung Injury (TRALI) In patients receiving IVIg, there have been reports of acute non-cardiogenic pulmonary edema (Transfusion Related Acute Lung Injury, (TRALI) in patients administered IVIg (including KIOVIG). TRALI is characterised by severe hypoxia, dyspnoea, tachypnoea, cyanosis, fever and hypotension. Symptoms of TRALI typically develop during or within 6 hours of a transfusion, often within 1-2 hours. Therefore, IVIg recipients must be monitored for and IVIg infusion must be immediately stopped in case of pulmonary adverse reactions. TRALI is a potentially lifethreatening condition requiring immediate intensive-care-unit management. Aseptic meningitis syndrome (AMS) Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. The syndrome usually begins within several hours to 2 days following IVIg treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly 8 from the granulocytic series, and elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high-dose (2 g/kg) IVIg treatment. Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae. From post-marketing data with KIOVIG no clear correlation of AMS to higher doses was observed. Higher incidences of AMS were seen in women. Haemolytic anaemia IVIg products can contain blood group antibodies that may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis. (See section 4.8.) Neutropenia/Leukopenia A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after treatment with IVIgs. This typically occurs within hours or days after IVIg administration and resolves spontaneously within 7 to 14 days. Interference with serological testing After infusion of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing. Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D, may interfere with some serological tests for red cell antibodies, for example the direct antiglobulin test (DAT, direct Coombs’ test). Administration of KIOVIG can lead to false positive readings in assays that depend on detection of beta-D-glucans for diagnosis of fungal infections. This may persist during the weeks following infusion of the product. Transmissible agents KIOVIG is made from human plasma. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19. There is reassuring clinical experience regarding the lack of hepatitis A or Parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety. 9 Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Paediatric population There are no paediatric specific risks with regard to any of the above adverse events. Paediatric patients may be more susceptible to volume overload (see Section 4.9). 4.5 Interactions with other medicinal products and other forms of interactions Live attenuated virus vaccines Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked. Dilution of KIOVIG with a 5% glucose solution may result in increased blood glucose levels. Loop diuretics Avoidance of concomitant use of loop diuretics. Paediatric population The listed interactions apply both to adults and children. 4.6 Fertility, pregnancy and lactation Pregnancy The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore it should only be given with caution to pregnant women and breast-feeding mothers. IVIg products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected. Breast-feeding Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry. No negative effects on the breastfed newborn/infants are anticipated. Fertility Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected. 4.7 Effects on ability to drive and use machines The ability to drive and operate machines may be impaired by some adverse reactions associated with KIOVIG. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines. 10 4.8 Undesirable effects Summary of the safety profile Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally. Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration. Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions (including cutaneous lupus erythematosus - frequency unknown) have been observed with human normal immunoglobulin. Reversible haemolytic reactions have been observed in patients, especially those with blood groups A, B, and AB. Rarely, haemolytic anaemia requiring transfusion may develop after high dose IVIg treatment (see also Section 4.4). Increase in serum creatinine level and/or acute renal failure have been observed. Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, and deep vein thromboses. Cases of Transfusion Related Acute Lung Injury (TRALI). Tabulated list of adverse reactions The tables presented below are according to the MedDRA system organ classification (SOC and Preferred Term Level). Table 1 shows the adverse reactions from clinical trials and Table 2 shows the post-marketing ARs. Frequencies have been evaluated according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Frequency of Adverse Reactions (ADRs) in clinical studies with KIOVIG MedDRA System Organ Class (SOC) Adverse reaction Frequency Infections and infestations Bronchitis, nasopharyngitis Common Chronic sinusitis, fungal infection, infection, kidney infection, sinusitis, upper respiratory tract infection, urinary tract infection, bacterial urinary tract infection, meningitis aseptic Uncommon Blood and lymphatic system disorders Anaemia, lymphadenopathy Common Immune system disorders Hypersensitivity, anaphylactic reaction Uncommon Endocrine disorders Thyroid disorder Uncommon Metabolism and nutrition disorders Decreased appetite Common Psychiatric disorders Insomnia, anxiety Common Irritability Uncommon Nervous system disorders Headache Very common Dizziness, migraine, paresthesia, hypoesthesia Common 11 Table 1 Frequency of Adverse Reactions (ADRs) in clinical studies with KIOVIG MedDRA System Organ Class (SOC) Adverse reaction Frequency Amnesia, dysarthria, dysgeusia, balance disorder, tremor Uncommon Eye disorders Conjunctivitis Common Eye pain, eye swelling Uncommon Ear and labyrinth disorders Vertigo, fluid in middle ear Uncommon Cardiac disorders Tachycardia Common Vascular disorders Hypertension Very common Flushing Common Peripheral coldness, phlebitis Uncommon Respiratory, thoracic and mediastinal disorders Cough, rhinorrhoea, asthma, nasal congestion, oropharyngeal pain, dyspnea Common Oropharyngeal swelling Uncommon Gastrointestinal disorders Nausea Very common Diarrhoea, vomiting, abdominal pain, dyspepsia Common Abdominal distension Uncommon Skin and subcutaneous tissue disorders Rash Very common Contusion, pruritus, urticaria, dermatitis, erythema Common Angioedema, acute urticaria, cold sweat, photosensitivity reaction, night sweats, hyperhidrosis Uncommon Musculoskeletal and connective tissue disorders Back pain, arthralgia, pain in extremity, myalgia, muscle spasms, muscular weakness Common Muscle twitching Uncommon Renal and urinary disorders Proteinuria Uncommon General disorders and administration site conditions Local reactions (e.g. infusion site pain/swelling/reaction/pruritus), pyrexia, fatigue Very common Chills, edema, influenza-like illness, chest discomfort, chest pain, asthenia, malaise, rigors Common Chest tightness, feeling hot, burning sensation, swelling Uncommon Investigations Blood cholesterol increased, blood creatinine increased, blood urea increased, white blood cell count decreased, alanine aminotransferase increased, haematocrit decreased, red blood cell count decreased, respiratory rate increased Uncommon Table 2 Post-Marketing Adverse Reactions (ARs) MedDRA System Organ Class (SOC) Adverse reaction Frequency Blood and lymphatic system disorders Haemolysis Not known Immune system disorders Anaphylactic shock Not known Nervous system disorders Transient ischemic attack, cerebral vascular accident Not known Cardiac disorders Myocardial infarction Not known Vascular disorders Hypotension, deep vein thrombosis Not known Respiratory, thoracic and mediastinal disorders Pulmonary embolism, pulmonary edema Not known 12 Table 2 Post-Marketing Adverse Reactions (ARs) MedDRA System Organ Class (SOC) Adverse reaction Frequency Investigations Coombs direct test positive, oxygen saturation decreased Not known Injury, poisoning and procedural complications Transfusion-related acute lung injury Not known Description of selected adverse reactions Muscle twitching and weakness were reported only in patients with MMN. Paediatric population Frequency, type and severity of adverse reactions in children are the same as in adults. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. For safety with respect to transmissible agents, see section 4.4. 4.9 Overdose Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with cardiac or renal impairment (see section 4.4 ). Paediatric population Smaller children below the age of 5 years may be particularly susceptible to volume overload. Therefore, dosing should be carefully calculated for this population. In addition, children with Kawasaki Disease are at especially high risk due to underlying cardiac compromise so dose and rate of administration should be carefully controlled. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06BA02 Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range. The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects. 13 Paediatric population There are no theoretical or observed differences in the action of immunoglobulins in children compared to adults. 5.2 Pharmacokinetic properties Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid; after approximately 3 to 5 days equilibrium is reached between the intra- and extravascular compartments. Pharmacokinetic parameters for KIOVIG were determined in the two clinical studies in PID patients performed in Europe and the US. In these studies, a total of 83 subjects at least 2 years of age were treated with doses of 300 to 600 mg/kg body weight every 21 to 28 days for 6 to 12 months. The median IgG half-life after administration of KIOVIG was 32.5 days. This half-life may vary from patient to patient, in particular in primary immunodeficiency. Pharmacokinetic parameters for the product are summarized in the table below. All parameters were analysed separately for three age groups, children (below 12 years, n=5), adolescents (13 to 17 years, n=10), and adults (above 18 years of age, n=64). The values obtained in the studies are comparable to parameters reported for other human immunoglobulins. Summary of KIOVIG pharmacokinetic parameters Parameter Children (12 years or below) Adolescents (13 to 17 years) Adults (18 years or above) Median 95% CI* Median 95% CI Median 95% CI Terminal half-life (days) 41.3 20.2 to 86.8 45.1 27.3 to 89.3 31.9 29.6 to 36.1 Cmin (mg/dl)/(mg/kg) (trough level) 2.28 1.72 to 2.74 2.25 1.98 to 2.64 2.24 1.92 to 2.43 Cmax (mg/dl)/(mg/kg) (peak level) 4.44 3.30 to 4.90 4.43 3.78 to 5.16 4.50 3.99 to 4.78 In-vivo recovery (%) 121 87 to 137 99 75 to 121 104 96 to 114 Incremental recovery (mg/dl)/(mg/kg) 2.26 1.70 to 2.60 2.09 1.78 to 2.65 2.17 1.99 to 2.44 AUC0-21d (g·h/dl) (area under the curve) 1.49 1.34 to 1.81 1.67 1.45 to 2.19 1.62 1.50 to 1.78 *CI – Confidence Interval IgG and IgG-complexes are broken down in cells of the reticuloendothelial system. 5.3 Preclinical safety data Immunoglobulins are normal constituents of the human body. The safety of KIOVIG has been demonstrated in several non-clinical studies. Non-clinical data reveal no special risk for humans based on conventional studies of safety pharmacology and toxicity. Studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction in animals are impracticable due to induction of and interference by developing antibodies to heterologous proteins. Since clinical experience provides no evidence for carcinogenic potential of immunoglobulins, no experimental studies in heterogeneous species were performed. 14 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Glycine Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, nor with any other IVIg products. 6.3 Shelf life 2 years. If dilution to lower concentrations is required, immediate use after dilution is recommended. The in-use stability of KIOVIG after dilution with a 5% glucose solution to a final concentration of 50 mg/ml (5%) immunoglobulin has been demonstrated for 21 days at 2°C to 8°C as well as 28°C to 30°C; however, these studies did not include the microbial contamination and safety aspect. 6.4 Special precautions for storage Do not store above 25°C. Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 10, 25, 50, 100, 200 or 300 ml of solution in a vial (Type I glass) with a stopper (bromobutyl). Pack size: 1 vial Not all presentations may be marketed. 6.6 Special precautions for disposal and other handling The product should be brought to room or body temperature before use. If dilution is required, 5% glucose solution is recommended. For obtaining an immunoglobulin solution of 50 mg/ml (5%), KIOVIG 100 mg/ml (10%) should be diluted with an equal volume of the glucose solution. It is recommended that during dilution the risk of microbial contamination is minimised. The product should be inspected visually for particulate matter and discolouration prior to administration. The solution should be clear or slightly opalescent and colourless or pale yellow. Solutions that are cloudy or have deposits should not be used. KIOVIG should only be administered intravenously. Other routes of administration have not been evaluated. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 15 7. MARKETING AUTHORISATION HOLDER Takeda Manufacturing Austria AG Industriestrasse 67 A-1221 Vienna, Austria 8. MARKETING AUTHORISATION NUMBER(S) EU/1/05/329/001 EU/1/05/329/002 EU/1/05/329/003 EU/1/05/329/004 EU/1/05/329/005 EU/1/05/329/006 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorization: 19 January 2006 Date of latest renewal: 06 December 2010 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/. 16 ANNEX II A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION/THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES 17 A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers of the biological active substance Baxalta Belgium Manufacturing SA Boulevard René Branquart 80 B-7860 Lessines Belgium Name and address of the manufacturers responsible for batch release Baxalta Belgium Manufacturing SA Boulevard René Branquart 80 B-7860 Lessines Belgium The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription.  Official batch release In accordance with Article 114 Directive 2001/83/EC, the official batch release will be undertaken by a state laboratory or a laboratory designated for that purpose. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 18  Additional risk minimisation measures Not applicable.  Obligation to conduct post-authorisation measures Not applicable. E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION/THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES Not applicable. 19 ANNEX III LABELLING AND PACKAGE LEAFLET 20 A. LABELLING 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON (1G, 2.5G, 5G, 10G, 20G AND 30G) 1. NAME OF THE MEDICINAL PRODUCT KIOVIG 100 mg/ml solution for infusion (10%) human normal immunoglobulin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Human protein, 100 mg/ml, at least 98% is IgG. Maximum immunoglobulin A (IgA) content: 140 micrograms/ml. 1 g / 10 ml 2.5 g / 25 ml 5 g / 50 ml 10 g / 100 ml 20 g / 200 ml 30 g / 300 ml 3. LIST OF EXCIPIENTS Glycine Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for infusion (10%) 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: 22 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Do not freeze. Keep the container in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Takeda Manufacturing Austria AG Industriestrasse 67 A-1221 Vienna Austria 12. MARKETING AUTHORISATION NUMBER(S) EU/1/05/329/001 1 g / 10 ml EU/1/05/329/002 2.5 g / 25 ml EU/1/05/329/003 5 g / 50 ml EU/1/05/329/004 10 g / 100 ml EU/1/05/329/005 20 g / 200 ml EU/1/05/329/006 30 g / 300 ml 13. BATCH NUMBER Lot: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE KIOVIG 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 23 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA National unique code included. 24 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING VIAL LABEL (5G, 10G, 20G AND 30G) 1. NAME OF THE MEDICINAL PRODUCT KIOVIG 100 mg/ml solution for infusion human normal immunoglobulin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Human protein, 100 mg/ml, at least 98% is IgG. Maximum immunoglobulin A (IgA) content: 140 micrograms/ml. 5 g / 50 ml 10 g / 100 ml 20 g / 200 ml 30 g / 300 ml 3. LIST OF EXCIPIENTS Glycine Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for infusion (10%) 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: 25 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Do not freeze. Keep the container in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Takeda Manufacturing Austria AG Industriestrasse 67 A-1221 Vienna Austria 12. MARKETING AUTHORISATION NUMBER(S) EU/1/05/329/003 5 g / 50 ml EU/1/05/329/004 10 g / 100 ml EU/1/05/329/005 20 g / 200 ml EU/1/05/329/006 30 g / 300 ml 13. BATCH NUMBER Lot: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA National unique code included. 26 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL (1G) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION KIOVIG 100 mg/ml solution for infusion human normal immunoglobulin Intravenous use. 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 g / 10 ml 6. OTHER 27 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL (2.5G) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION KIOVIG 100 mg/ml solution for infusion human normal immunoglobulin Intravenous use. 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Lot: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2.5 g / 25 ml 6. OTHER Do not store above 25°C. Do not freeze. Keep the container in the outer carton in order to protect from light. 28 B. PACKAGE LEAFLET 29 Package leaflet: Information for the user KIOVIG 100 mg/ml solution for infusion human normal immunoglobulin Read all of this leaflet carefully before you start using this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor, pharmacist or nurse.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What KIOVIG is and what it is used for 2. What you need to know before you use KIOVIG 3. How to use KIOVIG 4. Possible side effects 5. How to store KIOVIG 6. Contents of the pack and other information 1. What KIOVIG is and what it is used for KIOVIG belongs to a class of medications called immunoglobulins. These medicines contain human antibodies, which are also present in your blood. Antibodies help your body to fight infections. Medicines like KIOVIG are used in patients who do not have enough antibodies in their blood and tend to get frequent infections. They can also be used in patients who need additional antibodies for the cure of certain inflammatory disorders (autoimmune diseases). KIOVIG is used for Treatment of patients who do not have sufficient antibodies (replacement therapy). There are two groups: 1. Patients with inborn lack of antibody production (primary immunodeficiency syndromes). 2. Patients with secondary immunodeficiencies (SID) who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or serum IgG level of <4 g/l. *PSAF = failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines Treatment of patients with certain inflammatory disorders (immunomodulation). There are five groups: 1. Patients who do not have enough blood platelets (primary immune thrombocytopenia, ITP), and who are at high risk of bleeding or will have surgery in the near future. 2. Patients with a disease that is associated with multiple inflammations of the nerves in the whole body (Guillain Barré syndrome). 3. Patients with a disease which results in multiple inflammations of several organs of the body (Kawasaki disease). 4. Patients who suffer from a rare condition characterized by slow progressive asymmetrical weakness of limbs without sensory loss (multifocal motor neuropathy, MMN). 30 5. Patients who suffer from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). 2. What you need to know before you use KIOVIG Do not use KIOVIG if you are allergic to immunoglobulins or to any other ingredients of this medicine (listed in section 6). For example, if you have an immunoglobulin A deficiency, you may have antibodies against immunoglobulin A in your blood. Since KIOVIG contains trace amounts of immunoglobulin A (less than 0.14 mg/ml), you might get an allergic reaction. Warnings and precautions Talk to your doctor, pharmacist or nurse before using KIOVIG. How long monitoring is required during the infusion  You will be carefully observed during the infusion period with KIOVIG to make sure that you do not suffer a reaction. Your doctor will make sure that the rate at which KIOVIG is infused is suitable for you.  If KIOVIG is administered at a high rate, if you suffer from a condition with low antibody levels in your blood (hypo- or agammaglobulinemia), if you have not received this medicine before or if there has been a long interval (e.g. several weeks) since you last received it, there may be a higher risk of side effects. In such cases, you will be closely monitored during your infusion and for an hour after your infusion has stopped.  If you have already received KIOVIG previously and received the last treatment recently, then you will only be observed during the infusion and for at least 20 minutes after your infusion. When slowing or stopping the infusion may be required In rare cases your body may have previously reacted to specific antibodies and therefore will be sensitive to medicines containing antibodies. This may happen particularly if you suffer from immunoglobulin A deficiency. In these rare cases, you may get allergic reactions such as a sudden fall in blood pressure or shock even if you have already received treatment with medicines containing antibodies in the past. If you experience a reaction during the infusion of KIOVIG, tell your doctor immediately. Depending on your doctor’s decision the rate of infusion can be slowed or the infusion can be stopped altogether. Special patient groups  Your doctor will take special care if you are overweight, elderly, diabetic, or if you suffer from high blood pressure, low blood volume (hypovolaemia), or problems with your blood vessels (vascular diseases). In these conditions, immunoglobulins may increase the risk of cardiac infarction, stroke, lung embolism, or deep vein thrombosis, although only in very rare cases. Tell your doctor if you are diabetic. Although KIOVIG does not contain sugar, it may be diluted with a special sugar solution (5% glucose), which could affect your blood sugar level.  Your doctor will also take special care if you have or had previously problems with your kidneys, or if you receive medicinal products that may harm your kidney (nephrotoxic medicinal products), as there is a very rare chance of acute kidney failure. Please tell your doctor if you have a kidney disorder. Your doctor will choose the appropriate intravenous immunoglobulin for you. 31 Information on the source material of KIOVIG KIOVIG is made from human plasma (the liquid part of blood). When medicines are made from human blood or plasma, a number of measures are put in place to prevent infections being passed on to patients. These include careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and the testing of each donation and pools of plasma for signs of virus/infections. Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections. The measures taken for the manufacture of KIOVIG are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, and for the non-enveloped hepatitis A virus and parvovirus B19. KIOVIG also contains certain antibodies that can prevent an infection with hepatitis A virus and parvovirus B19. Other medicines and KIOVIG Tell your doctor or pharmacist if you are taking, or have recently taken or might take any other medicines. If you have received a vaccination during the last six weeks and up to three months, the infusion of immunoglobulins like KIOVIG may impair the effect of some live virus vaccines such as measles, rubella, mumps and chicken pox. Therefore, after receiving immunoglobulins you may have to wait up to 3 months before receiving your live-attenuated vaccine. You may have to wait for up to 1 year after receiving immunoglobulins before you receive your measles vaccine. Effects on blood tests KIOVIG contains a wide variety of different antibodies, some of which can affect blood tests. If you have a blood test after receiving KIOVIG, please inform the person taking your blood or your doctor that you have received the medication. Pregnancy, breast-feeding and fertility  If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.  No clinical trials have been made with KIOVIG in pregnant or breast-feeding women. However, medicines that contain antibodies have been used in pregnant or breast-feeding women, and it has been shown that there are no harmful effects on the course of pregnancy or the baby to be expected.  If you are breast-feeding and receive KIOVIG, the antibodies of the medicine can also be found in the breast milk. Therefore, your baby may be protected from certain infections. Driving and using machines Patients may experience reactions (for example dizziness or nausea) during the treatment with KIOVIG, which might affect the ability to drive and use machines. If this happens, you should wait until the reactions have disappeared. 3. How to use KIOVIG KIOVIG is intended for intravenous administration (infusion into a vein). It is given to you by your doctor or nurse. Dose and frequency of the infusion will vary depending on your condition and your body weight. 32 At the beginning of your infusion you will receive KIOVIG at a slow rate. Dependent on how comfortable you are, your doctor may then gradually increase the infusion rate. Use in children and adolescents The same indications, dose and frequency of infusion as for adults apply for children and adolescents (age 0 to 18). If you use more KIOVIG than you should If you get more KIOVIG than you should, your blood may become too thick (hyperviscous). This could particularly happen when you are a patient at risk, e.g. an elderly patient or a patient having problems with your kidneys. Be sure that you take adequate fluids so you are not dehydrated and notify your physician if you are known to have medical problems. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Certain side effects, e.g. headache or flushing, may be reduced by slowing the infusion rate. Below is a list of side effects reported with KIOVIG:  Very common side effects (may affect more than 1 in 10 people): Headache, high blood pressure, nausea, rash, local reactions (e.g. pain and swelling or other reactions at the infusion site), fever, tiredness.  Common side effects (may affect up to 1 in 10 people): Bronchitis, common cold, low red blood cell count, swollen lymph glands, decreased appetite, difficulty in sleeping, anxiety, dizziness, migraine, numbness or tingling of the skin or of a limb, reduced sense of touch, eye inflammation, rapid heartbeat, flushing, cough, runny nose, chronic cough or wheezing (asthma), stuffy nose, sore throat, shortness of breath, diarrhoea, vomiting, abdominal pain, indigestion, contusion, itchingand hives, dermatitis, reddened skin, pain in your back, pain in your joints, pain in your arms or legs, muscle pain, muscle cramps, muscular weakness, chills, accumulation of fluid under the skin, influenza-like illness, pain or discomfort in the chest, lack of strength or feeling of weakness, indisposition, shaking chills.  Uncommon side effects (may affect up to 1 in 100 people): Chronic infection of the nose, fungal infections, various infections (of the nose and throat, kidney or bladder), sterile inflammation of the layers lining the brain, serious allergic reactions, disorder of the thyroid, excessive response to stimuli, memory impairment, difficulty in speaking, unusual taste in the mouth, impaired balance, involuntary trembling, eye pain or swelling, vertigo, fluid in middle ear, peripheral coldness, vein inflammation, ear and throat swelling, abdominal distension, rapid swelling of the skin, acute inflammation of the skin, cold sweat, increased reaction of the skin to sunlight, excessive sweating also during sleep, muscle twitching, excess of serum protein in the urine, chest tightness, feeling hot, burning sensation, swelling, increased rate of breathing, changes to blood test results.  Frequency not known (cannot be estimated from available data): Destruction of red blood cells, life-threatening allergic shock, transient stroke, stroke, low blood pressure, heart attack, blood clot in a major vein, blood clot in the main artery of the lung, accumulation of fluid in the lung, positive result of Coombs test, decreased oxygen saturation in blood, transfusion-related acute lung injury. 33 Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store KIOVIG  Keep this medicine out of the sight and reach of children.  Do not use this medicine after the expiry date which is printed on the label and carton after EXP. The expiry date refers to the last day of that month.  Do not use this medicine if you notice particulate matter or discolouration.  Do not store above 25°C.  Do not freeze.  Keep the container in the outer carton in order to protect from light. 6. Contents of the pack and other information What KIOVIG contains  The active substance of KIOVIG is human normal immunoglobulin.  1 ml of KIOVIG contains 100 mg of human protein of which at least 98% is immunoglobulin G (IgG).  The other ingredients (excipients) are glycine and water for injections. What KIOVIG looks like and contents of the pack KIOVIG is a solution for infusion in vials of 10, 25, 50, 100, 200 or 300 ml. The solution is clear or slightly opalescent and colourless or pale-yellow. Not all presentations may be marketed. Marketing Authorisation Holder Takeda Manufacturing Austria AG Industriestrasse 67 A-1221 Vienna Austria Tel.: +800 66838470 E-mail: medinfoEMEA@shire.com Manufacturer Baxalta Belgium Manufacturing SA Boulevard René Branquart, 80 B-7860 Lessines Belgium This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/ 34 The following information is intended for healthcare professionals only: Method of administration  KIOVIG must only be administered intravenously. Other routes of administration have not been evaluated.  KIOVIG should be infused intravenously at an initial rate of 0.5 ml/kg bodyweight/hour for 30 minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 6 ml/kg bodyweight/hour. Clinical data obtained from a limited number of patients also indicate that adult PID patients may tolerate an infusion rate of up to 8 ml/kg BW/hr.  If dilution to lower concentrations is required prior to infusion, KIOVIG may be diluted with 5% glucose solution to a final concentration of 50 mg/ml (5% immunoglobulin).  Any infusion-related adverse events should be treated by lowering infusion rates or by stopping the infusion. Special precautions  Any infusion-related adverse events should be treated by lowering the infusion rate or by stopping the infusion.  It is recommended that every time KIOVIG is administered, the name and batch number of the product is recorded. Incompatibilities This medicinal product must not be mixed with other medicinal products. Special precautions for storage  After dilution to lower concentrations, immediate use is recommended. The in-use stability of KIOVIG after dilution with a 5% glucose solution to a final concentration of 50 mg/ml (5% immunoglobulin) has been demonstrated for 21 days at 2°C to 8°C as well as at 28°C to 30°C; however, these studies did not include the microbial contamination and safety aspects. Instructions for handling and disposal  The product must be brought to room or body temperature before use.  KIOVIG should be inspected visually for particulate matter and discoloration prior to administration. Only clear to slightly opalescent and colourless to pale yellow solutions are to be administered. Do not use if particulate matter or discolouration is observed.  If dilution is required, 5% glucose solution is recommended. For obtaining an immunoglobulin solution of 50 mg/ml (5%), KIOVIG 100 mg/ml (10%) should be diluted with an equal volume of the glucose solution. It is recommended that during dilution the risk of microbial contamination is minimised.  Any unused product or waste material should be disposed of in accordance with local requirements. 35 Dose recommendations Indication Dose Frequency of injections Replacement therapy in primary immunodeficiency starting dose: 0.4-0.8 g/kg maintenance dose: 0.2-0.8 g/kg every 3-4 weeks to obtain IgG trough level of at least 5-6 g/l Replacement therapy in secondary immunodeficiency 0.2-0.4 g/kg every 3-4 weeks to obtain IgG trough level of at least 5-6 g/l Immunomodulation: Primary immune thrombocytopenia 0.8-1 g/kg or 0.4 g/kg/d on day 1, possibly repeated once within 3 days for 2-5 days Guillain Barré syndrome 0.4 g/kg/d for 5 days Kawasaki disease 2 g/kg in one dose in association with acetylsalicylic acid Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Starting dose 2g/kg maintenance dose 1g/kg In divided doses over 2-5 days Every 3 weeks over 1-2 days Multifocal Motor Neuropathy (MMN) starting dose: 2 g/kg maintenance dose: 1 g/kg or 2 g/kg given over 2-5 days every 2-4 weeks or every 4-8 weeks over 2-5 days SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION/THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what kiovig is and what it is used for', 'Section_Content': 'kiovig belongs to a class of medications called immunoglobulins. these medicines contain human antibodies, which are also present in your blood. antibodies help your body to fight infections. medicines like kiovig are used in patients who do not have enough antibodies in their blood and tend to get frequent infections. they can also be used in patients who need additional antibodies for the cure of certain inflammatory disorders (autoimmune diseases). kiovig is used for treatment of patients who do not have sufficient antibodies (replacement therapy). there are two groups: 1. patients with inborn lack of antibody production (primary immunodeficiency syndromes). 2. patients with secondary immunodeficiencies (sid) who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (psaf)* or serum igg level of <4 g/l. *psaf = failure to mount at least a 2-fold rise in igg antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines treatment of patients with certain inflammatory disorders (immunomodulation). there are five groups: 1. patients who do not have enough blood platelets (primary immune thrombocytopenia, itp), and who are at high risk of bleeding or will have surgery in the near future. 2. patients with a disease that is associated with multiple inflammations of the nerves in the whole body (guillain barré syndrome). 3. patients with a disease which results in multiple inflammations of several organs of the body (kawasaki disease). 4. patients who suffer from a rare condition characterized by slow progressive asymmetrical weakness of limbs without sensory loss (multifocal motor neuropathy, mmn). 5. patients who suffer from chronic inflammatory demyelinating polyradiculoneuropathy (cidp).', 'Entity_Recognition': [{'Text': 'kiovig', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 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{'Title': '2. what you need to know before you use kiovig', 'Section_Content': "do not use kiovig if you are allergic to immunoglobulins or to any other ingredients of this medicine (listed in section 6). for example, if you have an immunoglobulin a deficiency, you may have antibodies against immunoglobulin a in your blood. since kiovig contains trace amounts of immunoglobulin a (less than 0.14 mg/ml), you might get an allergic reaction. warnings and precautions talk to your doctor, pharmacist or nurse before using kiovig. how long monitoring is required during the infusion you will be carefully observed during the infusion period with kiovig to make sure that you do not suffer a reaction. your doctor will make sure that the rate at which kiovig is infused is suitable for you. if kiovig is administered at a high rate, if you suffer from a condition with low antibody levels in your blood (hypo- or agammaglobulinemia), if you have not received this medicine before or if there has been a long interval (e.g. several weeks) since you last received it, there may be a higher risk of side effects. in such cases, you will be closely monitored during your infusion and for an hour after your infusion has stopped. if you have already received kiovig previously and received the last treatment recently, then you will only be observed during the infusion and for at least 20 minutes after your infusion. when slowing or stopping the infusion may be required in rare cases your body may have previously reacted to specific antibodies and therefore will be sensitive to medicines containing antibodies. this may happen particularly if you suffer from immunoglobulin a deficiency. in these rare cases, you may get allergic reactions such as a sudden fall in blood pressure or shock even if you have already received treatment with medicines containing antibodies in the past. if you experience a reaction during the infusion of kiovig, tell your doctor immediately. depending on your doctor's decision the rate of infusion can be slowed or the infusion can be stopped altogether. special patient groups your doctor will take special care if you are overweight, elderly, diabetic, or if you suffer from high blood pressure, low blood volume (hypovolaemia), or problems with your blood vessels (vascular diseases). in these conditions, immunoglobulins may increase the risk of cardiac infarction, stroke, lung embolism, or deep vein thrombosis, although only in very rare cases. tell your doctor if you are diabetic. although kiovig does not contain sugar, it may be diluted with a special sugar solution (5% glucose), which could affect your blood sugar level. your doctor will also take special care if you have or had previously problems with your kidneys, or if you receive medicinal products that may harm your kidney (nephrotoxic medicinal products), as there is a very rare chance of acute kidney failure. please tell your doctor if you have a kidney disorder. your doctor will choose the appropriate intravenous immunoglobulin for you. information on the source material of kiovig kiovig is made from human plasma (the liquid part of blood). when medicines are made from human blood or plasma, a number of measures are put in place to prevent infections being passed on to patients. these include careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and the testing of each donation and pools of plasma for signs of virus/infections. manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. this also applies to any unknown or emerging viruses or other types of infections. the measures taken for the manufacture of kiovig are considered effective for enveloped viruses such as human immunodeficiency virus (hiv), hepatitis b virus and hepatitis c virus, and for the non-enveloped hepatitis a virus and parvovirus b19. kiovig also contains certain antibodies that can prevent an infection with hepatitis a virus and parvovirus b19. other medicines and kiovig tell your doctor or pharmacist if you are taking, or have recently taken or might take any other medicines. if you have received a vaccination during the last six weeks and up to three months, the infusion of immunoglobulins like kiovig may impair the effect of some live virus vaccines such as measles, rubella, mumps and chicken pox. therefore, after receiving immunoglobulins you may have to wait up to 3 months before receiving your live-attenuated vaccine. you may have to wait for up to 1 year after receiving immunoglobulins before you receive your measles vaccine. effects on blood tests kiovig contains a wide variety of different antibodies, some of which can affect blood tests. if you have a blood test after receiving kiovig, please inform the person taking your blood or your doctor that you have received the medication. pregnancy, breast-feeding and fertility if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. no clinical trials have been made with kiovig in pregnant or breast-feeding women. however, medicines that contain antibodies have been used in pregnant or breast-feeding women, and it has been shown that there are no harmful effects on the course of pregnancy or the baby to be expected. if you are breast-feeding and receive kiovig, the antibodies of the medicine can also be found in the breast milk. therefore, your baby may be protected from certain infections. driving and using machines patients may experience reactions (for example dizziness or nausea) during the treatment with kiovig, which might affect the ability to drive and use machines. if this happens, you 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{'Title': '3. how to use kiovig', 'Section_Content': 'kiovig is intended for intravenous administration (infusion into a vein). it is given to you by your doctor or nurse. dose and frequency of the infusion will vary depending on your condition and your body weight. at the beginning of your infusion you will receive kiovig at a slow rate. dependent on how comfortable you are, your doctor may then gradually increase the infusion rate. use in children and adolescents the same indications, dose and frequency of infusion as for adults apply for children and adolescents (age 0 to 18). if you use more kiovig than you should if you get more kiovig than you should, your blood may become too thick (hyperviscous). this could particularly happen when you are a patient at risk, e.g. an elderly patient or a patient having problems with your kidneys. be sure that you take adequate fluids so you are not dehydrated and notify your physician if you are known to have medical problems.', 'Entity_Recognition': [{'Text': 'kiovig', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'kiovig', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 6}, {'Text': 'intravenous administration', 'Type': 'TREATMENT', 'BeginOffset': 23, 'EndOffset': 49}, {'Id': 0, 'BeginOffset': 67, 'EndOffset': 71, 'Score': 0.7415896654129028, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the infusion', 'Type': 'TREATMENT', 'BeginOffset': 140, 'EndOffset': 152}, {'Text': 'your body weight', 'Type': 'TEST', 'BeginOffset': 195, 'EndOffset': 211}, {'Text': 'your infusion', 'Type': 'TREATMENT', 'BeginOffset': 233, 'EndOffset': 246}, {'Text': 'kiovig', 'Type': 'TREATMENT', 'BeginOffset': 264, 'EndOffset': 270}, {'Text': 'the infusion rate', 'Type': 'TREATMENT', 'BeginOffset': 365, 'EndOffset': 382}, {'Id': 5, 'BeginOffset': 460, 'EndOffset': 468, 'Score': 0.44728365540504456, 'Text': 'infusion', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': '0', 'Type': 'NUMBER', 'BeginOffset': 523, 'EndOffset': 524}, {'Id': 2, 'BeginOffset': 588, 'EndOffset': 594, 'Score': 0.37498021125793457, 'Text': 'kiovig', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'your blood', 'Type': 'TEST', 'BeginOffset': 612, 'EndOffset': 622}, {'Text': 'too thick', 'Type': 'PROBLEM', 'BeginOffset': 634, 'EndOffset': 643}, {'Text': 'your kidneys', 'Type': 'PROBLEM', 'BeginOffset': 781, 'EndOffset': 793}, {'Id': 3, 'BeginOffset': 848, 'EndOffset': 858, 'Score': 0.8554569482803345, 'Text': 'dehydrated', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6707650423049927}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9248562455177307, 'RelationshipScore': 0.5341456532478333, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 786, 'EndOffset': 793, 'Text': 'kidneys', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'medical problems', 'Type': 'PROBLEM', 'BeginOffset': 910, 'EndOffset': 926}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. certain side effects, e.g. headache or flushing, may be reduced by slowing the infusion rate. below is a list of side effects reported with kiovig: very common side effects (may affect more than 1 in 10 people): headache, high blood pressure, nausea, rash, local reactions (e.g. pain and swelling or other reactions at the infusion site), fever, tiredness. common side effects (may affect up to 1 in 10 people): bronchitis, common cold, low red blood cell count, swollen lymph glands, decreased appetite, difficulty in sleeping, anxiety, dizziness, migraine, numbness or tingling of the skin or of a limb, reduced sense of touch, eye inflammation, rapid heartbeat, flushing, cough, runny nose, chronic cough or wheezing (asthma), stuffy nose, sore throat, shortness of breath, diarrhoea, vomiting, abdominal pain, indigestion, contusion, itchingand hives, dermatitis, reddened skin, pain in your back, pain in your joints, pain in your arms or legs, muscle pain, muscle cramps, muscular weakness, chills, accumulation of fluid under the skin, influenza-like illness, pain or discomfort in the chest, lack of strength or feeling of weakness, indisposition, shaking chills. uncommon side effects (may affect up to 1 in 100 people): chronic infection of the nose, fungal infections, various infections (of the nose and throat, kidney or bladder), sterile inflammation of the layers lining the brain, serious allergic reactions, disorder of the thyroid, excessive response to stimuli, memory impairment, difficulty in speaking, unusual taste in the mouth, impaired balance, involuntary trembling, eye pain or swelling, vertigo, fluid in middle ear, peripheral coldness, vein inflammation, ear and throat swelling, abdominal distension, rapid swelling of the skin, acute inflammation of the skin, cold sweat, increased reaction of the skin to sunlight, excessive sweating also during sleep, muscle twitching, excess of serum protein in the urine, chest tightness, feeling hot, burning sensation, swelling, increased rate of breathing, changes to blood test results. frequency not known (cannot be estimated from available data): destruction of red blood cells, life-threatening allergic shock, transient stroke, stroke, low blood pressure, heart attack, blood clot in a major vein, blood clot in the main artery of the lung, accumulation of fluid in the lung, positive result of coombs test, decreased oxygen saturation in blood, transfusion-related acute lung injury. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': 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legs', 'Type': 'PROBLEM', 'BeginOffset': 1015, 'EndOffset': 1040}, {'Id': 88, 'BeginOffset': 1042, 'EndOffset': 1053, 'Score': 0.743918776512146, 'Text': 'muscle pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9748544692993164}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9993207454681396, 'RelationshipScore': 0.7195102572441101, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 11, 'BeginOffset': 1028, 'EndOffset': 1032, 'Text': 'arms', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 89, 'BeginOffset': 1055, 'EndOffset': 1068, 'Score': 0.8949332237243652, 'Text': 'muscle cramps', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9830605387687683}]}, {'Id': 90, 'BeginOffset': 1070, 'EndOffset': 1087, 'Score': 0.954373300075531, 'Text': 'muscular weakness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9868974089622498}]}, {'Id': 91, 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28, 'BeginOffset': 1732, 'EndOffset': 1735, 'Text': 'ear', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 119, 'BeginOffset': 1737, 'EndOffset': 1756, 'Score': 0.7820689082145691, 'Text': 'peripheral coldness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.973680853843689}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.8023372292518616, 'RelationshipScore': 0.9263556599617004, 'RelationshipType': 'DIRECTION', 'Id': 29, 'BeginOffset': 1737, 'EndOffset': 1747, 'Text': 'peripheral', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 120, 'BeginOffset': 1758, 'EndOffset': 1775, 'Score': 0.9236246943473816, 'Text': 'vein inflammation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9445583820343018}]}, {'Id': 121, 'BeginOffset': 1777, 'EndOffset': 1800, 'Score': 0.3490542471408844, 'Text': 'ear and throat swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.990710437297821}]}, {'Id': 32, 'BeginOffset': 1785, 'EndOffset': 1791, 'Score': 0.9981980919837952, 'Text': 'throat', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 122, 'BeginOffset': 1802, 'EndOffset': 1822, 'Score': 0.9645493030548096, 'Text': 'abdominal distension', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9791395664215088}]}, {'Text': 'rapid swelling of the skin', 'Type': 'PROBLEM', 'BeginOffset': 1824, 'EndOffset': 1850}, {'Text': 'acute inflammation of the skin', 'Type': 'PROBLEM', 'BeginOffset': 1852, 'EndOffset': 1882}, {'Id': 126, 'BeginOffset': 1884, 'EndOffset': 1894, 'Score': 0.7376344203948975, 'Text': 'cold sweat', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.884092390537262}], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.984058678150177, 'RelationshipScore': 0.6977078914642334, 'RelationshipType': 'ACUITY', 'Id': 124, 'BeginOffset': 1852, 'EndOffset': 1857, 'Text': 'acute', 'Category': 'MEDICAL_CONDITION', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9965391159057617, 'RelationshipScore': 0.5030778050422668, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 34, 'BeginOffset': 1878, 'EndOffset': 1882, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'increased reaction of the skin', 'Type': 'PROBLEM', 'BeginOffset': 1896, 'EndOffset': 1926}, {'Id': 139, 'BeginOffset': 1940, 'EndOffset': 1958, 'Score': 0.4454633891582489, 'Text': 'excessive sweating', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9037904739379883}]}, {'Id': 140, 'BeginOffset': 1978, 'EndOffset': 1994, 'Score': 0.8184137344360352, 'Text': 'muscle twitching', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9474698305130005}]}, {'Text': 'excess of serum protein in the urine', 'Type': 'PROBLEM', 'BeginOffset': 1996, 'EndOffset': 2032}, {'Id': 142, 'BeginOffset': 2034, 'EndOffset': 2049, 'Score': 0.8839526176452637, 'Text': 'chest tightness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.941148579120636}]}, {'Id': 143, 'BeginOffset': 2051, 'EndOffset': 2062, 'Score': 0.964739978313446, 'Text': 'feeling hot', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9005588293075562}]}, {'Id': 144, 'BeginOffset': 2064, 'EndOffset': 2081, 'Score': 0.8922035098075867, 'Text': 'burning sensation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9703234434127808}]}, {'Id': 145, 'BeginOffset': 2083, 'EndOffset': 2091, 'Score': 0.9980145692825317, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9722439050674438}]}, {'Id': 146, 'BeginOffset': 2093, 'EndOffset': 2120, 'Score': 0.5582517385482788, 'Text': 'increased rate of breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9304441213607788}]}, {'Id': 165, 'BeginOffset': 2133, 'EndOffset': 2143, 'Score': 0.841230571269989, 'Text': 'blood test', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 147, 'BeginOffset': 2216, 'EndOffset': 2246, 'Score': 0.470460444688797, 'Text': 'destruction of red blood cells', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6003122329711914}]}, {'Text': 'life-threatening allergic shock', 'Type': 'PROBLEM', 'BeginOffset': 2248, 'EndOffset': 2279}, {'Text': 'transient stroke', 'Type': 'PROBLEM', 'BeginOffset': 2281, 'EndOffset': 2297}, {'Id': 151, 'BeginOffset': 2299, 'EndOffset': 2305, 'Score': 0.9974873065948486, 'Text': 'stroke', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8431938290596008}]}, {'Id': 152, 'BeginOffset': 2307, 'EndOffset': 2325, 'Score': 0.8597930669784546, 'Text': 'low blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6312434077262878}, {'Name': 'DIAGNOSIS', 'Score': 0.46395814418792725}]}, {'Id': 153, 'BeginOffset': 2327, 'EndOffset': 2339, 'Score': 0.9848330616950989, 'Text': 'heart attack', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8127798438072205}]}, {'Id': 154, 'BeginOffset': 2341, 'EndOffset': 2351, 'Score': 0.9803014397621155, 'Text': 'blood clot', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5375062823295593}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.919239342212677, 'RelationshipScore': 0.9441195726394653, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 132, 'BeginOffset': 2363, 'EndOffset': 2367, 'Text': 'vein', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'a major vein', 'Type': 'PROBLEM', 'BeginOffset': 2355, 'EndOffset': 2367}, {'Id': 155, 'BeginOffset': 2369, 'EndOffset': 2379, 'Score': 0.8773807287216187, 'Text': 'blood clot', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.45921796560287476}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.6891943216323853, 'RelationshipScore': 0.9666600227355957, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 133, 'BeginOffset': 2392, 'EndOffset': 2398, 'Text': 'artery', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9924829602241516, 'RelationshipScore': 0.9800171852111816, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 134, 'BeginOffset': 2406, 'EndOffset': 2410, 'Text': 'lung', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 133, 'BeginOffset': 2392, 'EndOffset': 2398, 'Score': 0.6891943216323853, 'Text': 'artery', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 134, 'BeginOffset': 2406, 'EndOffset': 2410, 'Score': 0.9924829602241516, 'Text': 'lung', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'accumulation of fluid in the lung', 'Type': 'PROBLEM', 'BeginOffset': 2412, 'EndOffset': 2445}, {'Id': 166, 'BeginOffset': 2466, 'EndOffset': 2477, 'Score': 0.7054272890090942, 'Text': 'coombs test', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'decreased oxygen saturation in blood', 'Type': 'PROBLEM', 'BeginOffset': 2479, 'EndOffset': 2515}, {'Text': 'transfusion', 'Type': 'TREATMENT', 'BeginOffset': 2517, 'EndOffset': 2528}, {'Text': 'acute lung injury', 'Type': 'PROBLEM', 'BeginOffset': 2537, 'EndOffset': 2554}, {'Id': 159, 'BeginOffset': 2569, 'EndOffset': 2581, 'Score': 0.9419428706169128, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6936765313148499}]}, {'Id': 160, 'BeginOffset': 2597, 'EndOffset': 2609, 'Score': 0.9095843434333801, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7320847511291504}]}, {'Id': 161, 'BeginOffset': 2680, 'EndOffset': 2692, 'Score': 0.9538949131965637, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6293585300445557}]}, {'Id': 162, 'BeginOffset': 2741, 'EndOffset': 2753, 'Score': 0.8630495667457581, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6964070796966553}]}, {'Id': 163, 'BeginOffset': 2807, 'EndOffset': 2818, 'Score': 0.3814258575439453, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6072842478752136}]}, {'Id': 164, 'BeginOffset': 2832, 'EndOffset': 2844, 'Score': 0.8611790537834167, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.735820472240448}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2900, 'EndOffset': 2913}]}

{'Title': '5. how to store kiovig', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is printed on the label and carton after exp. the expiry date refers to the last day of that month. do not use this medicine if you notice particulate matter or discolouration. do not store above 25. do not freeze. keep the container in the outer carton in order to protect from light.', 'Entity_Recognition': [{'Text': 'kiovig', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 71, 'EndOffset': 84}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 224, 'EndOffset': 237}, {'Text': 'particulate matter', 'Type': 'PROBLEM', 'BeginOffset': 252, 'EndOffset': 270}, {'Text': 'discolouration', 'Type': 'PROBLEM', 'BeginOffset': 274, 'EndOffset': 288}, {'Text': '25.', 'Type': 'NUMBER', 'BeginOffset': 309, 'EndOffset': 312}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 350, 'EndOffset': 366}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what kiovig contains the active substance of kiovig is human normal immunoglobulin. 1 ml of kiovig contains 100 mg of human protein of which at least 98% is immunoglobulin g (igg). the other ingredients (excipients) are glycine and water for injections. what kiovig looks like and contents of the pack kiovig is a solution for infusion in vials of 10, 25, 50, 100, 200 or 300 ml. the solution is clear or slightly opalescent and colourless or pale-yellow. not all presentations may be marketed.', 'Entity_Recognition': [{'Text': 'kiovig', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 84, 'EndOffset': 85}, {'Text': 'kiovig', 'Type': 'TREATMENT', 'BeginOffset': 92, 'EndOffset': 98}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 108, 'EndOffset': 111}, {'Text': 'human protein', 'Type': 'TREATMENT', 'BeginOffset': 118, 'EndOffset': 131}, {'Text': '98', 'Type': 'NUMBER', 'BeginOffset': 150, 'EndOffset': 152}, {'Text': 'glycine', 'Type': 'TREATMENT', 'BeginOffset': 220, 'EndOffset': 227}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 242, 'EndOffset': 252}, {'Text': 'infusion in vials', 'Type': 'TREATMENT', 'BeginOffset': 327, 'EndOffset': 344}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 348, 'EndOffset': 350}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 352, 'EndOffset': 354}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 356, 'EndOffset': 358}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 360, 'EndOffset': 363}, {'Text': '200', 'Type': 'NUMBER', 'BeginOffset': 365, 'EndOffset': 368}, {'Text': '300', 'Type': 'NUMBER', 'BeginOffset': 372, 'EndOffset': 375}, {'Text': 'slightly opalescent', 'Type': 'PROBLEM', 'BeginOffset': 405, 'EndOffset': 424}]}

656C3533BF06E19D8AF505AF291867F2

https://www.ema.europa.eu/documents/product-information/lorviqua-epar-product-information_en.pdf

Lorviqua

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Lorviqua 25 mg film-coated tablets Lorviqua 100 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Lorviqua 25 mg film-coated tablets Each film-coated tablet contains 25 mg of lorlatinib. Excipient with known effect Each film-coated tablet contains 1.58 mg of lactose monohydrate. Lorviqua 100 mg film-coated tablets Each film-coated tablet contains 100 mg of lorlatinib. Excipient with known effect Each film-coated tablet contains 4.20 mg of lactose monohydrate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Lorviqua 25 mg film-coated tablets Round (8 mm) light pink immediate release film-coated tablet, debossed with “Pfizer” on one side and “25” and “LLN” on the other side. Lorviqua 100 mg film-coated tablets Oval (8.5 × 17 mm) dark pink immediate release film-coated tablet, debossed with “Pfizer” on one side and “LLN 100” on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after: • alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy; or • crizotinib and at least one other ALK TKI. 3 4.2 Posology and method of administration Treatment with lorlatinib should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Posology The recommended dose is 100 mg lorlatinib taken orally once daily. Duration of treatment Treatment with lorlatinib is recommended as long as the patient is deriving clinical benefit from therapy without unacceptable toxicity. Delayed or missed doses If a dose of Lorviqua is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose. Dose modifications Dosing interruption or dose reduction may be required based on individual safety and tolerability. Lorlatinib dose reduction levels are summarised below: • First dose reduction: 75 mg taken orally once daily • Second dose reduction: 50 mg taken orally once daily Lorlatinib should be permanently discontinued if the patient is unable to tolerate the 50 mg dose taken orally once daily. Dose modification recommendations for toxicities and for patients who develop atrioventricular (AV) block are provided in Table 1. Table 1. Recommended lorlatinib dose modifications for adverse reactions Adverse reactiona Lorlatinib dosing Hypercholesterolaemia or hypertriglyceridaemia Mild hypercholesterolaemia (cholesterol between ULN and 300 mg/dL or between ULN and 7.75 mmol/L) OR Moderate hypercholesterolaemia (cholesterol between 301 and 400 mg/dL or between 7.76 and 10.34 mmol/L) OR Mild hypertriglyceridaemia (triglycerides between 150 and 300 mg/dL or 1.71 and 3.42 mmol/L) OR Moderate hypertriglyceridaemia (triglycerides between 301 and 500 mg/dL or 3.43 and 5.7 mmol/L) Introduce or modify lipid-lowering therapyb in accordance with respective prescribing information; continue lorlatinib at same dose. 4 Table 1. Recommended lorlatinib dose modifications for adverse reactions Adverse reactiona Lorlatinib dosing Severe hypercholesterolaemia (cholesterol between 401 and 500 mg/dL or between 10.35 and 12.92 mmol/L) OR Severe hypertriglyceridaemia (triglycerides between 501 and 1,000 mg/dL or 5.71 and 11.4 mmol/L) Introduce the use of lipid-lowering therapy b; if currently on lipid-lowering therapy, increase the dose of this therapyb in accordance with respective prescribing information; or change to a new lipid-lowering therapyb. Continue lorlatinib at the same dose without interruption. Life-threatening hypercholesterolaemia (cholesterol over 500 mg/dL or over 12.92 mmol/L) OR Life-threatening hypertriglyceridaemia (triglycerides over 1,000 mg/dL or over 11.4 mmol/L) Introduce the use of lipid-lowering therapyb or increase the dose of this therapyb in accordance with respective prescribing information or change to a new lipid-lowering therapyb. Withhold lorlatinib until recovery of hypercholesterolaemia and/or hypertriglyceridaemia to moderate or mild severity grade. Re-challenge at same lorlatinib dose while maximising lipid-lowering therapyb in accordance with respective prescribing information. If severe hypercholesterolaemia and/or hypertriglyceridaemia recur despite maximal lipid-lowering therapyb in accordance with respective prescribing information, reduce lorlatinib by 1 dose level. Central nervous system effects (comprises psychotic effects and changes in cognition, mood, mental status or speech) Grade 2: Moderate OR Grade 3: Severe Withhold dose until toxicity is less than or equal to Grade 1. Then resume lorlatinib at 1 reduced dose level. Grade 4: Life-threatening/Urgent intervention indicated Permanently discontinue lorlatinib. Lipase/Amylase increase Grade 3: Severe OR Grade 4: Life-threatening/Urgent intervention indicated Withhold lorlatinib until lipase or amylase returns to baseline. Then resume lorlatinib at 1 reduced dose level. Interstitial lung disease (ILD)/Pneumonitis Grade 1: Mild OR Grade 2: Moderate Withhold lorlatinib until symptoms have returned to baseline and consider initiating corticosteroids. Resume lorlatinib at 1 reduced dose level. Permanently discontinue lorlatinib if ILD/pneumonitis recurs or fails to recover after 6 weeks of lorlatinib hold and steroid treatment. Grade 3: Severe OR Grade 4: Life-threatening/Urgent Permanently discontinue lorlatinib. 5 Table 1. Recommended lorlatinib dose modifications for adverse reactions Adverse reactiona Lorlatinib dosing intervention indicated PR interval prolongation/Atrioventricular (AV) block First degree AV block: Asymptomatic Continue lorlatinib at the same dose without interruption. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. First degree AV block: Symptomatic Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If symptoms resolve, resume lorlatinib at 1 reduced dose level. Second degree AV block Asymptomatic Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If subsequent ECG does not show second degree AV block, resume lorlatinib at 1 reduced dose level. Second degree AV block Symptomatic Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. Consider pacemaker placement if symptomatic AV block persists. If symptoms and the second-degree AV block resolve or if patients revert to asymptomatic first-degree AV block, resume lorlatinib at 1 reduced dose level. Complete AV block Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. Pacemaker placement may be indicated for severe symptoms associated with AV block. If AV block does not resolve, placement of a permanent pacemaker may be considered. If pacemaker placed, resume lorlatinib at full dose. If no pacemaker placed, resume lorlatinib at 1 reduced dose level only when symptoms resolve, and PR interval is less than 200 msec. 6 Table 1. Recommended lorlatinib dose modifications for adverse reactions Adverse reactiona Lorlatinib dosing Other adverse reactions Grade 1: Mild OR Grade 2: Moderate Consider no dose modification or reduce by 1 dose level, as clinically indicated. Greater than or equal to Grade 3: Severe Withhold lorlatinib until symptoms resolve to less than or equal to Grade 2 or baseline. Then resume lorlatinib at 1 reduced dose level. Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; ECG=electrocardiogram; HMG CoA=3-hydroxy-3-methylglutaryl coenzyme A; NCI=National Cancer Institute; ULN=upper limit of normal. a Grade categories are based on NCI CTCAE classifications. b Lipid-lowering therapy may include: HMG CoA reductase inhibitor, nicotinic acid, fibric acid derivatives, or ethyl esters of omega-3 fatty acids. Strong cytochrome P-450 (CYP) 3A4/5 inhibitors Concurrent use of lorlatinib with medicinal products that are strong CYP3A4/5 inhibitors and grapefruit juice products may increase lorlatinib plasma concentrations. An alternative concomitant medicinal product with less potential to inhibit CYP3A4/5 should be considered (see section 4.5). If a strong CYP3A4/5 inhibitor must be co-administered, the starting lorlatinib dose of 100 mg once daily should be reduced to once daily 75 mg dose (see sections 4.5 and 5.2). If concurrent use of the strong CYP3A4/5 inhibitor is discontinued, lorlatinib should be resumed at the dose used prior to the initiation of the strong CYP3A4/5 inhibitor and after a washout period of 3 to 5 half-lives of the strong CYP3A4/5 inhibitor. Special populations Elderly (≥ 65 years) Due to the limited data on this population, no dose recommendation can be made for patients aged 65 years and older (see section 5.2). Renal impairment No dose adjustment is needed for patients with normal renal function and mild or moderate (CLcr: ≥ 30mL/min) renal impairment based on a population pharmacokinetic analysis. Information for lorlatinib use in patients with severe (CLcr: < 30 mL/min) renal impairment is very limited. Therefore, lorlatinib is not recommended in patients with severe renal impairment (see section 5.2). Hepatic impairment No dose adjustments are recommended for patients with mild hepatic impairment. No information is available for lorlatinib in patients with moderate or severe hepatic impairment. Therefore, lorlatinib is not recommended in patients with moderate to severe hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of lorlatinib in paediatric patients below 18 years have not been established. No data are available. Method of administration Lorviqua is for oral use. Patients should be encouraged to take their dose of lorlatinib at approximately the same time each day with or without food (see section 5.2). The tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact. 7 4.3 Contraindications Hypersensitivity to lorlatinib or to any of the excipients listed in section 6.1. Concomitant use of strong CYP3A4/5 inducers (see sections 4.4 and 4.5). 4.4 Special warnings and precautions for use Hyperlipidaemia The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see section 4.8). Median time of occurrence of severe increase in serum cholesterol and triglycerides is 201 days (range: 42 to 518 days) and 127 days (range: 15 to 358 days), respectively. Serum cholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4 and 8 weeks after initiating lorlatinib; and regularly thereafter. Initiate or increase the dose of lipid-lowering medicinal products, if indicated (see section 4.2). Central nervous system effects Central nervous system (CNS) effects have been observed in patients receiving lorlatinib, including psychotic effects and changes in cognitive function, mood, mental status or speech (see section 4.8). Dose modification or discontinuation may be required for those patients who develop CNS effects (see section 4.2). Atrioventricular block Lorlatinib was studied in a population of patients that excluded those with second-degree or third-degree AV block (unless paced) or any AV block with PR interval > 220 msec. PR interval prolongation and AV block have been reported in patients receiving lorlatinib (see section 5.2). Monitor electrocardiogram (ECG) prior to initiating lorlatinib and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events. Dose modification may be required for those patients who develop AV block (see section 4.2). Left ventricular ejection fraction decrease Left ventricular ejection fraction (LVEF) decrease has been reported in patients receiving lorlatinib who had baseline and at least one follow-up LVEF assessment. Based on the available clinical study data, it is not possible to determine a causal relationship between effects on changes in cardiac contractility and lorlatinib. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring, including LVEF assessment, should be considered. Lipase and amylase increase Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib (see section 4.8). Median time of occurrence of increase in serum lipase and amylase is 70 days (range: 7 to 696 days) and 41 days (range: 7 to 489 days), respectively. Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism. Patients should be monitored for lipase and amylase elevations prior to the start of lorlatinib treatment and regularly thereafter as clinically indicated (see section 4.2). Interstitial lung disease/Pneumonitis Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis have occurred with lorlatinib (see section 4.8). Any patient who presents with worsening of respiratory 8 symptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough and fever) should be promptly evaluated for ILD/pneumonitis. Lorlatinib should be withheld and/or permanently discontinued based on severity (see section 4.2). Drug-drug interactions In a study conducted in healthy volunteers, the concomitant use of lorlatinib and rifampin, a strong CYP3A4/5 inducer, was associated with increases of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with no increase of total bilirubin and alkaline phosphatase (see section 4.5). Concomitant use of a strong CYP3A4/5 inducer is contraindicated (see sections 4.3 and 4.5). Concomitant use with moderate CYP3A4/5 inducers should be avoided, if possible, as they may also reduce lorlatinib plasma concentrations (see section 4.5). Concurrent administration of lorlatinib with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided since the concentration of these medicinal products may be reduced by lorlatinib (see section 4.5). Fertility and pregnancy During treatment with lorlatinib and for at least 14 weeks after the final dose, male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms (see section 4.6). Male fertility may be compromised during treatment with lorlatinib (see section 5.3). Men should seek advice on effective fertility preservation before treatment. Women of childbearing potential should be advised to avoid becoming pregnant while receiving lorlatinib. A highly effective non-hormonal method of contraception is required for female patients during treatment with lorlatinib, because lorlatinib can render hormonal contraceptives ineffective (see sections 4.5 and 4.6). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 35 days after completing therapy (see section 4.6). It is not known whether lorlatinib affects female fertility. Lactose intolerance This medicinal product contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Dietary sodium This medicinal product contains less than 1 mmol sodium (23 mg) per 25 mg or 100 mg tablet. Patients on low sodium diets should be informed that this product is essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction Pharmacokinetic interactions In vitro data indicate that lorlatinib is primarily metabolised by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT)1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5 and UGT1A3. 9 Effect of medicinal products on lorlatinib CYP3A4/5 inducers Rifampin, a strong inducer of CYP3A4/5, administered at oral doses of 600 mg once daily for 12 days, reduced the mean lorlatinib area under curve (AUCinf) by 85% and Cmax by 76% of a single 100 mg oral dose of lorlatinib in healthy volunteers; increases in AST and ALT were also observed. Concomitant administration of lorlatinib with strong CYP3A4/5 inducers (e.g. rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s wort) may decrease lorlatinib plasma concentrations. The use of a strong CYP3A4/5 inducer with lorlatinib is contraindicated (see sections 4.3 and 4.4). Concomitant use with moderate CYP3A4/5 inducers should be avoided, if possible, as they may also reduce lorlatinib plasma concentrations (see section 4.4). CYP3A4/5 inhibitors Itraconazole, a strong inhibitor of CYP3A4/5, administered at oral doses of 200 mg once daily for 5 days, increased the mean lorlatinib AUCinf by 42% and Cmax by 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers. Concomitant administration of lorlatinib with strong CYP3A4/5 inhibitors (e.g. boceprevir, cobicistat, itraconazole, ketoconazole, posaconazole, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either elvitegravir, indinavir, lopinavir or tipranavir) may increase lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasma concentrations and should be avoided. An alternative concomitant medicinal product with less potential to inhibit CYP3A4/5 should be considered. If a strong CYP3A4/5 inhibitor must be concomitantly administered, a dose reduction of lorlatinib is recommended (see section 4.2). Effect of lorlatinib on other medicinal products CYP3A4/5 substrates In vitro studies indicated that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A4/5. Lorlatinib 150 mg orally once daily for 15 days decreased AUCinf and Cmax of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate) by 61% by 50%, respectively; hence, lorlatinib is a moderate CYP3A inducer. Thus, concurrent administration of lorlatinib with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided since the concentration of these medicinal products may be reduced by lorlatinib (see section 4.4). CYP2B6 substrates Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 100 mg dose of bupropion (a combined CYP2B6 and CYP3A4 substrate) by 49.5% and 53%, respectively. Thus, lorlatinib is a weak inducer of CYP2B6, and no dose adjustment is necessary when lorlatinib is used in combination with medicinal products that are mainly metabolised by CYP2B6. CYP2C9 substrates Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 500 mg dose of tolbutamide (a sensitive CYP2C9 substrate) by 43% and 15%, respectively. Thus, lorlatinib is a weak inducer of CYP2C9, and no dose adjustment is required for medicinal products that are mainly metabolised by CYP2C9. However, patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by CYP2C9 (e.g. coumarin anticoagulants). UGT substrates 10 Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 500 mg dose of acetaminophen (a UGT, SULT and CYP1A2, 2A6, 2D6, and 3A4 substrate) by 45% and 28%, respectively. Thus, lorlatinib is a weak inducer of UGT, and no dose adjustment is required for medicinal products that are mainly metabolised by UGT. However, patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by UGT. P-glycoprotein substrates Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral dose of 60 mg fexofenadine [a sensitive P-glycoprotein (P-gp) substrate] by 67% and 63%, respectively. Thus, lorlatinib is a moderate inducer of P-gp. Medicinal products that are P-gp substrates with narrow therapeutic indices (e.g. digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the likelihood of reduced plasma concentrations of these substrates. In vitro inhibition and induction studies of other CYP enzymes In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2. In vitro studies with drug transporters other than P-gp In vitro studies indicated that lorlatinib may have the potential to inhibit BCRP (gastrointestinal tract), OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 at clinically relevant concentrations. Lorlatinib should be used with caution in combination with substrates of BCRP, OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 as clinically relevant changes in the plasma exposure of these substrates cannot be ruled out. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/Contraception in males and females Women of childbearing potential should be advised to avoid becoming pregnant while receiving lorlatinib. A highly effective non-hormonal method of contraception is required for female patients during treatment with lorlatinib, because lorlatinib can render hormonal contraceptives ineffective (see sections 4.4 and 4.5). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 35 days after completing therapy. During treatment with lorlatinib and for at least 14 weeks after the final dose, male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms. Pregnancy Studies in animals have shown embryo-foetal toxicity (see section 5.3). There are no data from the use of lorlatinib in pregnant women. Lorlatinib may cause foetal harm when administered to a pregnant woman. Lorlatinib is not recommended during pregnancy or for women of childbearing potential not using contraception. Breast-feeding It is unknown whether lorlatinib and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. 11 Lorlatinib should not be used during breast-feeding. Breast-feeding should be discontinued during treatment with lorlatinib and for 7 days after the final dose. Fertility Based on non-clinical safety findings, male fertility may be compromised during treatment with lorlatinib (see section 5.3). It is not known whether lorlatinib affects female fertility. Men should seek advice on effective fertility preservation before treatment. 4.7 Effects on ability to drive and use machines Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience CNS effects (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions were hypercholesterolaemia (84.4%), hypertriglyceridaemia (67.1%), oedema (54.6%), peripheral neuropathy (47.8%), cognitive effects (28.8%), fatigue (28.1%), weight increased (26.4%), arthralgia (24.7%), mood effects (22.7%) and diarrhoea (22.7%). Dose reductions due to adverse reactions occurred in 23.4% of patients receiving lorlatinib. The most common adverse reactions that led to dose reductions were oedema and peripheral neuropathy. Permanent treatment discontinuation associated with adverse reactions occurred in 3.1% of patients receiving lorlatinib. The most frequent adverse reactions that led to permanent discontinuations were cognitive effects and psychotic effects. Tabulated list of adverse reactions Table 2 presents adverse reactions occurring in 295 adult patients treated with lorlatinib 100 mg once daily with advanced NSCLC from Study A. The adverse reactions listed in Table 2 are presented by system organ class and frequency categories, defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing medical seriousness. 12 Table 2. Adverse reactions System organ class and adverse reaction Frequency category All Grades % Grades 3-4 % Blood and lymphatic system disorders Anaemia Very common 15.9 5.1 Metabolism and nutrition disorders Hypercholesterolaemiaa Hypertriglyceridaemiab Very common Very common 84.4 67.1 16.6 16.6 Psychiatric disorders Mood effectsc Psychotic effectsd Mental status changes Very common Common Common 22.7 7.8 2.0 1.7 1.0 1.7 Nervous system disorders Cognitive effectse Peripheral neuropathyf Headache Speech effectsg Very common Very common Very common Common 28.8 47.8 18.0 9.8 2.0 2.7 0.7 0.3 Eye disorders Vision disorderh Very common 15.3 0.3 Respiratory, thoracic and mediastinal disorders Pneumonitisi Common 1.4 1.0 Gastrointestinal disorders Diarrhoea Nausea Constipation Very common Very common Very common 22.7 18.3 15.9 1.0 0.7 0 Skin and subcutaneous tissue disorders Rashj Very common 14.2 0.3 Musculoskeletal and connective tissue disorders Arthralgia Myalgiak Very common Very common 24.7 19.3 0.7 0 General disorders and administration site conditions Oedemal Fatiguem Very common Very common 54.6 28.1 2.4 0.7 Investigations Weight increased Lipase increased Amylase increased Electrocardiogram PR prolongation Very common Very common Very common Uncommon 26.4 13.9 10.2 0.7 5.4 8.8 3.1 0 Adverse reactions that represent the same medical concept or condition were grouped together and reported as a single adverse reaction in the table above. Terms actually reported in the studies and contributing to the relevant adverse reaction are indicated in parentheses, as listed below. a Hypercholesterolaemia (including blood cholesterol increased, hypercholesterolaemia). b Hypertriglyceridaemia (including blood triglycerides increased, hypertriglyceridaemia). c Mood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress). d Psychotic effects (including auditory hallucination, hallucination, visual hallucination). e Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder). Within these effects, terms from SOC Nervous system disorders were more frequently reported than terms from SOC Psychiatric disorder. f Peripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysaesthesia, formication, gait disturbance, hypoaesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paraesthesia, peripheral sensory neuropathy, peroneal nerve palsy, sensory disturbance). g Speech effects (dysarthria, slow speech, speech disorder). 13 h Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). i Pneumonitis (including interstitial lung disease, pneumonitis). j Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash). k Myalgia (including musculoskeletal pain, myalgia). l Oedema (including generalised oedema, oedema, oedema peripheral, peripheral swelling, swelling). m Fatigue (including asthenia, fatigue). Description of selected adverse reactions Hypercholesterolaemia/hypertriglyceridaemia Adverse reactions of increase in serum cholesterol or triglycerides were reported in 84.4% and 67.1% of patients, respectively. Of those, mild or moderate adverse reactions of hypercholesterolaemia or hypertriglyceridaemia occurred in 67.8% and 50.5% of patients, respectively (see section 4.4). The median time to onset for both hypercholesterolaemia and hypertriglyceridaemia was 15 days (range: 1 to 399 days). The median duration of hypercholesterolaemia and hypertriglyceridaemia was 381 and 405 days, respectively. Central nervous system effects CNS adverse reactions were primarily cognitive effects (28.8%), mood effects (22.7%), speech effects (9.8%) and psychotic effects (7.8%), and were generally mild, transient, and reversible spontaneously upon dose delay and/or dose reduction (see sections 4.2 and 4.4). The most common cognitive effect of any grade was memory impairment (11.5%), and the most common Grade 3 or 4 reactions were cognitive effect and confusional state (0.7% each). The most common mood effect of any grade was irritability (6.1%), which was also the most common Grade 3 or 4 reaction (1.0%). The most common speech effect of any grade was dysarthria (4.1%), and the most common Grade 3 or 4 reaction was slow speech (0.3%). The most common psychotic effect of any grade was hallucination (3.7%) and the most common Grade 3 or 4 reactions were hallucination, hallucination auditory and hallucination visual (0.3% each). Median time to onset for cognitive, mood, speech and psychotic effects was 92, 44, 42 and 23 days, respectively. Median duration of cognitive, mood, speech and psychotic effects was 224, 83, 106 and 74 days, respectively. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Treatment of overdose with the medicinal product consists of general supportive measures. Given the dose-dependent effect on PR interval, ECG monitoring is recommended. There is no antidote for lorlatinib. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: anti-neoplastic agents, protein kinase inhibitors, ATC code: L01XE44 Mechanism of action Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive inhibitor of ALK and c-ros oncogene 1 (ROS1) tyrosine kinases. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 14 In non-clinical studies, lorlatinib inhibited catalytic activities of non-mutated ALK and clinically relevant ALK mutant kinases in recombinant enzyme and cell-based assays. Lorlatinib demonstrated marked antitumour activity in mice bearing tumour xenografts that express echinoderm microtubule-associated protein-like 4 (EML4) fusions with ALK variant 1 (v1), including ALK mutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T, are known to confer resistance to alectinib, brigatinib, ceritinib, and crizotinib. Lorlatinib was also capable of penetrating the blood-brain barrier. Lorlatinib demonstrated activity in mice bearing orthotopic EML4-ALK or EML4-ALKL1196M brain tumour implants. Clinical efficacy The use of lorlatinib in the treatment of ALK-positive advanced NSCLC after treatment with at least one second-generation ALK TKI was investigated in Study A, a single-arm, multicentre Phase 1/2 study. A total of 139 patients with ALK-positive advanced NSCLC after treatment with at least one second-generation ALK TKI were enrolled in the Phase 2 portion of the study. Patients received lorlatinib orally at the recommended dose of 100 mg once daily, continuously. The primary efficacy endpoint in the Phase 2 portion of the study was objective response rate (ORR), including intracranial (IC)-ORR, as per Independent Central Review (ICR) according to modified response evaluation criteria in solid tumours (modified RECIST version 1.1). Secondary endpoints included duration of response (DOR), IC-DOR, time-to-tumour response (TTR), and progression-free survival (PFS). Patient demographics of the 139 ALK-positive advanced NSCLC patients after treatment with at least one second-generation ALK TKI, were 56% female, 48% White, 38% Asian, and the median age was 53 years (range: 29-83 years) with 16% of patients ≥ 65 years of age. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 or 1 in 96% patients. Brain metastases were present at baseline in 67% of patients. Of the 139 patients, 20% received 1 prior ALK TKI, excluding crizotinib, 47% received 2 prior ALK TKIs, and 33% received 3 or more prior ALK TKIs. The main efficacy results for Study A are included in Tables 3 and 4. Table 3. Overall efficacy results in Study A by prior treatment Efficacy parameter One prior ALK TKIa with or without prior chemotherapy Two or more prior ALK TKIs with or without prior chemotherapy (N = 28) (N = 111) Objective response rateb (95% CI) Complete response, n Partial response, n 42.9% (24.5, 62.8) 1 11 39.6% (30.5, 49.4) 2 42 Duration of response Median, months (95% CI) 5.6 (4.2, NR) 9.9 (5.7, 24.4) Progression-free survival Median, months (95% CI) 5.5 (2.9, 8.2) 6.9 (5.4, 9.5) Abbreviations: ALK=anaplastic lymphoma kinase; CI=confidence interval; ICR=Independent Central Review; N/n=number of patients; NR=not reached; TKI=tyrosine kinase inhibitor. a Alectinib, brigatinib, or ceritinib. b Per ICR. 15 Table 4. Intracranial* efficacy results in Study A by prior treatment Efficacy parameter One prior ALK TKIa with or without prior chemotherapy Two or more prior ALK TKIs with or without prior chemotherapy (N = 9) (N = 48) Objective response rateb (95% CI) Complete response, n Partial response, n 66.7% (29.9, 92.5) 2 4 52.1% (37.2, 66.7) 10 15 Duration of intra-cranial response Median, months (95% CI) NR (4.1, NR) 12.4 (6.0, NR) Abbreviations: ALK=anaplastic lymphoma kinase; CI=confidence interval; ICR=Independent Central Review; N/n=number of patients; NR=not reached; TKI= tyrosine kinase inhibitor. * In patients with at least one measurable brain metastasis at baseline. a Alectinib, brigatinib, or ceritinib. b Per ICR. In the overall efficacy population of 139 patients, 56 patients had a confirmed objective response by ICR with a median TTR of 1.4 months (range: 1.2 to 16.6 months). The ORR for Asians was 49.1% (95% CI: 35.1, 63.2) and 31.5% for non-Asians (95% CI: 21.1, 43.4). Among the 31 patients with a confirmed IC objective tumour response and at least one measurable brain metastasis at baseline by ICR, the median IC-TTR was 1.4 months (range: 1.2 to 16.2 months). The IC ORR was 54.5% for Asians (95% CI: 32.2, 75.6) and 46.4% for non-Asians (95% CI: 27.5, 66.1). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with lorlatinib in all subsets of the paediatric population in lung carcinoma (small cell and non-small cell carcinoma) (see section 4.2 for information on paediatric use). This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary. 5.2 Pharmacokinetic properties Absorption Peak lorlatinib concentrations in plasma are rapidly reached with the median Tmax of 1.2 hours following a single 100 mg dose and 2.0 hours following multiple dosing of 100 mg once daily. After oral administration of lorlatinib tablets, the mean absolute bioavailability is 80.8% (90% CI: 75.7, 86.2) compared to intravenous administration. Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher exposure compared to fasted conditions. Lorlatinib may be administered with or without food. At 100 mg once daily, the geometric mean (% coefficient of variation [CV]) peak plasma concentration was 577 (42) ng/mL and the AUC24 was 5,650 (39) ng·h/mL in patients with cancer. The geometric mean (% CV) oral clearance was 17.7 (39) L/h. 16 Distribution In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to albumin or to α1-acid glycoprotein. Biotransformation In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways. In vitro data indicate that lorlatinib is metabolised primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5 and UGT1A3. In plasma, a benzoic acid metabolite of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib was observed as a major metabolite, accounting for 21% of the circulating radioactivity. The oxidative cleavage metabolite is pharmacologically inactive. Elimination The plasma half-life of lorlatinib after a single 100 mg dose was 23.6 hours. Following oral administration of a 100 mg radiolabelled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in faeces, with overall mean total recovery of 88.6%. Unchanged lorlatinib was the major component of human plasma and faeces, accounting for 44% and 9.1% of total radioactivity, respectively. Less than 1% of unchanged lorlatinib was detected in urine. Furthermore, lorlatinib is an inducer via human pregnane-X-receptor (PXR) and the human constitutive androstane receptor (CAR). Linearity/non-linearity At single dose, lorlatinib systemic exposure (AUCinf and Cmax) increased in a dose-related manner over the 10 to 200 mg dose range. Few data are available over the 10 to 200 mg dose range; however, no deviation from linearity was observed for AUCinf and Cmax after single dose. After multiple once daily dose administration, lorlatinib Cmax increased dose-proportionally and AUCtau increased slightly less than proportionally over the dose range of 10 to 200 mg once daily. Also, at steady-state lorlatinib plasma exposures are lower than those expected from single dose pharmacokinetics, indicative of a net time-dependent auto-induction effect. Hepatic impairment As lorlatinib is metabolised in the liver, hepatic impairment is likely to increase lorlatinib plasma concentrations. Clinical studies that were conducted excluded patients with AST or ALT > 2.5 × ULN, or if due to underlying malignancy, > 5.0 × ULN or with total bilirubin > 1.5 × ULN. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild hepatic impairment (n = 50). No dose adjustments are recommended for patients with mild hepatic impairment. No information is available for patients with moderate or severe hepatic impairment. Renal impairment Less than 1% of the administered dose is detected as unchanged lorlatinib in urine. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild (n = 103) or moderate (n = 41) renal impairment (CLcr > 30 mL/min). No starting 17 dose adjustments are recommended for patients with mild or moderate renal impairment. Information for lorlatinib use in patients with severe renal impairment (CLcr < 30 mL/min) is limited (n = 1). Age, gender, race, body weight, and phenotype Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight, and phenotypes for CYP3A5 and CYP2C19. Cardiac electrophysiology In Study A, 2 patients (0.7%) had absolute Fridericia’s correction QTc (QTcF) values > 500 msec and 5 patients (1.8%) had a change in QTcF from baseline > 60 msec. In addition, the effect of a single oral dose of lorlatinib (50 mg, 75 mg, and 100 mg) with and without 200 mg once daily itraconazole was evaluated in a 2-way crossover study in 16 healthy volunteers. No increases in the mean QTc were observed at the mean observed lorlatinib concentrations in this study. In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECG measurement in Study A, lorlatinib was studied in a population of patients that excluded those with QTc interval > 470 msec. In the study population, the maximum mean change from baseline for PR interval was 16.4 msec (2-sided 90% upper CI 19.4 msec) (see sections 4.2, 4.4 and 4.8). Of these, 7 patients had a baseline PR > 200 msec. Among the 284 patients with PR interval < 200 msec, 14% had PR interval prolongation ≥ 200 msec after starting lorlatinib. The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1.0% of patients. For those patients who develop PR prolongation, dose modification may be required (see section 4.2). 5.3 Preclinical safety data Repeat-dose toxicity The main toxicities observed were inflammation across multiple tissues (skin and cervix of rats and lung, trachea, skin, lymph nodes and/or the oral cavity including mandibular bone of dogs; associated with increases in white blood cells, fibrinogen, and/or globulin and decreases in albumin) and changes in the pancreas (with increases in amylase and lipase), hepatobiliary system (with increases in liver enzymes), male reproductive system, cardiovascular system, kidneys and gastrointestinal tract, peripheral nerves and the CNS (potential for cognitive functional impairment) at dose equivalent to human clinical exposure at the recommended posology. Changes in blood pressure and heart rate, and QRS complex and PR interval were also observed in animals after acute dosing (approximately 2.6 times the human clinical exposure at 100 mg after a single dose based on Cmax). All target organ findings with the exception of hepatic bile duct hyperplasia were partially to fully reversible. Genotoxicity Lorlatinib is not mutagenic but is aneugenic in vitro and in vivo with a no observed effect level for aneugenicity approximately 16.5 times human clinical exposure at 100 mg based on AUC. Carcinogenicity Carcinogenicity studies have not been conducted with lorlatinib. Reproductive toxicity Seminiferous tubular degeneration and/or atrophy in the testes, and epididymal changes (inflammation and/or vacuolation) were observed in the rat and dog. In the prostate, minimal to mild glandular 18 atrophy was observed in dogs at dose equivalent to human clinical exposure at the recommended posology). The effects on male reproductive organs were partially to fully reversible. In embryo-foetal toxicity studies, conducted in rats and rabbits, respectively, increased embryolethality and lower foetal body weights and malformations were observed. Foetal morphologic abnormalities included rotated limbs, supernumerary digits, gastroschisis, malformed kidneys, domed head, high arched palate, and dilation of ventricles of the brain. The exposure at the lowest doses with embryo-foetal effects in animals was equivalent to the human clinical exposure at 100 mg, based on AUC. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Microcrystalline cellulose Calcium hydrogen phosphate Sodium starch glycolate Magnesium stearate Film-coating Hypromellose Lactose monohydrate Macrogol Triacetin Titanium dioxide (E171) Iron oxide black (E172) Iron oxide red (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container OPA/Al/PVC blisters with aluminium foil backing containing 10 film-coated tablets. Lorviqua 25 mg film-coated tablets Each pack contains 90 film-coated tablets in 9 blisters or 120 film-coated tablets in 12 blisters. Lorviqua 100 mg film-coated tablets Each pack contains 30 film-coated tablets in 3 blisters. Not all pack sizes may be marketed. 19 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium 8. MARKETING AUTHORISATION NUMBER(S) EU/1/19/1355/001 EU/1/19/1355/002 EU/1/19/1355/003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 6 May 2019 Date of latest renewal: 3 April 2020 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 20 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST- AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION 21 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Pfizer Manufacturing Deutschland GmbH Betriebsstätte Freiburg Mooswaldallee 1 79090 Freiburg Germany B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 22 E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION This being a conditional marketing authorisation and pursuant to Article 14a(4) of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: Description Due date In order to further confirm the efficacy and safety of lorlatinib in the treatment of patients with ALK-positive NSCLC, the MAH should submit the clinical study report of the phase III study CROWN (1006) comparing lorlatinib versus crizotinib for the first-line treatment of advanced ALK-positive NSCLC. The clinical study report will be submitted by: 31 December 2021 In order to further confirm the efficacy of lorlatinib in patients who progressed after alectinib or ceritinib as the first ALK TKI therapy, the MAH should conduct a prospective single arm study investigating patients in that same setting. The clinical study report will be submitted by: 30 June 2024 23 ANNEX III LABELLING AND PACKAGE LEAFLET 24 A. LABELLING 25 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Lorviqua 25 mg film-coated tablets lorlatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 25 mg of lorlatinib. 3. LIST OF EXCIPIENTS Contains lactose (see leaflet for further information). 4. PHARMACEUTICAL FORM AND CONTENTS 90 film-coated tablets 120 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 26 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/19/1355/001 120 film-coated tablets EU/1/19/1355/003 90 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Lorviqua 25 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 27 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Lorviqua 25 mg tablets lorlatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER Pfizer (as MAH logo) 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 28 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Lorviqua 100 mg film-coated tablets lorlatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 100 mg of lorlatinib. 3. LIST OF EXCIPIENTS Contains lactose (see leaflet for further information). 4. PHARMACEUTICAL FORM AND CONTENTS 30 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 29 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/19/1355/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Lorviqua 100 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 30 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Lorviqua 100 mg tablets lorlatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER Pfizer (as MAH logo) 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 31 B. PACKAGE LEAFLET 32 Package leaflet: Information for the user Lorviqua 25 mg film-coated tablets Lorviqua 100 mg film-coated tablets lorlatinib This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist, or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Lorviqua is and what it is used for 2. What you need to know before you take Lorviqua 3. How to take Lorviqua 4. Possible side effects 5. How to store Lorviqua 6. Contents of the pack and other information 1. What Lorviqua is and what it is used for What Lorviqua is Lorviqua contains the active substance lorlatinib, a medicine that is used for treatment of adults with advanced stages of a form of lung cancer called non-small cell lung cancer (NSCLC). Lorviqua belongs to the group of medicines that inhibit an enzyme called anaplastic lymphoma kinase (ALK). Lorviqua is only given to patients who have an alteration in the ALK gene, see How Lorviqua works below. What Lorviqua is used for Lorviqua can be prescribed to you if - you have been previously treated with a medicine called alectinib or ceritinib, which are ALK inhibitors; or - you have been previously treated with crizotinib followed by another ALK inhibitor. How Lorviqua works Lorviqua inhibits a type of enzyme called tyrosine kinase and triggers the death of cancer cells in patients with alterations in genes for ALK. Lorviqua is only given to patients whose disease is due to an alteration in the gene for ALK tyrosine kinase. If you have any questions about how Lorviqua works or why this medicine has been prescribed for you, ask your doctor. 33 2. What you need to know before you take Lorviqua Do not take Lorviqua - if you are allergic to lorlatinib or any of the other ingredients of this medicine (listed in section 6). - if you are taking any of these medicines: • rifampicin (used to treat tuberculosis) • carbamazepine, phenytoin (used to treat epilepsy) • enzalutamide (used to treat prostate cancer) • mitotane (used to treat cancer of the adrenal glands) • medicines containing St. John’s wort (Hypericum perforatum, a herbal preparation) Warnings and precautions Talk to your doctor before taking Lorviqua: - if you have high levels of blood cholesterol or triglycerides - if you have high levels of the enzymes known as amylase or lipase in the blood or a condition such as pancreatitis that can raise the levels of these enzymes - if you have problems with your heart, including heart failure, slow heart rate, or if electrocardiogram (ECG) results show that you have an abnormality of the electrical activity of your heart known as prolonged PR interval or AV block. - if you have cough, chest pain, shortness of breath, or worsening of respiratory symptoms or have ever had a lung condition called pneumonitis. If you are not sure, talk to your doctor, pharmacist or nurse before taking Lorviqua. Tell your doctor immediately if you develop: - heart problems. Tell your doctor right away about changes in your heart beat (fast or slow), light-headedness, fainting, dizziness or shortness of breath. These symptoms could be signs of heart problems. Your doctor may check for problems with your heart during treatment with Lorviqua. If the results are abnormal, your doctor may decide to reduce the dose of Lorviqua or stop your treatment. - speech problems, difficulty speaking, including slurred or slow speech. Your doctor may investigate further and may decide to reduce your dose of Lorviqua or stop your treatment. - mental status changes, mood or memory problems, such as change in your mood (including depression, euphoria and mood swings), irritability, aggression, agitation, anxiety or a change in your personality and episodes of confusion or loss of contact with reality, such as believing, seeing or hearing things that are not real. Your doctor may investigate further and may decide to reduce your dose of Lorviqua or stop your treatment. - pain in the back or abdomen (belly), yellowing of the skin and eyes (jaundice), nausea or vomiting. These symptoms could be signs of pancreatitis. Your doctor may investigate further and may decide to reduce the dose of Lorviqua. - cough, chest pain, or a worsening of existing respiratory symptoms. Your doctor may investigate further and treat you with other medicines such as antibiotics and steroids. Your doctor may decide to reduce your dose of Lorviqua or stop your treatment. Your doctor may do further assessments and may decide to reduce the dose of Lorviqua or stop your treatment if you develop: - liver problems. Tell your doctor right away if you feel more tired than usual, your skin and whites of your eyes turn yellow, your urine turns dark or brown (tea colour), you have nausea, vomiting, or decreased appetite, you have pain on the right side of your stomach, you have itching, or if you bruise more easily than usual. Your doctor may do blood tests to check your liver function. See Possible side effects in section 4 for more information. Children and adolescents This medicine is only indicated in adults and it is not to be given to children and adolescents. 34 Tests and checks You will have blood tests before you start treatment and during your treatment. These tests are to check the level of cholesterol, triglycerides and the enzymes amylase or lipase in your blood before you start treatment with Lorviqua and regularly during treatment. Other medicines and Lorviqua Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines, including herbal medicines and medicines obtained over the counter. This is because Lorviqua can affect the way some other medicines work. Also some medicines can affect the way Lorviqua works. You must not take Lorviqua with certain medicines. These are listed under Do not take Lorviqua, at the start of section 2. In particular tell your doctor, pharmacist or nurse if you are taking any of the following medicines: - boceprevir – a medicine used to treat hepatitis C. - buproprion – a medicine used to treat depression or to help people quit smoking. - dihydroergotamine, ergotamine – medicines used to treat migraine headaches. - efavirenz, cobicistat, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either elvitegravir, indinavir, lopinavir or tipranavir – medicines used to treat AIDS/HIV. - ketoconazole, itraconazole, voriconazole, posaconazole – medicines used to treat fungal infections. Also troleandomycin, a medicine used to treat certain types of bacterial infections. - quinidine – a medicine used to treat irregular heartbeat and other heart problems. - pimozide – a medicine used to treat mental health problems. - alfentanil and fentanyl – medicines used to treat severe pain. - ciclosporin, sirolimus, and tacrolimus – medicines used in organ transplantation to prevent organ rejection. Lorviqua with food and drink You must not drink grapefruit juice or eat grapefruit while on treatment with Lorviqua as they may change the amount of Lorviqua in your body. Pregnancy, breast-feeding and fertility - Contraception – information for women You should not become pregnant while taking this medicine. If you are able to have children, you must use highly effective contraception (for example, double-barrier contraception such as condom and diaphragm) while on treatment and for at least 5 weeks after stopping treatment. Lorlatinib may reduce the effectiveness of hormonal contraceptive methods (for example, birth control pill); therefore, hormonal contraceptives may not be considered highly effective. If hormonal contraception is unavoidable it must be used in combination with a condom. Talk to your doctor about the right methods of contraception for you and your partner. - Contraception – information for men You should not father children during treatment with Lorviqua because this medicine could harm the baby. If there is any possibility that you may father a child while taking this medicine, you must use a condom during treatment, and for at least 14 weeks after completing therapy. Talk to your doctor about the right methods of contraception for you and your partner. - Pregnancy • Do not take Lorviqua if you are pregnant. This is because it may harm your baby. • If your male partner is being treated with Lorviqua, he must use a condom during treatment and for at least 14 weeks after completing therapy. • If you become pregnant when taking the medicine or during the 5 weeks after taking your last dose, tell your doctor straight away. 35 - Breast-feeding Do not breast-feed while taking this medicine and for 7 days after the last dose. This is because it is not known if Lorviqua can pass into breast milk and could therefore harm your baby. - Fertility Lorviqua may affect male fertility. Talk to your doctor about fertility preservation before taking Lorviqua. Driving and using machines You should take special care when driving and using machines when taking Lorviqua because of its effects on your mental state. Lorviqua contains lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Lorviqua contains sodium This medicine contains less than 1 mmol sodium (23 mg) per 25 mg or 100 mg tablet, that is to say essentially ‘sodium-free’. 3. How to take Lorviqua Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure. - The recommended dose is one tablet of 100 mg taken by mouth once daily. - Take the dose at about the same time each day. - You can take the tablets with food or between meals always avoiding grapefruit and grapefruit juice. - Swallow the tablets whole and do not crush, chew or dissolve the tablets. - Sometimes your doctor may lower your dose, stop your treatment for a short time or stop your treatment completely if you feel unwell. If you vomit after taking Lorviqua If you vomit after taking a dose of Lorviqua, do not take an extra dose, just take your next dose at the usual time. If you take more Lorviqua than you should If you accidentally take too many tablets, tell your doctor, pharmacist or nurse right away. You may require medical attention. If you forget to take Lorviqua What to do if you forget to take a tablet depends on how long it is until your next dose. - If your next dose is in 4 hours or more, take the missed tablet as soon as you remember. Then take the next tablet at the usual time. - If your next dose is in less than 4 hours away, skip the missed tablet. Then take the next tablet at the usual time. Do not take a double dose to make up for a forgotten dose. If you stop taking Lorviqua It is important to take Lorviqua every day, for as long as your doctor asks you to. If you are not able to take the medicine as your doctor has prescribed, or you feel you do not need it anymore, speak with your doctor right away. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 36 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some side effects could be serious. Tell your doctor straight away if you notice any of the following side effects (also section 2 What you need to know before you take Lorviqua). Your doctor may lower your dose, stop your treatment for a short time or stop your treatment completely: - cough, shortness of breath, chest pain or worsening breathing problems - slow pulse, (50 beats per minute or less), feeling tired, dizzy or faint or losing consciousness - abdominal (belly) pain, back pain, nausea, vomiting, itching or yellowing of the skin and eyes - mental status changes; changes in cognition including confusion, memory loss, reduced ability to concentrate; changes in mood including irritability and mood swings; changes in speech including difficulty speaking, such as slurred or slow speech; or loss of contact with reality, such as believing, seeing or hearing things that are not real Other side effects of Lorviqua may include: Very common: may affect more than 1 in 10 people - increase in cholesterol and triglycerides (fats in your blood that would be detected during blood tests) - limb or skin swelling - problems with your eyes, such as difficulty seeing out of one or both eyes, double vision, or perceived flashes of light - problems with the nerves in your arms and legs, such as pain, numbness, unusual sensations like burning or pins and needles, difficulty walking, or difficulty with usual activities of daily living such as writing - increased level of enzymes called lipase and/or amylase in the blood that would be detected during blood tests - low number of red blood cells known as anaemia that would be detected during blood tests - diarrhoea - constipation - pain in your joints - weight gain - headache - rash - muscle pain Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Lorviqua Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister foil and carton after “EXP”. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not use this medicine if you notice that the package is damaged or shows signs of tampering. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 37 Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Lorviqua contains - The active substance is lorlatinib. Lorviqua 25 mg: each film-coated tablet (tablet) contains 25 mg lorlatinib. Lorviqua 100 mg: each film-coated tablet (tablet) contains 100 mg lorlatinib. - The other ingredients are: Tablet core: microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycolate, magnesium stearate. Film-coating: Hypromellose, lactose monohydrate, macrogol, triacetin, titanium dioxide (E171), iron oxide black (E172), and iron oxide red (E172). See Lorviqua contains lactose and Lorviqua contains sodium in section 2. What Lorviqua looks like and contents of the pack Lorviqua 25 mg is supplied as round light pink film-coated tablets, debossed with “Pfizer” on one side and “25” and “LLN” on the other side. Lorviqua 25 mg is provided in blisters of 10 tablets, which are available in packs containing 90 tablets (9 blisters) or 120 tablets (12 blisters). Lorviqua 100 mg is supplied as oval dark pink film-coated tablets, debossed with “Pfizer” on one side and “LLN 100” on the other side. Lorviqua 100 mg is provided in blisters of 10 tablets, which are available in packs containing 30 tablets (3 blisters). Not all pack sizes may be marketed. Marketing Authorisation Holder Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium Manufacturer Pfizer Manufacturing Deutschland GmbH Betriebsstӓtte Freiburg Mooswaldallee 1 79090 Freiburg Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: Belgique/België/Belgien Pfizer S.A. / N.V. Tél/Tel: +32 (0)2 554 62 11 Lietuva Pfizer Luxembourg SARL filialas Lietuvoje Tel: +370 52 51 4000 България Пфайзер Люксембург САРЛ, Клон България Тел: +359 2 970 4333 Luxembourg/Luxemburg Pfizer S.A. Tél/Tel: +32 (0)2 554 62 11 38 Česká republika Pfizer, spol. s r.o. Tel: +420 283 004 111 Magyarország Pfizer Kft. Tel: +36-1-488-37-00 Danmark Pfizer ApS Tlf: +45 44 20 11 00 Malta Vivian Corporation Ltd. Tel: +35621 344610 Deutschland Pfizer Pharma GmbH Tel: +49 (0)30 550055 51000 Nederland Pfizer BV Tel: +31 (0)10 406 43 01 Eesti Pfizer Luxembourg SARL Eesti filiaal Tel: +372 666 7500 Norge Pfizer AS Tlf: +47 67 52 61 00 Ελλάδα Pfizer Ελλάς A.E. Τηλ: +30 210 6785 800 Österreich Pfizer Corporation Austria Ges.m.b.H. Tel: +43 (0)1 521 15-0 España Pfizer, S.L. Tel: +34 91 490 99 00 Polska Pfizer Polska Sp. z o.o. Tel: +48 22 335 61 00 France Pfizer Tél: +33 (0)1 58 07 34 40 Portugal Laboratórios Pfizer, Lda. Tel: +351 21 423 5500 Hrvatska Pfizer Croatia d.o.o. Tel: +385 1 3908 777 România Pfizer Romania S.R.L. Tel: +40 (0) 21 207 28 00 Ireland Pfizer Healthcare Ireland Tel: 1800 633 363 (toll free) +44 (0)1304 616161 Slovenija Pfizer Luxembourg SARL Pfizer, podružnica za svetovanje s področja farmacevtske dejavnosti, Ljubljana Tel: +386 (0)1 52 11 400 Ísland Icepharma hf. Sími: +354 540 8000 Slovenská republika Pfizer Luxembourg SARL, organizačná zložka Tel: +421 2 3355 5500 Italia Pfizer S.r.l. Tel: +39 06 33 18 21 Suomi/Finland Pfizer Oy Puh/Tel: +358 (0)9 43 00 40 Kύπρος Pfizer Ελλάς Α.Ε. (Cyprus Branch) Τηλ: +357 22 817690 Sverige Pfizer AB Tel: +46 (0)8 550 520 00 Latvija Pfizer Luxembourg SARL filiāle Latvijā Tel: +371 670 35 775 United Kingdom Pfizer Limited Tel: +44 (0) 1304 616161 This leaflet was last revised in {MM/YYYY}. 39 This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine. The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary. Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. https://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take lorviqua', 'Section_Content': "do not take lorviqua - if you are allergic to lorlatinib or any of the other ingredients of this medicine (listed in section 6). - if you are taking any of these medicines: rifampicin (used to treat tuberculosis) carbamazepine, phenytoin (used to treat epilepsy) enzalutamide (used to treat prostate cancer) mitotane (used to treat cancer of the adrenal glands) medicines containing st. john's wort (hypericum perforatum, a herbal preparation) warnings and precautions talk to your doctor before taking lorviqua: - if you have high levels of blood cholesterol or triglycerides - if you have high levels of the enzymes known as amylase or lipase in the blood or a condition such as pancreatitis that can raise the levels of these enzymes - if you have problems with your heart, including heart failure, slow heart rate, or if electrocardiogram (ecg) results show that you have an abnormality of the electrical activity of your heart known as prolonged pr interval or av block. - if you have cough, chest pain, shortness of breath, or worsening of respiratory symptoms or have ever had a lung condition called pneumonitis. if you are not sure, talk to your doctor, pharmacist or nurse before taking lorviqua. tell your doctor immediately if you develop: - heart problems. tell your doctor right away about changes in your heart beat (fast or slow), light-headedness, fainting, dizziness or shortness of breath. these symptoms could be signs of heart problems. your doctor may check for problems with your heart during treatment with lorviqua. if the results are abnormal, your doctor may decide to reduce the dose of lorviqua or stop your treatment. - speech problems, difficulty speaking, including slurred or slow speech. your doctor may investigate further and may decide to reduce your dose of lorviqua or stop your treatment. - mental status changes, mood or memory problems, such as change in your mood (including depression, euphoria and mood swings), irritability, aggression, agitation, anxiety or a change in your personality and episodes of confusion or loss of contact with reality, such as believing, seeing or hearing things that are not real. your doctor may investigate further and may decide to reduce your dose of lorviqua or stop your treatment. - pain in the back or abdomen (belly), yellowing of the skin and eyes (jaundice), nausea or vomiting. these symptoms could be signs of pancreatitis. your doctor may investigate further and may decide to reduce the dose of lorviqua. - cough, chest pain, or a worsening of existing respiratory symptoms. your doctor may investigate further and treat you with other medicines such as antibiotics and steroids. your doctor may decide to reduce your dose of lorviqua or stop your treatment. your doctor may do further assessments and may decide to reduce the dose of lorviqua or stop your treatment if you develop: - liver problems. tell your doctor right away if you feel more tired than usual, your skin and whites of your eyes turn yellow, your urine turns dark or brown (tea colour), you have nausea, vomiting, or decreased appetite, you have pain on the right side of your stomach, you have itching, or if you bruise more easily than usual. your doctor may do blood tests to check your liver function. see possible side effects in section 4 for more information. children and adolescents this medicine is only indicated in adults and it is not to be given to children and adolescents. tests and checks you will have blood tests before you start treatment and during your treatment. these tests are to check the level of cholesterol, triglycerides and the enzymes amylase or lipase in your blood before you start treatment with lorviqua and regularly during treatment. other medicines and lorviqua tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines, including herbal medicines and medicines obtained over the counter. this is because lorviqua can affect the way some other medicines work. also some medicines can affect the way lorviqua works. you must not take lorviqua with certain medicines. these are listed under do not take lorviqua, at the start of section 2. in particular tell your doctor, pharmacist or nurse if you are taking any of the following medicines: - boceprevir a medicine used to treat hepatitis c. - buproprion a medicine used to treat depression or to help people quit smoking. - dihydroergotamine, ergotamine medicines used to treat migraine headaches. - efavirenz, cobicistat, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either elvitegravir, indinavir, lopinavir or tipranavir medicines used to treat aids/hiv. - ketoconazole, itraconazole, voriconazole, posaconazole medicines used to treat fungal infections. also troleandomycin, a medicine used to treat certain types of bacterial infections. - quinidine a medicine used to treat irregular heartbeat and other heart problems. - pimozide a medicine used to treat mental health problems. - alfentanil and fentanyl medicines used to treat severe pain. - ciclosporin, sirolimus, and tacrolimus medicines used in organ transplantation to prevent organ rejection. lorviqua with food and drink you must not drink grapefruit juice or eat grapefruit while on treatment with lorviqua as they may change the amount of lorviqua in your body. pregnancy, breast-feeding and fertility - contraception information for women you should not become pregnant while taking this medicine. if you are able to have children, you must use highly effective contraception (for example, double-barrier contraception such as condom and diaphragm) while on treatment and for at least 5 weeks after stopping treatment. lorlatinib may reduce the effectiveness of hormonal contraceptive methods (for example, birth control pill); therefore, hormonal contraceptives may not be considered highly effective. if hormonal contraception is unavoidable it must be used in combination with a condom. talk to your doctor about the right methods of contraception for you and your partner. - contraception information for men you should not father children during treatment with lorviqua because this medicine could harm the baby. if there is any possibility that you may father a child while taking this medicine, you must use a condom during treatment, and for at least 14 weeks after completing therapy. talk to your doctor about the right methods of contraception for you and your partner. - pregnancy do not take lorviqua if you are pregnant. this is because it may harm your baby. if your male partner is being treated with lorviqua, he must use a condom during treatment and for at least 14 weeks after completing therapy. if you become pregnant when taking the medicine or during the 5 weeks after taking your last dose, tell your doctor straight away. - breast-feeding do not breast-feed while taking this medicine and for 7 days after the last dose. this is because it is not known if lorviqua can pass into breast milk and could therefore harm your baby. - fertility lorviqua may affect male fertility. talk to your doctor about fertility preservation before taking lorviqua. driving and using machines you should take special care when driving and using machines when taking lorviqua because of its effects on your mental state. lorviqua contains lactose if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. lorviqua contains sodium this medicine contains less than 1 mmol sodium (23 mg) per 25 mg or 100 mg tablet, that is to say essentially 'sodium-free'.", 'Entity_Recognition': [{'Text': 'lorviqua', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 12, 'BeginOffset': 12, 'EndOffset': 20, 'Score': 0.9799121022224426, 'Text': 'lorviqua', 'Category': 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{'Title': '3. how to take lorviqua', 'Section_Content': 'always take this medicine exactly as your doctor, pharmacist or nurse has told you. check with your doctor, pharmacist or nurse if you are not sure. - the recommended dose is one tablet of 100 mg taken by mouth once daily. - take the dose at about the same time each day. - you can take the tablets with food or between meals always avoiding grapefruit and grapefruit juice. - swallow the tablets whole and do not crush, chew or dissolve the tablets. - sometimes your doctor may lower your dose, stop your treatment for a short time or stop your treatment completely if you feel unwell. if you vomit after taking lorviqua if you vomit after taking a dose of lorviqua, do not take an extra dose, just take your next dose at the usual time. if you take more lorviqua than you should if you accidentally take too many tablets, tell your doctor, pharmacist or nurse right away. you may require medical attention. if you forget to take lorviqua what to do if you forget to take a tablet depends on how long it is until your next dose. - if your next dose is in 4 hours or more, take the missed tablet as soon as you remember. then take the next tablet at the usual time. - if your next dose is in less than 4 hours away, skip the missed tablet. then take the next tablet at the usual time. do not take a double dose to make up for a forgotten dose. if you stop taking lorviqua it is important to take lorviqua every day, for as long as your doctor asks you to. if you are not able to take the medicine as your doctor has prescribed, or you feel you do not need it anymore, speak with your doctor right away. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'lorviqua', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 189, 'EndOffset': 192}, {'Id': 0, 'BeginOffset': 205, 'EndOffset': 210, 'Score': 0.3290887475013733, 'Text': 'mouth', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'swallow', 'Type': 'TREATMENT', 'BeginOffset': 377, 'EndOffset': 384}, {'Text': 'your treatment', 'Type': 'TREATMENT', 'BeginOffset': 501, 'EndOffset': 515}, {'Text': 'your treatment', 'Type': 'TREATMENT', 'BeginOffset': 541, 'EndOffset': 555}, {'Id': 12, 'BeginOffset': 574, 'EndOffset': 585, 'Score': 0.4878641366958618, 'Text': 'feel unwell', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9128112196922302}]}, {'Id': 13, 'BeginOffset': 594, 'EndOffset': 599, 'Score': 0.907507598400116, 'Text': 'vomit', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6465770602226257}]}, {'Id': 5, 'BeginOffset': 613, 'EndOffset': 621, 'Score': 0.9676620364189148, 'Text': 'lorviqua', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 629, 'EndOffset': 634, 'Score': 0.8221256136894226, 'Text': 'vomit', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4305436611175537}]}, {'Text': 'a dose of lorviqua', 'Type': 'TREATMENT', 'BeginOffset': 648, 'EndOffset': 666}, {'Text': 'an extra dose', 'Type': 'TREATMENT', 'BeginOffset': 680, 'EndOffset': 693}, {'Id': 7, 'BeginOffset': 756, 'EndOffset': 764, 'Score': 0.8918910622596741, 'Text': 'lorviqua', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'medical attention', 'Type': 'TREATMENT', 'BeginOffset': 890, 'EndOffset': 907}, {'Id': 8, 'BeginOffset': 931, 'EndOffset': 939, 'Score': 0.9493564963340759, 'Text': 'lorviqua', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 1056, 'EndOffset': 1057}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 1202, 'EndOffset': 1203}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 1297, 'EndOffset': 1310}, {'Id': 9, 'BeginOffset': 1363, 'EndOffset': 1371, 'Score': 0.98197340965271, 'Text': 'lorviqua', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5217058062553406}], 'Attributes': [{'Type': 'FREQUENCY', 'Score': 0.9022073745727539, 'RelationshipScore': 0.8927069902420044, 'RelationshipType': 'FREQUENCY', 'Id': 11, 'BeginOffset': 1405, 'EndOffset': 1414, 'Text': 'every day', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 10, 'BeginOffset': 1396, 'EndOffset': 1404, 'Score': 0.9914843440055847, 'Text': 'lorviqua', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'FREQUENCY', 'Score': 0.9022073745727539, 'RelationshipScore': 0.9999921321868896, 'RelationshipType': 'FREQUENCY', 'Id': 11, 'BeginOffset': 1405, 'EndOffset': 1414, 'Text': 'every day', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1651, 'EndOffset': 1664}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects could be serious. tell your doctor straight away if you notice any of the following side effects (also section 2 what you need to know before you take lorviqua). your doctor may lower your dose, stop your treatment for a short time or stop your treatment completely: - cough, shortness of breath, chest pain or worsening breathing problems - slow pulse, (50 beats per minute or less), feeling tired, dizzy or faint or losing consciousness - abdominal (belly) pain, back pain, nausea, vomiting, itching or yellowing of the skin and eyes - mental status changes; changes in cognition including confusion, memory loss, reduced ability to concentrate; changes in mood including irritability and mood swings; changes in speech including difficulty speaking, such as slurred or slow speech; or loss of contact with reality, such as believing, seeing or hearing things that are not real other side effects of lorviqua may include: very common: may affect more than 1 in 10 people - increase in cholesterol and triglycerides (fats in your blood that would be detected during blood tests) - limb or skin swelling - problems with your eyes, such as difficulty seeing out of one or both eyes, double vision, or perceived flashes of light - problems with the nerves in your arms and legs, such as pain, numbness, unusual sensations like burning or pins and needles, difficulty walking, or difficulty with usual activities of daily living such as writing - increased level of enzymes called lipase and/or amylase in the blood that would be detected during blood tests - low number of red blood cells known as anaemia that would be detected during blood tests - diarrhoea - constipation - pain in your joints - weight gain - headache - rash - muscle pain reporting of side effects if you get any side effects, talk to your doctor, 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{'Title': '5. how to store lorviqua', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister foil and carton after "exp". the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. do not use this medicine if you notice that the package is damaged or shows signs of tampering. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what lorviqua contains - the active substance is lorlatinib. lorviqua 25 mg: each film-coated tablet (tablet) contains 25 mg lorlatinib. lorviqua 100 mg: each film-coated tablet (tablet) contains 100 mg lorlatinib. - the other ingredients are: tablet core: microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycolate, magnesium stearate. film-coating: hypromellose, lactose monohydrate, macrogol, triacetin, titanium dioxide (e171), iron oxide black (e172), and iron oxide red (e172). see lorviqua contains lactose and lorviqua contains sodium in section 2. what lorviqua looks like and contents of the pack lorviqua 25 mg is supplied as round light pink film-coated tablets, debossed with "pfizer" on one side and "25" and "lln" on the other side. lorviqua 25 mg is provided in blisters of 10 tablets, which are available in packs containing 90 tablets (9 blisters) or 120 tablets (12 blisters). lorviqua 100 mg is supplied as oval dark pink film-coated tablets, debossed with "pfizer" on one side and "lln 100" on the other side. lorviqua 100 mg is provided in blisters of 10 tablets, which are available in packs containing 30 tablets (3 blisters). not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'lorviqua', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 49, 'EndOffset': 59, 'Score': 0.9801914691925049, 'Text': 'lorlatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.8411228060722351, 'RelationshipScore': 0.9893088340759277, 'RelationshipType': 'STRENGTH', 'Id': 2, 'BeginOffset': 70, 'EndOffset': 75, 'Text': '25 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.3119533956050873, 'RelationshipScore': 0.9991616010665894, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 77, 'EndOffset': 86, 'Text': 'each film', 'Category': 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FF20679A00B6324E35178EF95C3BEED4

https://www.ema.europa.eu/documents/product-information/pifeltro-epar-product-information_en.pdf

Pifeltro

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Pifeltro 100 mg film-coated tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 100 mg of doravirine. Excipient with known effect Each film-coated tablet contains 222 mg lactose (as monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet White, oval-shaped, tablet of dimensions 19.00 mm x 9.50 mm, debossed with the corporate logo and 700 on one side and plain on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Pifeltro is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class (see sections 4.4 and 5.1). 4.2 Posology and method of administration Therapy should be initiated by a physician experienced in the management of HIV infection. Posology The recommended dose is one 100 mg tablet taken orally once daily with or without food. Dose adjustment If Pifeltro is co-administered with rifabutin, one 100 mg tablet of Pifeltro should be taken twice daily (approximately 12 hours apart) (see section 4.5). Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, one 100 mg tablet of Pifeltro should be taken twice daily (approximately 12 hours apart). Missed dose If the patient misses a dose of Pifeltro within 12 hours of the time it is usually taken, the patient should take as soon as possible and resume the normal dosing schedule. If a patient misses a dose by more 3 than 12 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not take 2 doses at one time. Special populations Elderly No dose adjustment of doravirine is needed in elderly patients (see section 5.2). Renal impairment No dose adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease and has not been studied in dialysis patients (see section 5.2). Hepatic impairment No dose adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). It is not known whether the exposure to doravirine will increase in patients with severe hepatic impairment. Therefore, caution is advised when doravirine is administered to patients with severe hepatic impairment (see section 5.2). Paediatric population Safety and efficacy of doravirine have not been established in patients younger than 18 years of age. No data are available. Method of administration Pifeltro must be taken orally, once daily with or without food and swallowed whole (see section 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with medicinal products that are strong cytochrome P450 CYP3A enzyme inducers is contraindicated as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of Pifeltro (see sections 4.4 and 4.5). These medicinal products include, but are not limited, to the following:  carbamazepine, oxcarbazepine, phenobarbital, phenytoin  rifampicin, rifapentine  St. John’s wort (Hypericum perforatum)  mitotane  enzalutamide  lumacaftor 4.4 Special warnings and precautions for use While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission of HIV-1, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines. NNRTI substitutions and use of doravirine Doravirine has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. NNRTI-associated mutations detected at screening were part of exclusion criteria in the Phase 2b/3-studies. A breakpoint for a reduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established (see section 5.1). There is not sufficient clinical evidence to support the use of doravirine in patients infected with HIV-1 with evidence of resistance to the NNRTI class. 4 Use with CYP3A inducers Caution should be given to prescribing doravirine with medicinal products that may reduce the exposure of doravirine (see sections 4.3 and 4.5). Immune reactivation syndrome Immune reactivation syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, autoimmune hepatitis, polymyositis, and Guillain- Barré syndrome) have also been reported to occur in the setting of immune reactivation; however, the time to onset is more variable and can occur many months after initiation of treatment. Lactose The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Effects of other medicinal products on doravirine Doravirine is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of doravirine (see section 5.2). Doravirine should not be co- administered with medicinal products that are strong CYP3A enzyme inducers as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of doravirine (see sections 4.3 and 5.2). Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2). Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2). Co-administration of doravirine and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. However, no dose adjustment is needed when doravirine is co-administered with CYP3A inhibitors. Effects of doravirine on other medicinal products Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of medicinal products that are dependent on transport proteins for absorption and/or elimination or that are metabolized by CYP enzymes. However, co-administration of doravirine and the sensitive CYP3A substrate midazolam resulted in a 18 % decrease in midazolam exposure, suggesting that doravirine may be a weak CYP3A inducer. Therefore caution should be used when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that also have a narrow therapeutic window (e.g., tacrolimus and sirolimus). Interactions table Table 1 shows the established and other potential medicinal product interactions with doravirine but is not all inclusive (increase is indicated as , decrease is indicated as ↓, and no change as ↔). 5 Table 1: Interactions of doravirine with other medicinal products Medicinal Product by Therapeutic Area Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)* Recommendation Concerning Co-administration with doravirine Acid-Reducing Agents antacid (aluminium and magnesium hydroxide oral suspension) (20 mL SD, doravirine 100 mg SD)  doravirine AUC 1.01 (0.92, 1.11) Cmax 0.86 (0.74, 1.01) C24 1.03 (0.94, 1.12) No dose adjustment is required. pantoprazole (40 mg QD, doravirine 100 mg SD)  doravirine AUC 0.83 (0.76, 0.91) Cmax 0.88 (0.76, 1.01) C24 0.84 (0.77, 0.92) No dose adjustment is required. omeprazole Interaction not studied. Expected:  doravirine No dose adjustment is required. Angiotensin Converting Enzyme Inhibitors lisinopril Interaction not studied. Expected: ↔ lisinopril No dose adjustment is required. Antiandrogens enzalutamide Interaction not studied. Expected:  doravirine (Induction of CYP3A) Co-administration is contraindicated. Antibiotics nafcillin Interaction not studied. Expected: ↓ doravirine (Induction of CYP3A) Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). 6 Medicinal Product by Therapeutic Area Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)* Recommendation Concerning Co-administration with doravirine Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin Interaction not studied. Expected:  doravirine (Induction of CYP3A) Co-administration is contraindicated. Antidiabetics metformin (1000 mg SD, doravirine 100 mg QD)  metformin AUC 0.94 (0.88, 1.00) Cmax 0.94 (0.86, 1.03) No dose adjustment is required. canagliflozin liraglutide sitagliptin Interaction not studied. Expected: ↔ canagliflozin ↔ liraglutide ↔ sitagliptin No dose adjustment is required. Antidiarrhoeals telotristat ethyl Interaction not studied. Expected: ↓ doravirine (Induction of CYP3A) Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). Antigout and Uricosuric Agents lesinurad Interaction not studied. Expected: ↓ doravirine (Induction of CYP3A) Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). Antimycobacterials Single dose rifampicin (600 mg SD, doravirine 100 mg SD) Multiple dose rifampicin (600 mg QD, doravirine 100 mg SD)  doravirine AUC 0.91 (0.78, 1.06) Cmax 1.40 (1.21, 1.63) C24 0.90 (0.80, 1.01)  doravirine AUC 0.12 (0.10, 0.15) Cmax 0.43 (0.35, 0.52) C24 0.03 (0.02, 0.04) (Induction of CYP3A) Co-administration is contraindicated. rifapentine Interaction not studied. Expected:  doravirine (Induction of CYP3A) Co-administration is contraindicated. rifabutin (300 mg QD, doravirine 100 mg SD)  doravirine AUC 0.50 (0.45, 0.55) Cmax 0.99 (0.85, 1.15) C24 0.32 (0.28, 0.35) (Induction of CYP3A) If doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (approximately 12 hours apart). 7 Medicinal Product by Therapeutic Area Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)* Recommendation Concerning Co-administration with doravirine Antineoplastics mitotane Interaction not studied. Expected:  doravirine (Induction of CYP3A) Co-administration is contraindicated. Antipsychotics thioridazine Interaction not studied. Expected: ↓ doravirine (Induction of CYP3A) Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). Azole Antifungal Agents ketoconazole (400 mg QD, doravirine 100 mg SD)  doravirine AUC 3.06 (2.85, 3.29) Cmax 1.25 (1.05, 1.49) C24 2.75 (2.54, 2.98) (Inhibition of CYP3A) No dose adjustment is required. fluconazole itraconazole posaconazole voriconazole Interaction not studied. Expected:  doravirine (Inhibition of CYP3A4) No dose adjustment is required. Calcium Channel Blockers diltiazem verapamil Interaction not studied. Expected:  doravirine (CYP3A inhibition) No dose adjustment is required. Cystic Fibrosis Treatment lumacaftor Interaction not studied. Expected:  doravirine (Induction of CYP3A) Co-administration is contraindicated. Endothelin Receptor Antagonists bosentan Interaction not studied. Expected: ↓ doravirine (Induction of CYP3A) Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). 8 Medicinal Product by Therapeutic Area Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)* Recommendation Concerning Co-administration with doravirine Hepatitis C Antiviral Agents elbasvir + grazoprevir (50 mg elbasvir QD + 200 mg grazoprevir QD, doravirine 100 mg QD)  doravirine AUC 1.56 (1.45, 1.68) Cmax 1.41 (1.25, 1.58) C24 1.61 (1.45, 1.79) (Inhibition of CYP3A)  elbasvir AUC 0.96 (0.90, 1.02) Cmax 0.96 (0.91, 1.01) C24 0.96 (0.89, 1.04)  grazoprevir AUC 1.07 (0.94, 1.23) Cmax 1.22 (1.01, 1.47) C24 0.90 (0.83, 0.96) No dose adjustment is required. ledipasvir + sofosbuvir (90 mg ledipasvir SD + 400 mg sofosbuvir SD, doravirine 100 mg SD)  doravirine AUC 1.15 (1.07, 1.24) Cmax 1.11 (0.97, 1.27) C24 1.24 (1.13, 1.36)  ledipasvir AUC 0.92 (0.80, 1.06) Cmax 0.91 (0.80, 1.02)  sofosbuvir AUC 1.04 (0.91, 1.18) Cmax 0.89 (0.79, 1.00)  GS-331007 AUC 1.03 (0.98, 1.09) Cmax 1.03 (0.97, 1.09) No dose adjustment is required. sofosbuvir/velpatasvir Interaction not studied. Expected:  doravirine No dose adjustment is required. sofosbuvir Interaction not studied. Expected:  doravirine No dose adjustment is required. daclatasvir Interaction not studied. Expected: ↔ doravirine No dose adjustment is required. ombitasvir/ paritaprevir/ritonavir and dasabuvir+/-ritonavir Interaction not studied. Expected:  doravirine (Inhibition of CYP3A due to ritonavir) No dose adjustment is required. 9 Medicinal Product by Therapeutic Area Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)* Recommendation Concerning Co-administration with doravirine dasabuvir Interaction not studied. Expected:  doravirine No dose adjustment is required. glecaprevir, pibrentasvir Interaction not studied. Expected:  doravirine (inhibition of CYP3A) No dose adjustment is required. ribavirin Interaction not studied. Expected:  doravirine No dose adjustment is required. Herbal Supplements St. John’s wort (Hypericum perforatum) Interaction not studied. Expected:  doravirine (Induction of CYP3A) Co-administration is contraindicated. HIV Antiviral Agents Fusion and Entry Inhibitors enfuvirtide Interaction not studied. Expected: ↔ doravirine ↔ enfuviritide No dose adjustment is required. maraviroc Interaction not studied. Expected: ↔ doravirine ↔ maraviroc No dose adjustment is required. Protease Inhibitors ritonavir†- boosted PIs (atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir, tipranavir) Interaction not studied. Expected:  doravirine (Inhibition of CYP3A) ↔ boosted PIs No dose adjustment is required. cobicistat-boosted PIs (darunavir, atazanavir) Interaction not studied. Expected:  doravirine (Inhibition of CYP3A) ↔ boosted PIs No dose adjustment is required. 10 Medicinal Product by Therapeutic Area Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)* Recommendation Concerning Co-administration with doravirine Integrase Strand Transfer Inhibitors dolutegravir (50 mg QD, doravirine 200 mg QD)  doravirine AUC 1.00 (0.89, 1.12) Cmax 1.06 (0.88, 1.28) C24 0.98 (0.88, 1.09)  dolutegravir AUC 1.36 (1.15, 1.62) Cmax 1.43 (1.20, 1.71) C24 1.27 (1.06, 1.53) (Inhibition of BCRP) No dose adjustment is required. raltegravir Interaction not studied. Expected: ↔ doravirine ↔ raltegravir No dose adjustment is required. ritonavir†-boosted elvitegravir Interaction not studied. Expected:  doravirine (CYP3A inhibition) ↔ elvitegravir No dose adjustment is required. cobicistat-boosted elvitegravir Interaction not studied. Expected:  doravirine (CYP3A inhibition) ↔ elvitegravir No dose adjustment is required. Nucleoside Reverse Transcriptase Inhibitors tenofovir disoproxil (245 mg QD, doravirine 100 mg SD)  doravirine AUC 0.95 (0.80, 1.12) Cmax 0.80 (0.64, 1.01) C24 0.94 (0.78, 1.12) No dose adjustment is required. lamivudine + tenofovir disoproxil (300 mg lamivudine SD + 245 mg tenofovir disoproxil SD, doravirine 100 mg SD)  doravirine AUC 0.96 (0.87, 1.06) Cmax 0.97 (0.88, 1.07) C24 0.94 (0.83, 1.06)  lamivudine AUC 0.94 (0.88, 1.00) Cmax 0.92 (0.81, 1.05)  tenofovir AUC 1.11 (0.97, 1.28) Cmax 1.17 (0.96, 1.42) No dose adjustment is required. abacavir Interaction not studied. Expected: ↔ doravirine ↔ abacavir No dose adjustment is required. 11 Medicinal Product by Therapeutic Area Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)* Recommendation Concerning Co-administration with doravirine emtricitabine Interaction not studied. Expected: ↔ doravirine ↔ emtricitabine No dose adjustment is required. tenofovir alafenamide Interaction not studied. Expected: ↔ doravirine ↔ tenofovir alafenamide No dose adjustment is required. Immunosuppressants tacrolimus sirolimus Interaction not studied. Expected:  doravirine ↓ tacrolimus, sirolimus (Induction of CYP3A) Monitor blood concentrations of tacrolimus and sirolimus as the dose of these agents may need to be adjusted. Kinase Inhibitors dabrafenib Interaction not studied. Expected: ↓ doravirine (Induction of CYP3A) Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). Opioid Analgesics methadone 20-200 mg QD individualised dose, doravirine 100 mg QD  doravirine AUC 0.74 (0.61, 0.90) Cmax 0.76 (0.63, 0.91) C24 0.80 (0.63, 1.03)  R-methadone AUC 0.95 (0.90, 1.01) Cmax 0.98 (0.93, 1.03) C24 0.95 (0.88, 1.03)  S-methadone AUC 0.98 (0.90, 1.06) Cmax 0.97 (0.91, 1.04) C24 0.97 (0.86, 1.10) No dose adjustment is required. buprenorphine naloxone Interaction not studied. Expected: ↔ buprenorphine ↔ naloxone No dose adjustment is required. 12 Medicinal Product by Therapeutic Area Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)* Recommendation Concerning Co-administration with doravirine Oral Contraceptives 0.03 mg ethinyl oestradiol/ 0.15 mg levonorgestrel SD, doravirine 100 mg QD  ethinyl oestradiol AUC 0.98 (0.94, 1.03) Cmax 0.83 (0.80, 0.87)  levonorgestrel AUC 1.21 (1.14, 1.28) Cmax 0.96 (0.88, 1.05) No dose adjustment is required. norgestimate/ethinyl oestradiol Interaction not studied. Expected:  norgestimate/ethinyl oestradiol No dose adjustment is required. Pharmacokinetic Enhancers ritonavir (100 mg BID, doravirine 50 mg SD)  doravirine AUC 3.54 (3.04, 4.11) Cmax 1.31 (1.17, 1.46) C24 2.91 (2.33, 3.62) (Inhibition of CYP3A) No dose adjustment is required. cobicistat Interaction not studied. Expected:  doravirine (Inhibition of CYP3A) No dose adjustment is required. Psychostimulants modafinil Interaction not studied. Expected: ↓doravirine (Induction of CYP3A) Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). Sedatives/Hypnotics midazolam (2 mg SD, doravirine 120 mg QD)  midazolam AUC 0.82 (0.70, 0.97) Cmax 1.02 (0.81, 1.28) No dose adjustment is required. Statins atorvastatin (20 mg SD, doravirine 100 mg QD)  atorvastatin AUC 0.98 (0.90, 1.06) Cmax 0.67 (0.52, 0.85) No dose adjustment is required. rosuvastatin simvastatin Interaction not studied. Expected: ↔ rosuvastatin ↔ simvastatin No dose adjustment is required.  = increase, ↓ = decrease, ↔ = no change CI = Confidence Interval; SD = Single Dose; QD = Once Daily; BID = Twice Daily *AUC0- for single dose, AUC0-24 for once daily. †The interaction was evaluated with ritonavir only. 13 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data from the use of doravirine in pregnant women. Antiretroviral pregnancy registry To monitor maternal-foetal outcomes in patients exposed to antiretroviral medicinal products while pregnant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry. Animal studies with doravirine do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of doravirine during pregnancy. Breast-feeding It is unknown whether doravirine is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk (see section 5.3). Because of the potential for HIV-1 transmission and the potential for serious adverse reactions in breast-feeding infants, mothers should be instructed not to breast-feed if they are receiving Pifeltro. Fertility No human data on the effect of doravirine on fertility are available. Animal studies do not indicate harmful effects of doravirine on fertility at exposure levels higher than the exposure in humans at the recommended clinical dose (see section 5.3). 4.7 Effects on ability to drive and use machines Pifeltro may have a minor influence on the ability to drive or use machines. Patients should be informed that fatigue, dizziness, and somnolence have been reported during treatment with doravirine (see section 4.8). This should be considered when assessing a patient's ability to drive or operate machinery. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions considered possibly or probably related to doravirine were nausea (4 %) and headache (3 %). Tabulated summary of adverse reactions The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). Table 2: Tabulated summary of adverse reactions associated with doravirine used in combination with other antiretrovirals Frequency Adverse reactions Infections and infestations Rare rash pustular Metabolism and nutrition disorders Uncommon hypophosphataemia Rare hypomagnesaemia 14 Frequency Adverse reactions Psychiatric disorders Common abnormal dreams, insomnia1 Uncommon nightmare, depression2, anxiety3, irritability, confusional state, suicidal ideation Rare aggression, hallucination, adjustment disorder, mood altered, somnambulism Nervous system disorders Common headache, dizziness, somnolence Uncommon disturbance in attention, memory impairment, paraesthesia, hypertonia, poor quality sleep Vascular disorders Uncommon hypertension Respiratory, thoracic and mediastinal disorders Rare dyspnoea, tonsillar hypertrophy Gastrointestinal disorders Common nausea, diarrhoea, flatulence, abdominal pain4, vomiting Uncommon constipation, abdominal discomfort5, abdominal distension, dyspepsia, faeces soft6, gastrointestinal motility disorder7 Rare rectal tenesmus Skin and subcutaneous tissue disorders Common rash8 Uncommon pruritus Rare dermatitis allergic, rosacea Musculoskeletal and connective tissue disorders Uncommon myalgia, arthralgia Rare musculoskeletal pain Renal and urinary disorders Rare acute kidney injury, renal disorder, calculus urinary, nephrolithiasis General disorders and administration site conditions Common fatigue Uncommon asthenia, malaise Rare chest pain, chills, pain, thirst Investigations Common alanine aminotransferase increased9 Uncommon lipase increased, aspartate aminotransferase increased, amylase increased, haemoglobin decreased Rare blood creatine phosphokinase increased 1insomnia includes: insomnia, initial insomnia and sleep disorder 2depression includes: depression, depressed mood, major depression, and persistent depressive disorder 3anxiety includes: anxiety and generalised anxiety disorder 4abdominal pain includes: abdominal pain, and abdominal pain upper 5abdominal discomfort includes: abdominal discomfort, and epigastric discomfort 6faeces soft includes: faeces soft and abnormal faeces 7gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent bowel movements 8rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular, and urticarial 9alanine aminotransferase increased includes: alanine aminotransferase increased and hepatocellular injury Immune reactivation syndrome In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 15 infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose There is no information on potential acute symptoms and signs of overdose with doravirine. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antivirals for systemic use, ATC code: J05AG06 Mechanism of action Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Doravirine does not inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ. Antiviral activity in cell culture Doravirine exhibited an EC50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100 % normal human serum using MT4-GFP reporter cells. Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 1.2 nM to 10.0 nM. Antiviral activity in combination with other HIV antiviral medicinal products The antiviral activity of doravirine was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, or zidovudine; the PIs darunavir or indinavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir. Resistance In cell culture Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106M, V106I, V108I, F227L, F227C, F227V, H221Y, M230I, L234I, P236L, and Y318F. Common NNRTI-resistant mutations (K103N, Y181C) were not selected in the in vitro study. V106A (yielding a fold change of around 19) appeared as an initial substitution in subtype B virus, and V106A or M in subtype A and C virus. Subsequently F227(L/C/V) or L234I emerged in addition to V106 substitution (double mutants yielding a fold change of > 100). http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 16 In clinical trials Treatment-naïve adult subjects The Phase 3 studies, DRIVE-FORWARD and DRIVE-AHEAD, included previously untreated patients (n = 747) where the following NNRTI substitutions were part of exclusion criteria: L100I, K101E, K101P, K103N, K103S, V106A, V106I, V106M, V108I, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, Y188C, Y188H, Y188L, G190A, G190S, H221Y, L234I, M230I, M230L, P225H, F227C, F227L, F227V. The following de novo resistance was seen in the resistance analysis subset (subjects with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having resistance data). Table 3: Resistance development up to week 96 in protocol defined virologic failure population + early discontinuation population DRIVE-FORWARD DRIVE-AHEAD DOR + NRTIs* (383) DRV + r + NRTIs* (383) DOR/TDF/3TC (364) EFV/TDF/FTC (364) Successful genotype, n 15 18 32 33 Genotypic resistance to DOR or control (DRV or EFV) 2 (DOR) 0 (DRV) 8 (DOR) 14 (EFV) NRTI backbone M184I/V only K65R only K65R + M184I/V 2** 2 0 0 0 0 0 0 6 4 1 1 5 4 0 1 *NRTIs in DOR arm: FTC/TDF (333) or ABC/3TC (50); NRTIs in DRV+r arm: FTC/TDF (335) or ABC/3TC (48) **Subjects received FTC/TDF ABC=abacavir; FTC=emtricitabine; DRV=darunavir; r=ritonavir Emergent doravirine associated resistance substitutions in RT included one or more of the following: A98G, V106I, V106A, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F. Virologically suppressed adult subjects The DRIVE-SHIFT study included virologically suppressed patients (N=670) with no history of treatment failure (see section, Clinical experience). A documented absence of genotypic resistance (prior to starting first therapy) to doravirine, lamivudine, and tenofovir was part of the inclusion criteria for patients who switched from a PI- or INI-based regimen. Exclusionary NNRTI substitutions were those listed above (DRIVE-FORWARD and DRIVE-AHEAD), with the exception of substitutions RT K103N, G190A and Y181C (accepted in DRIVE-SHIFT). Documentation of pre- treatment resistance genotyping was not required for patients who switched from a NNRTI-based regimen. In the DRIVE-SHIFT clinical trial, no subjects developed genotypic or phenotypic resistance to DOR, 3TC, or TDF during the initial 48 weeks (immediate switch, N=447) or 24 weeks (delayed switch, N=209) of treatment with DOR/3TC/TDF. One subject developed RT M184M/I mutation and phenotypic resistance to 3TC and FTC during treatment with their baseline regimen. None of the 24 subjects (11 in the immediate switch group, 13 in the delayed switch group) with baseline NNRTI mutations (RT K103N, G190A, or Y181C) experienced virologic failure through Week 48, or at time of discontinuation. Cross-resistance Doravirine has been evaluated in a limited number of patients with NNRTI resistance (K103N n=7, G190A n=1); all patients were suppressed to < 40 copies/mL at week 48. A breakpoint for a reduction 17 in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established. Laboratory strains of HIV-1 harbouring the common NNRTI-associated mutations K103N, Y181C, or K103N/Y181C substitutions in RT exhibit less than a 3-fold decrease in susceptibility to doravirine compared to wild-type virus when evaluated in the presence of 100 % normal human serum. In in vitro studies, doravirine was able to suppress the following NNRTI-associated substitutions; K103N, Y181C, and G190A under clinically relevant concentrations. A panel of 96 diverse clinical isolates containing NNRTI-associated mutations was evaluated for susceptibility to doravirine in the presence of 10 % foetal bovine serum. Clinical isolates containing the Y188L substitution or V106 substitutions in combination with A98G, H221Y, P225H, F227C or Y318F showed a greater than 100-fold reduced susceptibility to doravirine. Other established NNRTI substitutions yielded a fold change of 5-10 (G190S (5.7), K103N/P225H (7.9), V108I/Y181C (6.9), Y181V (5.1)). The clinical relevance of a 5-10 fold reduction in susceptibility is unknown. Treatment emergent doravirine resistance associated substitutions may confer cross resistance to efavirenz, rilpivirine, nevirapine, and etravirine. Of the 7 subjects who developed high level doravirine resistance in the pivotal studies, 6 had phenotypic resistance to EFV and nevirapine, 3 to rilpivirine, and 2 had partial resistance to etravirine based on the Monogram Phenosense assay. Clinical experience Treatment-naïve adult subjects The efficacy of doravirine is based on the analyses of 96-week data from two randomised, multicentre, double-blind, active controlled Phase 3 trials, (DRIVE-FORWARD and DRIVE-AHEAD) in antiretroviral treatment-naïve, HIV-1 infected subjects (n = 1494). Refer to Resistance section for NNRTI substitutions that were part of exclusion criteria. In DRIVE-FORWARD, 766 subjects were randomised and received at least 1 dose of either doravirine 100 mg or darunavir + ritonavir 800+100 mg once daily, each in combination with emtricitabine/tenofovir disoproxil (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of subjects was 33 years (range 18 to 69 years), 86 % had CD4+ T cell count greater than 200 cells per mm3, 84 % were male, 27 % were non-white, 4 % had hepatitis B and/or C virus co-infection, 10 % had a history of AIDS, 20 % had HIV-1 RNA greater than 100,000 copies per mL, 13 % received ABC/3TC and 87 % received FTC/TDF; these characteristics were similar between treatment groups. In DRIVE-AHEAD, 728 subjects were randomized and received at least 1 dose of either doravirine/lamivudine/tenofovir disoproxil 100/300/245 mg (DOR/3TC/TDF) or efavirenz/emtricitabine/tenofovir disoproxil (EFV/FTC/TDF) once daily. At baseline, the median age of subjects was 31 years (range 18-70 years), 85 % were male, 52 % were non-white, 3% had hepatitis B or C co-infection, 14 % had a history of AIDS, 21 % had HIV-1 RNA > 100,000 copies per mL, and 12 % had CD4+ T cell count < 200 cells per mm3; these characteristics were similar between treatment groups. Week 48 and 96 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 4. The doravirine-based regimens demonstrated consistent efficacy across demographic and baseline prognostic factors. 18 Table 4: Efficacy response (< 40 copies/mL, Snapshot approach) in the pivotal studies DRIVE-FORWARD DRIVE-AHEAD DOR + 2 NRTIs (383) DRV + r + 2 NRTIs (383) DOR/3TC/TDF (364) EFV/FTC/TDF (364) Week 48 83 % 79 % 84 % 80 % Difference (95 % CI) 4.2 % (-1.4%, 9.7 %) 4.1 % (-1.5 %, 9.7 %) Week 96* 72 % (N=379) 64 % (N=376) 76 % (N=364) 73 % (N=364) Difference (95 % CI) 7.6 % (1.0 %, 14.2 %) 3.3 % (-3.1 %, 9.6 %) Week 48 outcome (< 40 copies/mL) by baseline factors HIV-1 RNA copies/mL ≤ 100,000 256/285 (90 %) 248/282 (88 %) 251/277 (91 %) 234/258 (91 %) > 100,000 63/79 (80 %) 54/72 (75 %) 54/69 (78 %) 56/73 (77 %) CD4 count, cells/µL ≤ 200 34/41 (83 %) 43/61 (70 %) 27/42 (64 %) 35/43 (81 %) > 200 285/323 (88 %) 260/294 (88 %) 278/304 (91 %) 255/288 (89 %) NRTI background therapy TDF/FTC 276/316 (87 %) 267/312 (86 %) NA ABC/3TC 43/48 (90 %) 36/43 (84 %) Viral subtype B 222/254 (87 %) 219/255 (86 %) 194/222 (87 %) 199/226 (88 %) non-B 97/110 (88 %) 84/100 (84 %) 109/122 (89 %) 91/105 (87 %) Mean CD4 change from baseline Week 48 193 186 198 188 Week 96 224 207 238 223 *For Week 96, certain subjects with missing HIV-1 RNA were excluded from the analysis. P007 was a Phase 2b trial in antiretroviral treatment-naïve HIV-1 infected adult subjects (n = 340). In Part I, subjects were randomized to receive one of 4 doses of doravirine or EFV, each in combination with FTC/TDF. After week 24, all subjects randomized to receive doravirine were switched to (or maintained on) doravirine 100 mg. Additional subjects were randomized in Part II to receive either doravirine 100 mg or EFV, each in combination with FTC/TDF. In both parts of the trial, doravirine and EFV were administered as blinded-therapy and FTC/TDF was administered open-label. 19 Table 5: Efficacy response at week 24 (Snapshot approach) Doravirine 25 mg (N=40) n (%) Doravirine 50 mg (N=43) n (%) Doravirine 100 mg (N=42) n (%) Doravirine 200 mg (N=41) n (%) Efavirenz 600 mg (N=42) n (%) HIV-1 RNA < 40 copies/mL 32 (80) 32 (74) 30 (71) 33 (80) 27 (64) Treatment differences † (95 % CI) †† 16 (-4, 34) 10 (-10, 29) 6.6 (-13, 26) 16 (-3, 34) Mean CD4 change from baseline (cells/mm3) ** 154 113 134 141 121 †A positive value favours doravirine over efavirenz. ††The 95 % CIs were calculated using Miettinen and Nurminen’s method with weights proportional to the size of each stratum (screening HBV-1 RNA > 100,000 copies/mL or ≤ 100,000 copies/mL. **Approach to handle missing data: Observed Failure (OF) approach. Baseline CD4 cell count was carried forward for subjects who discontinued assigned therapy due to lack of efficacy. Note: Both doravirine and efavirenz were administered with emtricitabine/tenofovir disoproxil (FTC/TDF). Virologically suppressed adult subjects The efficacy of switching from a baseline regimen consisting of two nucleoside reverse transcriptase inhibitors in combination with a ritonavir- or cobicistat-boosted PI, or cobicistat-boosted elvitegravir, or an NNRTI to DOR/3TC/TDF was evaluated in a randomized, open-label trial (DRIVE-SHIFT), in virologically suppressed HIV-1 infected adults. Subjects must have been virologically suppressed (HIV-1 RNA < 40 copies/mL) on their baseline regimen for at least 6 months prior to trial entry, with no history of virologic failure, and a documented absence of RT substitutions conferring resistance to doravirine, lamivudine and tenofovir (see section Resistance). Subjects were randomized to either switch to DOR/3TC/TDF at baseline [N = 447, Immediate Switch Group (ISG)], or stay on their baseline regimen until Week 24, at which point they switched to DOR/3TC/TDF [N = 223, Delayed Switch Group (DSG)]. At baseline, the median age of subjects was 43 years, 16 % were female, and 24 % were non-white. In the DRIVE-SHIFT trial, an immediate switch to DOR/3TC/TDF was demonstrated to be non- inferior at Week 48 compared to continuation of the baseline regimen at Week 24 as assessed by the proportion of subjects with HIV-1 RNA < 40 copies/mL. Treatment results are shown in Table 6. Consistent results were seen for the comparison at study Week 24 in each treatment group. 20 Table 6: Efficacy response (Snapshot approach) in the DRIVE-SHIFT study Outcome DOR/3TC/TDF Once Daily ISG Baseline Regimen DSG Week 48 N=447 Week 24 N=223 HIV-1 RNA < 40 copies/mL 90 % 93 % ISG-DSG, Difference (95 % CI)* -3.6 % (-8.0 %, 0.9 %) Proportion (%) of Subjects With HIV-1 RNA < 40 copies/mL by Baseline Regimen Received Ritonavir- or Cobicistat-boosted PI 280/316 (89 %) 145/156 (93 %) Cobicistat-boosted elvitegravir 23/25 (92 %) 11/12 (92 %) NNRTI 98/106 (92 %) 52/55 (95 %) Proportion (%) of Subjects With HIV-1 RNA < 40 copies/mL by Baseline CD4+ T cell Count (cells/mm3) < 200 cells/mm3 10/13 (77 %) 3/4 (75 %) ≥ 200 cells/mm3 384/426 (90 %) 202/216 (94 %) HIV-1 RNA ≥ 40 copies/mL† 3 % 4 % No Virologic Data Within the Time Window 8 % 3 % Discontinued study due to AE or Death‡ 3 % 0 Discontinued study for Other Reasons§ 4 % 3 % On study but missing data in window 0 0 *The 95 % CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method. †Includes subjects who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and subjects with HIV-1 RNA ≥ 40 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG. ‡Includes subjects who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window. §Other reasons include: lost to follow-up, non-compliance with study drug, physician decision, protocol deviation, withdrawal by subject. Baseline Regimen = ritonavir or cobicistat-boosted PI (specifically atazanavir, darunavir, or lopinavir), or cobicistat-boosted elvitegravir, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs. Discontinuation due to adverse events In a pooled analysis combining data from two treatment-naïve trials (P007 and DRIVE-AHEAD), a lower proportion of subjects who discontinued due to an adverse event by week 48 was seen for the combined doravirine (100 mg) treatment groups (2.8 %) compared with the combined EFV treatment group (6.1 %) (treatment difference -3.4 %, p-value 0.012). Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with doravirine in one or more subsets of the paediatric population in treatment of human immunodeficiency virus-1 (HIV-1) infection, as per Paediatric Investigation Plan (PIP) decision in the granted indication. See section 4.2 for information on paediatric use. 21 5.2 Pharmacokinetic properties Absorption The pharmacokinetics of doravirine were studied in healthy subjects and HIV-1 infected subjects. Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Steady state was generally achieved by Day 2 of once daily dosing, with accumulation ratios of 1.2 to 1.4 for AUC0-24, Cmax, and C24. Doravirine steady state pharmacokinetics following administration of 100 mg once daily to HIV-1 infected subjects, based on a population pharmacokinetics analysis, are provided below. Parameter GM (% CV) AUC0-24 μM hr Cmax μM C24 nM Doravirine 100 mg once daily 37.8 (29) 2.26 (19) 930 (63) GM: Geometric mean, % CV: Geometric coefficient of variation Following oral dosing, peak plasma concentrations are achieved 2 hours after dosing. Doravirine has an estimated absolute bioavailability of approximately 64 % for the 100 mg tablet. Effect of food on oral absorption The administration of a single doravirine tablet with a high-fat meal to healthy subjects resulted in a 16 % and 36 % increase in doravirine AUC and C24, respectively, while Cmax was not significantly affected. Distribution Based on administration of an IV microdose, the volume of distribution of doravirine is 60.5 L. Doravirine is approximately 76 % bound to plasma proteins. Biotransformation Based on in vitro data, doravirine is primarily metabolized by CYP3A. Elimination Doravirine has a terminal half-life (t1/2) of approximately 15 hours. Doravirine is primarily eliminated via oxidative metabolism mediated by CYP3A4. Biliary excretion of unchanged medicinal product may contribute to the elimination of doravirine, but this elimination route is not expected to be significant. Excretion of unchanged medicinal product via urinary excretion is minor. Renal impairment Renal excretion of doravirine is minor. In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 31 % higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, which included subjects with CrCl between 17 and 317 mL/min, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. No dose adjustment is required in patients with mild, moderate or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis (see section 4.2). Hepatic impairment Doravirine is primarily metabolized and eliminated by the liver. There was no clinically relevant difference in the pharmacokinetics of doravirine in a study comparing 8 subjects with moderate hepatic impairment (classified as Child-Pugh score B primarily due to increased encephalopathy and ascites scores) to 8 subjects without hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) (see section 4.2). 22 Elderly Although a limited number of subjects aged 65 years and over has been included (n=36), no clinically relevant differences in the pharmacokinetics of doravirine have been identified in subjects at least 65 years of age compared to subjects less than 65 years of age in a Phase 1 trial or in a population pharmacokinetic analysis. No dose adjustment is required. Gender No clinically relevant pharmacokinetic differences have been identified between men and women for doravirine. Race No clinically relevant racial differences in the pharmacokinetics of doravirine have been identified based on a population pharmacokinetic analysis of doravirine in healthy and HIV-1 infected subjects. 5.3 Preclinical safety data Reproductive toxicity Reproduction studies with orally administered doravirine have been performed in rats and rabbits at exposures approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the recommended human dose (RHD) with no effects on embryo-foetal (rats and rabbits) or pre/postnatal (rats) development. Studies in pregnant rats and rabbits showed that doravirine is transferred to the foetus through the placenta, with foetal plasma concentrations of up to 40 % (rabbits) and 52 % (rats) that of maternal concentrations observed on gestation Day 20. Doravirine was excreted into the milk of lactating rats following oral administration, with milk concentrations approximately 1.5 times that of maternal plasma concentrations. Carcinogenesis Long-term oral carcinogenicity studies of doravirine in mice and rats showed no evidence of carcinogenic potential at estimated exposures up to 6 times (mice) and 7 times (rats) the human exposures at the RHD. Mutagenesis Doravirine was not genotoxic in a battery of in vitro or in vivo assays. Impairment of fertility There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats up to 7 times the exposure in humans at the RHD. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Croscarmellose sodium (E468) Hypromellose acetate succinate Lactose monohydrate Magnesium stearate (E470b) Microcrystalline cellulose (E460) Silica, colloidal anhydrous (E551) Film-coating Carnauba wax (E903) Hypromellose (E464) Lactose monohydrate Titanium dioxide (E171) 23 Triacetin (E1518) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 30 months After first opening of the bottle use within 35 days. 6.4 Special precautions for storage Store in the original bottle and keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant. This medicinal product does not require any special temperature storage conditions. For storage conditions after first opening of the bottle see section 6.3. 6.5 Nature and contents of container Each carton contains a high density polyethylene (HDPE) bottle with a polypropylene child-resistant closure with silica gel desiccant. The following pack sizes are available:  1 bottle with 30 film-coated tablets.  90 film-coated tablets (3 bottles of 30 film-coated tablets). Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1332/001 EU/1/18/1332/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 22 November 2018 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 24 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 25 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem NETHERLANDS B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorization holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 26 ANNEX III LABELLING AND PACKAGE LEAFLET 27 A. LABELLING 28 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Outer carton 1. NAME OF THE MEDICINAL PRODUCT Pifeltro 100 mg film-coated tablets doravirine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 100 mg of doravirine. 3. LIST OF EXCIPIENTS Contains lactose. See package leaflet for further information 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets 30 film-coated tablets 90 (3 bottles of 30) film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. Swallow whole. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Keep the bottle tightly closed in order to protect from moisture. 29 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1332/001 EU/1/18/1332/002 90 (3 x 30) tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Pifeltro 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 30 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Bottle label 1. NAME OF THE MEDICINAL PRODUCT Pifeltro 100 mg film-coated tablets doravirine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 100 mg of doravirine. 3. LIST OF EXCIPIENTS Contains lactose. See package leaflet for further information 4. PHARMACEUTICAL FORM AND CONTENTS 30 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Keep the bottle tightly closed in order to protect from moisture. 31 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. 12. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1332/001 EU/1/18/1332/002 90 (3 x 30) tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 32 B. PACKAGE LEAFLET 33 Package leaflet: Information for the user Pifeltro 100 mg film-coated tablets doravirine This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor, pharmacist, or nurse.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Pifeltro is and what it is used for 2. What you need to know before you take Pifeltro 3. How to take Pifeltro 4. Possible side effects 5. How to store Pifeltro 6. Contents of the pack and other information 1. What Pifeltro is and what it is used for What Pifeltro is Pifeltro is used to treat HIV (‘human immunodeficiency virus’) infection. It belongs to a group of medicines called ‘antiretroviral medicines’. Pifeltro contains the active substance doravirine - a non-nucleoside reverse transcriptase inhibitor (NNRTI). What Pifeltro is used for Pifeltro is used to treat HIV infection in people 18 years of age and older. HIV is the virus that causes AIDS (‘acquired immune deficiency syndrome’). You should not take Pifeltro if your doctor has told you that the virus causing your infection is resistant to doravirine. Pifeltro must be used in combination with other medicines for HIV. How Pifeltro works When used with other medicines, Pifeltro works by preventing HIV from making more viruses in your body. This will help by:  reducing the amount of HIV in your blood (this is called your ‘viral load’)  increasing the number of white blood cells called ‘CD4+ T’. This can make your immune system stronger. This may reduce your risk of early death or catching infections because your immune system is weak. 34 2. What you need to know before you take Pifeltro Do not take Pifeltro:  if you are allergic to doravirine or any of the other ingredients of this medicine listed in section 6.  if you are taking the following medicines:  carbamazepine, oxcarbazepine, phenobarbital, phenytoin (medicines for seizures)  rifampicin, rifapentine (medicines for tuberculosis) St. John’s wort (Hypericum perforatum, a herbal remedy used for depression and anxiety) or products that contain it mitotane (a medicine to treat cancer)  enzalutamide (a medicine to treat prostate cancer)  lumacaftor (a medicine to treat cystic fibrosis) Do not take Pifeltro if the above applies to you. If you are not sure, talk to your doctor, pharmacist, or nurse before taking Pifeltro. See also “Other Medicines and Pifeltro” section. Warnings and precautions Talk to your doctor, pharmacist, or nurse before taking Pifeltro. Passing HIV to others HIV is spread by contact with blood or through sexual contact with a person with HIV. You can still pass on HIV when taking Pifeltro, although effective therapy lowers the risk. Talk to your doctor about what you can do to avoid infecting other people. Immune reactivation syndrome This can happen when you start taking any HIV medicine, including this medicine. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor right away if you start having any new symptoms after starting your HIV medicine. Autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also occur after you start taking medicines for the treatment of your HIV infection. Autoimmune disorders may occur many months after the start of treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment. Children and adolescents Do not give this medicine to anybody aged less than 18 years. The use of Pifeltro in people aged less than 18 years has not yet been studied. Other medicines and Pifeltro Tell your doctor, pharmacist, or nurse if you are taking, have recently taken or might take any other medicines. This is because other medicines may affect how Pifeltro works, and Pifeltro might affect the way some other medicines work. There are some medicines you must not take with Pifeltro. See list under “Do not take Pifeltro” section. Talk to your doctor before taking the following medicines with Pifeltro, as your doctor may need to change the dose of your medicines:  bosentan (a medicine to treat lung disease)  dabrafenib (a medicine to treat skin cancer) 35  lesinurad (a medicine to treat gout)  modafinil (a medicine to treat excessive sleepiness)  nafcillin (a medicine to treat some bacterial infections)  rifabutin (a medicine to treat some bacterial infections such as tuberculosis)  telotristat ethyl (a medicine to treat diarrhoea in people with carcinoid syndrome)  thioridazine (a medicine to treat psychiatric conditions such as schizophrenia) If your doctor decides you should take these medicines with Pifeltro, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). Your doctor may check your blood levels or monitor for side effects if you take the following medicines with Pifeltro:  sirolimus (a medicine used to control your body’s immune response after a transplant)  tacrolimus (a medicine used to control your body’s immune response after a transplant) Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, talk to your doctor about the risks and benefits of taking Pifeltro. It is preferable to avoid the use of this medicine during pregnancy. This is because it has not been studied in pregnancy and it is not known if it will harm your baby while you are pregnant. Women with HIV should not breast-feed because HIV can be passed on to their babies through breast milk. Talk with your doctor about the best way to feed your baby. Driving and using machines Use caution when driving or riding a bicycle, or operating machines if you feel dizzy, tired, or sleepy after taking this medicine. Pifeltro tablets contain lactose If you have been told by your doctor that you have an intolerance to lactose, talk to your doctor before taking this medicine. 3. How to take Pifeltro Always take this medicine exactly as your doctor, pharmacist, or nurse has told you. Check with your doctor, pharmacist, or nurse if you are not sure. This medicine must be used in combination with other medicines for HIV. How much to take The recommended dose is 1 tablet once a day. If you take certain medicines, your doctor may need to change the amount of doravirine you take. See “Other medicines and Pifeltro” section for a list of medicines. Taking this medicine  Swallow the tablet whole (do not crush or chew).  This medicine can be taken with food or between meals. If you take more Pifeltro than you should Do not take more than the recommended dose. If you accidentally take more, contact your doctor. If you forget to take Pifeltro  It is important that you do not miss or skip doses of this medicine.  If you forget to take a dose, take it as soon as you remember. But if your next dose is due within 12 hours, skip the dose you missed and take the next one at the usual time. Then continue your treatment as before. 36  Do not take a double dose to make up for a missed dose.  If you are not sure what to do, call your doctor or pharmacist. If you stop taking Pifeltro Do not run out of this medicine. Refill your prescription or talk to your doctor before it is all gone. If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Do not stop taking this medicine without first talking to your doctor. Common: may affect up to 1 in 10 people:  abnormal dreams, difficulty in sleeping (insomnia)  headache, dizziness, sleepiness  feeling sick (nausea), diarrhoea, stomach pain, vomiting, wind (flatulence)  rash  feeling tired Blood tests may also show:  increased levels of liver enzymes (ALT) Uncommon: may affect up to 1 in 100 people:  nightmares, depression, anxiety, irritability, confusion, suicidal thoughts  trouble concentrating, memory problems, tingling of hands and feet, stiff muscles, poor quality sleep  high blood pressure  constipation, stomach discomfort, swollen or bloated stomach (abdominal distension), indigestion, soft stools, stomach spasms  itchiness  muscle pain, joint pain  feeling weak, general feeling of being unwell Blood tests may also show:  decreased levels of phosphate  increased levels of liver enzymes (AST)  increased levels of lipase  increased levels of amylase  decreased levels of haemoglobin Rare: may affect up to 1 in 1,000 people  aggression, hallucinations, difficulty adjusting to changes, mood changes, sleep walking  difficulty breathing, enlarged tonsils  feeling of incomplete defecation  inflammation of the skin due to allergy, redness on the cheeks, nose, chin or forehead, bumps or pimples on the face  kidney damage, kidney problems, kidney stones  pain in the chest, feeling cold, pain, thirst Blood tests may also show:  decreased levels of magnesium  increased levels of creatine phosphokinase 37 Reporting of side effects If you get any side effects, talk to your doctor,pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Pifeltro  Keep this medicine out of the sight and reach of children.  Do not use this medicine after the expiry date which is stated on the bottle after EXP. This medicine should be used within 35 days after first opening of the bottle.  The bottle contains a desiccant protecting the tablets from moisture. Keep the desiccant inside the bottle and do not throw away until you have finished taking all of the medicine.  Keep the bottle tightly closed in order to protect from moisture.  This medicinal product does not require any special temperature storage conditions.  Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Pifeltro contains  The active substance is doravirine 100 mg.  The other ingredients are croscarmellose sodium E468; hypromellose acetate succinate; lactose monohydrate; magnesium stearate E470b; microcrystalline cellulose E460; and silica, colloidal anhydrous E551. The tablets are film-coated with a coating material containing the following ingredients: carnauba wax E903; hypromellose E464; lactose monohydrate; titanium dioxide E171; and triacetin E1518. What Pifeltro looks like and contents of the pack Pifeltro is available as a white, oval-shaped, film-coated tablet, and is debossed with the corporate logo and 700 on one side and plain on the other side. The following pack sizes are available:  1 bottle with 30 film-coated tablets  90 film-coated tablets (3 bottles of 30 film-coated tablets) Not all pack sizes may be available in your country. Marketing Authorisation Holder and Manufacturer Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien MSD Belgium BVBA/SPRL Tél/Tel: +32(0)27766211 dpoc_belux@merck.com Lietuva UAB Merck Sharp & Dohme Tel. + 370 5 278 02 47 msd_lietuva@merck.com България Luxembourg/Luxemburg http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 38 Мерк Шарп и Доум България ЕООД Тел.: +359 2 819 3737 info-msdbg@merck.com MSD Belgium BVBA/SPRL Tél/Tel: +32(0)27766211 dpoc_belux@merck.com Česká republika Merck Sharp & Dohme s.r.o. Tel: +420 233 010 111 dpoc_czechslovak@merck.com Magyarország MSD Pharma Hungary Kft. Tel.: +36 1 888 5300 hungary_msd@merck.com Danmark MSD Danmark ApS Tlf: + 45 4482 4000 dkmail@merck.com Malta Merck Sharp & Dohme Cyprus Limited Tel: 8007 4433 (+356 99917558) malta_info@merck.com Deutschland MSD SHARP & DOHME GMBH Tel: 0800 673 673 673 (+49 (0) 89 4561 2612) e-mail@msd.de Nederland Merck Sharp & Dohme B.V. Tel: 0800 9999000 (+31 23 5153153) medicalinfo.nl@merck.com Eesti Merck Sharp & Dohme OÜ Tel.: +372 6144 200 msdeesti@merck.com Norge MSD (Norge) AS Tlf: +47 32 20 73 00 msdnorge@msd.no Ελλάδα MSD Α.Φ.Β.Ε.Ε. Τηλ: +30 210 98 97 300 dpoc_greece@merck.com Österreich Merck Sharp & Dohme Ges.m.b.H. Tel: +43 (0) 1 26 044 msd-medizin@merck.com España Merck Sharp & Dohme de España, S.A. Tel: +34 91 321 06 00 msd_info@merck.com Polska MSD Polska Sp. z o.o. Tel: +48 22 549 51 00 msdpolska@merck.com France MSD France Tél: + 33 (0) 1 80 46 40 40 Portugal Merck Sharp & Dohme, Lda Tel: +351 21 4465700 inform_pt@merck.com Hrvatska: Merck Sharp & Dohme d.o.o. Tel: + 385 1 6611 333 croatia_info@merck.com România Merck Sharp & Dohme Romania S.R.L. Tel: +40 21 529 29 00 msdromania@merck.com Ireland Merck Sharp & Dohme Ireland (Human Health) Limited Tel: +353 (0)1 2998700 medinfo_ireland@merck.com Slovenija Merck Sharp & Dohme, inovativna zdravila d.o.o. Tel: +386 1 5204 201 msd.slovenia@merck.com Ísland Vistor hf. Sími: + 354 535 7000 Slovenská republika Merck Sharp & Dohme, s. r. o. Tel: +421 2 58282010 dpoc_czechslovak@merck.com mailto:msd.slovenia@merck.com mailto:croatia_info@merck.com mailto:msdpolska@merck.com mailto:msd_info@merck.com 39 Italia MSD Italia S.r.l. Tel: +39 06 361911 medicalinformation.it@merck.com Suomi/Finland MSD Finland Oy Puh/Tel: +358 (0)9 804 650 info@msd.fi Κύπρος Merck Sharp & Dohme Cyprus Limited Τηλ.: 800 00 673 (+357 22866700) cyprus_info@merck.com Sverige Merck Sharp & Dohme (Sweden) AB Tel: +46 77 5700488 medicinskinfo@merck.com Latvija SIA Merck Sharp & Dohme Latvija Tel: + 371 67364224 msd_lv@merck.com United Kingdom Merck Sharp & Dohme Limited Tel: +44 (0) 1992 467272 medicalinformationuk@merck.com This leaflet was last revised in {MM/YYYY} Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu . mailto:cyprus_info@merck.com mailto:medicalinformation.it@merck.com SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take pifeltro', 'Section_Content': 'do not take pifeltro: if you are allergic to doravirine or any of the other ingredients of this medicine listed in section 6. if you are taking the following medicines: carbamazepine, oxcarbazepine, phenobarbital, phenytoin (medicines for seizures) rifampicin, rifapentine (medicines for tuberculosis) st. john\'s wort (hypericum perforatum, a herbal remedy used for depression and anxiety) or products that contain it mitotane (a medicine to treat cancer) enzalutamide (a medicine to treat prostate cancer) lumacaftor (a medicine to treat cystic fibrosis) do not take pifeltro if the above applies to you. if you are not sure, talk to your doctor, pharmacist, or nurse before taking pifeltro. see also "other medicines and pifeltro" section. warnings and precautions talk to your doctor, pharmacist, or nurse before taking pifeltro. passing hiv to others hiv is spread by contact with blood or through sexual contact with a person with hiv. you can still pass on hiv when taking pifeltro, although effective therapy lowers the risk. talk to your doctor about what you can do to avoid infecting other people. immune reactivation syndrome this can happen when you start taking any hiv medicine, including this medicine. your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. tell your doctor right away if you start having any new symptoms after starting your hiv medicine. autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also occur after you start taking medicines for the treatment of your hiv infection. autoimmune disorders may occur many months after the start of treatment. if you notice any symptoms of infection or other symptoms such as muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment. children and adolescents do not give this medicine to anybody aged less than 18 years. the use of pifeltro in people aged less than 18 years has not yet been studied. other medicines and pifeltro tell your doctor, pharmacist, or nurse if you are taking, have recently taken or might take any other medicines. this is because other medicines may affect how pifeltro works, and pifeltro might affect the way some other medicines work. there are some medicines you must not take with pifeltro. see list under "do not take pifeltro" section. talk to your doctor before taking the following medicines with pifeltro, as your doctor may need to change the dose of your medicines: bosentan (a medicine to treat lung disease) dabrafenib (a medicine to treat skin cancer) 35 lesinurad (a medicine to treat gout) modafinil (a medicine to treat excessive sleepiness) nafcillin (a medicine to treat some bacterial infections) rifabutin (a medicine to treat some bacterial infections such as tuberculosis) telotristat ethyl (a medicine to treat diarrhoea in people with carcinoid syndrome) thioridazine (a medicine to treat psychiatric conditions such as schizophrenia) if your doctor decides you should take these medicines with pifeltro, one tablet of doravirine should be taken twice daily (approximately 12 hours apart). your doctor may check your blood levels or monitor for side effects if you take the following medicines with pifeltro: sirolimus (a medicine used to control your body\'s immune response after a transplant) tacrolimus (a medicine used to control your body\'s immune response after a transplant) pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, talk to your doctor about the risks and benefits of taking pifeltro. it is preferable to avoid the use of this medicine during pregnancy. this is because it has not been studied in pregnancy and it is not known if it will harm your baby while you are pregnant. women with hiv should not breast-feed because hiv can be passed on to their babies through breast milk. talk with your doctor about the best way to feed your baby. driving and using machines use caution when driving or riding a bicycle, or operating machines if you feel dizzy, tired, or sleepy after taking this medicine. pifeltro tablets contain lactose if you have been told by your doctor that you have an intolerance to lactose, talk to your doctor before taking this medicine.', 'Entity_Recognition': [{'Text': 'pifeltro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 11, 'BeginOffset': 12, 'EndOffset': 20, 'Score': 0.5035440325737, 'Text': 'pifeltro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.7266687750816345}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 33, 'EndOffset': 41}, {'Id': 12, 'BeginOffset': 45, 'EndOffset': 55, 'Score': 0.9862974882125854, 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{'Title': '3. how to take pifeltro', 'Section_Content': 'always take this medicine exactly as your doctor, pharmacist, or nurse has told you. check with your doctor, pharmacist, or nurse if you are not sure. this medicine must be used in combination with other medicines for hiv. how much to take the recommended dose is 1 tablet once a day. if you take certain medicines, your doctor may need to change the amount of doravirine you take. see "other medicines and pifeltro" section for a list of medicines. taking this medicine swallow the tablet whole (do not crush or chew). this medicine can be taken with food or between meals. if you take more pifeltro than you should do not take more than the recommended dose. if you accidentally take more, contact your doctor. if you forget to take pifeltro it is important that you do not miss or skip doses of this medicine. if you forget to take a dose, take it as soon as you remember. but if your next dose is due within 12 hours, skip the dose you missed and take the next one at the usual time. then continue your treatment as before. do not take a double dose to make up for a missed dose. if you are not sure what to do, call your doctor or pharmacist. if you stop taking pifeltro do not run out of this medicine. refill your prescription or talk to your doctor before it is all gone. if you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.', 'Entity_Recognition': [{'Text': 'pifeltro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 151, 'EndOffset': 164}, {'Text': 'other medicines', 'Type': 'TREATMENT', 'BeginOffset': 198, 'EndOffset': 213}, {'Id': 7, 'BeginOffset': 218, 'EndOffset': 221, 'Score': 0.6609531044960022, 'Text': 'hiv', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6595960259437561}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 264, 'EndOffset': 265}, {'Text': 'certain medicines', 'Type': 'TREATMENT', 'BeginOffset': 297, 'EndOffset': 314}, {'Id': 2, 'BeginOffset': 361, 'EndOffset': 371, 'Score': 0.9945979118347168, 'Text': 'doravirine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 407, 'EndOffset': 415, 'Score': 0.5553513169288635, 'Text': 'pifeltro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 439, 'EndOffset': 448}, {'Text': 'this medicine swallow', 'Type': 'TREATMENT', 'BeginOffset': 457, 'EndOffset': 478}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 520, 'EndOffset': 533}, {'Id': 4, 'BeginOffset': 592, 'EndOffset': 600, 'Score': 0.30842021107673645, 'Text': 'pifeltro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 735, 'EndOffset': 743, 'Score': 0.5593210458755493, 'Text': 'pifeltro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 798, 'EndOffset': 811}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 912, 'EndOffset': 914}, {'Text': 'your treatment', 'Type': 'TREATMENT', 'BeginOffset': 1002, 'EndOffset': 1016}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 1040, 'EndOffset': 1053}, {'Id': 6, 'BeginOffset': 1167, 'EndOffset': 1175, 'Score': 0.6153852343559265, 'Text': 'pifeltro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.6588630676269531}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1194, 'EndOffset': 1207}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1328, 'EndOffset': 1341}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. do not stop taking this medicine without first talking to your doctor. common: may affect up to 1 in 10 people: abnormal dreams, difficulty in sleeping (insomnia) headache, dizziness, sleepiness feeling sick (nausea), diarrhoea, stomach pain, vomiting, wind (flatulence) rash feeling tired blood tests may also show: increased levels of liver enzymes (alt) uncommon: may affect up to 1 in 100 people: nightmares, depression, anxiety, irritability, confusion, suicidal thoughts trouble concentrating, memory problems, tingling of hands and feet, stiff muscles, poor quality sleep high blood pressure constipation, stomach discomfort, swollen or bloated stomach (abdominal distension), indigestion, soft stools, stomach spasms itchiness muscle pain, joint pain feeling weak, general feeling of being unwell blood tests may also show: decreased levels of phosphate increased levels of liver enzymes (ast) increased levels of lipase increased levels of amylase decreased levels of haemoglobin rare: may affect up to 1 in 1,000 people aggression, hallucinations, difficulty adjusting to changes, mood changes, sleep walking difficulty breathing, enlarged tonsils feeling of incomplete defecation inflammation of the skin due to allergy, redness on the cheeks, nose, chin or forehead, bumps or pimples on the face kidney damage, kidney problems, kidney stones pain in the chest, feeling cold, pain, thirst blood tests may also show: decreased levels of magnesium increased levels of creatine phosphokinase 37 reporting of side effects if you get any side effects, talk to your doctor,pharmacist, or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of 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0.7131097316741943, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 3, 'BeginOffset': 631, 'EndOffset': 635, 'Text': 'feet', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'tingling of hands and feet', 'Type': 'PROBLEM', 'BeginOffset': 609, 'EndOffset': 635}, {'Id': 50, 'BeginOffset': 637, 'EndOffset': 650, 'Score': 0.719258725643158, 'Text': 'stiff muscles', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8662124872207642}]}, {'Text': 'poor quality sleep high blood pressure constipation', 'Type': 'PROBLEM', 'BeginOffset': 652, 'EndOffset': 703}, {'Id': 54, 'BeginOffset': 705, 'EndOffset': 723, 'Score': 0.9393826127052307, 'Text': 'stomach discomfort', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.989155113697052}]}, {'Text': 'swollen or bloated stomach', 'Type': 'PROBLEM', 'BeginOffset': 725, 'EndOffset': 751}, {'Id': 57, 'BeginOffset': 753, 'EndOffset': 773, 'Score': 0.8747138381004333, 'Text': 'abdominal distension', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9877181053161621}]}, {'Id': 58, 'BeginOffset': 776, 'EndOffset': 787, 'Score': 0.9839597344398499, 'Text': 'indigestion', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9804285168647766}]}, {'Id': 59, 'BeginOffset': 789, 'EndOffset': 800, 'Score': 0.8180568814277649, 'Text': 'soft stools', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9673471450805664}]}, {'Text': 'stomach spasms itchiness', 'Type': 'PROBLEM', 'BeginOffset': 802, 'EndOffset': 826}, {'Id': 62, 'BeginOffset': 827, 'EndOffset': 838, 'Score': 0.85589998960495, 'Text': 'muscle pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9782730340957642}]}, {'Id': 63, 'BeginOffset': 840, 'EndOffset': 850, 'Score': 0.9159042835235596, 'Text': 'joint pain', 'Category': 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102, 'BeginOffset': 989, 'EndOffset': 992, 'Score': 0.744941771030426, 'Text': 'ast', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.9740910530090332, 'RelationshipScore': 0.9995438456535339, 'RelationshipType': 'TEST_VALUE', 'Id': 103, 'BeginOffset': 994, 'EndOffset': 1003, 'Text': 'increased', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'increased levels of lipase increased levels', 'Type': 'PROBLEM', 'BeginOffset': 994, 'EndOffset': 1037}, {'Text': 'amylase decreased levels of haemoglobin rare', 'Type': 'PROBLEM', 'BeginOffset': 1041, 'EndOffset': 1085}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1104, 'EndOffset': 1105}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 1109, 'EndOffset': 1114}, {'Id': 68, 'BeginOffset': 1134, 'EndOffset': 1148, 'Score': 0.9907551407814026, 'Text': 'hallucinations', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9477570652961731}]}, {'Id': 69, 'BeginOffset': 1150, 'EndOffset': 1181, 'Score': 0.9799102544784546, 'Text': 'difficulty adjusting to changes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.891186535358429}]}, {'Id': 70, 'BeginOffset': 1183, 'EndOffset': 1195, 'Score': 0.9529248476028442, 'Text': 'mood changes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9736992716789246}]}, {'Id': 71, 'BeginOffset': 1197, 'EndOffset': 1210, 'Score': 0.9818485975265503, 'Text': 'sleep walking', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9474887847900391}]}, {'Id': 72, 'BeginOffset': 1211, 'EndOffset': 1231, 'Score': 0.9758303761482239, 'Text': 'difficulty breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9814862608909607}]}, {'Id': 73, 'BeginOffset': 1233, 'EndOffset': 1249, 'Score': 0.9130160808563232, 'Text': 'enlarged tonsils', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9143754243850708}]}, {'Text': 'incomplete defecation inflammation of the skin', 'Type': 'PROBLEM', 'BeginOffset': 1261, 'EndOffset': 1307}, {'Id': 76, 'BeginOffset': 1315, 'EndOffset': 1322, 'Score': 0.8009814023971558, 'Text': 'allergy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.795653760433197}]}, {'Text': 'redness on the cheeks, nose, chin or forehead', 'Type': 'PROBLEM', 'BeginOffset': 1324, 'EndOffset': 1369}, {'Id': 78, 'BeginOffset': 1371, 'EndOffset': 1376, 'Score': 0.9690272212028503, 'Text': 'bumps', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9181218147277832}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9986227750778198, 'RelationshipScore': 0.5306554436683655, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 14, 'BeginOffset': 1347, 'EndOffset': 1351, 'Text': 'nose', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9992666840553284, 'RelationshipScore': 0.5144003033638, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 15, 'BeginOffset': 1353, 'EndOffset': 1357, 'Text': 'chin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 79, 'BeginOffset': 1380, 'EndOffset': 1387, 'Score': 0.9746914505958557, 'Text': 'pimples', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8906052112579346}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9676895141601562, 'RelationshipScore': 0.9650061130523682, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 17, 'BeginOffset': 1395, 'EndOffset': 1399, 'Text': 'face', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the face kidney damage', 'Type': 'PROBLEM', 'BeginOffset': 1391, 'EndOffset': 1413}, {'Id': 81, 'BeginOffset': 1415, 'EndOffset': 1430, 'Score': 0.9706225991249084, 'Text': 'kidney problems', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9403908252716064}]}, {'Id': 82, 'BeginOffset': 1432, 'EndOffset': 1445, 'Score': 0.972939133644104, 'Text': 'kidney stones', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6972762942314148}]}, {'Text': 'pain in the chest', 'Type': 'PROBLEM', 'BeginOffset': 1446, 'EndOffset': 1463}, {'Id': 84, 'BeginOffset': 1465, 'EndOffset': 1477, 'Score': 0.525201141834259, 'Text': 'feeling cold', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9150127172470093}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9952210783958435, 'RelationshipScore': 0.626925528049469, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 21, 'BeginOffset': 1458, 'EndOffset': 1463, 'Text': 'chest', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 85, 'BeginOffset': 1479, 'EndOffset': 1483, 'Score': 0.9929062128067017, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9046745896339417}]}, {'Text': 'thirst blood tests', 'Type': 'TEST', 'BeginOffset': 1485, 'EndOffset': 1503}, {'Id': 87, 'BeginOffset': 1519, 'EndOffset': 1591, 'Score': 0.44050219655036926, 'Text': 'decreased levels of magnesium increased levels of creatine phosphokinase', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.4214537739753723}]}, {'Text': '37', 'Type': 'NUMBER', 'BeginOffset': 1592, 'EndOffset': 1594}, {'Id': 88, 'BeginOffset': 1608, 'EndOffset': 1620, 'Score': 0.905579149723053, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7699762582778931}]}, {'Id': 89, 'BeginOffset': 1636, 'EndOffset': 1648, 'Score': 0.908833920955658, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.792314887046814}]}, {'Id': 90, 'BeginOffset': 1719, 'EndOffset': 1731, 'Score': 0.9531998038291931, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7012381553649902}]}, {'Id': 91, 'BeginOffset': 1780, 'EndOffset': 1792, 'Score': 0.8624669313430786, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7125977873802185}]}, {'Id': 92, 'BeginOffset': 1846, 'EndOffset': 1857, 'Score': 0.35989588499069214, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6513243317604065}]}, {'Id': 93, 'BeginOffset': 1871, 'EndOffset': 1883, 'Score': 0.9225315451622009, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7624827027320862}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1940, 'EndOffset': 1953}]}

{'Title': '5. how to store pifeltro', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle after exp. this medicine should be used within 35 days after first opening of the bottle. the bottle contains a desiccant protecting the tablets from moisture. keep the desiccant inside the bottle and do not throw away until you have finished taking all of the medicine. keep the bottle tightly closed in order to protect from moisture. this medicinal product does not require any special temperature storage conditions. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'pifeltro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 71, 'EndOffset': 84}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 148, 'EndOffset': 161}, {'Text': '35', 'Type': 'NUMBER', 'BeginOffset': 184, 'EndOffset': 186}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 394, 'EndOffset': 406}, {'Text': 'the bottle', 'Type': 'TREATMENT', 'BeginOffset': 413, 'EndOffset': 423}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what pifeltro contains the active substance is doravirine 100 mg. the other ingredients are croscarmellose sodium e468; hypromellose acetate succinate; lactose monohydrate; magnesium stearate e470b; microcrystalline cellulose e460; and silica, colloidal anhydrous e551. the tablets are film-coated with a coating material containing the following ingredients: carnauba wax e903; hypromellose e464; lactose monohydrate; titanium dioxide e171; and triacetin e1518. what pifeltro looks like and contents of the pack pifeltro is available as a white, oval-shaped, film-coated tablet, and is debossed with the corporate logo and 700 on one side and plain on the other side. the following pack sizes are available: 1 bottle with 30 film-coated tablets 90 film-coated tablets (3 bottles of 30 film-coated tablets) not all pack sizes may be available in your country.', 'Entity_Recognition': [{'Text': 'pifeltro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 47, 'EndOffset': 57, 'Score': 0.9963323473930359, 'Text': 'doravirine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.866254448890686, 'RelationshipScore': 0.9999996423721313, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 58, 'EndOffset': 65, 'Text': '100 mg.', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 58, 'EndOffset': 61}, {'Id': 2, 'BeginOffset': 92, 'EndOffset': 118, 'Score': 0.9231790900230408, 'Text': 'croscarmellose sodium e468', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 120, 'EndOffset': 150, 'Score': 0.8940216898918152, 'Text': 'hypromellose acetate succinate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 152, 'EndOffset': 171, 'Score': 0.8137514591217041, 'Text': 'lactose monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 173, 'EndOffset': 191, 'Score': 0.9975728392601013, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.49982237815856934, 'RelationshipScore': 0.999923825263977, 'RelationshipType': 'STRENGTH', 'Id': 6, 'BeginOffset': 192, 'EndOffset': 197, 'Text': 'e470b', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'microcrystalline cellulose e', 'Type': 'TREATMENT', 'BeginOffset': 199, 'EndOffset': 227}, {'Text': 'silica, colloidal anhydrous', 'Type': 'TREATMENT', 'BeginOffset': 236, 'EndOffset': 263}, {'Text': 'the tablets are film', 'Type': 'TREATMENT', 'BeginOffset': 270, 'EndOffset': 290}, {'Text': 'a coating material', 'Type': 'TREATMENT', 'BeginOffset': 303, 'EndOffset': 321}, {'Text': 'carnauba wax', 'Type': 'TREATMENT', 'BeginOffset': 360, 'EndOffset': 372}, {'Text': 'hypromellose e', 'Type': 'TREATMENT', 'BeginOffset': 379, 'EndOffset': 393}, {'Id': 13, 'BeginOffset': 398, 'EndOffset': 417, 'Score': 0.8383169174194336, 'Text': 'lactose monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 419, 'EndOffset': 435, 'Score': 0.9979889392852783, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 446, 'EndOffset': 455, 'Score': 0.5308223366737366, 'Text': 'triacetin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 468, 'EndOffset': 476, 'Score': 0.26357701420783997, 'Text': 'pifeltro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'the pack pifeltro', 'Type': 'TREATMENT', 'BeginOffset': 504, 'EndOffset': 521}, {'Text': 'film', 'Type': 'TEST', 'BeginOffset': 560, 'EndOffset': 564}, {'Text': '700', 'Type': 'NUMBER', 'BeginOffset': 624, 'EndOffset': 627}, {'Text': 'the following pack sizes', 'Type': 'TREATMENT', 'BeginOffset': 669, 'EndOffset': 693}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 709, 'EndOffset': 710}, {'Text': '30 film-coated tablets 90 film-coated tablets (3 bottles of 30 film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 723, 'EndOffset': 805}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 746, 'EndOffset': 748}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 783, 'EndOffset': 785}, {'Text': 'all pack sizes', 'Type': 'TREATMENT', 'BeginOffset': 811, 'EndOffset': 825}]}

F633DD14B429B6B0E65E2DC3F1DCE6FA

https://www.ema.europa.eu/documents/product-information/shingrix-epar-product-information_en.pdf

Shingrix

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Shingrix powder and suspension for suspension for injection Herpes zoster vaccine (recombinant, adjuvanted) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION After reconstitution, one dose (0.5 ml) contains: Varicella Zoster Virus1 glycoprotein E antigen2,3 50 micrograms 1 Varicella Zoster Virus = VZV 2 adjuvanted with AS01B containing: plant extract Quillaja saponaria Molina, fraction 21 (QS-21) 50 micrograms 3-O-desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota 50 micrograms 3 glycoprotein E (gE) produced in Chinese Hamster Ovarian (CHO) cells by recombinant DNA technology For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder and suspension for suspension for injection. The powder is white. The suspension is an opalescent, colourless to pale brownish liquid. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Shingrix is indicated for prevention of herpes zoster (HZ) and post-herpetic neuralgia (PHN), in adults 50 years of age or older (see section 5.1). The use of Shingrix should be in accordance with official recommendations. 4.2 Posology and method of administration Posology The primary vaccination schedule consists of two doses of 0.5 ml each: an initial dose followed by a second dose 2 months later. If flexibility in the vaccination schedule is necessary, the second dose can be administered between 2 and 6 months after the first dose (see section 5.1). The need for booster doses following the primary vaccination schedule has not been established (see section 5.1). Shingrix can be given with the same schedule in individuals previously vaccinated with live attenuated HZ vaccine (see section 5.1). 3 Shingrix is not indicated for prevention of primary varicella infection (chickenpox). Paediatric population The safety and efficacy of Shingrix in children and adolescents have not been established. No data are available. Method of administration For intramuscular injection only, preferably in the deltoid muscle. For instructions on reconstitution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Prior to immunisation As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of the vaccine. As with other vaccines, vaccination with Shingrix should be postponed in subjects suffering from an acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination. As with any vaccine, a protective immune response may not be elicited in all vaccinees. The vaccine is for prophylactic use only and is not intended for treatment of established clinical disease. Do not administer the vaccine intravascularly or intradermally. Subcutaneous administration is not recommended. Maladministration via the subcutaneous route may lead to an increase in transient local reactions. Shingrix should be given with caution to individuals with thrombocytopenia or any coagulation disorder since bleeding may occur following intramuscular administration to these subjects. Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints. There are no safety, immunogenicity or efficacy data to support replacing a dose of Shingrix with a dose of another HZ vaccine. 4 There are limited data to support the use of Shingrix in individuals with a history of HZ and in frail individuals including those with multiple comorbidities (see section 5.1). Healthcare professionals therefore need to weigh the benefits and risks of HZ vaccination on an individual basis. Systemic immunosuppressive medications and immunodeficiency Safety and immunogenicity data on a limited number of immunocompromised subjects with human immunodeficiency virus (HIV) or haematopoietic stem cell transplant (HCT) are available (see section 5.1). The use of Shingrix in subjects with other confirmed or suspected immunosuppressive or immunodeficient conditions is under investigation. As with other vaccines, an adequate immune response may not be elicited in these individuals. The administration of Shingrix to immunocompromised subjects should be based on careful consideration of potential benefits and risks. 4.5 Interaction with other medicinal products and other forms of interaction Shingrix can be given concomitantly with unadjuvanted inactivated seasonal influenza vaccine, 23-valent pneumococcal polysaccharide vaccine (PPV23) or reduced antigen diphtheria-tetanus- acellular pertussis vaccine (dTpa). The vaccines should be administered at different injection sites. In three phase III, controlled, open-label clinical studies, adults ≥ 50 years of age were randomised to receive 2 doses of Shingrix 2 months apart administered either concomitantly at the first dose or non- concomitantly with an unadjuvanted inactivated seasonal influenza vaccine (N=828; Zoster-004), a PPV23 vaccine (N=865; Zoster-035) or a dTpa vaccine formulated with 0.3 milligrams Al3+ (N=830; Zoster-042). The immune responses of the co-administered vaccines were unaffected, with the exception of lower geometric mean concentrations (GMCs) for one of the pertussis antigens (pertactin) when Shingrix is co-administered with the dTpa vaccine. The clinical relevance of this data is not known. The adverse reactions of fever and shivering were more frequent when PPV23 vaccine is co- administered with Shingrix. Concomitant use with other vaccines is not recommended due to lack of data. 4.6 Fertility, pregnancy and lactation Pregnancy There are no data from the use of Shingrix in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Shingrix during pregnancy. Breast-feeding The effect on breast-fed infants of administration of Shingrix to their mothers has not been studied. It is unknown whether Shingrix is excreted in human milk. Fertility Animal studies do not indicate direct or indirect effects with respect to fertility in males or females (see section 5.3). 4.7 Effects on ability to drive and use machines No studies on the effects of Shingrix on the ability to drive and use machines have been performed. 5 Shingrix may have a minor influence on the ability to drive and use machines in the 2-3 days following vaccination. Fatigue and malaise may occur following administration (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions were pain at the injection site (68.1% overall/dose; 3.8% severe/dose), myalgia (32.9% overall/dose; 2.9% severe/dose), fatigue (32.2% overall/dose; 3.0% severe/dose) and headache (26.3% overall/dose; 1.9% severe/dose). Most of these reactions were not long-lasting (median duration of 2 to 3 days). Reactions reported as severe lasted 1 to 2 days. The incidence of adverse reactions was higher in subjects aged 50-69 years compared to those aged ≥70 years, especially for general adverse reactions such as myalgia, fatigue, headache, shivering, fever and gastrointestinal symptoms. Tabulated list of adverse reactions The safety profile presented below is based on a pooled analysis of data generated in placebo- controlled clinical studies on 5,887 adults 50-69 years of age and 8,758 adults ≥ 70 years of age. Adverse reactions reported during post-marketing surveillance are also tabulated below. Adverse reactions reported are listed according to the following frequency: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) System Organ Class Frequency Adverse reactions Blood and lymphatic system disorders Uncommon lymphadenopathy Immune system disorders Rare hypersensitivity reactions including rash, urticaria, angioedema1 Nervous system disorders Very common headache Gastrointestinal disorders Very common gastrointestinal symptoms (including nausea, vomiting, diarrhoea and/or abdominal pain) Musculoskeletal and connective tissue disorders Very common myalgia Uncommon arthralgia General disorders and administration site conditions Very common injection site reactions (such as pain, redness, swelling), fatigue, chills, fever Common injection site pruritus, malaise 1Adverse reactions from spontaneous reporting Reporting of suspected adverse reactions 6 Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose No case of overdose has been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Varicella zoster vaccines, ATC code: J07BK03. Mechanism of action By combining the VZV specific antigen (gE) with an adjuvant system (AS01B), Shingrix is designed to induce antigen-specific cellular and humoral immune responses in individuals with pre-existing immunity against VZV. Non-clinical data show that AS01B induces a local and transient activation of the innate immune system through specific molecular pathways. This facilitates the recruitment and activation of antigen presenting cells carrying gE-derived antigens in the draining lymph node, which in turn leads to the generation of gE-specific CD4+ T cells and antibodies. The adjuvant effect of AS01B is the result of interactions between MPL and QS-21 formulated in liposomes. Efficacy of Shingrix Efficacy against Herpes Zoster (HZ) and Post-Herpetic Neuralgia (PHN) In two phase III, placebo-controlled, observer-blind efficacy studies of Shingrix: - ZOE-50 (Zoster-006): 15,405 adults ≥ 50 years were randomised to receive two doses of either Shingrix (N=7,695) or placebo (N=7,710) administered 2 months apart, - ZOE-70 (Zoster-022): 13,900 adults ≥ 70 years were randomised to receive two doses of either Shingrix (N=6,950) or placebo (N=6,950) administered 2 months apart. The studies were not designed to demonstrate efficacy in subgroups of frail individuals, including those with multiple comorbidities, although these subjects were not excluded from the studies. Efficacy results against HZ and PHN observed in the modified Total Vaccinated Cohort (mTVC), i.e. excluding adults who did not receive the second dose of vaccine or who had a confirmed diagnosis of HZ within one month after the second dose, are presented in Table 1 and Table 2, respectively. Shingrix significantly decreased the incidence of HZ compared with placebo in subjects ≥ 50 years (6 vs. 210 cases in ZOE-50) and in subjects ≥ 70 years (25 vs. 284 cases in the pooled analysis of ZOE- 50 and ZOE-70). Table 1: Shingrix efficacy against HZ Age (years) Shingrix Placebo Vaccine efficacy (%) [95% CI] Number of evaluable subjects Number of HZ cases Incidence rate per 1000 person years Number of evaluable subjects Number of HZ cases Incidence rate per 1000 person years 7 ZOE-50* ≥ 50 7,344 6 0.3 7,415 210 9.1 97.2 [93.7; 99.0] 50-59 3,492 3 0.3 3,525 87 7.8 96.6 [89.6; 99.4] ≥ 60 3,852 3 0.2 3,890 123 10.2 97.6 [92.7; 99.6] 60-69 2,141 2 0.3 2,166 75 10.8 97.4 [90.1; 99.7] Pooled ZOE-50 and ZOE-70** ≥ 70 8,250 25 0.8 8,346 284 9.3 91.3 [86.8; 94.5] 70-79 6,468 19 0.8 6,554 216 8.9 91.3 [86.0; 94.9] ≥ 80 1,782 6 1.0 1,792 68 11.1 91.4 [80.2; 97.0] CI Confidence interval * Over a median follow-up period of 3.1 years ** Over a median follow-up period of 4.0 years Data in subjects ≥ 70 years of age are sourced from the pre-specified pooled analyses of ZOE-50 and ZOE- 70 (mTVC) as these analyses provide the most robust estimates for vaccine efficacy in this age group. Approximately 13,000 subjects with underlying medical conditions, including conditions associated with a higher risk of HZ, were enrolled in ZOE-50 and ZOE-70. Post-hoc analysis of efficacy against confirmed HZ undertaken in patients with common conditions (chronic kidney disease, chronic obstructive pulmonary disease, coronary artery disease, depression or diabetes mellitus), indicates that the vaccine efficacy is aligned with the overall HZ efficacy. Shingrix significantly decreased the incidence of PHN compared with placebo in adults ≥ 50 years (0 vs. 18 cases in ZOE-50) and in adults ≥ 70 years (4 vs. 36 cases in the pooled analysis of ZOE-50 and ZOE-70). Table 2: Shingrix efficacy against PHN Age (years) Shingrix Placebo Vaccine efficacy (%) [95% CI] Number of evaluable subjects Number of PHN* cases Incidence rate per 1000 person years Number of evaluable subjects Number of PHN cases Incidence rate per 1000 person years ZOE-50** ≥ 50 7,340 0 0.0 7,413 18 0.6 100 [77.1; 100] 50-59 3,491 0 0.0 3,523 8 0.6 100 [40.8; 100] ≥ 60 3,849 0 0.0 3,890 10 0.7 100 [55.2; 100] 60-69 2,140 0 0.0 2,166 2 0.2 100 § [< 0; 100] Pooled ZOE-50 and ZOE-70*** ≥ 70 8,250 4 0.1 8,346 36 1.2 88.8 [68.7; 97.1] 70-79 6,468 2 0.1 6,554 29 1.2 93.0 [72.4; 99.2] ≥ 80 1,782 2 0.3 1,792 7 1.1 71.2§ 8 [< 0; 97.1] * PHN was defined as zoster-associated pain rated as ≥3 (on a 0-10 scale), persisting or appearing more than 90 days after onset of zoster rash using Zoster Brief Pain Inventory (ZBPI) CI Confidence interval ** Over a median follow-up period of 4.1 years *** Over a median follow-up period of 4.0 years Data in subjects ≥ 70 years of age are sourced from the pre-specified pooled analyses of ZOE-50 and ZOE-70 (mTVC) as these analyses provide the most robust estimates for vaccine efficacy in this age group. § Not statistically significant The benefit of Shingrix in the prevention of PHN can be attributed to the effect of the vaccine on the prevention of HZ. A further reduction of PHN incidence in subjects with confirmed HZ could not be demonstrated due to the limited number of HZ cases in the vaccine group. In the fourth year after vaccination, the efficacy against HZ was 93.1 % (95% CI: 81.2; 98.2) and 87.9% (95% CI: 73.3; 95.4) in adults ≥ 50 years and adults ≥ 70 years, respectively. The duration of protection beyond 4 years is currently under investigation. Efficacy against HZ-related complications other than PHN The evaluated HZ-related complications were: HZ vasculitis, disseminated disease, ophthalmic disease, neurologic disease, visceral disease, and stroke. In the pooled analysis of ZOE-50 and ZOE- 70, Shingrix significantly reduced these HZ-related complications by 93.7% (95% CI: 59.5; 99.9) and 91.6% (95% CI: 43.3; 99.8) in adults ≥ 50 years (1 vs. 16 cases) and adults ≥ 70 years (1 vs. 12 cases), respectively. No cases of visceral disease or stroke were reported during these studies. Effect of Shingrix on HZ-related pain Overall there was a general trend towards less severe HZ-related pain in subjects vaccinated with Shingrix compared to placebo. As a consequence of the high vaccine efficacy against HZ, a low number of breakthrough cases were accrued, and it was therefore not possible to draw firm conclusions on these study objectives. In subjects ≥ 70 years with at least one confirmed HZ episode (ZOE-50 and ZOE-70 pooled), Shingrix significantly reduced the use and the duration of HZ-related pain medication by 39.0% (95% CI: 11.9; 63.3) and 50.6% (95% CI: 8.8; 73.2), respectively. The median duration of pain medication use was 32.0 and 44.0 days in the Shingrix and placebo group, respectively. In subjects with at least one confirmed HZ episode, Shingrix significantly reduced the maximum average pain score versus placebo over the entire HZ episode (mean = 3.9 vs. 5.5, P-value = 0.049 and mean = 4.5 vs. 5.6, P-value = 0.043, in subjects ≥ 50 years (ZOE-50) and ≥ 70 years (ZOE-50 and ZOE-70 pooled), respectively). In addition, in subjects ≥ 70 years (ZOE-50 and ZOE-70 pooled), Shingrix significantly reduced the maximum worst pain score versus placebo over the entire HZ episode (mean = 5.7 vs. 7.0, P-value = 0.032). The burden-of-illness (BOI) score incorporates the incidence of HZ with the severity and duration of acute and chronic HZ-related pain over a 6 month period following rash onset. The efficacy in reducing BOI was 98.4% (95% CI: 92.2; 100) in subjects ≥ 50 years (ZOE-50) and 92.1% (95% CI: 90.4; 93.8) in subjects ≥ 70 years (ZOE-50 and ZOE-70 pooled). Immunogenicity of Shingrix An immunological correlate of protection has not been established; therefore the level of immune response that provides protection against HZ is unknown. The immune responses to Shingrix were evaluated in a subset of subjects from the phase III efficacy studies ZOE-50 [humoral immunity and cell-mediated immunity (CMI)] and ZOE-70 (humoral 9 immunity). Shingrix elicited higher gE-specific immune responses (humoral and CMI) at 1 month post-dose 2 when compared to pre-vaccination levels. The humoral immunogenicity and CMI results are presented in Tables 3 and 4, respectively. Table 3: Humoral immunogenicity of Shingrix in adults ≥ 50 years (ATP cohort for immunogenicity) Anti-gE immune response^ Age group (years) Month 3* Month 38** N GMC (mIU/ml) (95% CI) Median fold increase of concentrations vs. pre- vaccination (Q1; Q3) N GMC (mIU/ml) (95% CI) Median fold increase of concentrations vs. pre- vaccination (Q1; Q3) ZOE-50 ≥ 50 1,070 52,376.6 (50,264.1; 54,577.9) 41.9 (20.8; 86.9) 967 11,919.6 (11,345.6; 12,522.7) 9.3 (4.9; 19.5) Pooled ZOE-50 and ZOE-70 ≥ 70 742 49,691.5 (47,250.8; 52,258.2) 34.3 (16.7; 68.5) 648 10,507.7 (9,899.2; 11,153.6) 7.2 (3.5; 14.5) ATP According-To-Protocol ^ Anti-gE immune response = anti-gE antibody levels, measured by anti-gE enzyme-linked immunosorbent assay (gE ELISA) * Month 3 = 1 month post-dose 2 ** Month 38 = 3 years post-dose 2 N Number of evaluable subjects at the specified time point (for the GMC) CI Confidence interval GMC Geometric Mean Concentration Q1; Q3 First and third quartiles Table 4: Cell-mediated immunogenicity of Shingrix in adults ≥ 50 years (ATP cohort for immunogenicity) gE-specific CD4[2+] T cell response^ Age group (years) Month 3* Month 38** N Median frequency (Q1; Q3) Median fold increase of frequency vs. pre- vaccination (Q1; Q3) N Median frequency (Q1; Q3) Median fold increase of frequency vs. pre-vaccination (Q1; Q3) ZOE-50 ≥ 50 164 1,844.1 (1,253.6; 2,932.3) 24.6 (9.9; 744.2) 152 738.9 (355.7; 1,206.5) 7.9 (2.7; 31.6) ≥ 70*** 52 1,494.6 (922.9; 2,067.1) 33.2 (10.0; 1,052.0) 46 480.2 (196.1; 972.4) 7.3 (1.7; 31.6) ATP According-To-Protocol ^ gE-specific CD4[2+] T cell response = gE-specific CD4+ T cell activity, measured by intracellular cytokine staining (ICS) assay (CD4[2+] T cells = CD4+ T cells expressing at least 2 of 4 selected immune markers) * Month 3 = 1 month post-dose 2 ** Month 38 = 3 years post-dose 2 N Number of evaluable subjects at the specified time point Q1; Q3 First and third quartiles *** The gE-specific CD4[2+] data in the ≥70 years of age group were generated in ZOE-50 because CD4+ T cell activity was not assessed in ZOE-70 10 Data from a phase II, open-label, single group, follow-up clinical study in adults ≥ 60 years (Zoster- 024) indicate that the vaccine-induced immune response (humoral and CMI) persists up to approximately 6 years following a 0, 2-month schedule (N= 119). The median anti-gE antibody concentration was greater than 7-fold above the baseline pre-vaccination median concentration. The median frequency of gE-specific CD4[2+] T cells was greater than 3.7-fold above baseline pre- vaccination median frequency. Immunogenicity in subjects receiving 2 doses of Shingrix 6 months apart Efficacy has not been assessed for the 0, 6-month schedule. In a phase III, open-label clinical study (Zoster-026) where 238 adults ≥ 50 years of age were equally randomised to receive 2 doses of Shingrix 2 or 6 months apart, the humoral immune response following the 0, 6-month schedule was demonstrated to be non-inferior to the response with the 0, 2- month schedule. The anti-gE GMC at 1 month after the last vaccine dose was 38,153.7 mIU/ml (95% CI: 34,205.8; 42,557.3) and 44,376.3 mIU/ml (95% CI: 39,697.0; 49,607.2) following the 0, 6-month schedule and the 0, 2-month schedule, respectively. Subjects with a history of HZ prior to vaccination Subjects with a history of HZ were excluded from ZOE-50 and ZOE-70. In a phase III, uncontrolled, open-label clinical study (Zoster-033), 96 adults ≥ 50 years of age with a physician-documented history of HZ received 2 doses of Shingrix 2 months apart. Laboratory confirmation of HZ cases was not part of the study procedures. The anti-gE GMC at 1 month after the last vaccine dose was 47,758.7 mIU/ml (95% CI: 42,258.8; 53,974.4). There were 9 reports of suspected HZ in 6 subjects over a one-year follow up period. This is a higher recurrence rate than generally reported in observational studies in unvaccinated individuals with a history of HZ. (See section 4.4) Immunocompromised subjects Two phase I/II clinical studies, Zoster-001 and Zoster-015, were conducted in subjects with autologous hematopoietic stem cell transplant or HIV infection. A total of 135 adults, of whom 73 were ≥50 years of age, received at least one dose of Shingrix, which was shown to be immunogenic and well-tolerated. Immunogenicity in individuals previously vaccinated with live attenuated herpes zoster (HZ) vaccine In a phase III, open-label, multicentre clinical study (Zoster-048), a 2 dose schedule of Shingrix 2 months apart was assessed in 215 adults ≥ 65 years of age with a previous history of vaccination with live attenuated HZ vaccine ≥ 5 years earlier compared to 215 matched subjects who had never received live attenuated HZ vaccine. The immune response to Shingrix was unaffected by prior vaccination with live attenuated HZ vaccine. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Shingrix in one or more subsets of the paediatric population in prevention of Varicella Zoster Virus reactivation (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Not applicable. 5.3 Preclinical safety data 11 Non-clinical data reveal no special hazard for humans based on conventional studies of acute and repeated dose toxicity, local tolerance, cardiovascular/respiratory safety pharmacology and toxicity to reproduction and development. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder (gE antigen): Sucrose Polysorbate 80 Sodium dihydrogen phosphate dihydrate Dipotassium phosphate Suspension (AS01B Adjuvant System): Dioleoyl phosphatidylcholine Cholesterol Sodium chloride Disodium phosphate anhydrous Potassium dihydrogen phosphate Water for injections For adjuvant see also section 2. 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 3 years After reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C. From a microbiological point of view, the vaccine should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 6 hours at 2°C to 8°C. 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect from light. For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container • Powder for 1 dose in a vial (type I glass) with a stopper (butyl rubber) • Suspension for 1 dose in a vial (type I glass) with a stopper (butyl rubber). Shingrix is available in a pack size of 1 vial of powder plus 1 vial of suspension or in a pack size of 10 vials of powder plus 10 vials of suspension. 12 Not all pack sizes may be marketed 6.6 Special precautions for disposal and other handling Shingrix is presented as a vial with a brown flip-off cap containing the powder (antigen) and a vial with a blue-green flip-off cap containing the suspension (adjuvant). The powder and the suspension must be reconstituted prior to administration. The powder and suspension should be inspected visually for any foreign particulate matter and/or variation of appearance. If either is observed, do not reconstitute the vaccine. How to prepare Shingrix: Shingrix must be reconstituted prior to administration. 1. Withdraw the entire contents of the vial containing the suspension into the syringe. 2. Add the entire contents of the syringe into the vial containing the powder. 3. Shake gently until the powder is completely dissolved. The reconstituted vaccine is an opalescent, colourless to pale brownish liquid. The reconstituted vaccine should be inspected visually for any foreign particulate matter and/or variation of appearance. If either is observed, do not administer the vaccine. After reconstitution, the vaccine should be used promptly; if this is not possible, the vaccine should be stored in a refrigerator (2°C – 8°C). If not used within 6 hours it should be discarded. Before administration: 1. Withdraw the entire contents of the vial containing the reconstituted vaccine into the syringe. 2. Change the needle so that you are using a new needle to administer the vaccine. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER GlaxoSmithKline Biologicals S.A. Rue de l’Institut 89 B-1330 Rixensart Belgium Antigen Powder Adjuvant Suspension 1 dose (0.5 ml) 13 8. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1272/001 EU/1/18/1272/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 21 March 2018 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 14 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SYPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS FOR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 15 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance GlaxoSmithKline Biologicals SA Parc de la Noire Epine 20, Avenue Fleming 1300 Wavre BELGIUM Name and address of the manufacturer responsible for batch release GlaxoSmithKline Biologicals SA Rue de l’Institut, 89 1330 Rixensart BELGIUM B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. • Official batch release In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be undertaken by a state laboratory or a laboratory designated for that purpose. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or 16 as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 17 ANNEX III LABELLING AND PACKAGE LEAFLET 18 A. LABELLING 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING 1 VIAL AND 1 VIAL 10 VIALS AND 10 VIALS 1. NAME OF THE MEDICINAL PRODUCT Shingrix powder and suspension for suspension for injection Herpes zoster vaccine (recombinant, adjuvanted) 2. STATEMENT OF ACTIVE SUBSTANCE(S) After reconstitution, 1 dose (0.5 ml) contains 50 micrograms of recombinant Varicella Zoster Virus glycoprotein E adjuvanted with AS01B 3. LIST OF EXCIPIENTS Excipients: sucrose polysorbate 80 sodium dihydrogen phosphate dihydrate dipotassium phosphate dioleoyl phosphatidylcholine cholesterol sodium chloride disodium phosphate anhydrous potassium dihydrogen phosphate water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Powder and suspension for suspension for injection 1 vial: powder (antigen) 1 vial: suspension (adjuvant) 10 vials: powder (antigen) 10 vials: suspension (adjuvant) 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intramuscular use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 20 1 dose (0.5 ml) 7. OTHER SPECIAL WARNING(S), IF NECESSARY Powder and suspension to be reconstituted before administration 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER GlaxoSmithKline Biologicals s.a. Rue de l’Institut 89 B-1330 Rixensart, Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1272/001 – 1 vial and 1 vial EU/1/18/1272/002 – 10 vials and 10 vials 13. BATCH NUMBER LOT 14. GENERAL CLASSIFICATION FOR SUPPLY Antigen Adjuvant 21 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 22 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL WITH POWDER 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Antigen for Shingrix I.M. 2. METHOD OF ADMINISTRATION Mix with adjuvant 3. EXPIRY DATE EXP 4. BATCH NUMBER LOT 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 dose 6. OTHER 23 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL WITH SUSPENSION 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Adjuvant for Shingrix 2. METHOD OF ADMINISTRATION Mix with antigen 3. EXPIRY DATE EXP 4. BATCH NUMBER LOT 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 dose (0.5 ml) 6. OTHER 24 B. PACKAGE LEAFLET 25 Package leaflet: Information for the user Shingrix powder and suspension for suspension for injection Herpes zoster vaccine (recombinant, adjuvanted) This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you receive this vaccine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Shingrix is and what it is used for 2. What you need to know before you receive Shingrix 3. How Shingrix is given 4. Possible side effects 5. How to store Shingrix 6. Contents of the pack and other information 1. What Shingrix is and what it is used for What Shingrix is used for Shingrix is a vaccine that helps to protect adults against shingles (herpes zoster) and post-herpetic neuralgia (PHN), the long-lasting nerve pain that follows shingles. Shingrix is given to adults 50 years and above. Shingrix cannot be used to prevent chickenpox (varicella). What shingles is • Shingles is a rash with blisters that is often painful. It usually occurs in one part of the body and can last for several weeks. • Shingles is caused by the same virus that causes chickenpox. • After you have had chickenpox, the virus that caused it stays in your body in nerve cells. • Sometimes, after many years, if your immune system (the body’s natural defences) becomes weaker (due to age, an illness or a medicine you are taking), the virus can cause shingles. Complications related to shingles Shingles may lead to complications. The most common complication of shingles is: • long-lasting nerve pain – called post-herpetic neuralgia or PHN. After the shingles blisters heal, you may get pain which can last for months or years and may be severe. Other complications of shingles are: • scars where the blisters have been. • skin infections, weakness, muscle paralysis and loss of hearing or vision – these are less common. 26 How Shingrix works Shingrix reminds your body about the virus that causes shingles. This helps your immune system (the body’s natural defences) stay prepared to fight the virus and protect you against shingles and its complications. 2. What you need to know before you receive Shingrix You should not receive Shingrix if • you are allergic (hypersensitive) to the active substances or any of the other ingredients of this vaccine (listed in section 6). Signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the face or tongue. You should not receive Shingrix if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist. Warnings and precautions Talk to your doctor or pharmacist before you receive Shingrix if: • you have a severe infection with a high temperature (fever). In these cases, the vaccination may have to be postponed until you have recovered. A minor infection such as a cold should not be a problem, but talk to your doctor first; • you have a bleeding problem or bruise easily. If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before you receive Shingrix. Fainting can occur before or after any needle injection. Therefore tell the doctor or nurse if you fainted with a previous injection. Shingrix cannot be used as a treatment if you already have shingles or shingles-related complications. As with all vaccines, Shingrix may not fully protect all people who are vaccinated. Other medicines and Shingrix Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription, or have recently received any other vaccine. Shingrix can be given at the same time as other vaccines. A different injection site will be used for each vaccine. You may be more likely to experience fever and/or shivering when 23-valent pneumococcal polysaccharide vaccine is given at the same time as Shingrix. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before you are given this vaccine. Driving and using machines It is not known if Shingrix affects your ability to drive or use machines. However, do not drive or use machines if you are feeling unwell. Shingrix contains sodium and potassium This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium- free’. This medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially ‘potassium- free’. 27 3. How Shingrix is given • Shingrix is given as an injection into a muscle (usually in the upper arm). • You will receive 2 injections with an interval of 2 months. If flexibility in the vaccination schedule is necessary, the second dose can be administered between 2 and 6 months after the first dose. The first injection can be given from the age of 50 years onwards. • You will be informed when you should come back for the second dose of Shingrix. Make sure you finish the complete vaccination course. This will maximise the protection offered by Shingrix. Shingrix can be given if you have already been vaccinated with a live attenuated herpes zoster vaccine. Speak to your doctor for more information. 4. Possible side effects Like all medicines, this vaccine can cause side effects, although not everybody gets them. Side effects reported during clinical trials with Shingrix: Very common (these may occur with more than 1 in 10 doses of the vaccine): • headache • stomach and digestive complaints (including nausea, vomiting, diarrhoea and/or stomach pain) • muscle pain (myalgia) • pain, redness and swelling where the injection is given • feeling tired, chills, fever Common (these may occur with up to 1 in 10 doses of the vaccine): • itching where the injection is given (pruritus) • generally feeling unwell Uncommon (these may occur with up to 1 in 100 doses of vaccine) • swollen glands in the neck, armpit or groin • joint pain Most of these side effects are mild to moderate in intensity and are not long-lasting. Adults aged 50-69 years may experience more side effects compared to adults aged ≥ 70 years. Side effects reported after the marketing of Shingrix: Rare (these may occur with up to 1 in 1,000 doses of the vaccine) • allergic reactions including rash, hives (urticaria), swelling of the face, tongue or throat which may cause difficulty in swallowing or breathing (angioedema) Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Shingrix • Keep this medicine out of the sight and reach of children. 28 • Do not use this medicine after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month. • Store in a refrigerator (2°C – 8°C). • Do not freeze. • Store in the original package in order to protect from light. • Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Shingrix contains • The active substances are: After reconstitution, one dose (0.5 ml) contains: Varicella Zoster Virus1 glycoprotein E antigen2 50 micrograms 1 Varicella Zoster Virus = VZV 2 adjuvanted with AS01B containing: plant extract Quillaja saponaria Molina, fraction 21 (QS-21) 50 micrograms 3-O-desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota 50 micrograms The glycoprotein E is a protein present in the Varicella Zoster Virus. This protein is not infectious. The adjuvant (AS01B) is used to improve the body’s response to the vaccine. • The other ingredients are: o Powder: Sucrose, polysorbate 80, sodium dihydrogen phosphate dihydrate, dipotassium phosphate. o Suspension: Dioleoyl phosphatidylcholine, cholesterol, sodium chloride, disodium phosphate anhydrous, potassium dihydrogen phosphate and water for injections. What Shingrix looks like and contents of the pack • Powder and suspension for suspension for injection. • The powder is white. • The suspension is an opalescent, colourless to pale brownish liquid. One pack of Shingrix consists of: • Powder for 1 dose in a vial • Suspension for 1 dose in a vial Shingrix is available in a pack size of 1 vial of powder plus 1 vial of suspension or in a pack size of 10 vials of powder plus 10 vials of suspension. Not all pack sizes may be marketed Marketing Authorisation Holder and Manufacturer GlaxoSmithKline Biologicals s.a. Rue de l’Institut 89 29 B-1330 Rixensart Belgium For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien GlaxoSmithKline Pharmaceuticals s.a./n.v. Tél/Tel: + 32 10 85 52 00 Lietuva GlaxoSmithKline Lietuva UAB Tel: +370 5 264 90 00 info.lt@gsk.com България ГлаксоСмитКлайн ЕООД Тел. + 359 2 953 10 34 Luxembourg/Luxemburg GlaxoSmithKline Pharmaceuticals s.a./n.v. Tél/Tel: + 32 10 85 52 00 Česká republika GlaxoSmithKline s.r.o. Tel: + 420 2 22 00 11 11 cz.info@gsk.com Magyarország GlaxoSmithKline Kft. Tel.: + 36-1-2255300 Danmark GlaxoSmithKline Pharma A/S Tlf: + 45 36 35 91 00 dk-info@gsk.com Malta GlaxoSmithKline (Malta) Ltd Tel: + 356 21 238131 Deutschland GlaxoSmithKline GmbH & Co. KG Tel: + 49 (0)89 360448701 produkt.info@gsk.com Nederland GlaxoSmithKline BV Tel: + 31 (0)33 2081100 Eesti GlaxoSmithKline Eesti OÜ Tel: +372 667 6900 estonia@gsk.com Norge GlaxoSmithKline AS Tlf: + 47 22 70 20 00 Ελλάδα GlaxoSmithKline Μονοπρόσωπη A.E.B.E Tηλ: + 30 210 68 82 100 Österreich GlaxoSmithKline Pharma GmbH Tel: + 43 (0)1 97075 0 at.info@gsk.com España GlaxoSmithKline, S.A. Tel: + 34 900 202 700 es-ci@gsk.com Polska GSK Services Sp. z o.o. Tel.: + 48 (22) 576 9000 France Laboratoire GlaxoSmithKline Tél: + 33 (0) 1 39 17 84 44 diam@gsk.com Hrvatska GlaxoSmithKline d.o.o. Tel.: + 385 (0)1 6051999 Portugal GlaxoSmithKline - Produtos Farmacêuticos, Lda. Tel: + 351 21 412 95 00 FI.PT@gsk.com România GlaxoSmithKline (GSK) SRL Tel: +40 (0)21 3028 208 Ireland GlaxoSmithKline (Ireland) Ltd Slovenija GlaxoSmithKline d.o.o. 30 Tel: + 353 (0)1 495 5000 Tel: + 386 (0) 1 280 25 00 medical.x.si@gsk.com Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika GlaxoSmithKline Slovakia s.r.o. Tel.: + 421 (0)2 48 26 11 11 recepcia.sk@gsk.com Italia GlaxoSmithKline S.p.A. Tel: + 39 (0)45 9218 111 Suomi/Finland GlaxoSmithKline Oy Puh/Tel: + 358 10 30 30 30 Κύπρος GlaxoSmithKline (Cyprus) Ltd Τηλ: + 357 22 39 70 00 gskcyprus@gsk.com Sverige GlaxoSmithKline AB Tel: + 46 (0)8 638 93 00 info.produkt@gsk.com Latvija GlaxoSmithKline Latvia SIA Tel: + 371 67312687 lv-epasts@gsk.com United Kingdom GlaxoSmithKline UK Tel: +44 (0)800 221 441 customercontactuk@gsk.com This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. This leaflet is available in all EU/EEA languages on the European Medicines Agency website ------------------------------------------------------------------------------------------------------------------------ The following information is intended for healthcare professionals only: Shingrix is presented as a vial with a brown flip-off cap containing the powder (antigen) and a vial with a blue-green flip-off cap containing the suspension (adjuvant). The powder and the suspension must be reconstituted prior to administration. Antigen Powder Adjuvant Suspension 1 dose (0.5 ml) 31 The powder and suspension should be inspected visually for any foreign particulate matter and/or variation of appearance. If either is observed, do not reconstitute the vaccine. How to prepare Shingrix: Shingrix must be reconstituted prior to administration. 1. Withdraw the entire contents of the vial containing the suspension into the syringe. 2. Add the entire contents of the syringe into the vial containing the powder. 3. Shake gently until the powder is completely dissolved. The reconstituted vaccine is an opalescent, colourless to pale brownish liquid. The reconstituted vaccine should be inspected visually for any foreign particulate matter and/or variation of appearance. If either is observed, do not administer the vaccine. After reconstitution, the vaccine should be used promptly; if this is not possible, the vaccine should be stored in a refrigerator (2°C – 8°C). If not used within 6 hours it should be discarded. Before administration: 1. Withdraw the entire contents of the vial containing the reconstituted vaccine into the syringe. 2. Change the needle so that you are using a new needle to administer the vaccine. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what shingrix is and what it is used for', 'Section_Content': "what shingrix is used for shingrix is a vaccine that helps to protect adults against shingles (herpes zoster) and post-herpetic neuralgia (phn), the long-lasting nerve pain that follows shingles. shingrix is given to adults 50 years and above. shingrix cannot be used to prevent chickenpox (varicella). what shingles is shingles is a rash with blisters that is often painful. it usually occurs in one part of the body and can last for several weeks. shingles is caused by the same virus that causes chickenpox. after you have had chickenpox, the virus that caused it stays in your body in nerve cells. sometimes, after many years, if your immune system (the body's natural defences) becomes weaker (due to age, an illness or a medicine you are taking), the virus can cause shingles. complications related to shingles shingles may lead to complications. the most common complication of shingles is: long-lasting nerve pain called post-herpetic neuralgia or phn. after the shingles blisters heal, you may get pain which can last for months or years and may be severe. other complications of shingles are: scars where the blisters have been. skin infections, weakness, muscle paralysis and loss of hearing or vision these are less common. how shingrix works shingrix reminds your body about the virus that causes shingles. this helps your immune system (the body's natural defences) stay prepared to fight the virus and protect you against shingles and its complications.", 'Entity_Recognition': [{'Text': 'shingrix', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a vaccine', 'Type': 'TREATMENT', 'BeginOffset': 38, 'EndOffset': 47}, {'Text': 'shingles (herpes zoster', 'Type': 'PROBLEM', 'BeginOffset': 85, 'EndOffset': 108}, {'Text': 'post-herpetic neuralgia (phn)', 'Type': 'PROBLEM', 'BeginOffset': 114, 'EndOffset': 143}, {'Text': 'the long-lasting nerve pain', 'Type': 'PROBLEM', 'BeginOffset': 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{'Title': '2. what you need to know before you receive shingrix', 'Section_Content': "you should not receive shingrix if you are allergic (hypersensitive) to the active substances or any of the other ingredients of this vaccine (listed in section 6). signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the face or tongue. you should not receive shingrix if any of the above apply to you. if you are not sure, talk to your doctor or pharmacist. warnings and precautions talk to your doctor or pharmacist before you receive shingrix if: you have a severe infection with a high temperature (fever). in these cases, the vaccination may have to be postponed until you have recovered. a minor infection such as a cold should not be a problem, but talk to your doctor first; you have a bleeding problem or bruise easily. if any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before you receive shingrix. fainting can occur before or after any needle injection. therefore tell the doctor or nurse if you fainted with a previous injection. shingrix cannot be used as a treatment if you already have shingles or shingles-related complications. as with all vaccines, shingrix may not fully protect all people who are vaccinated. other medicines and shingrix tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription, or have recently received any other vaccine. shingrix can be given at the same time as other vaccines. a different injection site will be used for each vaccine. you may be more likely to experience fever and/or shivering when 23-valent pneumococcal polysaccharide vaccine is given at the same time as shingrix. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before you are given this vaccine. driving and using machines it is not known if shingrix affects your ability to drive or use machines. however, do not drive or use machines if you are feeling unwell. shingrix contains sodium and potassium this medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium- free'. this medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially 'potassium- free'.", 'Entity_Recognition': [{'Text': 'shingrix', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 3, 'BeginOffset': 23, 'EndOffset': 31, 'Score': 0.46849730610847473, 'Text': 'shingrix', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.43399253487586975}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 43, 'EndOffset': 51}, {'Id': 11, 'BeginOffset': 53, 'EndOffset': 67, 'Score': 0.7651059627532959, 'Text': 'hypersensitive', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 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{'Title': '3. how shingrix is given', 'Section_Content': ' shingrix is given as an injection into a muscle (usually in the upper arm). you will receive 2 injections with an interval of 2 months. if flexibility in the vaccination schedule is necessary, the second dose can be administered between 2 and 6 months after the first dose. the first injection can be given from the age of 50 years onwards. you will be informed when you should come back for the second dose of shingrix. make sure you finish the complete vaccination course. this will maximise the protection offered by shingrix. shingrix can be given if you have already been vaccinated with a live attenuated herpes zoster vaccine. speak to your doctor for more information.', 'Entity_Recognition': [{'Text': 'shingrix', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 3, 'BeginOffset': 1, 'EndOffset': 9, 'Score': 0.5210036039352417, 'Text': 'shingrix', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.33580082654953003, 'RelationshipScore': 0.9999903440475464, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 4, 'BeginOffset': 25, 'EndOffset': 34, 'Text': 'injection', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 8, 'BeginOffset': 25, 'EndOffset': 34, 'Score': 0.3039190173149109, 'Text': 'injection', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Id': 0, 'BeginOffset': 42, 'EndOffset': 48, 'Score': 0.8562717437744141, 'Text': 'muscle', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 2, 'BeginOffset': 71, 'EndOffset': 74, 'Score': 0.9439243078231812, 'Text': 'arm', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '2 injections', 'Type': 'TREATMENT', 'BeginOffset': 94, 'EndOffset': 106}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 127, 'EndOffset': 128}, {'Text': 'the vaccination schedule', 'Type': 'TREATMENT', 'BeginOffset': 155, 'EndOffset': 179}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 238, 'EndOffset': 239}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 244, 'EndOffset': 245}, {'Text': 'the first injection', 'Type': 'TREATMENT', 'BeginOffset': 275, 'EndOffset': 294}, {'Id': 7, 'BeginOffset': 324, 'EndOffset': 326, 'Score': 0.999758780002594, 'Text': '50', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'AGE', 'Traits': []}, {'Id': 5, 'BeginOffset': 412, 'EndOffset': 420, 'Score': 0.40460142493247986, 'Text': 'shingrix', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the complete vaccination course', 'Type': 'TREATMENT', 'BeginOffset': 443, 'EndOffset': 474}, {'Text': 'a live attenuated herpes zoster vaccine', 'Type': 'TREATMENT', 'BeginOffset': 594, 'EndOffset': 633}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this vaccine can cause side effects, although not everybody gets them. side effects reported during clinical trials with shingrix: very common (these may occur with more than 1 in 10 doses of the vaccine): headache stomach and digestive complaints (including nausea, vomiting, diarrhoea and/or stomach pain) muscle pain (myalgia) pain, redness and swelling where the injection is given feeling tired, chills, fever common (these may occur with up to 1 in 10 doses of the vaccine): itching where the injection is given (pruritus) generally feeling unwell uncommon (these may occur with up to 1 in 100 doses of vaccine) swollen glands in the neck, armpit or groin joint pain most of these side effects are mild to moderate in intensity and are not long-lasting. adults aged 50-69 years may experience more side effects compared to adults aged ≥ 70 years. side effects reported after the marketing of shingrix: rare (these may occur with up to 1 in 1,000 doses of the vaccine) allergic reactions including rash, hives (urticaria), swelling of the face, tongue or throat which may cause difficulty in swallowing or breathing (angioedema) reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'shingrix', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 32}, {'Id': 12, 'BeginOffset': 43, 'EndOffset': 55, 'Score': 0.9676685929298401, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': 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{'Title': '5. how to store shingrix', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton. the expiry date refers to the last day of that month. store in a refrigerator (2 8). do not freeze. store in the original package in order to protect from light. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what shingrix contains the active substances are: after reconstitution, one dose (0.5 ml) contains: varicella zoster virus1 glycoprotein e antigen2 50 micrograms 1 varicella zoster virus = vzv 2 adjuvanted with as01b containing: plant extract quillaja saponaria molina, fraction 21 (qs-21) 50 micrograms 3-o-desacyl-4'-monophosphoryl lipid a (mpl) from salmonella minnesota 50 micrograms the glycoprotein e is a protein present in the varicella zoster virus. this protein is not infectious. the adjuvant (as01b) is used to improve the body's response to the vaccine. the other ingredients are: o powder: sucrose, polysorbate 80, sodium dihydrogen phosphate dihydrate, dipotassium phosphate. o suspension: dioleoyl phosphatidylcholine, cholesterol, sodium chloride, disodium phosphate anhydrous, potassium dihydrogen phosphate and water for injections. what shingrix looks like and contents of the pack powder and suspension for suspension for injection. the powder is white. the suspension is an opalescent, colourless to pale brownish liquid. one pack of shingrix consists of: powder for 1 dose in a vial suspension for 1 dose in a vial shingrix is available in a pack size of 1 vial of powder plus 1 vial of suspension or in a pack size of 10 vials of powder plus 10 vials of suspension. not all pack sizes may be marketed", 'Entity_Recognition': [{'Text': 'shingrix', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 100, 'EndOffset': 147, 'Score': 0.9761801362037659, 'Text': 'varicella zoster virus1 glycoprotein e antigen2', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9403776526451111, 'RelationshipScore': 0.9999958276748657, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 148, 'EndOffset': 161, 'Text': '50 micrograms', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '50', 'Type': 'NUMBER', 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'suspension', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 10, 'BeginOffset': 735, 'EndOffset': 746, 'Score': 0.47416940331459045, 'Text': 'cholesterol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 748, 'EndOffset': 763, 'Score': 0.9996823072433472, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 765, 'EndOffset': 793, 'Score': 0.9919021725654602, 'Text': 'disodium phosphate anhydrous', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5166536569595337, 'RelationshipScore': 0.9642593264579773, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 840, 'EndOffset': 850, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 13, 'BeginOffset': 795, 'EndOffset': 825, 'Score': 0.9943473935127258, 'Text': 'potassium dihydrogen phosphate', 'Category': 'MEDICATION', 'Type': 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19D1556A958E1BF6BEC9BD88A12A46CF

https://www.ema.europa.eu/documents/product-information/tegsedi-epar-product-information_en.pdf

Tegsedi

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See Section 4.8 for how to report adverse reactions 1. NAME OF THE MEDICINAL PRODUCT Tegsedi 284 mg solution for injection in pre-filled syringe 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre-filled syringe contains 284 mg inotersen (as sodium). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection) Clear, colourless to pale yellow solution (pH 7.5 – 8.8) 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Tegsedi is indicated for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR). 4.2 Posology and method of administration Treatment should be initiated by and remain under the supervision of a physician experienced in the treatment of patients with hereditary transthyretin amyloidosis. Posology The recommended dose is 284 mg inotersen by subcutaneous injection. Doses should be administered once every week. For consistency of dosing, patients should be instructed to receive the injection on the same day every week. Dose adjustment in case of reduction in platelet count Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia. Dosing should be adjusted according to laboratory values as follows: Table 1 . Inotersen monitoring and treatment recommendations for platelet count Platelet count (x109/L) Monitoring frequency Dosing > 100 Every 2 weeks Weekly dosing should be continued. ≥ 75 to < 100* Every week Dosing frequency should be reduced to 284 mg every 2 weeks < 75* Twice weekly until 3 successive values above 75 then weekly monitoring. Dosing should be paused until 3 successive values > 100. On reinitiation of treatment dose 3 frequency should be reduced to 284 mg every 2 weeks. < 50‡† Twice weekly until 3 successive values above 75 then weekly monitoring. Consider more frequent monitoring if additional risk factors for bleeding are present. Dosing should be paused until 3 successive values > 100. On reinitiation of treatment dose frequency should be reduced to 284 mg every 2 weeks. Consider corticosteroids if additional risk factors for bleeding are present. < 25† Daily until 2 successive values above 25. Then monitor twice weekly until 3 successive values above 75. Then weekly monitoring until stable. Treatment should be discontinued. Corticosteroids recommended. * If the subsequent test confirms the initial test result, then monitoring frequency and dosing should be adjusted as recommended in the table. ‡ Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, and /or prior history of major bleeding events † It is strongly recommended that, unless corticosteroids are contraindicated, the patient receives glucocorticoid therapy to reverse the platelet decline. Patients who discontinue therapy with inotersen due to platelet counts below 25 x 109/L should not reinitiate therapy. Missed doses If a dose of inotersen is missed, then the next dose should be administered as soon as possible, unless the next scheduled dose is within two days, in which case the missed dose should be skipped and the next dose administered as scheduled. Special populations Elderly No dose adjustment is required in patients aged 65 and over (see section 5.2). Renal impairment No dose adjustment is required for patients with mild or moderate renal impairment (see section 5.2). Inotersen should not be used in patients with a urine protein to creatinine ratio (UPCR) ≥ 113 mg/mmol (1 g/g) or estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73m2 (see section 4.3). Because of the risk of glomerulonephritis and possible renal function decline, UPCR and eGFR should be monitored during treatment with inotersen (see section 4.4). If acute glomerulonephritis is confirmed, permanent discontinuation of the treatment should be considered. Hepatic impairment No dose adjustment is required for patients with mild or moderate hepatic impairment (see section 5.2). Inotersen must not be used in patients with severe hepatic impairment (see section 4.3). Patients undergoing liver transplant Inotersen has not been evaluated in patients undergoing liver transplant. It is, therefore, recommended that dosing of inotersen should be discontinued in subjects undergoing liver transplantation. Paediatric population The safety and efficacy of inotersen in children and adolescents below 18 years of age have not been established. No data are available. Method of administration Subcutaneous use only. 4 The first injection administered by the patient or caregiver should be performed under the guidance of an appropriately qualified health care professional. Patients and/or caregivers should be trained in the subcutaneous administration of Tegsedi. Sites for injection include the abdomen, upper thigh region, or outer area of the upper arm. It is important to rotate sites for injection. If injected in the upper arm, the injection should be administered by another person. Injection should be avoided at the waistline and other sites where pressure or rubbing from clothing may occur. Tegsedi should not be injected into areas of skin disease or injury. Tattoos and scars should also be avoided. The pre-filled syringe should be allowed to reach room temperature prior to injection. It should be removed from refrigerated storage at least 30 minutes before use. Other warming methods should not be used. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Platelet count < 100 x 109/L prior to treatment. Urine protein to creatinine ratio (UPCR) ≥ 113 mg/mmol (1 g/g) prior to treatment. Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73m2 . Severe hepatic impairment. 4.4 Special warnings and precautions for use Thrombocytopenia Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia (see section 4.8). Platelet count should be monitored every 2 weeks during treatment with inotersen and for 8 weeks following discontinuation of treatment. Recommendations for adjustments to monitoring frequency and inotersen dosing are specified in Table 1 (see section 4.2). Patients should be instructed to report to their physician immediately if they experience any signs of unusual or prolonged bleeding (e.g. petechia, spontaneous bruising, subconjunctival bleeding, nosebleeds), neck stiffness or atypical severe headache. Special caution should be used in elderly patients, in patients taking anithrombotic medicinal products, antiplatelet medicinal products, or medicinal products that may lower platelet count (see section 4.5), and in patients with prior history of major bleeding events. Glomerulonephritis/ renal function decline Glomerulonephritis has occurred in patients treated with inotersen (see section 4.8). Renal function decline has also been observed in a number of subjects without signs of glomerulonephritis (see section 4.8). UPCR and eGFR should be monitored every 3 months or more frequently, as clinically indicated, based on history of chronic kidney disease and/or renal amyloidosis. UPCR and eGFR should be monitored for 8 weeks following discontinuation of treatment. Patients with UPCR more than or equal to twice the upper limit of normal, or eGFR < 60 ml/min, which is confirmed on repeat testing and in the absence of an alternative explanation, should be monitored every 4 weeks. In the case of a decrease in eGFR >30%, in the absence of an alternative explanation, pausing of inotersen dosing should be considered pending further evaluation of the cause. 5 In the case of UPCR ≥ 2 g/g (226 mg/mmol), which is confirmed on repeat testing, dosing of inotersen should be paused while further evaluation for acute glomerulonephritis is performed. Inotersen should permanently be discontinued if acute glomerulonephritis is confirmed. If glomerulonephritis is excluded, dosing may be resumed if clinically indicated and following improvement of renal function (see section 4.3). Early initiation of immunosuppressive therapy should be considered if a diagnosis of glomerulonephritis is confirmed. Caution should be used with nephrotoxic medicinal products and other medicinal products that may impair renal function (see section 4.5). Vitamin A deficiency Based on the mechanism of action, inotersen is expected to reduce plasma vitamin A (retinol) below normal levels (see section 5.1). Plasma vitamin A (retinol) levels below lower limit of normal should be corrected and any ocular symptoms or signs of vitamin A deficiency should have resolved prior to initiation of inotersen. Patients receiving inotersen should take oral supplementation of approximately 3,000 IU vitamin A per day in order to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms consistent with vitamin A deficiency, incuding: reduced night vision or night blindness, persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening, corneal perforation. During the first 60 days of pregnancy, both too high and too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before treatment initiation and women of childbearing potential should practise effective contraception (see section 4.6). If a woman intends to become pregnant, inotersen and vitamin A supplementation should be discontinued and plasma vitamin A levels should be monitored and have returned to normal before conception is attempted. In the event of an unplanned pregnancy, inotersen should be discontinued. Due to the long half-life of inotersen (see section 5.2), a vitamin A deficit may even develop after cessation of treatment. No recommendation can be given whether to continue or discontinue vitamin A supplementation during the first trimester of an unplanned pregnancy. If vitamin A supplementation is continued, the daily dose should not exceed 3000 IU per day, due to the lack of data supporting higher doses. Thereafter, vitamin A supplementation of 3000 IU per day should be resumed in the second and third trimester if plasma retinol levels have not yet returned to normal, because of the increased risk of vitamin A deficiency in the third trimester. It is not known whether vitamin A supplementation in pregnancy will be sufficient to prevent vitamin A deficiency if the pregnant female continues to receive inotersen. However, increasing vitamin A supplementation to above 3000 IU per day during pregnancy is unlikely to correct plasma retinol levels due to the mechanism of action of inotersen and may be harmful to the mother and foetus. Liver monitoring Hepatic enzymes should be measured 4 months after initiation of treatment with inotersen and annually thereafter or more frequently as clinically indicated, in order to detect cases of hepatic impairment (see section 4.8). 6 Liver Transplant Rejection Inotersen was not evaluated in patients undergoing liver transplantation in clinical trials (section 4.2). Cases of liver transplant rejection have been reported in patients treated with Inotersen. Patients should be monitored for signs and symptoms of transplant rejection during treatment with Inotersen. Discontinuation of Inotersen should be considered in patients who develop liver transplant rejection during treatment. Precautions prior to initiation of inotersen Platelet count, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR) and hepatic enzymes should be measured prior to treatment with Tegsedi. Transient increases of CRP and platelet levels may occur in some patients after initiation of inotersen. This reaction typically resolves spontaneously after a few days of treatment. 4.5 Interaction with other medicinal products and other forms of interaction Caution should be used with anithrombotic medicinal products, antiplatelet medicinal products, and medicinal products that may lower platelet count, for example acetylsalicyclic acid, clopidogrel, warfarin, heparin, low-molecular weight heparins, Factor Xa inhibitors such as rivaroxaban and apixaban, and thrombin inhibitors such as dabigatran (see section 4.4). Caution should be exercised with concomitant use of nephrotoxic medicinal products and other medicines that may impair renal function, such as sulfonamides, aldosterone antagonists, anilides, natural opium alkaloids and other opiods (see section 4.4). Although the population PK analysis did not identify clinically relevant effects of some nephrotoxic medicines on the clearance of inotersen or on the potential for an effect on renal function, a systematic assessment of co-administration of inotersen and potentially nephrotoxic medicinal products has not been conducted. 4.6 Fertility, pregnancy and lactation Women of child-bearing potential Inotersen will reduce the plasma levels of vitamin A, which is crucial for normal foetal development. It is not known whether vitamin A supplementation will be sufficient to reduce the risk to the foetus (see section 4.4). For this reason, pregnancy should be excluded before initiation of inotersen therapy and women of child-bearing potential should practise effective contraception. Pregnancy There are no or limited amount of data from the use of inotersen in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Due to the potential teratogenic risk arising from unbalanced vitamin A levels, inotersen should not be used during pregnancy, unless the clinical condition of the woman requires treatment with inotersen. Women of child-bearing potential have to use effective contraception during treatment with inotersen. Breast-feeding It is unknown whether inotersen/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of inotersen metabolites in milk (see section 5.3). A risk to the breastfed newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Tegsedi therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. 7 Fertility There is no information available on the effects of inotersen on human fertility. Animal studies did not indicate any impact of inotersen on male or female fertility. 4.7 Effects on ability to drive and use machines Tegsedi has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most frequently observed adverse reactions during treatment with inotersen were events associated with injection site reactions (50.9%). Other most commonly reported adverse reactions with inotersen were nausea (31.3%), anaemia (27.7%), headache (23.2%), pyrexia (19.6%), peripheral oedema (18.8%), chills (17.9%), vomiting (15.2%), thrombocytopenia (13.4%) and platelet count decreased (10.7%). Tabulated summary of adverse reactions Table 2 presents the adverse reactions (ADRs) listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each ADR is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Table 2. List of adverse reactions in clinical studies System Organ Class Very Common Common Blood and lymphatic system disorders Thrombocytopenia Anaemia Platelet count decreased Eosinophilia Metabolism and nutrition disorders Decreased appetite Nervous system disorders Headache Vascular disorders Orthostatic hypotension Hypotension Haematoma Gastrointestinal disorders Vomiting Nausea Hepatobiliary disorders Transaminases increased Skin and subcutaneous disorders Pruritus Rash Renal and urinary disorders Glomerulonephritis Proteinuria Renal failure 8 System Organ Class Very Common Common Acute kidney injury Renal impairment General disorders and administration site conditions Pyrexia Chills Injection site reactions Peripheral oedema Influenza like illness Peripheral swelling Injection site discolouration Injury, poisoning and procedural complications Contusion Description of selected adverse reactions Injection site reactions The most frequently observed events included events associated with injection site reactions (includes injection site pain, erythema, pruritus, swelling, rash, induration, bruising and haemorrhage). These events are usually either self-limiting or can be managed using symptomatic treatment. Thrombocytopenia Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia. In the Phase 3, NEURO-TTR trial, platelet count reductions to below normal (140 x 109/L ) were observed in 54% of patients treated with inotersen and 13% of placebo patients; reductions to below 100 x 109/L were observed in 23% of patients treated with inotersen and 2% of the patients receiving placebo; confirmed platelet counts of < 75 x 109/L were observed in 10.7% of inotersen-treated patients. Three (3%) patients developed platelet counts < 25 x 109/L; one of these patients experienced a fatal intracranial haemorrhage. Patients should be monitored for thrombocytopenia during treatment with inotersen (see section 4.4). Glomerulonephritis / renal function decline Patients should be monitored for signs of increased proteinuria and reduction in eGFR during treatment with inotersen (see section 4.4). Immunogenicity In the pivotal Phase 2/3 study, 30.4% of patients treated with inotersen tested positive for anti-drug antibodies following 15 months of treatment. Development of anti-drug antibodies to inotersen was characterised by late onset (median onset > 200 days) and low titer (median peak titer of 284 in the pivotal study). No effect on the pharmacokinetic properties (Cmax, AUC or half-life) and efficacy of inotersen was observed in the presence of anti-drug antibodies, but patients with anti-drug antibodies had more reactions at the injection site. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In the event of an overdose, supportive medical care should be provided including consulting with a healthcare professional and close observation of the clinical status of the patient. Platelet and renal function tests should be monitored regularly. 9 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other Nervous System Drugs, ATC code: N07XX15 Mechanism of action Inotersen is a 2′-O-2-methoxyethyl (2′-MOE) phosphorothioate antisense oligonucleotide (ASO) inhibitor of human transthyretin (TTR) production. The selective binding of inotersen to the TTR messenger RNA (mRNA) causes the degradation of both mutant and wild type (normal) TTR mRNA. This prevents the synthesis of TTR protein in the liver, resulting in significant reductions in the levels of mutated and wild type TTR protein secreted by the liver into the circulation. TTR is a carrier protein for retinol binding protein 4 (RBP4) which is the principal carrier of vitamin A (retinol). Therefore, reduction in plasma TTR is expected to result in reduction of plasma retinol levels to below the lower limit of normal. Pharmacodynamic effects In the pivotal NEURO-TTR study, in the inotersen treatment group, robust reduction in circulating TTR levels was observed throughout the 15-month treatment period, with mean percent changes from baseline in serum TTR ranging from 68.41% to 74.03% (median range: 74.64% to 78.98%) from Week 13 to Week 65 (Figure 1). In the placebo group, mean serum TTR concentration decreased by 8.50% at Week 3 and then remained fairly constant throughout the treatment period. 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 - 8 0 - 7 0 - 6 0 - 5 0 - 4 0 - 3 0 - 2 0 - 1 0 0 S t u d y W e e k T T R % C h a n g e f r o m B a s e li n e L S M (  S E ) P la c e b o I n o t e r s e n Figure 1 Percent Change from Baseline in Serum TTR Over Time Clinical efficacy and safety The NEURO-TTR multicentre, double-blind, placebo-controlled trial was comprised of 172 treated patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN). The disease hATTR-PN is classified into 3 stages such that i) Stage 1 patients do not require assistance with ambulation, ii) Stage 2 patients do require assistance with ambulation, and iii) Stage 3 patients are bound to wheelchair. Subjects with Stage 1 and Stage 2 hATTR-PN and an NIS ≥10 and ≤130 were recruited in the pivotal NEURO-TTR study. The study evaluated 284 mg inotersen administered as one subcutaneous injection once per week, for 65 weeks of treatment. Patients were randomised 2:1 to receive either inotersen or placebo. The primary efficacy endpoints were the change from baseline to Week 66 in the modified Neuropathy Impairment Score + 7 tests (mNIS+7) composite score and in the Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) questionnaire total score. Patients were stratified for stage of disease (Stage 1 versus Stage 2), TTR mutation (V30M versus non-V30M) and previous treatment with either tafamidis or diflunisal (yes versus no). Baseline demographic and disease characteristics are shown in Table 3. 10 Table 3. Baseline demographics Placebo (N=60) Inotersen (N=112) Age (years), mean (SD) 59.5 (14.05) 59.0 (12.53) Age 65 years and older, n (%) 26 (43.3) 48 (42.9) Male, n (%) 41 (68.3) 77 (68.8) mNIS+7, mean (SD) 74.75 (39.003) 79.16 (36.958) Norfolk QoL-DN, mean (SD) 48.68 (26.746) 48.22 (27.503) Disease stage, n (%) Stage 1 42 (70.0) 74 (66.1) Stage 2 18 (30.0) 38 (33.9) V30M TTR mutation1, n (%) Yes 33 (55.0) 56 (50.0) No 27 (45.0) 56 (50.0) Previous treatment with tafamidis or diflunisal1, n (%) Yes 36 (60.0) 63 (56.3) No 24 (40.0) 49 (43.8) hATTR-CM2, n (%) 33 (55.0) 75 (66.4) hATTR-PN Disease Duration3 (months) mean (SD) 64.0 (52.34) 63.9 (53.16) hATTR-CM Disease Duration3 (months) mean (SD) 34.1 (29.33) 44.7 (58.00) 1 Based on clinical database 2 Defined as all patients with a diagnosis of hereditary transthyretin amyloidosis with cardiomyopathy (hATTR-CM) at study entry or left ventricular wall thickness >1.3 cm on echocardiogram without a known history of persistent hypertension 3 Duration from symptom onset to informed consent date The changes from baseline in both primary endpoints (mNIS+7 and Norfolk QoL-DN) demonstrated statistically significant benefit in favour of inotersen treatment at Week 66 (Table 4). Results across multiple disease characteristics [TTR mutation (V30M, non-V30M)], disease stage (Stage 1, Stage 2), previous treatment with tafamidis or diflunisal (yes, no), presence of hATTR-CM (yes, no) at Week 66 showed statistically significant benefit in all subgroups based on mNIS+7 composite score and all but one of these subgroups (CM-Echo Set; p=0.067) based on Norfolk QoL-DN total score (Table 5). Furthermore, results across the components of mNIS+7 and domains of Norfolk QoL-DN composite scores were consistent with the primary endpoint analysis, showing benefit in motor, sensory and autonomic neuropathies (Figure 2). Table 4. Primary Endpoint Analysis mNIS+7 and Norfolk QoL-DN mNIS+7 Norfolk-QOL-DN Placebo (N=60) Inotersen (N=112) Placebo (N=60) Inotersen (N=112) Baseline n Mean (SD) 60 74.75 (39.003) 112 79.16 (36.958) 59 48.68 (26.746) 111 48.22 (27.503) 11 Week 66 Change n LSM (SE) 95% CI Difference in LSM (Tegsedi – Placebo) 95% CI P-value 60 25.43 (3.225) 19.11, 31.75 112 10.54 (2.397) 5.85, 15.24 -14.89 -22.55, -7.22 <0.001 59 12.94 (2.840) 7.38, 18.51 111 4.38 (2.175) 0.11, 8.64 -8.56 -15.42, -1.71 0.015 Table 5. Subgroup Analysis of mNIS+7 and Norfolk QoL-DN mNIS+7 Norfolk QoL-DN Change from Baseline Inotersen – Placebo Change from Baseline Inotersen – Placebo Subgroup n (Placebo, Inotersen) LSM Difference (SE) P-value n (Placebo, Inotersen) LSM Difference (SE) P-value Week 66 V30M 32, 58 -13.52 (3.795) p<0.001 32, 58 -8.14 (3.998) p=0.042 Non-V30 28, 54 -19.06 (5.334) p<0.001 27, 53 -9.87 (4.666) p=0.034 Stage I Disease 39, 74 -12.13 (3.838) P=0.002 38, 73 -8.44 (3.706) p=0.023 Stage II Disease 21, 38 -24.79 (5.601) p<0.001 21, 38 -11.23 (5.271) p=0.033 Previous use of stabilisers 33, 61 -18.04 (4.591) p<0.001 32, 60 -9.26 (4.060) p=0.022 Treatment naïve 27, 51 -14.87 (4.377) p<0.001 27, 51 -10.21 (4.659) p=0.028 CM-Echo Set 33, 75 -14.94 (4.083) p<0.001 33, 75 -7.47 (4.075) p=0.067 Non-CM- Echo Set 27, 37 -18.79 (5.197) p<0.001 26, 36 -11.67 (4.213) p=0.006 12 Figure 2 Difference in Least Squares Mean (LSM) Change from Baseline Between Treatment Groups in mNIS+7 and Components A responder analysis of mNIS+7 using thresholds ranging from a 0- to 30-point increase from baseline (using the safety set), showed the inotersen group had approximately a 2-fold higher response rate than the placebo group at each threshold tested, demonstrating consistency of response. A responder was defined as a subject who had a change from baseline that was less than or equal to the threshold value. Subjects that terminate the treatment early irrespective of the reason or have missing week 66 data are considered as non-responders. Statistical significance in favour of inotersen was demonstrated at all thresholds beyond a 0-point change. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Tegsedi in all subsets of the paediatric population in transthyretin amyloidosis (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Following subcutaneous administration, inotersen is absorbed rapidly into systemic circulation in a dose-dependent fashion with the median time to maximum plasma concentrations (Cmax) of inotersen typically reached within 2 to 4 hours. Distribution Inotersen is highly bound to human plasma protein (> 94%) and the fraction bound is independent of drug concentration. The apparent volume of distribution of inotersen at steady-state is 293 L in patients with hATTR. The high volume of distribution suggests inotersen extensively distributes into tissues following SC administration. Biotransformation Inotersen is not a substrate for CYP450 metabolism, and is metabolised in tissues by endonucleases to form shorter inactive oligonucleotides that are the substrates for additional metabolism by exonucleases. Unchanged inotersen is the predominant circulating component. Elimination The elimination of inotersen involves both metabolism in tissues and excretion in urine. Both inotersen and its shorter oligonucleotide metabolites are excreted in human urine. Urinary recovery of the parent medicinal product is limited to less than 1% within the 24 hours post dose. Following subcutaneous administration, elimination half-life for inotersen is approximately 1 month. Special populations Based on the population pharmacokinetic analysis, age, body weight, sex or race has no clinically relevant effect on inotersen exposure. Definitive assessments were limited in some cases as covariates were limited by the overall low numbers. Elderly population No overall differences in pharmacokinetics were observed between other adult and elderly patients. Renal impairment 13 A population pharmacokinetic analysis suggests that mild and moderate renal impairment has no clinically relevant effect on the systemic exposure of inotersen. No data are available in patients with severe renal impairment. Hepatic impairment The pharmacokinetics of inotersen in patients with hepatic impairment has not been studied. Inotersen is not primarily cleared by metabolism in the liver, not a substrate for CYP450 oxidation, and metabolized broadly by nucleases in all tissues of distribution. Thus, pharmacokinetics should not be altered in mild to moderate hepatic impairment. 5.3 Preclinical safety data Toxicology Decreased platelet counts were observed in chronic toxicity studies in mice, rats and monkeys at 1.4 to 2-fold the human AUC at the recommended therapeutic inotersen dose. Severe platelet declines in association with increased bleeding or bruising were observed in individual monkeys. Platelet counts returned to normal when treatment was stopped but dropped to even lower levels when inotersen aministration was resumed. This suggests an immunologically related mechanism. Extensive and persistent uptake of inotersen was observed by various cell types in multiple organs of all tested animal species including monocytes/macrophages, kidney proximal tubular epithelia, Kupffer cells of the liver, and histiocytic cell infiltrates in lymph nodes and injection sites. The kidney accumulation of inotersen was associated with proteinuria in rats at 13.4-fold the human AUC at the recommended therapeutic inotersen dose. In addition, reduced thymus weight due to lymphocyte depletion was observed in mice and rats. In monkeys, perivascular cell infiltration by lymphohistiocytic cells in multiple organs was noted. These pro-inflammatory organ changes were observed at 1.4 to 6.6-fold the human AUC at the recommeded therapeutic dose in all animal species tested and were accompanied by increases of various plasma cytokines/chemokines. Genotoxicity/ carcinogenicity Inotersen did not exhibit genotoxic potential in in vitro and in vivo and was not carcinogenic in transgenic rasH2 mice. Reproductive toxicology Inotersen showed no effects on fertility, embryo-foetal, or postnatal development in mice and rabbits at approximately 3-fold the maximum recommended human equivalent dose. Milk transfer of inotersen was low in mice. However, inotersen is not pharmacologically active in mice and rabbits. Consequently, only effects related to the chemistry of inotersen could be captured in these investigations. Still, no effect on embryo-foetal development was noted with a mouse-specific analogue of inotersen in mice, which was associated with ~60% inhibition (individual range up to 90% reduction) of TTR mRNA expression. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Water for injections Hydrochloric acid (for pH adjustment) Sodium hydroxide (for pH adjustment) 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 14 6.3 Shelf life 3 years. Tegsedi may be stored unrefrigerated for up to 6 weeks below 30 °C. If not used within 6 weeks, it should be discarded. 6.4 Special precautions for storage Store in a refrigerator (2 °C – 8 °C). Do not freeze. Store in the original package in order to protect from light. 6.5 Nature and contents of container 1.5 mL solution in a clear Type 1 glass pre-filled syringe. Tray with tear-off lid. Pack sizes of 1 or 4 pre-filled syringes. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Tegsedi should be inspected visually prior to administration. The solution should be clear and colourless to pale yellow. If the solution is cloudy or contains visible particulate matter, the contents must not be injected. Each pre-filled syringe should be used only once and then placed in a sharps disposal container for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Akcea Therapeutics Ireland Ltd Regus House, Harcourt Centre, Harcourt Road Dublin 2, Ireland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1296/001 EU/1/18/1296/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 06 July 2018 10. DATE OF REVISION OF THE TEXT 15 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 16 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 17 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release ABF Pharmaceutical Services GmbH Brunnerstraße 63/18-19 1230 Vienna AUSTRIA B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures Prior to the launch of Tegsedi in each Member State (MS), the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational materials, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority (NCA). The MAH shall ensure that in each MS where Tegsedi is marketed, all patients who are expected to been administered the products are provided with a patient alert card (wallet size), aiming at preventing and/or minimising the important identified risks of thrombocytopenia, glomerulonephritis, and the important potential risk of ocular toxicity due to vitamin A deficiency, and reminding patients: 18 • To carry the card with them at all times during the treatment and up to 8 weeks following treatment discontinuation; • The list of signs and symptoms of thrombocytopenia, glomerulonephritis, and ocular toxicity due to vitamin A deficiency, highlighting that these might be severe or life-threatening, and advising patients to call immediately their doctor or attend the emergency room if such signs and symptoms appear; • To undergo all blood or urine tests as arranged by their doctor; • To have a list of all other medicines they are using for any visit to a Health Care Professionals (HCP); In addition to a prompt to include the contact details of the patient’s physician and a call for reporting, the patient card should also: • Alert HCPs that the patient is taking Tegsedi, its indication and the key safety concerns; • Advise HCPs that, due to the risks of thrombocytopenia and glomerulonephritis, patients should have their platelet count monitored at least every 2 weeks, and urine to protein creatinine ratio and estimated glomerular filtration rate monitored at least every 3 months; • Advise HCPs that if the platelet count falls below 25 x 109/L, Tegsedi treatment should be permanently discontinued and corticosteroid therapy is recommended; • Advise HCPs that if glomerulonephritis is confirmed, Tegsedi treatment should be permanently discontinued and early initiation of immunosuppressive therapy should be considered. 19 ANNEX III LABELLING AND PACKAGE LEAFLET 20 A. LABELLING 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Tegsedi 284 mg solution for injection in pre-filled syringe inotersen 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled syringe contains 284 mg inotersen (as sodium). 3. LIST OF EXCIPIENTS Also contains: hydrochloric acid, sodium hydroxide, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled syringe 4 pre-filled syringes 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use. For single use only Lift here and pull to open 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Following distribution to the patient, can be stored 6 weeks below 30°C. If not used, should be discarded. Store in the original package in order to protect from light. 22 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Akcea Therapeutics Ireland Ltd Regus House, Harcourt Centre, Harcourt Road Dublin 2, Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1296/001 EU/1/18/1296/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Tegsedi 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 23 PARTICULARS TO APPEAR ON BLISTERS OR STRIPS TRAY TEAR-OFF LID 1. NAME OF THE MEDICINAL PRODUCT Tegsedi 284 mg solution for injection in pre-filled syringe inotersen 2. NAME OF THE MARKETING AUTHORIZATION HOLDER Akcea Therapeutics 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Subcutaneous use . 1. Bend and snap 2. Pull to open 24 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Tegsedi 284 mg injection inotersen SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1.5 mL 6. OTHER 25 B. PACKAGE LEAFLET 26 Package leaflet: Information for the user Tegsedi 284 mg solution for injection in pre-filled syringe inotersen This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Tegsedi is and what it is used for 2. What you need to know before you use Tegsedi 3. How to use Tegsedi 4. Possible side effects 5. How to store Tegsedi 6. Contents of the pack and other information 1. What Tegsedi is and what it is used for Tegsedi contains the active substance inotersen. It is used to treat adults with hereditary transthyretin amyloidosis. Hereditary transthyretin amyloidosis is a genetic disease, which causes build-up of small fibres of a protein called transthyretin in the organs of your body stopping them from working properly. Tegsedi is used when the disease is causing symptoms of polyneuropathy (nerve damage). The active substance in Tegsedi, inotersen, is a type of medicine called an antisense oligonucleotide inhibitor. It works by reducing production of transthyretin by the liver and so lowers the risk of fibres of transthyretin being deposited in body organs and causing symptoms. 2. What you need to know before you use Tegsedi Do not use Tegsedi if: - you are allergic to inotersen or any of the other ingredients of this medicine (listed in section 6). - tests show you have excessively low numbers of platelets, the cells in your blood which stick together helping it clot - tests of kidney function or protein in the urine show signs of severe kidney problems - you have severe reduction in liver function (hepatic impairment) Warnings and precautions Before you begin treatment with Tegsedi, your doctor will measure your blood cells, liver function, kidney function, and protein levels in your urine. You will only be treated with Tegsedi if these are all at acceptable levels and your doctor will repeat these checks regularly during treatment. 27 Thrombocytopenia Tegsedi may reduce cells in the blood responsible for clotting of the blood (platelets), which may result in a condition called thrombocytopenia (see section 4). When you do not have enough platelets, like in thrombocytopenia, your blood may not clot quickly enough to stop bleeding. This can lead to bruising as well as other more serious problems such as excessive bleeding and internal bleeding. Your doctor will check your blood for levels of platelets before treatment and regularly during treatment with Tegsedi. If you stop taking Tegsedi then your blood levels should be checked 8 weeks after discontinuation. If you are taking any medicines that can lower platelet count or stop blood from clotting, for example acetylsalicylic acid, clopidogrel, warfarin, heparin, rivoraxaban and dabigatran, you must tell your doctor before you use Tegsedi. You should see your doctor immediately if you have unexplained bruising or a rash of small patches of red appearing on the skin (called petechiae), bleeding from skin cuts that does not stop or oozes, bleeding from the gums or nose, blood in urine or stools, bleeding in the whites of your eyes. Call for immediate help if you have stiffness of the neck or an unusual and severe headache because these symptoms may be caused by bleeding in the brain. Glomerulonephritis / kidney problems Glomerulonephritis is a condition of your kidneys, where they do not work properly due to inflammation and kidney damage. Some patients treated with inotersen have developed this condition. Symptoms of glomerulonephritis are foaming urine, pink or brown coloured urine, blood in the urine, and passing less urine than usual. Some patients treated with inotersen have also developed a decline in their kidney function without having had glomerulonephritis. Your doctor will check your kidney function before treatment and regularly during treatment with Tegsedi. If you stop taking Tegsedi then your kidney function should be checked 8 weeks after discontinuation. If you develop glomerulonephritis, your doctor will treat you for this condition. If you are using any medicines that damage the kidney or affect kidney function, for example sulfonamides, aldosterone antagonists, and some types of painkillers, you should tell your doctor. Vitamin A deficiency Tegsedi can lower your body’s levels of vitamin A (also called retinol). You doctor will measure these, and if they are already low, this should be corrected and any symptoms resolved before you start treatment with Tegsedi. Symptoms of low vitamin A include: • dry eyes, poor vision, decrease in night vision, hazy or cloudy vision If you have problems with your sight or any other eye problems when you are using Tegsedi, you should speak to your doctor. Your doctor may refer you to an eye specialist for a check-up if it is necessary. Your doctor will ask you to take a daily vitamin A supplement during treatment with Tegsedi. Both excess and deficient levels of vitamin A can harm the development of your unborn child. Therefore women of child-bearing age should exclude any pregnancy, before treatment initiation with Tegsedi and should practise effective contraception (see section “Pregnancy and breast-feeding” below). If you are planning to become pregnant you should stop taking inotersen including vitamin A supplementation and ensure that your vitamin A levels have returned to normal before conception is attempted. If you have an unplanned pregnancy you should stop taking inotersen. Due to the prolonged activity of Tegsedi, however, your reduced vitamin A levels may persist. It is unknown if continuation of your 28 vitamin A supplementation with 3000 IU per day will be harmful to your unborn child in the first trimester of your pregnancy, but this dose should not be exceeded. You should resume the vitamin A supplementation during your second and third trimesters of your pregnancy if your vitamin A levels have not yet returned to normal, because of the increased risk of vitamin A deficiency in the third trimester. Liver Transplant Rejection Talk to your doctor before using TEGSEDI if you have previously received a liver transplant. Cases of liver transplant rejection have been reported in patients being treated with Tegsedi. Your doctor will monitor you regularly for this during treatment with Tegsedi. Children and adolescents Tegsedi should not be used in children and adolescents under 18 years old. Other medicines and Tegsedi Tell your doctor or pharmacist if you are taking, have recently taken or might use any other medicines. It is important that you tell your doctor if you are already being treated with any of the following: - Medicines to prevent blood clots or that lower the platelet numbers in your blood, e.g., acetylsalicylic acid, heparin, warfarin, clopidogrel, rivoraxaban and dabigatran. - Any medicines that may alter your kidney function or may damage the kidneys, e.g., sulfonamides (used as an antibacterial), anilides (used to treat fever, aches and pains), aldosterone antagonists (used as a diuretic) and natural opium alkaloids and other opiods (used for treatment of pain). Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before using this medicine. Women of child-bearing age Tegsedi will reduce the level of vitamin A in your body, which is important for normal foetal development during pregnancy. It is unknown if vitamin A supplementation can compensate for the risk of vitamin A deficiency that might affect your unborn child (see “Warnings and precautions” above). If you are a woman of child-bearing age, you should practise effective contraception and any pregnancy should be excluded before starting the treatment with Tegsedi. Pregnancy You should not use Tegsedi if you are pregnant, unless explicitly advised by your doctor. If you are of child-bearing age and intend to use Tegsedi, you should practise effective contraception. Breast-feeding Tegsedi may pass into breast milk. You should consult your doctor if you should either stop breast- feeding or stop the treatment with Tegsedi. Driving and using machines Use of Tegsedi has not been shown to affect ability to drive or use machinery. 3. How to use Tegsedi Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. The recommended dose of Tegsedi is one dose of 284 mg inotersen. Doses should be administered once every week. All subsequent doses should be injected once weekly on the same day each week. 29 Route and method of administration Tegsedi is for injection under the skin (subcutaneous use) only. Instructions for use Before using your pre-filled syringe, your doctor should show you or your caregiver how to use it the right way. If you or your caregiver have any questions, ask your doctor. Read the Instructions for Use before you start using your pre-filled syringe and each time you get a repeat prescription. There may be new information. Guide to parts Each pre-filled syringe contains one dose and is for one-time use only. Before use Plunger Finger Grip Safety Spring (inside body) Body Needle Cap Needle Inspection Area After use After use, the safety spring is automatically activated and retracts the needle. 30 WARNINGS Do not remove needle cap until you have reached Step 6 of these instructions and are ready to inject Tegsedi; Do not share your syringe with another person or re-use your syringe; Do not use if the pre-filled syringe is dropped onto a hard surface or is damaged; Do not freeze the pre-filled syringe; If any of the above happens, throw away the pre-filled syringe in a puncture-resistant (sharps) container and use a new pre-filled syringe. PREPARATION 1. Gather supplies - 1 Pre-filled syringe from the refrigerator - 1 Alcohol wipe (not supplied) - 1 Gauze pad or cotton ball (not supplied) - 1 Puncture-resistant (sharps) container (not supplied) Do not inject the medicine until you have gathered the supplies listed. 2. Prepare to use your pre-filled syringe • Remove the plastic tray from the carton and check the expiry date. Do not use if the expiry date has passed. • Let the pre-filled syringe reach room temperature (20 °C to 25 °C) for 30 minutes before injecting it. Do not warm the pre-filled syringe in any other way. For example, do not warm in a microwave or hot water, or near other heat sources. • Remove the pre-filled syringe from the tray by holding onto the syringe body. Do not move the plunger. 3. Check medicine in the pre-filled syringe Look in the inspection area to check that the solution is clear and colourless or pale yellow. It is normal to see air bubbles in the solution. You do not need to do anything about it. Do not use if the solution looks cloudy, discoloured, or has particles. If the solution looks cloudy, discoloured or has particles, throw the pre-filled syringe away in a puncture resistant (sharps) container, and use a new pre-filled syringe. 31 4. Choose the injection site Choose an injection site on your abdomen (belly) or the front of your thigh. The injection site may also be on the outer area of the upper arm if Tegsedi is administered by a caregiver. Do not inject into the 3cm area around the belly-button (navel). Do not inject into the same site each time. Do not inject where skin is bruised, tender, red or hard. Do not inject into tattoos, scars or damaged skin. Do not inject through clothing. 5. Clean the injection site Wash your hands with soap and water. Clean the injection site with an alcohol wipe in a circular motion. Let the skin air dry. Do not touch the area again before injecting. 32 INJECTION 6. Remove the needle cap Hold the pre-filled syringe by the body, with the needle facing away from you. Remove needle cap by pulling it straight off. Do not twist it off. You may see a drop of liquid at the end of the needle. This is normal. Keep your hands away from the plunger to avoid pushing the plunger before you are ready to inject. Do not remove the needle cap until right before you inject. Do not pull the cap off while holding the pre-filled syringe by the plunger. Always hold by the body of the syringe. Do not let the needle touch any surface. Do not remove any air bubbles from the pre-filled syringe. Do not put the needle cap back onto the pre-filled syringe. 7. Insert the needle Hold the pre-filled syringe in 1 hand. Hold the skin around at the injection site as your healthcare provider has instructed you. You should either gently pinch the skin at the injection site or give the injection without pinching the skin. Slowly insert the needle into the chosen injection site at a 90° angle until it is fully inserted. Do not hold the pre-filled syringe by the plunger or push against the plunger to insert the needle. 33 8. Start the injection Slowly and firmly push the plunger all the way down until the medicine is injected. Make sure the needle stays fully inserted in the injection site while you are injecting the medicine. It is important to push the plunger all the way down. Your pre-filled syringe may make a click sound as you push the plunger down. This is normal. This does not mean that the injection is finished. The plunger can feel stiff towards the end of the injection. You may need to press a little harder on the plunger to make sure you have pushed it as far as it will go. Do not let go of the plunger. 9. Push the plunger down Push firmly on the plunger at the end of the injection. Hold the plunger fully down and wait for 5 seconds. If you let go of the plunger too quickly, you may lose some of the medicine. The plunger will start to lift automatically which means that the plunger has been pushed fully down. Press down again if the plunger does not start to lift automatically. Slowly and firmly push the plunger down Hold the plunger fully down and wait 5 seconds Wait 5 seconds 34 10. Complete the injection Slowly lift up on the plunger and let the safety spring push the plunger up automatically. The needle should now be retracted safely inside the pre-filled syringe, and the safety mechanism spring visible on the outside of the plunger. When the plunger comes to a stop, your injection is complete. If the plunger does not rise up automatically when you release the pressure, it means the safety spring did not activate and you should push the plunger again but harder. Do not pull the plunger up by hand. Lift the whole pre-filled syringe straight up. Do not try to replace the cap on the retracted needle. Do not rub the injection site. DISPOSAL AND CARE Dispose of the used pre-filled syringe Put the used pre-filled syringe in a sharps disposal container right away after use. Do not throw away the pre-filled syringe in your household waste. If you use more Tegsedi than you should Contact your doctor or pharmacist, or go to a hospital emergency department immediately, even if you have no symptoms. If you forget to use Tegsedi If you miss your dose of Tegsedi, then you should have your next dose as soon as possible, unless the next scheduled dose is within two days, in which case the missed dose should be skipped and the next dose given at the scheduled time. Do not take a double dose to make up for a forgotten dose. Lift thumb slowly back up 35 If you stop using Tegsedi Do not stop using Tegsedi unless your doctor tells you to. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects If you get any of the following side effects, stop using Tegsedi and contact your doctor immediately: - Symptoms that could indicate glomerulonephritis, (where your kidneys do not work properly), such as foaming urine, pink or brown coloured urine, blood in the urine, or passing less urine than usual. - Symptoms that could indicate thrombocytopenia (where blood will not clot), such as unexplained bruising or a rash of small patches of red appearing on the skin (called petechiae), bleeding from skin cuts that does not stop or oozes, bleeding from the gums or nose, blood in urine or stools, or bleeding in the whites of your eyes. Call for immediate help if you have stiffness of the neck or an unusual and severe headache because these symptoms may be caused by bleeding in the brain. Other side effects Very common (may affect more than 1 in 10 people) - Reduction in red blood cells which can make the skin pale and cause weakness or breathlessness (anaemia) - Headache - Vomiting, or nausea (feeling sick) - Increase in body temperature - Feeling cold (chills) or shivering - Injection site pain, redness, itching or bruising - Swelling of the ankles, feet or fingers (peripheral oedema) Common (may affect up to 1 in 10 people) - An increase in the number of white blood cells called eosinophils in your blood (eosinophilia) - Decreased appetite - Feeling faint or dizzy, especially on standing up (low blood pressure, hypotension) - Bruising - Collection of blood within the tissues, that may look similar to severe bruising (haematoma) - Itching - Rash - Kidney damage leading to poor kidney function or kidney failure - Changes to your blood and urine test results (this may indicate infection or liver or kidney damage) - Flu like symptoms, such as high temperature, aches and chills (influenza-like illness) - Injection site swelling or skin discolouration 36 Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Tegsedi Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date, which is stated on the carton, tray and on the pre-filled syringe after “EXP”. The expiry date refers to the last day of that month. Store in a refrigerator (2°C - 8°C). Do not freeze. Tegsedi may be stored unrefrigerated for up to 6 weeks at a temperature below 30°C. If unrefrigerated and not used within 6 weeks then this medicine should be discarded. Store in the original package in order to protect from light. Do not use this medicine if you notice that the contents are cloudy or contains particles. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Tegsedi contains - The active substance is inotersen. - Each pre-filled syringe contains 284mg of inotersen. - The other ingredients are water for injections, sodium hydroxide, and hydrochloric acid. What Tegsedi looks like and contents of the pack Tegsedi is a clear, colourless to pale yellow solution (pH 7.5 – 8.8) for injection (injection) in a pre-filled syringe. Tegsedi is available in pack sizes of either 1 or 4 pre-filled syringes. Not all pack sizes may be marketed. Marketing Authorisation Holder Akcea Therapeutics Ireland Ltd Regus House, Harcourt Centre, Harcourt Road Dublin 2, Ireland Manufacturer ABF Pharmaceutical Services GmbH Brunnerstraße 63/18-19 1230 Vienna Austria This leaflet was last revised in 37 Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what tegsedi is and what it is used for', 'Section_Content': 'tegsedi contains the active substance inotersen. it is used to treat adults with hereditary transthyretin amyloidosis. hereditary transthyretin amyloidosis is a genetic disease, which causes build-up of small fibres of a protein called transthyretin in the organs of your body stopping them from working properly. tegsedi is used when the disease is causing symptoms of polyneuropathy (nerve damage). the active substance in tegsedi, inotersen, is a type of medicine called an antisense oligonucleotide inhibitor. it works by reducing production of transthyretin by the liver and so lowers the risk of fibres of transthyretin being deposited in body organs and causing symptoms.', 'Entity_Recognition': [{'Text': 'tegsedi', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'tegsedi', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 7}, {'Id': 3, 'BeginOffset': 81, 'EndOffset': 117, 'Score': 0.6060634255409241, 'Text': 'hereditary transthyretin amyloidosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.961622953414917}]}, {'Id': 4, 'BeginOffset': 119, 'EndOffset': 155, 'Score': 0.779940128326416, 'Text': 'hereditary transthyretin amyloidosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.930834174156189}]}, {'Text': 'a genetic disease', 'Type': 'PROBLEM', 'BeginOffset': 159, 'EndOffset': 176}, {'Text': 'small fibres', 'Type': 'PROBLEM', 'BeginOffset': 203, 'EndOffset': 215}, {'Text': 'tegsedi', 'Type': 'TREATMENT', 'BeginOffset': 314, 'EndOffset': 321}, {'Text': 'the disease', 'Type': 'PROBLEM', 'BeginOffset': 335, 'EndOffset': 346}, {'Text': 'symptoms', 'Type': 'PROBLEM', 'BeginOffset': 358, 'EndOffset': 366}, {'Text': 'polyneuropathy (nerve damage)', 'Type': 'PROBLEM', 'BeginOffset': 370, 'EndOffset': 399}, {'Text': 'an antisense oligonucleotide inhibitor', 'Type': 'TREATMENT', 'BeginOffset': 474, 'EndOffset': 512}, {'Id': 1, 'BeginOffset': 570, 'EndOffset': 575, 'Score': 0.7145779728889465, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'fibres of transthyretin', 'Type': 'PROBLEM', 'BeginOffset': 602, 'EndOffset': 625}, {'Id': 2, 'BeginOffset': 645, 'EndOffset': 649, 'Score': 0.4354117512702942, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'symptoms', 'Type': 'PROBLEM', 'BeginOffset': 669, 'EndOffset': 677}]}

{'Title': '2. what you need to know before you use tegsedi', 'Section_Content': 'do not use tegsedi if: - you are allergic to inotersen or any of the other ingredients of this medicine (listed in section 6). - tests show you have excessively low numbers of platelets, the cells in your blood which stick together helping it clot - tests of kidney function or protein in the urine show signs of severe kidney problems - you have severe reduction in liver function (hepatic impairment) warnings and precautions before you begin treatment with tegsedi, your doctor will measure your blood cells, liver function, kidney function, and protein levels in your urine. you will only be treated with tegsedi if these are all at acceptable levels and your doctor will repeat these checks regularly during treatment. thrombocytopenia tegsedi may reduce cells in the blood responsible for clotting of the blood (platelets), which may result in a condition called thrombocytopenia (see section 4). when you do not have enough platelets, like in thrombocytopenia, your blood may not clot quickly enough to stop bleeding. this can lead to bruising as well as other more serious problems such as excessive bleeding and internal bleeding. your doctor will check your blood for levels of platelets before treatment and regularly during treatment with tegsedi. if you stop taking tegsedi then your blood levels should be checked 8 weeks after discontinuation. if you are taking any medicines that can lower platelet count or stop blood from clotting, for example acetylsalicylic acid, clopidogrel, warfarin, heparin, rivoraxaban and dabigatran, you must tell your doctor before you use tegsedi. you should see your doctor immediately if you have unexplained bruising or a rash of small patches of red appearing on the skin (called petechiae), bleeding from skin cuts that does not stop or oozes, bleeding from the gums or nose, blood in urine or stools, bleeding in the whites of your eyes. call for immediate help if you have stiffness of the neck or an unusual and severe headache because these symptoms may be caused by bleeding in the brain. glomerulonephritis / kidney problems glomerulonephritis is a condition of your kidneys, where they do not work properly due to inflammation and kidney damage. some patients treated with inotersen have developed this condition. symptoms of glomerulonephritis are foaming urine, pink or brown coloured urine, blood in the urine, and passing less urine than usual. some patients treated with inotersen have also developed a decline in their kidney function without having had glomerulonephritis. your doctor will check your kidney function before treatment and regularly during treatment with tegsedi. if you stop taking tegsedi then your kidney function should be checked 8 weeks after discontinuation. if you develop glomerulonephritis, your doctor will treat you for this condition. if you are using any medicines that damage the kidney or affect kidney function, for example sulfonamides, aldosterone antagonists, and some types of painkillers, you should tell your doctor. vitamin a deficiency tegsedi can lower your body\'s levels of vitamin a (also called retinol). you doctor will measure these, and if they are already low, this should be corrected and any symptoms resolved before you start treatment with tegsedi. symptoms of low vitamin a include: dry eyes, poor vision, decrease in night vision, hazy or cloudy vision if you have problems with your sight or any other eye problems when you are using tegsedi, you should speak to your doctor. your doctor may refer you to an eye specialist for a check-up if it is necessary. your doctor will ask you to take a daily vitamin a supplement during treatment with tegsedi. both excess and deficient levels of vitamin a can harm the development of your unborn child. therefore women of child-bearing age should exclude any pregnancy, before treatment initiation with tegsedi and should practise effective contraception (see section "pregnancy and breast-feeding" below). if you are planning to become pregnant you should stop taking inotersen including vitamin a supplementation and ensure that your vitamin a levels have returned to normal before conception is attempted. if you have an unplanned pregnancy you should stop taking inotersen. due to the prolonged activity of tegsedi, however, your reduced vitamin a levels may persist. it is unknown if continuation of your 28 vitamin a supplementation with 3000 iu per day will be harmful to your unborn child in the first trimester of your pregnancy, but this dose should not be exceeded. you should resume the vitamin a supplementation during your second and third trimesters of your pregnancy if your vitamin a levels have not yet returned to normal, because of the increased risk of vitamin a deficiency in the third trimester. liver transplant rejection talk to your doctor before using tegsedi if you have previously received a liver transplant. cases of liver transplant rejection have been reported in patients being treated with tegsedi. your doctor will monitor you regularly for this during treatment with tegsedi. children and adolescents tegsedi should not be used in children and adolescents under 18 years old. other medicines and tegsedi tell your doctor or pharmacist if you are taking, have recently taken or might use any other medicines. it is important that you tell your doctor if you are already being treated with any of the following: - medicines to prevent blood clots or that lower the platelet numbers in your blood, e.g., acetylsalicylic acid, heparin, warfarin, clopidogrel, rivoraxaban and dabigatran. - any medicines that may alter your kidney function or may damage the kidneys, e.g., sulfonamides (used as an antibacterial), anilides (used to treat fever, aches and pains), aldosterone antagonists (used as a diuretic) and natural opium alkaloids and other opiods (used for treatment of pain). pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before using this medicine. women of child-bearing age tegsedi will reduce the level of vitamin a in your body, which is important for normal foetal development during pregnancy. it is unknown if vitamin a supplementation can compensate for the risk of vitamin a deficiency that might affect your unborn child (see "warnings and precautions" above). if you are a woman of child-bearing age, you should practise effective contraception and any pregnancy should be excluded before starting the treatment with tegsedi. pregnancy you should not use tegsedi if you are pregnant, unless explicitly advised by your doctor. if you are of child-bearing age and intend to use tegsedi, you should practise effective contraception. breast-feeding tegsedi may pass into breast milk. you should consult your doctor if you should either stop breast- feeding or stop the treatment with tegsedi. driving and using machines use of tegsedi has not been shown to affect ability to drive or use machinery.', 'Entity_Recognition': [{'Text': 'tegsedi', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 33, 'EndOffset': 41}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 90, 'EndOffset': 103}, {'Id': 45, 'BeginOffset': 129, 'EndOffset': 134, 'Score': 0.29919350147247314, 'Text': 'tests', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.306998074054718, 'RelationshipScore': 0.9999974966049194, 'RelationshipType': 'TEST_VALUE', 'Id': 46, 'BeginOffset': 149, 'EndOffset': 185, 'Text': 'excessively low numbers of platelets', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'excessively low numbers of platelets', 'Type': 'PROBLEM', 'BeginOffset': 149, 'EndOffset': 185}, {'Text': 'the cells', 'Type': 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{'Title': '3. how to use tegsedi', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. the recommended dose of tegsedi is one dose of 284 mg inotersen. doses should be administered once every week. all subsequent doses should be injected once weekly on the same day each week. route and method of administration tegsedi is for injection under the skin (subcutaneous use) only. instructions for use before using your pre-filled syringe, your doctor should show you or your caregiver how to use it the right way. if you or your caregiver have any questions, ask your doctor. read the instructions for use before you start using your pre-filled syringe and each time you get a repeat prescription. there may be new information. guide to parts each pre-filled syringe contains one dose and is for one-time use only. before use plunger finger grip safety spring (inside body) body needle cap needle inspection area after use after use, the safety spring is automatically activated and retracts the needle. warnings do not remove needle cap until you have reached step 6 of these instructions and are ready to inject tegsedi; do not share your syringe with another person or re-use your syringe; do not use if the pre-filled syringe is dropped onto a hard surface or is damaged; do not freeze the pre-filled syringe; if any of the above happens, throw away the pre-filled syringe in a puncture-resistant (sharps) container and use a new pre-filled syringe. preparation 1. gather supplies - 1 pre-filled syringe from the refrigerator - 1 alcohol wipe (not supplied) - 1 gauze pad or cotton ball (not supplied) - 1 puncture-resistant (sharps) container (not supplied) do not inject the medicine until you have gathered the supplies listed. 2. prepare to use your pre-filled syringe remove the plastic tray from the carton and check the expiry date. do not use if the expiry date has passed. let the pre-filled syringe reach room temperature (20 to 25 ) for 30 minutes before injecting it. do not warm the pre-filled syringe in any other way. for example, do not warm in a microwave or hot water, or near other heat sources. remove the pre-filled syringe from the tray by holding onto the syringe body. do not move the plunger. 3. check medicine in the pre-filled syringe look in the inspection area to check that the solution is clear and colourless or pale yellow. it is normal to see air bubbles in the solution. you do not need to do anything about it. do not use if the solution looks cloudy, discoloured, or has particles. if the solution looks cloudy, discoloured or has particles, throw the pre-filled syringe away in a puncture resistant (sharps) container, and use a new pre-filled syringe. 4. choose the injection site choose an injection site on your abdomen (belly) or the front of your thigh. the injection site may also be on the outer area of the upper arm if tegsedi is administered by a caregiver. do not inject into the 3cm area around the belly-button (navel). do not inject into the same site each time. do not inject where skin is bruised, tender, red or hard. do not inject into tattoos, scars or damaged skin. do not inject through clothing. 5. clean the injection site wash your hands with soap and water. clean the injection site with an alcohol wipe in a circular motion. let the skin air dry. do not touch the area again before injecting. injection 6. remove the needle cap hold the pre-filled syringe by the body, with the needle facing away from you. remove needle cap by pulling it straight off. do not twist it off. you may see a drop of liquid at the end of the needle. this is normal. keep your hands away from the plunger to avoid pushing the plunger before you are ready to inject. do not remove the needle cap until right before you inject. do not pull the cap off while holding the pre-filled syringe by the plunger. always hold by the body of the syringe. do not let the needle touch any surface. do not remove any air bubbles from the pre-filled syringe. do not put the needle cap back onto the pre-filled syringe. 7. insert the needle hold the pre-filled syringe in 1 hand. hold the skin around at the injection site as your healthcare provider has instructed you. you should either gently pinch the skin at the injection site or give the injection without pinching the skin. slowly insert the needle into the chosen injection site at a 90° angle until it is fully inserted. do not hold the pre-filled syringe by the plunger or push against the plunger to insert the needle. 8. start the injection slowly and firmly push the plunger all the way down until the medicine is injected. make sure the needle stays fully inserted in the injection site while you are injecting the medicine. it is important to push the plunger all the way down. your pre-filled syringe may make a click sound as you push the plunger down. this is normal. this does not mean that the injection is finished. the plunger can feel stiff towards the end of the injection. you may need to press a little harder on the plunger to make sure you have pushed it as far as it will go. do not let go of the plunger. 9. push the plunger down push firmly on the plunger at the end of the injection. hold the plunger fully down and wait for 5 seconds. if you let go of the plunger too quickly, you may lose some of the medicine. the plunger will start to lift automatically which means that the plunger has been pushed fully down. press down again if the plunger does not start to lift automatically. slowly and firmly push the plunger down hold the plunger fully down and wait 5 seconds wait 5 seconds 34 10. complete the injection slowly lift up on the plunger and let the safety spring push the plunger up automatically. the needle should now be retracted safely inside the pre-filled syringe, and the safety mechanism spring visible on the outside of the plunger. when the plunger comes to a stop, your injection is complete. if the plunger does not rise up automatically when you release the pressure, it means the safety spring did not activate and you should push the plunger again but harder. do not pull the plunger up by hand. lift the whole pre-filled syringe straight up. do not try to replace the cap on the retracted needle. do not rub the injection site. disposal and care dispose of the used pre-filled syringe put the used pre-filled syringe in a sharps disposal container right away after use. do not throw away the pre-filled syringe in your household waste. if you use more tegsedi than you should contact your doctor or pharmacist, or go to a hospital emergency department immediately, even if you have no symptoms. if you forget to use tegsedi if you miss your dose of tegsedi, then you should have your next dose as soon as possible, unless the next scheduled dose is within two days, in which case the missed dose should be skipped and the next dose given at the scheduled time. do not take a double dose to make up for a forgotten dose. lift thumb slowly back up 35 if you stop using tegsedi do not stop using tegsedi unless your doctor tells you to. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'tegsedi', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Id': 1, 'BeginOffset': 144, 'EndOffset': 151, 'Score': 0.20100992918014526, 'Text': 'tegsedi', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8456194996833801, 'RelationshipScore': 0.998497724533081, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 155, 'EndOffset': 163, 'Text': 'one dose', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8343023657798767, 'RelationshipScore': 0.9666866660118103, 'RelationshipType': 'DOSAGE', 'Id': 3, 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects if you get any of the following side effects, stop using tegsedi and contact your doctor immediately: - symptoms that could indicate glomerulonephritis, (where your kidneys do not work properly), such as foaming urine, pink or brown coloured urine, blood in the urine, or passing less urine than usual. - symptoms that could indicate thrombocytopenia (where blood will not clot), such as unexplained bruising or a rash of small patches of red appearing on the skin (called petechiae), bleeding from skin cuts that does not stop or oozes, bleeding from the gums or nose, blood in urine or stools, or bleeding in the whites of your eyes. call for immediate help if you have stiffness of the neck or an unusual and severe headache because these symptoms may be caused by bleeding in the brain. other side effects very common (may affect more than 1 in 10 people) - reduction in red blood cells which can make the skin pale and cause weakness or breathlessness (anaemia) - headache - vomiting, or nausea (feeling sick) - increase in body temperature - feeling cold (chills) or shivering - injection site pain, redness, itching or bruising - swelling of the ankles, feet or fingers (peripheral oedema) common (may affect up to 1 in 10 people) - an increase in the number of white blood cells called eosinophils in your blood (eosinophilia) - decreased appetite - feeling faint or dizzy, especially on standing up (low blood pressure, hypotension) - bruising - collection of blood within the tissues, that may look similar to severe bruising (haematoma) - itching - rash - kidney damage leading to poor kidney function or kidney failure - changes to your blood and urine test results (this may indicate infection or liver or kidney damage) - flu like symptoms, such as high temperature, aches and chills (influenza-like illness) - injection site swelling or skin discolouration 36 reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'tegsedi', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 21, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9671430587768555, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7467672228813171}]}, {'Text': 'serious side effects', 'Type': 'PROBLEM', 'BeginOffset': 92, 'EndOffset': 112}, {'Id': 23, 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'EndOffset': 2269, 'Score': 0.8547387719154358, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7192063927650452}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2325, 'EndOffset': 2338}]}

{'Title': '5. how to store tegsedi', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date, which is stated on the carton, tray and on the pre-filled syringe after "exp". the expiry date refers to the last day of that month. store in a refrigerator (2 - 8). do not freeze. tegsedi may be stored unrefrigerated for up to 6 weeks at a temperature below 30. if unrefrigerated and not used within 6 weeks then this medicine should be discarded. store in the original package in order to protect from light. do not use this medicine if you notice that the contents are cloudy or contains particles. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'tegsedi', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Id': 2, 'BeginOffset': 335, 'EndOffset': 336, 'Score': 0.40968847274780273, 'Text': '6', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_NAME', 'Score': 0.6113829612731934, 'RelationshipScore': 0.7178388237953186, 'RelationshipType': 'OVERLAP', 'Id': 0, 'BeginOffset': 348, 'EndOffset': 359, 'Text': 'temperature', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 0, 'BeginOffset': 348, 'EndOffset': 359, 'Score': 0.6113829612731934, 'Text': 'temperature', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 366, 'EndOffset': 369}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 408, 'EndOffset': 409}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 421, 'EndOffset': 434}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 529, 'EndOffset': 542}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 579, 'EndOffset': 585}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what tegsedi contains - the active substance is inotersen. - each pre-filled syringe contains 284mg of inotersen. - the other ingredients are water for injections, sodium hydroxide, and hydrochloric acid. what tegsedi looks like and contents of the pack tegsedi is a clear, colourless to pale yellow solution (ph 7.5 8.8) for injection (injection) in a pre-filled syringe. tegsedi is available in pack sizes of either 1 or 4 pre-filled syringes. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'tegsedi', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'each pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 61, 'EndOffset': 84}, {'Id': 1, 'BeginOffset': 103, 'EndOffset': 112, 'Score': 0.500626802444458, 'Text': 'inotersen', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9088595509529114, 'RelationshipScore': 0.9999918937683105, 'RelationshipType': 'DOSAGE', 'Id': 0, 'BeginOffset': 94, 'EndOffset': 99, 'Text': '284mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 152, 'EndOffset': 162}, {'Id': 2, 'BeginOffset': 164, 'EndOffset': 180, 'Score': 0.9979140162467957, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 186, 'EndOffset': 203, 'Score': 0.995196521282196, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ph', 'Type': 'TEST', 'BeginOffset': 310, 'EndOffset': 312}, {'Text': '7.5', 'Type': 'NUMBER', 'BeginOffset': 313, 'EndOffset': 316}, {'Text': '8.8', 'Type': 'NUMBER', 'BeginOffset': 317, 'EndOffset': 320}, {'Text': 'a pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 351, 'EndOffset': 371}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 418, 'EndOffset': 419}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 423, 'EndOffset': 424}]}

1A8CFDB034D73903CD7A466779FC69FD

https://www.ema.europa.eu/documents/product-information/xyrem-epar-product-information_en.pdf

Xyrem

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Xyrem 500 mg/mL oral solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of solution contains 500 mg of sodium oxybate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Oral solution. The oral solution is clear to slightly opalescent. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of narcolepsy with cataplexy in adult patients, adolescents and children from the age of 7 years. 4.2 Posology and method of administration Treatment should be initiated by and remain under the guidance of a physician experienced in the treatment of narcolepsy. Physicians should strictly adhere to the contraindications, warnings and precautions. Posology Adult The recommended starting dose is 4.5 g/day sodium oxybate divided into two equal doses of 2.25 g/dose. The dose should be titrated to effect based on efficacy and tolerability (see section 4.4) up to a maximum of 9 g/day divided into two equal doses of 4.5 g/dose by adjusting up or down in dose increments of 1.5 g/day (i.e. 0.75 g/dose). A minimum of one to two weeks is recommended between dose increments. The dose of 9 g/day should not be exceeded due to the possible occurrence of severe symptoms at doses of 18 g/day or above (see section 4.4). Single doses of 4.5 g should not be given unless the patient has been titrated previously to that dose level. If sodium oxybate and valproate are used concomitantly (see section 4.5), a decrease in sodium oxybate dose by 20% is recommended. The recommended starting dose for sodium oxybate, when used concomitantly with valproate, is 3.6 g per day administered orally in two equal divided doses of approximately 1.8 g. If concomitant use is warranted, patient response and tolerability should be monitored and dose should be adapted accordingly (see section 4.4). Discontinuation of Xyrem The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials (see section 4.4). If the patient stops taking the medicinal product for more than 14 consecutive days, titration should be restarted from the lowest dose. 3 Special populations Elderly Elderly patients should be monitored closely for impaired motor and/or cognitive function when taking sodium oxybate (see section 4.4). Hepatic impairment The starting dose should be halved in all patients with hepatic impairment, and response to dose increments monitored closely (see section 4.4 and 5.2). Renal impairment All patients with impaired renal function should consider a recommendation to reduce sodium intake (see section 4.4). Paediatric population Adolescents and children from 7 years of age with a minimum body weight of 15kg: Xyrem is administered orally twice nightly. Dosing recommendations are provided in Table 1. Table 1 Sodium Oxybate Recommended Dose Initiation and Titration for Paediatric Patients Patient weight Initial total daily dose (taken in 2 divided doses)* Titration regimen (to clinical effect) Recommended maximum total daily dose 15kg - <20kg ≤ 1g/day ≤ 0.5g/day/week 0.2g/kg/day 20kg - <30kg ≤ 2g/day ≤ 1g/day/week 30kg - <45kg ≤ 3g/day ≤ 1g/day/week ≥45kg ≤ 4.5g/day ≤ 1.5g/day/week 9g/day *At bedtime and 2.5 to 4 hours later. For children who sleep more than 8 hours per night, sodium oxybate may be given after bedtime, while the child is in bed, in two equally divided doses 2.5 to 4 hours apart. The dose should be gradually titrated to effect based on efficacy and tolerability (see section 4.4). A minimum of one to two weeks is recommended between dosage increments. Sodium oxybate dose recommendations (initial dose, titration regimen and maximum dose) for paediatric patients are based on body weight. Therefore, patients should have their body weight checked at regular intervals especially during titration to ensure that the appropriate dose of sodium oxybate is administered. The recommended maximum total daily dose is 0.2g/kg/day in paediatric patients weighing less than 45kg. For paediatric patients weighing 45kg or more the maximum total daily dose is 9g/day. If sodium oxybate and valproate are used concomitantly (see section 4.5), a decrease in sodium oxybate dose by 20% is recommended e.g. 4.8g/day instead of 6g/day. The safety and efficacy of sodium oxybate in children below 7 years of age has not been established and therefore sodium oxybate is not recommended below 7 years of age. Children below 15kg should not receive sodium oxybate. 4 Method of administration Xyrem should be taken orally upon getting into bed and again between 2.5 to 4 hours later. It is recommended that both doses of Xyrem should be made up at the same time upon retiring to bed. Xyrem is provided for use with a graduated measuring syringe and two 90 mL dosing cups with child resistant caps. Each measured dose of Xyrem must be dispensed into the dosing cup and diluted with 60 mL of water prior to ingestion. Because food significantly reduces the bioavailability of sodium oxybate, both adult and paediatric patients should eat at least several (2-3) hours before taking the first dose of Xyrem at bedtime. Adult and paediatric patients should always observe the same timing of dosing in relation to meals. Doses should be taken within 24 hours after preparation, or else discarded. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with major depression. Patients with succinic semialdehyde dehydrogenase deficiency. Patients being treated with opioids or barbiturates. 4.4 Special warnings and precautions for use Xyrem has the potential to induce respiratory depression Respiratory and CNS depression Sodium oxybate also has the potential to induce respiratory depression. Patients should be assessed before treatment for sleep apnoea and caution should be exercised when considering treatment. Apnoea and respiratory depression have been observed in a fasting healthy subject after a single intake of 4.5g (twice the recommended starting dose). During post-marketing surveillance, it has been observed that the use of sodium oxybate may predispose the patients to choking sensation during sleep. Patients should be questioned regarding signs of Central Nervous System (CNS) or respiratory depression. Special caution should be observed in patients with an underlying respiratory disorder. Patients should be monitored for signs of respiratory depression during treatment. Because of the higher risk of sleep apnoea, patients with a BMI ≥40 kg/m2 should be monitored closely when taking sodium oxybate. Approximately 80% of patients who received sodium oxybate during clinical trials maintained CNS stimulant use. Whether this affected respiration during the night is unknown. Before increasing the sodium oxybate dose (see section 4.2), prescribers should be aware that sleep apnoea occurs in up to 50% of patients with narcolepsy.  Benzodiazepines Given the possibility of increasing the risk of respiratory depression, the concomitant use of benzodiazepines and sodium oxybate should be avoided.  Alcohol and CNS depressants The combined use of alcohol, or any CNS -depressant medicinal product, with sodium oxybate may result in potentiation of the CNS-depressant effects of sodium oxybate as well as increased risk of respiratory depression. Therefore, patients should be warned against the use of alcohol in conjunction with sodium oxybate.  Gamma hydroxybutyrate (GHB) dehydrogenase inhibitors Caution is required in patients who are treated concomitantly with valproate or other GHB dehydrogenase inhibitors as pharmacokinetic and pharmacodynamic interactions have been 5 observed when sodium oxybate is co-administered with valproate (see section 4.5). If concomitant use is warranted, dose adjustment is to be considered (see section 4.2). Additionally, patient response and tolerability should be carefully monitored and dose should be adapted accordingly.  Topiramate There have been clinical observation(s) of coma and increased plasma GHB concentration after co-administration of sodium oxybate with topiramate. Therefore, patients should be warned against the use of topiramate in conjunction with sodium oxybate (section 4.5). Abuse potential and dependence Sodium oxybate, which is as the sodium salt of GHB, is a CNS depressant active substance with well- known abuse potential. Prior to treatment physicians should evaluate patients for a history of or susceptibility to drug abuse. Patients should be routinely monitored and in the case of suspected abuse, treatment with sodium oxybate should be discontinued. There have been case reports of dependence after illicit use of GHB at frequent repeated doses (18 to 250 g/day) in excess of the therapeutic dose range. Whilst there is no clear evidence of emergence of dependence in patients taking sodium oxybate at therapeutic doses, this possibility cannot be excluded. Patients with porphyria Sodium oxybate is considered to be unsafe in patients with porphyria because it has been shown to be porphyrogenic in animals or in vitro systems. Neuropsychiatric events Patients may become confused while being treated with sodium oxybate. If this occurs, they should be evaluated fully, and appropriate intervention considered on an individual basis. Other neuropsychiatric events include anxiety, psychosis, paranoia, hallucinations, and agitation. The emergence of thought disorders including thoughts of committing violent acts (including harming others) and/or behavioural abnormalities when patients are treated with sodium oxybate requires careful and immediate evaluation. The emergence of depression when patients are treated with sodium oxybate requires careful and immediate evaluation. Patients with a previous history of affective disorders (including depressive illness, anxiety and bipolar disorder), suicide attempt and psychosis should be monitored especially carefully for the emergence of depressive symptoms and/or suicidal ideation while taking sodium oxybate. Major depression is contraindicated for use with sodium oxybate.(see section 4.3). If a patient experiences urinary or faecal incontinence during sodium oxybate therapy, the prescriber should consider pursuing investigations to rule out underlying aetiologies. Sleepwalking has been reported in patients treated in clinical trials with sodium oxybate. It is unclear if some or all of these episodes correspond to true somnambulism (a parasomnia occurring during non-REM sleep) or to any other specific medical disorder. The risk of injury or self-harm should be borne in mind in any patient with sleepwalking. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered. Paediatric Population: Monitoring during titration phase The patient’s tolerability, especially with regards to potential signs of central nervous system and respiratory depression, should be carefully monitored with each dose increase during titration. Careful monitoring should include that the parent/caregivers observe the child’s breath after sodium oxybate intake to assess if there is any abnormality in breathing during the first two hours, for example rude breathing, sleep apnoea, cyanosis of lips/face. If abnormality in breathing is observed medical support 6 should be sought. If any abnormality is noted after the first dose, the second dose should not be administered. If no abnormality is noted the second dose can be administered. The second dose should not be given earlier than 2.5 hours or later than 4 hours after the first dose. In individual cases, e.g. if it is uncertain that the parent/caregivers can manage careful monitoring as described, sodium oxybate is not recommended unless medical supervision of treatment can be organized. If in doubt about administration of a dose, do not re-administer the dose to reduce the risk of overdose. Weight Loss Weight decrease is common amongst patients treated with sodium oxybate (see section 4.8). For paediatric patients it is important that their weight is checked at regular intervals especially during dose titration to ensure that the appropriate dose of sodium oxybate is being administered (see section 4.2). Neuropsychiatric events For children and adolescents extra care should be taken to assess any potential suicidal or depressive conditions before starting treatment with sodium oxybate (see section 4.8) and to monitor any treatment-emergent events. Alcohol and CNS depressants Given the risk of alcohol intake among adolescents, it is noted that alcohol may further increase the CNS and respiratory depressant effects of sodium oxybate in children – adolescents taking sodium oxybate (see section 4.5). Sodium intake Patients taking sodium oxybate will have an additional daily intake of 0.18g of sodium per 1 gram of sodium oxybate dose. A recommendation to reduce sodium intake should be carefully considered in the management of patients with heart failure, hypertension or compromised renal function (see section 4.2 and 4.9) Elderly There is very limited experience with sodium oxybate in the elderly. Therefore, elderly patients should be monitored closely for impaired motor and/or cognitive function when taking sodium oxybate. Epileptic patients Seizures have been observed in patients treated with sodium oxybate. In patients with epilepsy, the safety and efficacy of sodium oxybate has not been established, therefore use is not recommended. Rebound effects and withdrawal syndrome The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials. In some patients, cataplexy may return at a higher frequency on cessation of sodium oxybate therapy, however this may be due to the normal variability of the disease. Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, in rare cases, events such as insomnia, headache, anxiety, dizziness, sleep disorder, somnolence, hallucination, and psychotic disorders were observed after GHB discontinuation. Educational Materials In order to assist prescribers, and patients/caregivers about the important information for Xyrem educational materials will be provided to them. In particular the materials will reinforce that for paediatric patients, an initial assessment of the patient should be performed with regard to growth and learning ability and that in addition to any side effects, any behaviour changes (social and learning), should be reported to the child’s healthcare provider. 7 4.5 Interaction with other medicinal products and other forms of interaction The combined use of alcohol with sodium oxybate may result in potentiation of the central nervous system-depressant effects of sodium oxybate. Patients should be warned against the use of any alcoholic beverages in conjunction with sodium oxybate. Sodium oxybate should not be used in combination with sedative hypnotics or other CNS depressants. Sedative hypnotics Drug interaction studies in healthy adults with sodium oxybate (single dose of 2.25 g) and lorazepam (single dose of 2 mg) and zolpidem tartrate (single dose of 5 mg) demonstrated no pharmacokinetic interactions. Increased sleepiness was observed after concomitant administration of sodium oxybate (2.25 g) and lorazepam (2 mg). The pharmacodynamic interaction with zolpidem has not been assessed. When higher doses up to 9 g/d of sodium oxybate are combined with higher doses of hypnotics (within the recommended dose range) pharmacodynamic interactions associated with symptoms of CNS depression and/or respiratory depression cannot be excluded (see section 4.3). Tramadol A drug interaction study in healthy adults with sodium oxybate (single dose of 2.25 g) and tramadol (single dose of 100 mg) demonstrated no pharmacokinetic/pharmacodynamic interaction. When higher doses up to 9 g/day of sodium oxybate are combined with higher doses of opioids (within the recommended dose range) pharmacodynamic interactions associated with symptoms of CNS depression and/or respiratory depression cannot be excluded (see sections 4.3). Antidepressants Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate (single dose of 2.25 g) and the antidepressants protriptyline hydrochloride (single dose of 10 mg) and duloxetine (60 mg at steady state). No additional effect on sleepiness was observed when comparing single doses of sodium oxybate alone (2.25 g) and sodium oxybate (2.25 g) in combination with duloxetine (60 mg at steady state). Antidepressants have been used in the treatment of cataplexy. A possible additive effect of antidepressants and sodium oxybate cannot be excluded. The rate of adverse reactions has increased when sodium oxybate is co-administered with tricyclic antidepressants. Modafinil A drug interaction study in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate (single dose of 4.5 g) and modafinil (single dose of 200 mg). Sodium oxybate has been administered concomitantly with CNS stimulant agents in approximately 80% of patients in clinical studies in narcolepsy. Whether this affected respiration during the night is unknown. Omeprazole The co-administration of omeprazole has no clinically significant effect on the pharmacokinetics of sodium oxybate. The dose of sodium oxybate therefore does not require adjustment when given concomitantly with proton pump inhibitors. Ibuprofen Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate and ibuprofen. Diclofenac Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate and diclofenac. Co-administration of sodium oxybate and diclofenac in healthy volunteers reduced the attention deficit caused by the administration of sodium oxybate alone as measured by psychometric tests. 8 GHB dehydrogenase inhibitors Since sodium oxybate is metabolised by GHB dehydrogenase there is a potential risk of an interaction with medicinal products that stimulate or inhibit this enzyme (e.g. valproate, phenytoin or ethosuximide) (see section 4.4). The co-administration of sodium oxybate (6 g per day) with valproate (1250 mg per day) resulted in an increase in systemic exposure to sodium oxybate by approximately 25% and no significant change in Cmax. No effect on the pharmacokinetics of valproate was observed. The resulting pharmacodynamic effects, including increased impairment in cognitive function and sleepiness, were greater with co-administration than those observed with either drug alone. If concomitant use is warranted, patient response and tolerability should be monitored and dose adjustments made if required (see section 4.2). Topiramate Possible pharmacodynamic and pharmacokinetic interactions when sodium oxybate is used concomitantly with topiramate cannot be excluded as clinical observation(s) of coma, and increased plasma GHB concentration were reported in a patient(s) under concomitant use of sodium oxybate and topiramate (section 4.4). Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly inhibit the activities of the human isoenzymes (see section 5.2). 4.6 Fertility, pregnancy and lactation Pregnancy Animal studies have shown no evidence of teratogenicity but embryo lethality was seen in both rat and rabbit studies (see section 5.3). Data from a limited number of pregnant women exposed in the first trimester indicate a possible increased risk of spontaneous abortions. To date no other relevant epidemiological data are available. Limited data from pregnant patients during second and third trimester indicate no malformative or foeto/neonatal toxicity of sodium oxybate. Sodium oxybate is not recommended during pregnancy. Breast-feeding Sodium oxybate and/or its metabolites are excreted into breast milk. Changes in sleep patterns have been observed in breastfed infants from exposed mothers, which may be consistent with the effects of sodium oxybate on the nervous system. Sodium Oxybate should not be used during breastfeeding. Fertility There is no clinical data available on the effect of sodium oxybate on fertility. Studies in male and female rats at doses up to 1,000 mg/kg/day GHB have shown no evidence of an adverse effect on fertility. 4.7 Effects on ability to drive and use machines Sodium oxybate has major influence on the ability to drive and use machines. For at least 6 hours after taking sodium oxybate, patients must not undertake activities requiring complete mental alertness or motor co-ordination, such as operating machinery or driving. When patients first start taking sodium oxybate, until they know whether this medicinal product will still have some carryover effect on them the next day, they should use extreme care while driving a car, operating heavy machines, or performing any other task that could be dangerous or require full mental alertness. 9 For paediatric patients, physicians and parents or caregivers are advised that if the daily dose to body weight ratio exceeds 0.1g/kg/day, the waiting time may be longer than 6 hours depending on individual sensitivity. 4.8 Undesirable effects Summary of the safety profile Clinical Studies The safety profile was qualitatively the same in adult and paediatric studies. In adults the most commonly reported adverse reactions were dizziness, nausea, and headache, all occurring in 10% to 20% of patients. The most serious adverse reactions are suicidal attempt, psychosis, respiratory depression and convulsion. In adults the efficacy and safety of sodium oxybate for the treatment of narcolepsy symptoms was established in four multicentre, randomised, double-blind, placebo-controlled, parallel-group trials in patients with narcolepsy with cataplexy except for one trial where cataplexy was not required for enrolment. Two Phase 3 and one Phase 2 double-blind, parallel-group, placebo-controlled studies were performed to assess the indication of sodium oxybate for fibromyalgia in adults. Additionally, randomised, double-blind, placebo-controlled, crossover drug-drug interaction studies with ibuprofen, diclofenac and valproate were performed in healthy adult subjects and are summarised in section 4.5. Post-marketing experience In addition to the adverse reactions reported during clinical studies, adverse reactions have been reported in post-marketing experience. It is not always possible to reliably estimate the frequency of their incidence in the population to be treated. Tabulated summary of adverse reactions Undesirable effects are listed according to MedDRA System Organ Class. Frequency estimate: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Infections and infestations Common: nasopharyngitis, sinusitis Immune system disorders Uncommon: hypersensitivity Metabolism and nutrition disorders Common: anorexia, decreased appetite Not known: Dehydration, increased appetite Psychiatric disorders Common: depression, cataplexy, anxiety, abnormal dreams, confusional state, disorientation, nightmares, sleepwalking, sleep disorder, insomnia, middle insomnia, nervousness Uncommon: suicide attempt, psychosis, paranoia, hallucination, abnormal thinking, agitation, initial insomnia Not known: suicidal ideation, homicidal ideation, aggression, euphoric mood, sleep-related eating disorder, panic attack, mania / bipolar disorder, delusion, bruxism, irritability and increased libido 10 Nervous system disorders Very common: dizziness, headache Common: sleep paralysis, somnolence, tremor, balance disorder, disturbance in attention, hypoaesthesia, paraesthesia, sedation, dysgeusia Uncommon: myoclonus, amnesia, restless legs syndrome Not known: convulsion, loss of consciousness, dyskinesia Eye disorders Common: blurred vision Ear and labyrinth disorders Common: vertigo Not known tinnitus Cardiac disorders Common: palpitations Vascular disorders Common: hypertension Respiratory, thoracic and mediastinal disorders Common: dyspnoea, snoring, nasal congestion Not known: respiratory depression, sleep apnoea, choking sensation Gastrointestinal disorders Very common: nausea (the frequency of nausea is higher in women than men) Common: vomiting, diarrhoea, abdominal pain upper, Uncommon: faecal incontinence Not known: dry mouth Skin and subcutaneous tissue disorders Common: hyperhidrosis, rash Not known: urticaria, angioedema, seborrhea Musculoskeletal and connective tissue disorders Common: arthralgia, muscle, spasms, back pain Renal and urinary disorders Common: enuresis nocturna, urinary incontinence Not known: pollakiuria / micturition urgency, nocturia General disorders and administration site conditions Common: asthenia, fatigue, feeling drunk, oedema peripheral Investigations Common: blood pressure increased, weight decreased Injury, poisoning and procedural complications Common: fall Description of selected adverse reactions In some patients, cataplexy may return at a higher frequency on cessation of sodium oxybate therapy, however this may be due to the normal variability of the disease. Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, in rare cases, adverse reactions such as insomnia, headache, 11 anxiety, dizziness, sleep disorder, somnolence, hallucination, and psychotic disorders were observed after GHB discontinuation. Special Populations Paediatric population In the paediatric population the efficacy and safety of sodium oxybate for the treatment of narcolepsy with cataplexy symptoms was established in a phase 2/3 double-blind, placebo-controlled, randomized-withdrawal multicenter study. In a study in children and adolescents the most frequently reported related TEAEs were enuresis (18.3%), nausea (12.5%), vomiting (8.7%), and weight decreased (8.7%), decreased appetite (6.7%), headache (5.8%), dizziness (5.8%). Adverse drug reactions of suicidal ideation (1%) and of acute psychosis (1%) were also reported. (see section 4.4 and section 6). In some children between 7 and < 18 years, postmarketing surveillance has shown that sodium oxybate was discontinued due to abnormal behaviour, aggression and mood alteration. Reporting of suspected adverse reactions Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Information about signs and symptoms associated with overdose with sodium oxybate is limited. Most data derives from the illicit use of GHB. Sodium oxybate is the sodium salt of GHB. Events associated with withdrawal syndrome have been observed outside the therapeutic range. Symptoms Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even with impaired consciousness), diaphoresis, headache, and impaired psychomotor skills may be observed. Blurred vision has been reported. An increasing depth of coma has been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. There are reports of compromise in the rate and depth of respiration and of life-threatening respiratory depression, necessitating intubation and ventilation. Cheyne-Stokes respiration and apnoea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact. Bradycardia has been responsive to atropine intravenous administration. Events of hypernatremia with metabolic alkalosis have been reported in the context of concomitant use of NaCl infusion. Management Gastric lavage may be considered if co-ingestants are suspected. Because emesis may occur in the presence of impaired consciousness, appropriate posture (left lateral recumbent position) and protection of the airway by intubation may be warranted. Although gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and rapid sequence induction (without the use of sedative) should be considered. No reversal of the central depressant effects of sodium oxybate can be expected from flumazenil administration. There is insufficient evidence to recommend the use of naloxone in the treatment of overdose with GHB. The use of haemodialysis and other forms of extracorporeal medicinal product removal have not been studied in sodium oxybate overdose. However, due to the rapid metabolism of sodium oxybate, these measures are not warranted. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 12 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX04. Mechanism of action Sodium oxybate is a central nervous system depressant which reduces excessive daytime sleepiness and cataplexy in patients with narcolepsy and modifies sleep architecture reducing fragmented nighttime sleep. The precise mechanism by which sodium oxybate produces an effect is unknown, however sodium oxybate is thought to act by promoting slow (delta) wave sleep and consolidating night-time sleep. Sodium oxybate administered before nocturnal sleep increases Stages 3 and 4 sleep and increases sleep latency, whilst reducing the frequency of sleep onset REM periods (SOREMPs). Other mechanisms, which have yet to be elucidated, may also be involved. In the clinical trial database, greater than 80 % of patients maintained concomitant stimulant use. Adults The effectiveness of sodium oxybate for the treatment of narcolepsy symptoms was established in four multicentre, randomised, double-blind, placebo-controlled, parallel-group trials (Trial 1, 2, 3 and 4) in patients with narcolepsy with cataplexy except for trial 2 where cataplexy was not required for enrolment Concomitant stimulant use was permitted in all trials (except for the active-treatment phase of Trial 2); antidepressants were withdrawn prior to active treatment in all trials with the exception of Trial 2. In each trial, the daily dose was divided into two equal doses. The first dose each night was taken at bedtime and the second dose was taken 2.5 to 4 hours later. Table 2 Summary of clinical trials performed using sodium oxybate for the treatment of narcolepsy Trial Primary Efficacy N Secondary Efficacy Duration Active treatment and Dose (g/d) Trial 1 EDS (ESS); CGIc 246 MWT/Sleep Architecture/ Cataplexy/Naps/FOSQ 8 weeks Sodium oxybate4.5 - 9 Trial 2 EDS (MWT) 231 Sleep Architecture/ ESS/CGIc/Naps 8 weeks Sodium oxybate 6 – 9 Modafinil 200-600 mg Trial 3 Cataplexy 136 EDS (ESS)/CGIc/Naps 4 weeks Sodium oxybate 3 - 9 Trial 4 Cataplexy 55 None 4 weeks Sodium oxybate 3 - 9 EDS – Excessive daytime sleepiness; ESS – Epworth Sleepiness Scale; MWT – Maintenance of Wakefulness Test; Naps – Number of inadvertent daytime naps; CGIc – Clinical Global Impression of Change; FOSQ – Functional Outcomes of Sleep Questionnaire 13 Trial 1 enrolled 246 patients with narcolepsy and incorporated a 1 week up-titration period. The primary measures of efficacy were changes in excessive daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS), and the change in the overall severity of the patient’s narcolepsy symptoms as assessed by the investigator using the Clinical Global Impressions of Change (CGI-c) measure. Table 3 Summary of ESS in Trial 1 Epworth Sleepiness Scale (ESS; range 0-24) Dose Group [g/d (n)] Baseline Endpoint Median Change from Baseline Change from Baseline Compared to Placebo (p-value) Placebo (60) 17.3 16.7 -0.5 - 4.5 (68) 17.5 15.7 -1.0 0.119 6 (63) 17.9 15.3 -2.0 0.001 9 (55) 17.9 13.1 -2.0 < 0.001 Table 4 Summary of CGI-c in Trial 1 Clinical Global Impressions of Change (CGI-c) Dose Group [g/d (n)] Responders* N (%) Change from Baseline Compared to Placebo (p-value) Placebo (60) 13 (21.7) - 4.5 (68) 32 (47.1) 0.002 6 (63) 30 (47.6) < 0.001 9 (55) 30 (54.4) < 0.001 * The CGI-c data were analysed by defining responders as those patients who were very much improved or much improved. Trial 2 compared the effects of orally administered sodium oxybate, modafinil and sodium oxybate + modafinil, with placebo in the treatment of daytime sleepiness in narcolepsy. During the 8 week double-blind period, patients took modafinil at their established dose or placebo equivalent. The sodium oxybate or placebo equivalent dose was 6 g/day for the first 4 weeks and was increased to 9 g/day for the remaining 4 weeks. The primary measure of efficacy was excessive daytime sleepiness as measured by objective response in MWT. Table 5 Summary of MWT in Trial 2 TRIAL 2 Dose Group Baseline Endpoint Mean Change from Baseline Endpoint Compared to Placebo Placebo (56) 9.9 6.9 -2.7 - Sodium Oxybate (55) 11.5 11.3 0.16 <0.001 Modafinil (63) 10.5 9.8 -0.6 0.004 Sodium Oxybate + Modafinil (57) 10.4 12.7 2.3 <0.001 Trial 3 enrolled 136 narcoleptic patients with moderate to severe cataplexy (median of 21 cataplexy attacks per week) at baseline. The primary efficacy measure in this trial was the frequency of cataplexy attacks. 14 Table 6 Summary of outcomes in Trial 3 Dosage Number of Subjects Cataplexy Attacks Trial 3 Baseline Median Change from Baseline Change from Baseline Compared to Placebo (p-value) Median attacks/week Placebo 33 20.5 -4 - 3.0 g/day 33 20.0 -7 0.5235 6.0 g/day 31 23.0 -10 0.0529 9.0 g/day 33 23.5 -16 0.0008 Trial 4 enrolled 55 narcoleptic patients who had been taking open-label sodium oxybate for 7 to 44 months. Patients were randomised to continued treatment with sodium oxybate at their stable dose or to placebo. Trial 4 was designed specifically to evaluate the continued efficacy of sodium oxybate after long-term use. The primary efficacy measure in this trial was the frequency of cataplexy attacks. Table 7 Summary of outcome in Trial 4 Treatment Group Number of Subjects Cataplexy Attacks Trial 4 Baseline Median Change from Baseline Change from Baseline Compared to Placebo (p-value) Median attacks/two weeks Placebo 29 4.0 21.0 - Sodium oxybate 26 1.9 0 p <0.001 In Trial 4, the response was numerically similar for patients treated with doses of 6 to 9 g/day, but there was no effect seen in patients treated with doses less than 6 g/day. Paediatric population The effectiveness of sodium oxybate in paediatric patients with narcolepsy with cataplexy, was established in a double-blind, placebo-controlled, randomized-withdrawal, multicentre trial. This study demonstrated the clinical efficacy of sodium oxybate in the treatment of cataplexy and Excess Daytime Sleepiness (EDS) in narcolepsy in pediatric subjects. 63 patients were randomized in the efficacy population where the primary efficacy endpoint in this trial was the change in number of weekly cataplexy attacks between the last two weeks of the stable dose period and the double-blind period. During the double-blind period, the median (Q1, Q3) change from baseline (i.e. the last 2 weeks of the stable dose period) in the weekly number of cataplexy attacks was 12.71 (3.44, 19.77) for patients randomized to placebo and 0.27 (-1.00, 2.50) for patients randomized to sodium oxybate. 15 Table 8 Summary of outcome in study 13-005 in children / adolescents Treatment Group Number of Patients Weekly Number of Cataplexy Attacks (median) Baseline (i.e. Last 2 weeks of stable dose period) Double-blind period Change from Baseline Placebo 32 4.67 21.25 12.71 Sodium oxybate 31 3.50 3.77 0.27 p-value < 0.0001 When subgroup analyses by age group (7-11 years and 12-17 years) were conducted for the primary endpoint, similar results were observed. During the Double-blind Treatment Period, among subjects aged 7 to 11 years, the median (Q1, Q3) change from baseline in the weekly number of cataplexy attacks was 18.32 (7.58, 35.75) for subjects randomized to Placebo and 0.13 (-1.15, 2.05) for subjects randomized to sodium oxybate (p < 0.0001). During the Double-blind Treatment Period, among subjects aged 12 to 17 years, the median (Q1, Q3) change from baseline in the weekly number of cataplexy attacks was 9.39 (1.08, 16.12) for subjects randomized to Placebo and 0.58 (-0.88, 2.58) for subjects randomized to sodium oxybate (p = 0.0044) During the Double-blind Treatment Period, the median (Q1, Q3) change of the secondary endpoint (change in ESS scores) from baseline (which occurred at Visit 3 – the end of the Stable Dose Period) in Epworth Sleepiness Scale for Children and Adolescent (ESS-CHAD) score was 3.0 (1.0, 5.0) for subjects randomized to Placebo and 0.0 (-1.0, 2.0) for subjects randomized to sodium oxybate. The comparison of the rank change from baseline between treatments was statistically significant (p = 0.0004) when analyzed by ANCOVA modeling containing treatment as a factor and rank baseline value as a covariate. Subjects randomized to Placebo had, on average, higher ESS (CHAD) scores at baseline compared to those on sodium oxybate. Table 9 Summary of ESS (CHAD) Score during the Double-blind Treatment Period (Efficacy Population) Treatment Group Number of Patients Change in ESS (CHAD) Score (median) Baseline (Visit 3-End of Stable Dose Period) End of Double- blind Treatment Period (Visit 4) Change from Baseline Placebo 32 11.0 12.0 3.0 Sodium oxybate 31 8.0 9.0 0.0 p-value 0.0004 Abbreviations: ESS (CHAD) = Epworth Sleepiness Scale for Children and Adolescents 5.2 Pharmacokinetic properties Sodium oxybate is rapidly and almost completely absorbed after oral administration; absorption is delayed and decreased by a high fat meal. It is eliminated mainly by metabolism with a half-life of 0.5 to 1 hour. Pharmacokinetics is nonlinear with the area under the plasma concentration curve (AUC) versus time curve increasing 3.8-fold as dose is doubled from 4.5 g to 9 g. The pharmacokinetics is not altered with repeat dosing. 16 Absorption Sodium oxybate is absorbed rapidly following oral administration with an absolute bioavailability of about 88 %. The average peak plasma concentrations (1st and 2nd peak) following administration of a 9 g daily dose divided into two equivalent doses given four hours apart were 78 and 142 µg/mL, respectively. The average time to peak plasma concentration (Tmax) ranged from 0.5 to 2 hours in eight pharmacokinetic studies. Following oral administration, the plasma levels of sodium oxybate increase more than proportionally with increasing dose. Single doses greater than 4.5 g have not been studied. Administration of sodium oxybate immediately after a high fat meal resulted in delayed absorption (average Tmax increased from 0.75 hr to 2.0 hr) and a reduction in peak plasma level (Cmax) by a mean of 58 and of systemic exposure (AUC) by 37 Distribution Sodium oxybate is a hydrophilic compound with an apparent volume of distribution averaging 190- 384 mL/kg. At sodium oxybate concentrations ranging from 3 to 300 µg/mL, less than 1% is bound to plasma proteins. Biotransformation Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by - oxidation. The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, that catalyses the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is metabolised to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyses the conversion to succinic semialdehyde in the presence of -ketoglutarate. An alternate pathway of biotransformation involves -oxidation via 3,4-dihydroxybutyrate to Acetyl CoA, which also enters the citric acid cycle to result in the formation of carbon dioxide and water. No active metabolites have been identified. Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly inhibit the activities of the human isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A up to the concentration of 3 mM (378 µg/mL). These levels are considerably higher than levels achieved with therapeutic doses. Elimination The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged medicinal product appears in human urine within 6 to 8 hours after dosing. Faecal excretion is negligible. Special populations Elderly In a limited number of patients greater than the age of 65 years the pharmacokinetics of sodium oxybate was not different compared to patients younger than 65 years of age. Paediatric population The major pharmacokinetic characteristics of sodium oxybate in paediatric subjects are the same as those reported in pharmacokinetic studies of sodium oxybate in adults Paediatric and adult subjects receiving the same mg/kg dose have similar plasma concentration-time profiles. (see section 4.2) Renal impairment Because the kidney does not have a significant role in the excretion of sodium oxybate, no pharmacokinetic study in patients with renal dysfunction has been conducted; no effect of renal function on sodium oxybate pharmacokinetics would be expected. 17 Hepatic impairment Sodium oxybate undergoes significant presystemic (hepatic first-pass) metabolism. After a single oral dose of 25 mg/kg, AUC values were double in cirrhotic patients, with apparent oral clearance reduced from 9.1 in healthy adults to 4.5 and 4.1 mL/min/kg in Class A (without ascites) and Class C (with ascites) patients, respectively. Elimination half-life was significantly longer in Class C and Class A patients than in control subjects (mean t1/2 of 59 and 32 versus 22 minutes). The starting dose should be halved in all patients with hepatic impairment, and response to dose increments monitored closely (see section 4.2). Race The effect of race on metabolism of sodium oxybate has not been evaluated. 5.3 Preclinical safety data Repeat administration of sodium oxybate to rats (90 days and 26 weeks) and dogs (52 weeks) did not result in any significant findings in clinical chemistry and micro- and macro pathology. Treatment- related clinical signs were mainly related to sedation, reduced food consumption and secondary changes in body weight, body weight gain and organ weights. The rat and dog exposures at the NOEL were lower (~50%) than that in humans. Sodium oxybate was non-mutagenic and non-clastogenic in in vitro and in vivo assays. Gamma Butyrolactone (GBL), a pro-drug of GHB tested at exposures similar to the expected in man (1.21-1.64 times) has been classified by NTP as non-carcinogenic in rats and equivocal carcinogen in mice, due to slight increase of pheochromocytomas which was difficult to interpret due to high mortality in the high dose group. In a rat carcinogenicity study with oxybate no compound-related tumours were identified. GHB had no effect on mating, general fertility or sperm parameters and did not produce embryo- foetal toxicity in rats exposed to up 1000 mg/kg/day GHB (1.64 times the human exposure calculated in nonpregnant animals). Perinatal mortality was increased and mean pup weight was decreased during the lactation period in high-dose F1 animals. The association of these developmental effects with maternal toxicity could not be established. In rabbits, slight foetotoxicity was observed. In a 10-week repeat dose toxicity study conducted in juvenile rats treated from postnatal day 21 to 90, sodium oxybate produced adverse effects including mortalities during the first week of treatment, when animals were 21 to 27 days old, corresponding to an approximate age of 3-4 years in children. Acute toxicity appeared at exposures below those expected in paediatric patients and mortality was preceded by sodium oxybate-related clinical signs (bradypnea, deep breathing, decreased activity, uncoordinated gait, impaired righting reflex), in line with its expected pharmacology. The reason for this relatively stronger toxicity during the first week of treatment is not fully clear. It could be related to the fact that young animals appear to exhibit higher systemic exposure than older juvenile rats. It could also be due to higher sensitivity of pups to sodium oxybate compared to older juvenile and adult rats and/or to a tolerance development phenomenon. Reduced body weight and food consumption similarly as in adults were also observed, with additional respiratory signs (deep and slow breathing). Sodium oxybate did not produce adverse effects on growth and development up to exposure levels 2- to 4-fold higher than the exposure expected at the maximum recommended dose in paediatric subjects (200mg/kg/day in paediatric patients with body weight less than 45kg or 9g/day for paediatric patients with body weight ≥45kg). Drug discrimination studies show that GHB produces a unique discriminative stimulus that in some respects is similar to that of alcohol, morphine and certain GABA-mimetic medicinal products. Self- administration studies in rats, mice and monkeys have produced conflicting results, whereas tolerance to GHB as well as cross-tolerance to alcohol and baclofen has been clearly demonstrated in rodents. 18 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Purified water Malic acid for pH adjustment Sodium hydroxide for pH adjustment 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 5 years After first opening: 90 days After dilution in the dosing cups, the preparation should be used within 24 hours. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. For storage conditions after first opening of the medicinal product, see section 6.3 For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container and special equipment for use 180 mL solution in an amber oval 240 mL PET bottle which is delivered with a plastic/foil seal and closed with a child resistant closure composed of HDPE/polypropylene with a pulpboard inner liner. Each carton contains one bottle, a press-in bottle adaptor, a graduated measuring device (polypropylene syringe), two polypropylene dosing cups and two HDPE child resistant screw closures. 6.6 Special precautions for disposal No special requirements 7. MARKETING AUTHORISATION HOLDER UCB Pharma SA Allée de la Recherche 60 B-1070 Brussels Belgium 8. MARKETING AUTHORISATION NUMBER EU/1/05/312/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION Date for first authorisation: 13 October 2005 19 Date of latest renewal: 08 September 2015 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/ 20 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 21 A MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release UCB Pharma Ltd or UCB Pharma S.A., 208 Bath Road, Chemin du Foriest, Slough, B-1420 Braine l'Alleud, Berkshire SL1 3WE, Belgium United Kingdom The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to special and restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). C OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.  Additional risk minimisation measures The Marketing Authorisation Holder (MAH) shall develop an educational programme for Xyrem to ensure that physicians who intend to prescribe Xyrem are aware about the posology of Xyrem and the important risks. The five components of this comprehensive program are:  Healthcare Professional Checklist (i.e. forms for treatment initiation and follow-up visits) : to remind physicians to check the following: 22 a. contraindications, warnings, and precautions in the SmPC and specifically highlighting that Xyrem can cause CNS and respiratory depression, that alcohol may result in the potentiation of CNS depression and that Xyrem has an abuse potential. b. For pediatric patients: height, weight, learning, social and psychiatric behaviour  Frequently Asked Questions (FAQ) for patients (to be given to the patient): to provide patients with responses to some questions they might have about taking Xyrem.  Patient instructions for administration of sodium oxybate (to be given to the patient): to provide patients with information related to the use of Xyrem.  Xyrem guide for pediatric patients and their caregivers to provide information about the safe use and handling of sodium oxybate.  Patient Alert Card (to be given to the patient): to remind patients, caregivers, and physicians of the important safety information related to the use of Xyrem. The MAH has established a controlled distribution program that enhances existing controls for Xyrem to allow reaching the intended population of narcolepsy patients while minimizing the risk of Xyrem being diverted by those seeking to misuse it. 23 ANNEX III LABELLING AND PACKAGE LEAFLET 24 A. LABELLING 25 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE OUTER PACKAGING Carton and bottle 1. NAME OF THE MEDICINAL PRODUCT Xyrem 500 mg/mL oral solution Sodium oxybate 2. STATEMENT OF ACTIVE SUBSTANCE Each mL of solution contains 500 mg sodium oxybate 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS One bottle of 180 mL oral solution 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS The medicinal product should be used within 90 days after the first opening. After dilution in the dosing cups the preparation should be used within 24 hours. 26 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER UCB Pharma SA Allée de la Recherche 60 B-1070 Brussels Belgium 12. MARKETING AUTHORISATION NUMBER EU/1/05/312/001 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Xyrem 500 mg/mL (applies to carton only) 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 27 B. PACKAGE LEAFLET 28 Package leaflet: Information for the user Xyrem 500 mg/mL oral solution Sodium oxybate Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or your pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What Xyrem is and what it is used for 2. What you need to know before you take Xyrem 3. How to take Xyrem 4. Possible side effects 5 How to store Xyrem 6. Contents of the pack and other information 1. What Xyrem is and what it is used for Xyrem contains the active substance sodium oxybate. Xyrem works by consolidating night-time sleep, though its exact mechanism of action is unknown. Xyrem is used to treat narcolepsy with cataplexy in adults, adolescents and children from 7 years of age. Narcolepsy is a sleep disorder that may include attacks of sleep during normal waking hours, as well as cataplexy, sleep paralysis, hallucinations and poor sleep. Cataplexy is the onset of sudden muscle weakness or paralysis without losing consciousness, in response to a sudden emotional reaction such as anger, fear, joy, laughter or surprise. 2. What you need to know before you take Xyrem Do not take Xyrem - if you are allergic to sodium oxybate or any of the other ingredients of this medicine (listed in section 6); - if you have succinic semialdehyde dehydrogenase deficiency (a rare metabolic disorder); - if you suffer from major depression; - if you are being treated with opioid or barbiturate medicines. Warnings and precautions Talk to your doctor or pharmacist before taking Xyrem: - if you have breathing or lung problems (and especially if you are obese), because Xyrem has the potential to cause difficulty in breathing; - if you have or have previously had depressive illness, suicidal thoughts, anxiety, psychosis (a mental disorder that may involve hallucinations, incoherent speech, or disorganized and agitated behaviour) or bipolar disorder - if you have heart failure, hypertension (high blood pressure), liver or kidney problems as your dose may need to be adjusted; 29 - if you have previously abused drugs; - if you suffer from epilepsy as the use of Xyrem is not recommended in this condition; - if you have porphyria (an uncommon metabolic disorder). If any of these apply to you, tell your doctor before you take Xyrem. While you are taking Xyrem, if you experience bed wetting and incontinence (both urine and faeces), confusion, hallucinations, episodes of sleepwalking or abnormal thinking you should tell your doctor straight away. Whilst these effects are uncommon, if they do occur they are usually mild-to-moderate in nature. If you are elderly, your doctor will monitor your condition carefully to check whether Xyrem is having the desired effects. Xyrem has a well-known abuse potential. Cases of dependency have occurred after the illicit use of sodium oxybate. Your doctor will ask if you have ever abused any drugs before you start taking Xyrem and whilst you are using the medicine. Children and adolescents Xyrem can be taken by adolescents and children from 7 years of age when they are over 15 kg in weight. Xyrem cannot be taken by children below 7 years of age or below 15 kg in weight. If you are a child or adolescent, your doctor will monitor your body weight regularly. Whilst the doctor is adjusting the dose which may take a number of weeks, parent/caregivers should carefully monitor the child’s breath during the first 2 hours after sodium oxybate intake to assess if there is any abnormality in breathing, for example stoppage of breathing for short periods while sleeping, noisy breathing and bluish colour of the lips and face. If abnormality in breathing is observed medical support should be sought and the doctor should be informed as soon as possible. If any abnormality is noted after the first dose, the second dose should not be administered. If no abnormality is noted the second dose can be administered. The second dose should not be given earlier than 2.5 hours or later than 4 hours after the first dose. If you have had or are having upsetting feelings particularly if you are feeling very sad or have lost interest in life it is important that you tell the doctor or caregiver. Other medicines and Xyrem Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. In particular Xyrem should not be taken together with sleep inducing medicines and medicines that reduce central nervous system activity (the central nervous system is the part of the body related to the brain and spinal cord). Also tell your doctor or pharmacist if you are taking any of the following types of medicines:  medicines that increase central nervous system activity  antidepressants  medicines that may be processed in a similar way by the body (e.g., valproate, phenytoin or ethosuximide which are used for the treatment of fits)  topiramate (used for treatment of epilepsy) 30 If you are taking Valproate, your daily dose of Xyrem will need to be adjusted (see section 3) as it may lead to interactions with Valproate Xyrem with alcohol You must not drink alcohol while taking Xyrem, as its effects can be increased. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. There have been very few women who have taken Xyrem sometime during their pregnancy and a few of them had spontaneous abortions. The risk of taking Xyrem during pregnancy is unknown, and, therefore, the use of Xyrem in pregnant women or women trying to become pregnant is not recommended. Patients taking Xyrem should not breast feed since it is known that Xyrem passes into breast milk. Changes in sleep patterns have been observed in breastfed infants from exposed mothers. Driving and using machines Xyrem will affect you if you drive or operate tools or machines. Do not drive a car, operate heavy machinery, or perform any activity that is dangerous or that requires mental alertness for at least 6 hours after taking Xyrem. When you first start taking Xyrem, until you know whether it makes you sleepy the next day, use extreme care while driving a car, operating heavy machinery or doing anything else that could be dangerous or needs you to be fully mentally alert. For paediatric patients, physicians, parents or caregivers are advised that the waiting time for performing activities that require mental alertness, motor co-ordination or any activities that may have a physical risk may have to be longer than 6 hours, depending on individual sensitivity. Xyrem contains sodium You need to monitor the amount of salt you take as Xyrem contains sodium (which is found in table salt) which may affect you if you have had high blood pressure, heart or kidney problems in the past.. In every 1 g dose of sodium oxybate (Xyrem), there is 0.18 g of sodium. You may need to moderate your intake of salt. 3. How to take Xyrem Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. It is important that you only use the syringe provided in the box when preparing doses of Xyrem. The Xyrem syringe has two different measurement scales, one scale may be more helpful for you than the other depending on which dose your doctor has prescribed. By looking at each scale you will see which one provides the exact mark for your dose. Adults – taking Xyrem on its own  For adults the recommended starting dose is 4.5 g each day, given as two seperate doses of 2.25 g.  Your doctor may gradually increase your dose up to a maximum of 9 g each day given as two separate doses of 4.5 g.  Take Xyrem orally two times each night: - Take the first dose upon getting into bed and the second dose 2½ to 4 hours later. You may need to set an alarm clock to make sure you wake up to take the second dose. - Food decreases the amount of Xyrem that is absorbed by your body. Therefore, it is best to take Xyrem at set times 2 to 3 hours after a meal. 31 - Prepare both doses before bedtime. - Take doses within 24 hours after preparation. Adolescents and children aged 7 years and over who weigh 15 kg or more - taking Xyrem on its own For those aged 7 years and over who weigh 15 kg or more, a doctor will work out the right dose based on your body weight. Your doctor will work out the right dose for you. Do not exceed the dose prescribed for you. Adults - taking Xyrem with Valproate If you are taking valproate together with Xyrem, the dose of Xyrem will be adapted by your doctor.  For adults the recommended starting dose for Xyrem, when used together with Valproate, is 3.6 g each day, given as two separate doses of 1.8 g.  Take the first dose when getting into bed and the second dose 2½ to 4 hours later. Adolescents and children aged 7 years and older who weigh 15 kg or more - taking Xyrem with Valproate If you are taking Valproate together with Xyrem, the dose of Xyrem will be adapted by your doctor. Kidney or liver problems  If you have kidney problems, you should consider a dietary recommendation to reduce sodium (salt) intake.If you have liver problems, the starting dose should be halved. Your doctor may gradually increase your dose. Instructions on how to dilute Xyrem The following instructions explain how to prepare Xyrem. Please read the instructions carefully and follow them step by step. Do not allow children to prepare Xyrem. To help you, the Xyrem carton contains 1 bottle of medicine, a measuring syringe (with two different measurement scales) and two dosing cups with child-resistant caps. Step 1  Remove the bottle cap by pushing down while turning the cap anticlockwise (to the left).  After removing the cap, set the bottle upright on a table-top.  There is a plastic covered foil seal on the top of the bottle, which must be removed before using the bottle for the first time.  While holding the bottle in its upright position, insert the press-in-bottle- adaptor into the neck of the bottle. This needs only to be done the first time that the bottle is opened. The adaptor can then be left in the bottle for all subsequent uses 32 Step 2  Next, insert the tip of the measuring syringe into the centre opening of the bottle and press down firmly  While holding the bottle and syringe with one hand, draw up the prescribed dose with the other hand by pulling on the plunger. NOTE: Medicine will not flow into the syringe unless you keep the bottle in its upright position Step 3  Remove the syringe from the centre opening of the bottle.  Empty the medicine from the syringe into one of the dosing cups provided by pushing on the plunger Repeat this step for the second dosing cup.  Then add about 60 ml of water to each dosing cup (60 mL is about 4 tablespoons). Step 4  Place the caps provided on the dosing cups and turn each cap clockwise (to the right) until it clicks and locks into its child-resistant position  Rinse out the syringe with water.  Just before going to sleep: - Adult patients should place the second dose near their bed . - The parent or caregiver of adolescents and children aged 7 years and over should not leave the second dose near the child’s bed or within easy reach of the child. - You may need to set an alarm so you wake up to take your second dose no earlier than 2½ hours and no later than 4 hours after your first dose. Then: o Remove the cap from the first dosing cup by pressing down on the child-resistant locking tab and turning the cap anticlockwise (to the left). o Drink all of the first dose while sitting in bed, recap the cup, and then lie down right away. For children who sleep longer than 8 hours but less than 12 hours, the first dose may be given after the child has been sleeping for 1 to 2 hours. -  When you wake up or wake up the child 2 ½ to 4 hours later, remove the cap from the second dosing cup. While sitting in bed, drink all of the second dose right before lying down to continue sleeping. Recap the second cup. If you have the impression that the effect of Xyrem is too strong or too weak, talk to your doctor or pharmacist. 33 If you take more Xyrem than you should Symptoms of Xyrem overdose may include agitation, confusion, impaired movement, impaired breathing, blurred vision, profuse sweating, headache, vomiting, decreased consciousness leading to coma and seizures, excessive thirst, muscle cramps and weakness. If you take more Xyrem than you were told to take, or take it by accident, get emergency medical help right away. You should take the labelled medicine bottle with you, even if it is empty. If you forget to take Xyrem If you forget to take the first dose, take it as soon as you remember and then continue as before. If you miss the second dose, skip that dose and do not take Xyrem again until the next night. Do not take a double dose to make up for a forgotten dose. If unsure if you took Xyrem If in doubt about administration of a dose, do not re-administer the dose to reduce the risk of overdose If you stop taking Xyrem You should continue to take Xyrem for as long as instructed by your doctor. You may find that your cataplexy attacks return if your medicine is stopped and you may experience insomnia, headache, anxiety, dizziness, sleeping problems, sleepiness, hallucination and abnormal thinking. If you stop taking Xyrem for more than 14 consecutive days, you should consult your doctor as you should restart taking Xyrem at a reduced dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. These are usually mild to moderate.. Adults - most common side effects observed in clinical studies (occurring in 10% to 20% of patients):  dizziness  nausea  headache. If you experience any of these side effects, tell your doctor straight away. Children and adolescents - most common side effects observed in a clinical study:  bed wetting (18.3%)  nausea (12.5%)  vomiting (8.7%)  weight decrease (8.7%)  decreased appetite (6.7%)  headache (5.8%)  dizziness (5.8%)  suicidal thoughts (1%)  feeling mentally unwell (loss of contact with reality) (1%) If you experience any of these side effects, tell your doctor straight away 34 The side effects in adults and children are the same. If you experience any of the side effects listed below, tell your doctor straight away: Very common (may affect more than 1 in 10 people):  nausea  dizziness  headache Common (may affect up to 1 in 10 people):  sleeping problems including insomnia, abnormal dreams, sleep paralysis, sleepiness, nightmares, sleep walking, bed wetting, excessive daytime sleepiness, difficulty in falling asleep in the middle of the night  feeling drunk, trembling, confusion/ disorientation, blurred vision, balance disorder, fall, feeling of “spinning” (vertigo),  feeling the heart beat, increased blood pressure, shortness of breath  vomiting, stomach pains, diarrhoea  anorexia, decreased appetite, weight loss  weakness, tiredness, sedation  sweating  depression  muscle cramps, swelling  joint pain, back pain  disturbance in attention, disturbed sensitivity particularly to touch, abnormal touch sensation, abnormal taste  anxiety, nervousness  urinary incontinence  snoring, congestion of the nose  rash  inflammation of the sinuses,inflammation of nose and throat Uncommon (may affect up to 1 in 100 people):  psychosis (a mental disorder that may involve hallucinations, incoherent speech, or disorganized and agitated behaviour)  paranoia, abnormal thinking, hallucination, agitation, suicide attempt  difficulty in falling asleep, restless legs  forgetfulness  myoclonus (involuntary contractions of muscles)  involuntary passage of faeces  hypersensitivity Not known (cannot be estimated from the available data):  convulsion  decreased breathing depth or rate, short cessation of breathing during sleep  hives  suicidal thoughts, delusion, thoughts of committing violent acts (including harming others)  irritability, aggression  euphoric mood  panic attack  mania / bipolar disorder  dry mouth, dehydration  swelling face (angioedema)  bruxism (teeth grinding and jaw clenching)  pollakiuria / micturition urgency (increase need to urinate)  tinnitus (noise in the ears such as ringing or buzzing)  sleep-related eating disorder  increased appetite 35  loss of consciousness  dyskinesia (e.g. abnormal, uncontrolled movements of the limbs)  dandruff  increased sexual desire  nocturia (excessive urination at night)  choking sensation If you experience any of the side effects listed above, tell your doctor straight away. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Xyrem Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date stated on the bottle after (EXP). The expiry date refers to the last day of that month. After dilution in the dosing cups, the preparation should be used within 24 hours. Once you open a bottle of Xyrem, any contents that you have not used with 90 days of opening should be disposed of. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Xyrem contains - The active substance is sodium oxybate. Each mL contains 500 mg of sodium oxybate. - The other ingredients are purified water, malic acid and sodium hydroxyde. What Xyrem looks like and contents of the pack Xyrem is supplied in a 240 mL amber plastic bottle containing 180 mL of oral solution and closed with a child-resistant cap. When the bottle is delivered, there is a plastic covered foil seal which is on the top of the bottle, underneath the cap. Each pack contains one bottle, a press-in-bottle-adaptor (PIBA), a plastic measuring syringe and two dosing cups with child-resistant caps. Xyrem is a clear to slightly opalescent solution. Marketing Authorisation Holder UCB Pharma SA, Allée de la Recherche 60, B-1070 Brussels, Belgium Manufacturer UCB Pharma S.A., Chemin du Foriest, B-1420 Braine l'Alleud, Belgium or UCB Pharma Ltd, 208 Bath Road, Slough, Berkshire, SL1 3WE, United Kingdom. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 36 You should have received a Xyrem Information Pack from your physician, which includes a booklet on how to take the medicine, a Frequently Asked Questions patient information sheet and a patient alert card. For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien UCB Pharma SA/NV Tel/Tél: +32 / (0)2 559 92 00 Lietuva UCB Pharma Oy Finland Tel: + 358 9 2514 4221 (Suomija) България Ю СИ БИ България ЕООД Teл.: + 359 (0) 2 962 30 49 Luxembourg/Luxemburg UCB Pharma SA/NV Tél/Tel: +32 / (0)2 559 92 00 Česká republika UCB s.r.o. Tel: + 420 221 773 411 Magyarország UCB Magyarország Kft. Tel.: + 36-(1) 391 0060 Danmark UCB Nordic A/S Tlf: + 45 / 32 46 24 00 Malta Pharmasud Ltd. Tel: +356 / 21 37 64 36 Deutschland UCB Pharma GmbH Tel: + 49 /(0) 2173 48 4848 Nederland UCB Pharma B.V. Tel.: +31 / (0)76-573 11 40 Eesti UCB Pharma Oy Finland Tel: + 358 9 2514 4221 (Soome) Norge UCB Nordic A/S Tel: +45 / 32 46 24 00 Ελλάδα UCB Α.Ε. Τηλ: +30 / 2109974000 Österreich UCB Pharma GmbH Tel: +43 (0) 1 291 80 00 España UCB Pharma, S.A. Tel: + 34 / 91 570 34 44 Polska UCB Pharma Sp. z o.o. Tel.: + 48 22 696 99 20 France UCB Pharma S.A. Tél: + 33 / (0)1 47 29 44 66 Portugal UCB Pharma (Produtos Farmacêuticos), Lda Tel: + 351 / 21 302 5300 Hrvatska Medis Adria d.o.o. Tel: +385 (0) 1 230 34 46 România UCB Pharma Romania S.R.L. Tel: +40 21 300 29 04 Ireland UCB (Pharma) Ireland Ltd. Tel: + 353 / (0)1-46 37 395 Slovenija Medis, d.o.o. Tel: + 386 1 589 69 00 Ísland Vistor hf. Tel: +354 535 7000 Slovenská republika UCB s.r.o., organizačná zložka Tel: + 421 (0) 2 5920 2020 37 Italia UCB Pharma S.p.A. Tel: + 39 / 02 300 791 Suomi/Finland UCB Pharma Oy Finland Puh/ Tel: + 358 9 2514 4221 Κύπρος Lifepharma (Z.A.M.) Ltd Τηλ: + 357 22 34 74 40 Sverige UCB Nordic A/S Tel: + 46 / (0) 40 29 49 00 Latvija UCB Pharma Oy Finland Tel: + 358 9 2514 4221 (Somija) United Kingdom UCB Pharma Ltd. Tel : +44 / (0)1753 534 655 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/ <------------------------------------------------------------------------------------------------------------------------------ SUMMARY OF PRODUCT CHARACTERISTICS A MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what xyrem is and what it is used for', 'Section_Content': 'xyrem contains the active substance sodium oxybate. xyrem works by consolidating night-time sleep, though its exact mechanism of action is unknown. xyrem is used to treat narcolepsy with cataplexy in adults, adolescents and children from 7 years of age. narcolepsy is a sleep disorder that may include attacks of sleep during normal waking hours, as well as cataplexy, sleep paralysis, hallucinations and poor sleep. cataplexy is the onset of sudden muscle weakness or paralysis without losing consciousness, in response to a sudden emotional reaction such as anger, fear, joy, laughter or surprise.', 'Entity_Recognition': [{'Text': 'xyrem', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 0, 'EndOffset': 5, 'Score': 0.30209749937057495, 'Text': 'xyrem', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the active substance sodium oxybate', 'Type': 'TREATMENT', 'BeginOffset': 15, 'EndOffset': 50}, {'Id': 3, 'BeginOffset': 52, 'EndOffset': 57, 'Score': 0.3884572982788086, 'Text': 'xyrem', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 171, 'EndOffset': 181, 'Score': 0.8390443921089172, 'Text': 'narcolepsy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8641538023948669}]}, {'Id': 5, 'BeginOffset': 187, 'EndOffset': 196, 'Score': 0.8210904598236084, 'Text': 'cataplexy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6685271263122559}]}, {'Text': '7', 'Type': 'NUMBER', 'BeginOffset': 238, 'EndOffset': 239}, {'Id': 6, 'BeginOffset': 254, 'EndOffset': 264, 'Score': 0.9771077632904053, 'Text': 'narcolepsy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8584753274917603}]}, {'Text': 'a sleep disorder', 'Type': 'PROBLEM', 'BeginOffset': 268, 'EndOffset': 284}, {'Id': 8, 'BeginOffset': 302, 'EndOffset': 318, 'Score': 0.8761782646179199, 'Text': 'attacks of sleep', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5355107188224792}]}, {'Id': 9, 'BeginOffset': 358, 'EndOffset': 367, 'Score': 0.9650206565856934, 'Text': 'cataplexy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8678696751594543}]}, {'Id': 10, 'BeginOffset': 369, 'EndOffset': 384, 'Score': 0.9427329897880554, 'Text': 'sleep paralysis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9481407403945923}]}, {'Id': 11, 'BeginOffset': 386, 'EndOffset': 400, 'Score': 0.9899219870567322, 'Text': 'hallucinations', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9527823328971863}]}, {'Id': 12, 'BeginOffset': 405, 'EndOffset': 415, 'Score': 0.9827624559402466, 'Text': 'poor sleep', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9061154723167419}]}, {'Id': 13, 'BeginOffset': 417, 'EndOffset': 426, 'Score': 0.9120736718177795, 'Text': 'cataplexy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8778605461120605}]}, {'Text': 'sudden muscle weakness', 'Type': 'PROBLEM', 'BeginOffset': 443, 'EndOffset': 465}, {'Id': 16, 'BeginOffset': 469, 'EndOffset': 478, 'Score': 0.9777448773384094, 'Text': 'paralysis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9170646667480469}], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.5516558289527893, 'RelationshipScore': 0.9612998366355896, 'RelationshipType': 'ACUITY', 'Id': 14, 'BeginOffset': 443, 'EndOffset': 449, 'Text': 'sudden', 'Category': 'MEDICAL_CONDITION', 'Traits': []}]}, {'Id': 17, 'BeginOffset': 487, 'EndOffset': 507, 'Score': 0.9582728147506714, 'Text': 'losing consciousness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9683706760406494}, {'Name': 'NEGATION', 'Score': 0.6313693523406982}]}, {'Text': 'a sudden emotional reaction', 'Type': 'PROBLEM', 'BeginOffset': 524, 'EndOffset': 551}, {'Id': 19, 'BeginOffset': 560, 'EndOffset': 565, 'Score': 0.6692340970039368, 'Text': 'anger', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6840553879737854}]}, {'Id': 20, 'BeginOffset': 567, 'EndOffset': 571, 'Score': 0.9257752895355225, 'Text': 'fear', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8770871758460999}]}, {'Id': 23, 'BeginOffset': 573, 'EndOffset': 576, 'Score': 0.2920863926410675, 'Text': 'joy', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'NAME', 'Traits': []}, {'Id': 22, 'BeginOffset': 578, 'EndOffset': 586, 'Score': 0.6228118538856506, 'Text': 'laughter', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}]}

{'Title': '2. what you need to know before you take xyrem', 'Section_Content': "do not take xyrem - if you are allergic to sodium oxybate or any of the other ingredients of this medicine (listed in section 6); - if you have succinic semialdehyde dehydrogenase deficiency (a rare metabolic disorder); - if you suffer from major depression; - if you are being treated with opioid or barbiturate medicines. warnings and precautions talk to your doctor or pharmacist before taking xyrem: - if you have breathing or lung problems (and especially if you are obese), because xyrem has the potential to cause difficulty in breathing; - if you have or have previously had depressive illness, suicidal thoughts, anxiety, psychosis (a mental disorder that may involve hallucinations, incoherent speech, or disorganized and agitated behaviour) or bipolar disorder - if you have heart failure, hypertension (high blood pressure), liver or kidney problems as your dose may need to be adjusted; 29 - if you have previously abused drugs; - if you suffer from epilepsy as the use of xyrem is not recommended in this condition; - if you have porphyria (an uncommon metabolic disorder). if any of these apply to you, tell your doctor before you take xyrem. while you are taking xyrem, if you experience bed wetting and incontinence (both urine and faeces), confusion, hallucinations, episodes of sleepwalking or abnormal thinking you should tell your doctor straight away. whilst these effects are uncommon, if they do occur they are usually mild-to-moderate in nature. if you are elderly, your doctor will monitor your condition carefully to check whether xyrem is having the desired effects. xyrem has a well-known abuse potential. cases of dependency have occurred after the illicit use of sodium oxybate. your doctor will ask if you have ever abused any drugs before you start taking xyrem and whilst you are using the medicine. children and adolescents xyrem can be taken by adolescents and children from 7 years of age when they are over 15 kg in weight. xyrem cannot be taken by children below 7 years of age or below 15 kg in weight. if you are a child or adolescent, your doctor will monitor your body weight regularly. whilst the doctor is adjusting the dose which may take a number of weeks, parent/caregivers should carefully monitor the child's breath during the first 2 hours after sodium oxybate intake to assess if there is any abnormality in breathing, for example stoppage of breathing for short periods while sleeping, noisy breathing and bluish colour of the lips and face. if abnormality in breathing is observed medical support should be sought and the doctor should be informed as soon as possible. if any abnormality is noted after the first dose, the second dose should not be administered. if no abnormality is noted the second dose can be administered. the second dose should not be given earlier than 2.5 hours or later than 4 hours after the first dose. if you have had or are having upsetting feelings particularly if you are feeling very sad or have lost interest in life it is important that you tell the doctor or caregiver. other medicines and xyrem tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. in particular xyrem should not be taken together with sleep inducing medicines and medicines that reduce central nervous system activity (the central nervous system is the part of the body related to the brain and spinal cord). also tell your doctor or pharmacist if you are taking any of the following types of medicines: medicines that increase central nervous system activity antidepressants medicines that may be processed in a similar way by the body (e.g., valproate, phenytoin or ethosuximide which are used for the treatment of fits) topiramate (used for treatment of epilepsy) 30 if you are taking valproate, your daily dose of xyrem will need to be adjusted (see section 3) as it may lead to interactions with valproate xyrem with alcohol you must not drink alcohol while taking xyrem, as its effects can be increased. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. there have been very few women who have taken xyrem sometime during their pregnancy and a few of them had spontaneous abortions. the risk of taking xyrem during pregnancy is unknown, and, therefore, the use of xyrem in pregnant women or women trying to become pregnant is not recommended. patients taking xyrem should not breast feed since it is known that xyrem passes into breast milk. changes in sleep patterns have been observed in breastfed infants from exposed mothers. driving and using machines xyrem will affect you if you drive or operate tools or machines. do not drive a car, operate heavy machinery, or perform any activity that is dangerous or that requires mental alertness for at least 6 hours after taking xyrem. when you first start taking xyrem, until you know whether it makes you sleepy the next day, use extreme care while driving a car, operating heavy machinery or doing anything else that could be dangerous or needs you to be fully mentally alert. for paediatric patients, physicians, parents or caregivers are advised that the waiting time for performing activities that require mental alertness, motor co-ordination or any activities that may have a physical risk may have to be longer than 6 hours, depending on individual sensitivity. xyrem contains sodium you need to monitor the amount of salt you take as xyrem contains sodium (which is found in table salt) which may affect you if you have had high blood pressure, heart or kidney problems in the past.. in every 1 g dose of sodium oxybate (xyrem), there is 0.18 g of sodium. you may need to moderate your intake of salt.", 'Entity_Recognition': [{'Text': 'xyrem', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, 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{'Title': '3. how to take xyrem', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. it is important that you only use the syringe provided in the box when preparing doses of xyrem. the xyrem syringe has two different measurement scales, one scale may be more helpful for you than the other depending on which dose your doctor has prescribed. by looking at each scale you will see which one provides the exact mark for your dose. adults taking xyrem on its own for adults the recommended starting dose is 4.5 g each day, given as two seperate doses of 2.25 g. your doctor may gradually increase your dose up to a maximum of 9 g each day given as two separate doses of 4.5 g. take xyrem orally two times each night: - take the first dose upon getting into bed and the second dose 2½ to 4 hours later. you may need to set an alarm clock to make sure you wake up to take the second dose. - food decreases the amount of xyrem that is absorbed by your body. therefore, it is best to take xyrem at set times 2 to 3 hours after a meal. - prepare both doses before bedtime. - take doses within 24 hours after preparation. adolescents and children aged 7 years and over who weigh 15 kg or more - taking xyrem on its own for those aged 7 years and over who weigh 15 kg or more, a doctor will work out the right dose based on your body weight. your doctor will work out the right dose for you. do not exceed the dose prescribed for you. adults - taking xyrem with valproate if you are taking valproate together with xyrem, the dose of xyrem will be adapted by your doctor. for adults the recommended starting dose for xyrem, when used together with valproate, is 3.6 g each day, given as two separate doses of 1.8 g. take the first dose when getting into bed and the second dose 2½ to 4 hours later. adolescents and children aged 7 years and older who weigh 15 kg or more - taking xyrem with valproate if you are taking valproate together with xyrem, the dose of xyrem will be adapted by your doctor. kidney or liver problems if you have kidney problems, you should consider a dietary recommendation to reduce sodium (salt) intake.if you have liver problems, the starting dose should be halved. your doctor may gradually increase your dose. instructions on how to dilute xyrem the following instructions explain how to prepare xyrem. please read the instructions carefully and follow them step by step. do not allow children to prepare xyrem. to help you, the xyrem carton contains 1 bottle of medicine, a measuring syringe (with two different measurement scales) and two dosing cups with child-resistant caps. step 1 remove the bottle cap by pushing down while turning the cap anticlockwise (to the left). after removing the cap, set the bottle upright on a table-top. there is a plastic covered foil seal on the top of the bottle, which must be removed before using the bottle for the first time. while holding the bottle in its upright position, insert the press-in-bottle- adaptor into the neck of the bottle. this needs only to be done the first time that the bottle is opened. the adaptor can then be left in the bottle for all subsequent uses 32 step 2 next, insert the tip of the measuring syringe into the centre opening of the bottle and press down firmly while holding the bottle and syringe with one hand, draw up the prescribed dose with the other hand by pulling on the plunger. note: medicine will not flow into the syringe unless you keep the bottle in its upright position step 3 remove the syringe from the centre opening of the bottle. empty the medicine from the syringe into one of the dosing cups provided by pushing on the plunger repeat this step for the second dosing cup. then add about 60 ml of water to each dosing cup (60 ml is about 4 tablespoons). step 4 place the caps provided on the dosing cups and turn each cap clockwise (to the right) until it clicks and locks into its child-resistant position rinse out the syringe with water. just before going to sleep: - adult patients should place the second dose near their bed . - the parent or caregiver of adolescents and children aged 7 years and over should not leave the second dose near the child's bed or within easy reach of the child. - you may need to set an alarm so you wake up to take your second dose no earlier than 2½ hours and no later than 4 hours after your first dose. then: o remove the cap from the first dosing cup by pressing down on the child-resistant locking tab and turning the cap anticlockwise (to the left). o drink all of the first dose while sitting in bed, recap the cup, and then lie down right away. for children who sleep longer than 8 hours but less than 12 hours, the first dose may be given after the child has been sleeping for 1 to 2 hours. - when you wake up or wake up the child 2 ½ to 4 hours later, remove the cap from the second dosing cup. while sitting in bed, drink all of the second dose right before lying down to continue sleeping. recap the second cup. if you have the impression that the effect of xyrem is too strong or too weak, talk to your doctor or pharmacist. if you take more xyrem than you should symptoms of xyrem overdose may include agitation, confusion, impaired movement, impaired breathing, blurred vision, profuse sweating, headache, vomiting, decreased consciousness leading to coma and seizures, excessive thirst, muscle cramps and weakness. if you take more xyrem than you were told to take, or take it by accident, get emergency medical help right away. you should take the labelled medicine bottle with you, even if it is empty. if you forget to take xyrem if you forget to take the first dose, take it as soon as you remember and then continue as before. if you miss the second dose, skip that dose and do not take xyrem again until the next night. do not take a double dose to make up for a forgotten dose. if unsure if you took xyrem if in 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. these are usually mild to moderate.. adults - most common side effects observed in clinical studies (occurring in 10% to 20% of patients): dizziness nausea headache. if you experience any of these side effects, tell your doctor straight away. children and adolescents - most common side effects observed in a clinical study: bed wetting (18.3%) nausea (12.5%) vomiting (8.7%) weight decrease (8.7%) decreased appetite (6.7%) headache (5.8%) dizziness (5.8%) suicidal thoughts (1%) feeling mentally unwell (loss of contact with reality) (1%) if you experience any of these side effects, tell your doctor straight away 34 the side effects in adults and children are the same. if you experience any of the side effects listed below, tell your doctor straight away: very common (may affect more than 1 in 10 people): nausea dizziness headache common (may affect up to 1 in 10 people): sleeping problems including insomnia, abnormal dreams, sleep paralysis, sleepiness, nightmares, sleep walking, bed wetting, excessive daytime sleepiness, difficulty in falling asleep in the middle of the night feeling drunk, trembling, confusion/ disorientation, blurred vision, balance disorder, fall, feeling of "spinning" (vertigo), feeling the heart beat, increased blood pressure, shortness of breath vomiting, stomach pains, diarrhoea anorexia, decreased appetite, weight loss weakness, tiredness, sedation sweating depression muscle cramps, swelling joint pain, back pain disturbance in attention, disturbed sensitivity particularly to touch, abnormal touch sensation, abnormal taste anxiety, nervousness urinary incontinence snoring, congestion of the nose rash inflammation of the sinuses,inflammation of nose and throat uncommon (may affect up to 1 in 100 people): psychosis (a mental disorder that may involve hallucinations, incoherent speech, or disorganized and agitated behaviour) paranoia, abnormal thinking, hallucination, agitation, suicide attempt difficulty in falling asleep, restless legs forgetfulness myoclonus (involuntary contractions of muscles) involuntary passage of faeces hypersensitivity not known (cannot be estimated from the available data): convulsion decreased breathing depth or rate, short cessation of breathing during sleep hives suicidal thoughts, delusion, thoughts of committing violent acts (including harming others) irritability, aggression euphoric mood panic attack mania / bipolar disorder dry mouth, dehydration swelling face (angioedema) bruxism (teeth grinding and jaw clenching) pollakiuria / micturition urgency (increase need to urinate) tinnitus (noise in the ears such as ringing or buzzing) sleep-related eating disorder increased appetite 35 loss of consciousness dyskinesia (e.g. abnormal, uncontrolled movements of the limbs) dandruff increased sexual desire nocturia (excessive urination at night) choking sensation if you experience any of the side effects listed above, tell your doctor straight away. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'xyrem', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 9, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9621488451957703, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6507944464683533}]}, {'Text': 'most common side effects', 'Type': 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pain', 'Type': 'PROBLEM', 'BeginOffset': 1521, 'EndOffset': 1540}, {'Id': 68, 'BeginOffset': 1552, 'EndOffset': 1576, 'Score': 0.8600823879241943, 'Text': 'disturbance in attention', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7426531314849854}]}, {'Id': 69, 'BeginOffset': 1578, 'EndOffset': 1599, 'Score': 0.5374859571456909, 'Text': 'disturbed sensitivity', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8882732391357422}]}, {'Id': 70, 'BeginOffset': 1623, 'EndOffset': 1647, 'Score': 0.846286952495575, 'Text': 'abnormal touch sensation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9784862995147705}]}, {'Text': 'abnormal taste anxiety', 'Type': 'PROBLEM', 'BeginOffset': 1649, 'EndOffset': 1671}, {'Id': 73, 'BeginOffset': 1673, 'EndOffset': 1684, 'Score': 0.990295946598053, 'Text': 'nervousness', 'Category': 'MEDICAL_CONDITION', 'Type': 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swelling face (angioedema)', 'Type': 'PROBLEM', 'BeginOffset': 2524, 'EndOffset': 2562}, {'Text': 'bruxism (teeth grinding', 'Type': 'PROBLEM', 'BeginOffset': 2563, 'EndOffset': 2586}, {'Text': 'jaw clenching)', 'Type': 'PROBLEM', 'BeginOffset': 2591, 'EndOffset': 2605}, {'Id': 132, 'BeginOffset': 2606, 'EndOffset': 2617, 'Score': 0.9089974761009216, 'Text': 'pollakiuria', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9049549102783203}]}, {'Text': 'micturition urgency', 'Type': 'PROBLEM', 'BeginOffset': 2620, 'EndOffset': 2639}, {'Id': 135, 'BeginOffset': 2641, 'EndOffset': 2665, 'Score': 0.414902001619339, 'Text': 'increase need to urinate', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.940702497959137}]}, {'Text': 'tinnitus (noise in the ears', 'Type': 'PROBLEM', 'BeginOffset': 2667, 'EndOffset': 2694}, {'Text': 'ringing or buzzing) sleep', 'Type': 'PROBLEM', 'BeginOffset': 2703, 'EndOffset': 2728}, {'Id': 139, 'BeginOffset': 2737, 'EndOffset': 2752, 'Score': 0.9388776421546936, 'Text': 'eating disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9435480237007141}]}, {'Id': 140, 'BeginOffset': 2753, 'EndOffset': 2771, 'Score': 0.5961263179779053, 'Text': 'increased appetite', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9567763209342957}]}, {'Text': '35', 'Type': 'NUMBER', 'BeginOffset': 2772, 'EndOffset': 2774}, {'Text': 'consciousness dyskinesia', 'Type': 'PROBLEM', 'BeginOffset': 2783, 'EndOffset': 2807}, {'Text': 'abnormal, uncontrolled movements of the limbs)', 'Type': 'PROBLEM', 'BeginOffset': 2814, 'EndOffset': 2860}, {'Id': 145, 'BeginOffset': 2861, 'EndOffset': 2869, 'Score': 0.3549175560474396, 'Text': 'dandruff', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9967892169952393, 'RelationshipScore': 0.9978664517402649, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 97, 'BeginOffset': 2854, 'EndOffset': 2859, 'Text': 'limbs', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 146, 'BeginOffset': 2880, 'EndOffset': 2902, 'Score': 0.5504434108734131, 'Text': 'sexual desire nocturia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9805640578269958}]}, {'Id': 147, 'BeginOffset': 2904, 'EndOffset': 2923, 'Score': 0.6185896992683411, 'Text': 'excessive urination', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9510383605957031}]}, {'Id': 148, 'BeginOffset': 2934, 'EndOffset': 2951, 'Score': 0.7334570288658142, 'Text': 'choking sensation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9387769103050232}]}, {'Id': 149, 'BeginOffset': 2981, 'EndOffset': 2993, 'Score': 0.7834944725036621, 'Text': 'side effects', 'Category': 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{'Title': '5 how to store xyrem', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date stated on the bottle after (exp). the expiry date refers to the last day of that month. after dilution in the dosing cups, the preparation should be used within 24 hours. once you open a bottle of xyrem, any contents that you have not used with 90 days of opening should be disposed of. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to dispose of medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'xyrem', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'dilution', 'Type': 'TREATMENT', 'BeginOffset': 200, 'EndOffset': 208}, {'Text': 'the dosing cups', 'Type': 'TREATMENT', 'BeginOffset': 212, 'EndOffset': 227}, {'Text': 'the preparation', 'Type': 'TREATMENT', 'BeginOffset': 229, 'EndOffset': 244}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 267, 'EndOffset': 269}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 351, 'EndOffset': 353}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 498, 'EndOffset': 507}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 527, 'EndOffset': 541}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what xyrem contains - the active substance is sodium oxybate. each ml contains 500 mg of sodium oxybate. - the other ingredients are purified water, malic acid and sodium hydroxyde. what xyrem looks like and contents of the pack xyrem is supplied in a 240 ml amber plastic bottle containing 180 ml of oral solution and closed with a child-resistant cap. when the bottle is delivered, there is a plastic covered foil seal which is on the top of the bottle, underneath the cap. each pack contains one bottle, a press-in-bottle-adaptor (piba), a plastic measuring syringe and two dosing cups with child-resistant caps. xyrem is a clear to slightly opalescent solution.', 'Entity_Recognition': [{'Text': 'xyrem', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 46, 'EndOffset': 60, 'Score': 0.996762752532959, 'Text': 'sodium oxybate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.2580842673778534, 'RelationshipScore': 0.9999716281890869, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 62, 'EndOffset': 69, 'Text': 'each ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 79, 'EndOffset': 82}, {'Id': 4, 'BeginOffset': 89, 'EndOffset': 103, 'Score': 0.9996218681335449, 'Text': 'sodium oxybate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.2580842673778534, 'RelationshipScore': 0.9701609015464783, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 62, 'EndOffset': 69, 'Text': 'each ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9467161893844604, 'RelationshipScore': 0.9991753697395325, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 79, 'EndOffset': 85, 'Text': '500 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 133, 'EndOffset': 147, 'Score': 0.9734892845153809, 'Text': 'purified water', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 149, 'EndOffset': 159, 'Score': 0.9993568062782288, 'Text': 'malic acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 164, 'EndOffset': 180, 'Score': 0.9971795082092285, 'Text': 'sodium hydroxyde', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.3926827907562256, 'RelationshipScore': 0.997671902179718, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 291, 'EndOffset': 297, 'Text': '180 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7950983643531799, 'RelationshipScore': 0.6609154939651489, 'RelationshipType': 'FORM', 'Id': 9, 'BeginOffset': 301, 'EndOffset': 314, 'Text': 'oral solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the pack xyrem', 'Type': 'TREATMENT', 'BeginOffset': 220, 'EndOffset': 234}, {'Text': '240', 'Type': 'NUMBER', 'BeginOffset': 252, 'EndOffset': 255}, {'Text': '180', 'Type': 'NUMBER', 'BeginOffset': 291, 'EndOffset': 294}, {'Text': 'oral solution', 'Type': 'TREATMENT', 'BeginOffset': 301, 'EndOffset': 314}, {'Text': 'a child-resistant cap', 'Type': 'TREATMENT', 'BeginOffset': 331, 'EndOffset': 352}, {'Text': 'a plastic covered foil seal', 'Type': 'TREATMENT', 'BeginOffset': 393, 'EndOffset': 420}, {'Text': 'a plastic measuring syringe', 'Type': 'TREATMENT', 'BeginOffset': 541, 'EndOffset': 568}, {'Text': 'two dosing cups', 'Type': 'TREATMENT', 'BeginOffset': 573, 'EndOffset': 588}, {'Text': 'child-resistant caps', 'Type': 'TREATMENT', 'BeginOffset': 594, 'EndOffset': 614}, {'Text': 'slightly opalescent solution', 'Type': 'TREATMENT', 'BeginOffset': 636, 'EndOffset': 664}]}

B5F4B1A6811BA7FB9024E509326CEA8B

https://www.ema.europa.eu/documents/product-information/intrarosa-epar-product-information_en.pdf

Intrarosa

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Intrarosa 6.5 mg pessary. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each pessary contains 6.5 mg of prasterone. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Pessary. White to off-white, bullet-shaped pessary approximately 28 mm long and 9 mm in diameter at its widest end. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Intrarosa is indicated for the treatment of vulvar and vaginal atrophy in postmenopausal women having moderate to severe symptoms. 4.2 Posology and method of administration Posology The recommended dose is 6.5 mg prasterone (one pessary) administered once daily, at bedtime. For the treatment of postmenopausal symptoms, Intrarosa should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be reassessed at least every 6 months and Intrarosa should only be continued as long as the benefit outweighs the risk. If a dose is forgotten, it should be taken as soon as the patient remembers. However, if the next dose is due in less than 8 hours, the patient should skip the missed pessary. Two pessaries should not be used to make up for a forgotten dose. Special populations Elderly No dose adjustment is considered necessary in elderly women. Patients with renal and/or hepatic impairment Since Intrarosa acts locally in the vagina, no dosage adjustment is needed for postmenopausal women having renal or hepatic impairment or any other systemic anomaly or disease. 3 Paediatric population There is no relevant use of Intrarosa in female children of any age group for the indication of vulvar and vaginal atrophy due to menopause. Method of administration Vaginal use. Intrarosa can be inserted in the vagina with the finger or with an applicator provided within the identified pack. The pessary should be inserted in the vagina as far as it can comfortably go without force. If inserted with an applicator, the following steps should be followed: 1. The applicator should be activated (by pulling back the plunger) before use. 2. The flat end of the pessary should be placed into the open end of the activated applicator. 3. The applicator should be inserted into the vagina as far as it can comfortably go without force. 4. The plunger of the applicator should be pressed to release the pessary. 5. The applicator should then be withdrawn and disassembled, and the two pieces of the applicator should be rinsed for 30 seconds under running water before wiping with paper towel and reassembled. The applicator should be kept in a clean place until next use. 6. Each applicator should be discarded after one week of usage (two extra applicators are provided). 4.3 Contraindications • Hypersensitivity to the active substance or to the excipient listed in section 6.1; • Undiagnosed genital bleeding; • Known, past or suspected breast cancer; • Known or suspected oestrogen-dependent malignant tumours (e.g endometrial cancer); • Untreated endometrial hyperplasia; • Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal • Previous or current venous thromboembolism (deep vein thrombosis, pulmonary embolism); • Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4); • Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction); • Porphyria. 4.4 Special warnings and precautions for use For the treatment of postmenopausal symptoms, Intrarosa should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be reassessed at least every 6 months and Intrarosa should only be continued as long as the benefit outweighs the risk following discussions with their doctor. Before initiating Intrarosa, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and special warnings and precautions for use according to the decision of their doctor. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast cancer’ below). Investigations, including Pap smears and blood pressure measurements should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual. 4 Conditions which need supervision • If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Intrarosa, in particular: – Leiomyoma (uterine fibroids) or endometriosis – Risk factors for thromboembolic disorders (see below) – Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer – Hypertension – Liver disorders (e.g. liver adenoma) – Diabetes mellitus with or without vascular involvement – Cholelithiasis – Migraine or (severe) headache – Systemic lupus erythematosus. – A history of endometrial hyperplasia (see below) – Epilepsy – Asthma – Otosclerosis Reasons for immediate withdrawal of therapy Therapy should be discontinued in case a contraindication is discovered and in the following situation: – Jaundice or deterioration in liver function – Significant increase in blood pressure – New onset of migraine-type headache – Pregnancy. Endometrial hyperplasia and carcinoma • Estrogen is a metabolite of prasterone. In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when exogenous oestrogens are administered for prolonged periods. No cases of endometrial hyperplasia have been reported in women treated for 52 weeks during the clinical studies. Intrarosa has not been studied in women with endometrial hyperplasia. • For oestrogen products for vaginal application of which the systemic exposure to oestrogen remains within the normal postmenopausal range, it is not recommended to add a progestagen. • Endometrial safety of long-term of local vaginally administered prasterone has not been studied for more than one year. Therefore, if repeated, treatment should be reviewed at least annually. • If bleeding or spotting appears at any time on therapy, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy. • Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore caution is advised when using this product in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis since intravaginal prasterone has not been studied in women with endometriosis. Prasterone is metabolised into estrogenic compounds. The following risks have been associated with systemic HRT and apply to a lesser extent for oestrogen products for vaginal application of which the systemic exposure to the oestrogen remains within the normal postmenopausal range. However, they should be considered in case of long term or repeated use of this product. Breast cancer The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen- progestagen and possibly also oestrogen-only systemic HRT, that is dependent on the duration of taking HRT. The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment. 5 Intrarosa has not been studied in women with active or past breast cancer. One case of breast cancer at week 52 has been reported on 1196 women who have been exposed with the 6.5 mg dose which is below the incidence rate observed in the normal population of the same age. Ovarian cancer Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only systemic HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Intrarosa has not been studied in women with active or past ovarian cancer. One Case of ovarian cancer has been reported on 1196 women who have been exposed with the 6.5 mg dose which is above the incidence rate observed in the normal population of the same age. Of note, this case was present before start of treatment and was bearing a BRCA1 mutation. Abnormal Pap smear Intrarosa has not been studied in women with abnormal Pap smears (Atypical Squamous Cells of Undetermined Significance (ASCUS)) or worse. Cases of abnormal Pap smears corresponding to ASCUS or Low Grade Squamous Intraepithelial Lesion (LSIL) have been reported in women treated with the 6.5 mg dose (common frequency). Venous thromboembolism Intrarosa has not been studied in women with current or previous venous thromboembolic disease. • Systemic HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8). • Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). • Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised. • In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g, antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated. • Women already on chronic anticoagulant treatment require careful consideration of the benefit- risk of use of HRT. • If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea). One case of pulmonary embolism has been reported in the 6.5 mg group and one in the placebo group during clinical trials. Coronary artery disease (CAD)/ Hypertension Intrarosa has not been studied in women with uncontrolled hypertension (blood pressure above 140/90 mmHg) and cardiovascular disease. Cases of hypertension have been reported in clinical trials with an uncommon frequency and similar incidence rates were observed in both groups (6.5 mg prasterone and placebo). No case of coronary artery disease has been reported during clinical trials. 6 Ischaemic stroke Systemic oestrogen-only therapy is associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8). Intrarosa has not been studied in women with current or previous arterial thromboembolic disease. No cases of arterial thromboembolic disease have been reported during clinical trials. Other conditions observed with HRT • Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. • Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition. • Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio- immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). • HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65. None of these conditions has been observed with Intrarosa during the clinical trials. Women with vaginal infection should be treated with appropriate antimicrobial therapy before starting Intrarosa. Due to melting of the hard fat base added to an expected increase in vaginal secretions due to treatment, vaginal discharge can occur although it does not require to stop the medication (see section 4.8). Use of Intrarosa with condoms, diaphragms or cervical caps made of latex must be avoided since the rubber may be damaged by the preparation. Intrarosa has not been studied in women with a current hormonal treatment: hormone replacement therapy (oestrogens alone or combined with progestogens) or androgens treatment. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use with systemic hormone replacement therapy (oestrogen-only or oestrogen- progestagen combination or androgen treatment) or vaginal oestrogens has not been investigated and is therefore not recommended. 4.6 Fertility, pregnancy and lactation Pregnancy Intrarosa is not indicated in pre-menopausal women of child-bearing age, including pregnancy. If pregnancy occurs during treatment with Intrarosa, the treatment should be withdrawn immediately. There are no data on the use of Intrarosa in pregnant women. No studies in animals were performed with regard to the reproductive toxicity (see section 5.3). The potential risk in humans is unknown. 7 Breast-feeding Intrarosa is not indicated during breast-feeding. Fertility Intrarosa is not indicated in fertile women. 4.7 Effects on ability to drive and use machines Intrarosa has no influence in the ability to drive and use machines. 4.8 Undesirable effects Summary of safety profile The most frequently observed adverse reaction was vaginal discharge. This is due to melting of the hard fat used as vehicle, added to the expected increase in vaginal secretions due to treatment. It is not required to stop Intrarosa if vaginal discharge occurs (see section 4.4). Tabulated list of adverse reactions The adverse reaction observed with prasterone 6.5 mg pessaries obtained from clinical studies is tabulated below. MedDRA System Organ Class Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) General disorders and administration site conditions Application site discharge Reproductive system and breast disorders Abnormal Pap smear (mostly ASCUS or LGSIL) Cervical/ uterine polyps Breast mass (benign) Investigations Weight fluctuation Breast cancer risk • An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years. • Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations. • The level of risk is dependent on the duration of use (see section 4.4). • Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented. Million Women study– Estimated additional risk of breast cancer after 5 years’ use Age range (years) Additional cases per 1000 never-users of HRT over a 5 year period*1 Risk ratio & 95%CI# Additional cases per 1000 HRT users over 5 years (95%CI) Oestrogen only HRT 50-65 9-12 1.2 1-2 (0-3) #Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately. 1 *Taken from baseline incidence rates in developed countries 8 US WHI studies - additional risk of breast cancer after 5 years’ use Age range (yrs) Incidence per 1000 women in placebo arm over 5 years Risk ratio & 95%CI Additional cases per 1000 HRT users over 5 years (95%CI) CEE oestrogen-only 50-79 21 0.8 (0.7 – 1.0) -4 (-6 – 0)*2 Ovarian cancer Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4). A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31- 1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period. Risk of venous thromboembolism HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented: WHI Studies - Additional risk of VTE over 5 years’ use Risk of coronary artery disease • The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4). Risk of ischaemic stroke • The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT. • This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4. WHI studies combined - Additional risk of ischaemic stroke*4 over 5 years’ use Age range (years) Incidence per 1000 women in placebo arm over 5 years Risk ratio and 95%CI Additional cases per 1000 HRT users over 5 years 50-59 8 1.3 (1.1-1.6) 3 (1-5) Other adverse reactions have been reported in association with oestrogen/progestagen treatment: – Gall bladder disease. 2 *WHI study in women with no uterus, which did not show an increase in risk of breast cancer 3 *Study in women with no uterus 4 *no differentiation was made between ischaemic and haemorrhagic stroke. Age range (years) Incidence per 1000 women in placebo arm over 5 years Risk ratio and 95%CI Additional cases per 1000 HRT users Oral oestrogen-only*3 50-59 7 1.2 (0.6 - 2.4) 1 (-3 – 10) 9 – Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura. – Probable dementia over the age of 65 (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In the event of overdose, vaginal douching is recommended. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other sex hormones and modulators of the genital system, ATC code: G03XX01. Mechanism of action Intrarosa contains the active ingredient prasterone, i.e. dehydroepiandrosterone (DHEA), which is biochemically and biologically identical to the endogenous human DHEA, a precursor steroid which is inactive by itself and it is converted into oestrogens and androgens. Intrarosa is thus different from the oestrogens preparations since it delivers also androgen metabolites. An oestrogen-mediated increase in the number of superficial and intermediate cells and decrease in the number of parabasal cells in the vaginal mucosa is noted. In addition, the vaginal pH decreased towards the normal range, thus facilitating the growth of the normal bacterial flora. Clinical efficacy Physiological responses (objective measures) Efficacy data were obtained from two US and Canadian randomised, double-blind, placebo-controlled, multicentre, pivotal phase III trials (ERC-231/Trial 1 and ERC-238/Trial 2) performed in postmenopausal women aged 40 to 80 years (mean age = 58.6 years in Trial 1 and 59.5 years in Trial 2) with vulvar and vaginal atrophy (VVA ). At baseline, women had ≤ 5.0% superficial cells in the vaginal smear, a vaginal pH ˃ 5.0 and they had identified dyspareunia (moderate to severe) as their most bothersome symptom (MBS) of VVA. After 12 weeks of daily treatment with a prasterone 6.5 mg pessary (n=81 in Trial 1 and n=325 in Trial 2), the change from baseline, in comparison with placebo treatment (n=77 in Trial 1 and n=157 in Trial 2), demonstrated significant improvements of the 3 co-primary endpoints compared to placebo in both studies, namely increase of the percentage of superficial cells (p<0.0001), decrease of the percentage of parabasal cells (p<0.0001), and decrease in the vaginal pH (p<0.0001). Symptoms (subjective measures) The most bothersome symptom (MBS) dyspareunia (co-primary endpoint) was assessed at baseline and 12 weeks with the severity scored as follows: None=0, Mild=1, Moderate=2, Severe=3. Table 1 shows the mean change in severity score in MBS dyspareunia after 12 weeks with associated statistical testing for the difference vs. placebo for Trial 1 (ERC-231) and Trial 2 (ERC-238). http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 10 Table 1: Primary Efficacy Analysis – Change from Baseline to Week 12 in the Most Bothersome Symptom Dyspareunia (ITT Population; LOCF) Study Dyspareunia Intrarosa 6.5 mg Placebo p-value Trial 1 -1.27 -0.87 0.0132 Trial 2 -1.42 -1.06 0.0002 Table 2 shows the percentage of subjects who reported a change from baseline in their MBS dyspareunia at week 12. “Improvement” was defined as a reduction in the severity score of 1 or more. “Relief” was defined as no or only mild symptoms at week 12. “Substantial improvement” was restricted to patients who had moderate or severe MBS at baseline and changed from severe to mild or severe or moderate to none. Table 2: Percentage of Patients with Improvement, Relief or Substantial Improvement of MBS Dyspareunia after 12 Weeks on Intrarosa vs. Placebo (ITT, LOCF) Improvement Relief Substantial improvement Intrarosa Placebo Intrarosa Placebo Intrarosa Placebo Trial 1 (Intrarosa: n= 81) (Placebo: n= 77) 72.8% (p=0.0565) 58.4% 58.0% (p=0.0813) 44.2% 43.2% (p=0.0821) 29.9% Trial 2 (Intrarosa: n= 325) (Placebo: n= 157) 80.3% (p=0.0003) 65.0% 68.6% (p=0.0003) 51.6% 47.1% (p=0.0179) 35.7% Clinical safety Apart from the main two 12-week phase III clinical studies, the safety data of Intrarosa has also been obtained from one non comparative open-label safety study of one year. Cases of breast and ovarian cancer have been reported in women treated with 6.5 mg of prasterone for 52 weeks (see section 4.4). Cases of abnormal Pap smears either Atypical Squamous Cells of Undetermined Significance (ASCUS) or Low Grade Squamous Intraepithelial Lesion (LSIL) have been reported with a common frequency in women treated with Intrarosa for 52 weeks (see section 4.4). Endometrial safety On the 389 evaluable end-of-study endometrial biopsies performed after 52 weeks of treatment with Intrarosa, no histological abnormalities were reported on the biopsies. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Intrarosa in all subsets of the paediatric population. 5.2 Pharmacokinetic properties Absorption Prasterone administered in the vagina is an inactive precursor that enters the vaginal cells and is converted intracellularly into cell-specific small amounts of both oestrogens and androgens depending upon the level of enzymes expressed in each cell type. The beneficial effects on the symptoms and 11 signs of vulvar and vaginal atrophy are exerted through activation of the vaginal oestrogen and androgen receptors. In a study conducted in postmenopausal women, administration of the Intrarosa pessary once daily for 7 days resulted in a mean prasterone Cmax and area under the curve from 0 to 24 hours (AUC0-24) at day 7 of 4.4 ng/mL and 56.2 ng h/mL, respectively, which were significantly higher than those in the group treated with placebo (Table 3; Figure 1). The Cmax and AUC0-24 of the metabolites testosterone and estradiol were also slightly higher in women treated with the Intrarosa pessary compared to those receiving placebo but all remained within normal values of postmenopausal women (< 10 pg estradiol/mL; < 0.26 ng testosterone/mL) as measured by validated mass spectrometry-based assays for both the study samples and reference values. Table 3: Cmax and AUC0-24 of Prasterone, Testosterone, and Estradiol on Day 7 Following Daily Administration of Placebo or Intrarosa (mean ± S.D.) Placebo (N=9) INTRAROSA (N=10) Prasterone Cmax (ng/mL) 1.60 (±0.95) 4.42 (±1.49) AUC0-24 (ng⋅h/mL) 24.82 (±14.31) 56.17 (±28.27) Testosterone Cmax (ng/mL) 0.12 (±0.04)1 0.15 (±0.05) AUC0-24 (ng⋅h/mL) 2.58 (±0.94)1 2.79 (±0.94) Estradiol Cmax (pg/mL) 3.33 (±1.31) 5.04 (±2.68) AUC0-24 (pg⋅h/mL) 66.49 (±20.70) 96.93 (±52.06) 1 : N=8 Figure 1: Serum Concentrations of Prasterone (A), Testosterone (B), and Estradiol (C) Measured Over a 24h Period on Day 7 Following Daily Administration of Placebo or Intrarosa (mean ± S.D.) Distribution The distribution of intravaginal (exogenous) prasterone is mainly local but some increase in systemic exposure is observed especially for the metabolites but within normal values. Biotransformation Exogenous prasterone is metabolized in the same manner as endogenous prasterone. Systemic metabolism has not been studied in this application. 12 Elimination Systemic elimination has not been studied specifically for this application. 5.3 Preclinical safety data Prasterone was not mutagenic or clastogenic in a standard battery of in vitro and in vivo studies. Carcinogenic and reproductive and development toxicity studies were not performed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Hard fat (adeps solidus). 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store below 30 °C. Do not freeze. 6.5 Nature and contents of container Blister composed of an outer layer of PVC and an inner layer of LDPE. Applicator made of LDPE and 1% colorant (Titanium dioxide). 28 pessaries are packed in a carton with 6 applicators. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Endoceutics S.A. Rue Belliard 40 1040 Brussels Belgium 8. MARKETING AUTHORISATION NUMBER(S) EU/1/17/1255/001 13 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 08 january 2018 10. DATE OF REVISION OF THE TEXT {MM/YYYY} Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 14 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 15 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Basic Pharma Manufacturing B.V. Burgemeester Lemmensstraat 352 6163 JT Geleen THE NETHERLANDS B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date Non-interventional PASS - Drug Utilisation Study (DUS) to describe the baseline characteristics, utilisation patterns of EU postmenopausal women initiating treatment with Intrarosa and to assess whether EU prescribers abide by the contraindications stated in the EU SmPC. Final study report by Q4 2021 16 ANNEX III LABELLING AND PACKAGE LEAFLET 17 A. LABELLING 18 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Intrarosa 6.5 mg pessary prasterone 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pessary contains 6.5 mg of prasterone. 3. LIST OF EXCIPIENTS Hard fat (adeps solidus). 4. PHARMACEUTICAL FORM AND CONTENTS Pessary 28 pessaries and 6 applicators. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Vaginal use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP. 9. SPECIAL STORAGE CONDITIONS Store below 30 °C. 19 Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Endoceutics S.A. Rue Belliard 40 1040 Brussels Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/17/1255/001 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> Lot. 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Intrarosa 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 20 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Intrarosa 6,5 mg pessary prasterone 2. NAME OF THE MARKETING AUTHORISATION HOLDER Endoceutics 3. EXPIRY DATE EXP 4. BATCH NUMBER<, DONATION AND PRODUCT CODES> Lot 5. OTHER 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON 1. NAME OF THE MEDICINAL PRODUCT Intrarosa 6.5 mg pessary prasterone 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pessary contains 6.5 mg of prasterone. 3. LIST OF EXCIPIENTS Hard fat (adeps solidus). 4. PHARMACEUTICAL FORM AND CONTENTS Pessary. 28 pessaries. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Vaginal use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP. 9. SPECIAL STORAGE CONDITIONS Store below 30 °C. Do not freeze. 22 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Endoceutics S.A. Rue Belliard 40 1040 Brussels Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/17/1255/001 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> Lot. 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 23 B. PACKAGE LEAFLET 24 Package leaflet: Information for the user Intrarosa 6.5 mg pessary prasterone This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Intrarosa is and what it is used for 2. What you need to know before you use Intrarosa 3. How to use Intrarosa 4. Possible side effects 5. How to store Intrarosa 6. Contents of the pack and other information 1. What Intrarosa is and what it is used for Intrarosa contains the active substance prasterone. What Intrarosa is used for Intrarosa is used to treat postmenopausal women having moderate to severe symptoms of vulvar and vaginal atrophy. It is used to relieve menopausal symptoms in the vagina such as dryness or irritation. It is caused by a drop in the levels of oestrogen in your body. This happens naturally after the menopause. How Intrarosa works Prasterone corrects the symptoms and signs of vulvar and vaginal atrophy by replacing the oestrogens which are normally produced before menopause by the ovaries of women. It is inserted into your vagina, so the hormone is released where it is needed. This may relieve discomfort in the vagina. 2. What you need to know before you use Intrarosa The use of HRT carries risks which need to be considered when deciding whether to start taking it, or whether to carry on taking it. The experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited. If you have a premature menopause the risks of using HRT may be different. Please talk to your doctor. Before you start (or restart) HRT, your doctor will ask about your own and your family’s medical history. Your doctor may decide to perform a physical examination. This may include an examination of your breasts and/or an internal examination, if necessary. 25 Once you have started on Intrarosa you should see your doctor for regular check-ups (at least every 6 months). At these check-ups, discuss with your doctor the benefits and risks of continuing with Intrarosa. Go for regular breast screening, as recommended by your doctor. Do not take Intrarosa if any of the following applies to you. If you are not sure about any of the points below, talk to your doctor before taking Intrarosa, • If you have or have ever had breast cancer, or if you are suspected of having it; • If you have cancer which is sensitive to oestrogens, such as cancer of the womb lining (endometrium), or if you are suspected of having it; • If you have any unexplained vaginal bleeding; • If you have excessive thickening of the womb lining (endometrial hyperplasia ) that is not being treated; • If you have or have ever had a blood clot in a vein (thrombosis), such as in the legs (deep venous thrombosis) or the lungs (pulmonary embolism); • If you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency); • If you have or recently have had a disease caused by blood clots in the arteries, such as a heart attack, stroke or angina; • If you have or have ever had a liver disease and your liver function tests have not returned to normal; • If you have a rare blood problem called “porphyria” which is passed down in families (inherited); • If you are allergic (hypersensitive) to prasterone or any of the other ingredients of Intrarosa (listed in section 6 Further information). If any of the above conditions appears for the first time while taking Intrarosa, stop taking it at once and consult your doctor immediately. Warnings and precautions When to take special care with Intrarosa Tell your doctor if you have ever had any of the following problems, before you start the treatment, as these may return or become worse during treatment with Intrarosa. If so, you should see your doctor more often for check-ups: • fibroids inside your womb; • growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia); • increased risk of developing blood clots (see “Blood clots in a vein (thrombosis)”); • increased risk of getting a oestrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer); • high blood pressure; • a liver disorder, such as a benign liver tumour; • diabetes; • gallstones; • migraine or severe headaches; • a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE); • epilepsy; • asthma; • a disease affecting the eardrum and hearing (otosclerosis); • a very high level of fat in your blood (triglycerides); • fluid retention due to cardiac or kidney problems. 26 Stop taking Intrarosa and see a doctor immediately If you notice any of the following when taking HRT: • any of the conditions mentioned in the ‘DO NOT take Intrarosa’ section; • yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease; • if you become pregnant; • a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness); • migraine-like headaches which happen for the first time; • if you notice signs of a blood clot, such as: - painful swelling and redness of the legs; - sudden chest pain; - difficulty in breathing. For more information, see ‘Blood clots in a vein (thrombosis)’ Note: Intrarosa is not a contraceptive. If it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your doctor for advice. HRT and cancer Intrarosa has not been studied in women with current or history of cancers. Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer) Taking oestrogen-only HRT tablets for a long time can increase the risk of developing cancer of the womb lining (the endometrium). Intrarosa does not stimulate the endometrium as shown by atrophy of the lining of the womb in all women treated with Intrarosa for one year during the clinical trials. It is uncertain whether a risk exists with Intrarosa used for long term (more than one year) treatments. However, Intrarosa has been shown to have very low absorption into the blood, therefore the addition of a progestagen is not necessary. If you get bleeding or spotting, it’s usually nothing to worry about, but you should make an appointment to see your doctor. It could be a sign that your endometrium has become thicker. The following risks apply to HRT medicines which circulate in the blood. However Intrarosa is for local treatment in the vagina and the absorption into the blood is very low. It is less likely that the conditions mentioned below will get worse or come back during treatment with Intrarosa, but you should see your doctor if you are concerned. Breast cancer Evidence suggests that taking combined oestrogen-progestogen and possibly also oestrogen-only HRT increases the risk of breast cancer. The extra risk depends on how long you take HRT. The additional risk becomes clear within a few years. However, it returns to normal within a few years (at most 5) after stopping treatment. • Regularly check your breasts. See your doctor if you notice any changes such as: • dimpling of the skin; • changes in the nipple; • any lumps you can see or feel. Additionally, you are advised to join mammography screening programs when offered to you. Ovarian cancer Ovarian cancer is rare - much rarer than breast cancer. The use of oestrogen-only HRT has been associated with a slightly increased risk of ovarian cancer. 27 The risk of ovarian cancer varies with age. For example, in women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period. For women who have been taking HRT for 5 years, there will be about 3 cases per 2000 users (i.e. about 1 extra case). Cases of ovarian and breast cancer have rarely been reported in women treated with 6.5 mg of prasterone for 52 weeks. Effect of HRT on heart and circulation Intrarosa has not been studied in women with history of thromboembolic diseases, uncontrolled hypertension or heart disease. Blood clots in a vein (thrombosis) The risk of blood clots in the veins is about 1.3 to 3-times higher in HRT users than in non-users, especially during the first year of taking it. Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death. You are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. Inform your doctor if any of these situations applies to you: • you are unable to walk for a long time because of major surgery, injury or illness (see also section 3, If you need to have surgery); • you are seriously overweight (BMI >30 kg/m2); • you have any blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots; • if any of your close relatives has ever had a blood clot in the leg, lung or another organ; • you have systemic lupus erythematosus (SLE); • you have cancer. For signs of a blood clot, see “Stop taking Intrarosa and see a doctor immediately”. In clinical trials, no deep vein thrombosis has been observed with intravaginal prasterone while one case of pulmonary embolism which corresponds to an incidence lower with Intrarosa than in the placebo group. Compare Looking at women in their 50s who are not taking HRT, on average, over a 5-year period, 4 to 7 in 1000 would be expected to get a blood clot in a vein. Heart disease (heart attack) / Hypertension For women taking oestrogen-only therapy there is no increased risk of developing a heart disease. Stroke The risk of getting stroke is about 1.5 times higher in HRT users than in non-users. The number of extra cases of stroke due to use of HRT will increase with age. No case of stroke has been observed with Intrarosa during clinical trials. Compare Looking at women in their 50s who are not taking HRT, on average, 8 in 1000 would be expected to have a stroke over a 5-year period. For women in their 50s who are taking HRT, there will be 11 cases in 1000 users, over 5 years (i.e. an extra 3 cases). Other conditions • HRT will not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start using HRT after the age of 65. Speak to your doctor for advice; • You may have vaginal discharge due to melting of the ‘hard fat base’ which adds to increased vaginal secretions due to treatment. If vaginal discharge occurs, it is not required to stop Intrarosa. 28 • Intrarosa may weaken condoms, diaphragms and cervical caps made of latex. • If you have a vaginal infection you will need a course of antibiotics before taking Intrarosa. Children and adolescents Intrarosa is only used in adult women. Other medicines and Intrarosa Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. No data on efficacy and safety are available in women currently treated with hormonal therapy such as: androgens, hormone replacement therapy (oestrogen alone or combined with progestogens). The use of Intraorsa in combination with hormone replacement therapy (oestrogen-only or oestrogen- progestagen combination or androgen treatment) or vaginal oestrogens is not recommended. Pregnancy, breast feeding and fertility Pregnancy and breast feeding Intrarosa is for use in postmenopausal women only. If you become pregnant, stop taking Intrarosa and contact your doctor. Fertility Intrarosa is not meant for women with child-bearing potential. It is not known if this medicine affects fertility. Driving and using machines Intrarosa does not affect your ability to drive and use machines. 3. How to use Intrarosa Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Your doctor will aim to prescribe the lowest dose to treat your symptom for as short as necessary. Speak to your doctor if you think this dose is too strong or not strong enough. How much to use Use one pessary once a day, at bedtime. How to use Insert the pessary into the vagina with your finger or with an applicator provided in the pack. Read the instructions on how to use Intrarosa at the end of the leaflet carefully before using this medicine. How long to use After initial use, see your doctor at least every 6 months to check if you need to keep using Intrarosa. If you use more Intrarosa than you should Vaginal douching is recommended. 29 If you forget to use Intrarosa If you forget to use a pessary, insert one as soon as you remember. However, if the next dose is due in less than 8 hours, skip the missed pessary. Do not use two pessaries to make up for a forgotten dose. If you need to have surgery If you are going to have surgery, tell the surgeon that you are taking Intrarosa. You may need to stop taking Intrarosa about 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, Blood clots in a vein). Ask your doctor when you can start taking Intrarosa again. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The following diseases are reported more often in women using HRT medicines which circulate in the blood compared to women not using HRT. These risks apply less to vaginally administered oestrogen treatments: • breast cancer; • ovarian cancer; • blood clots in the veins of the legs or lungs (venous thromboembolism); • stroke; • probable memory loss if HRT is started over the age of 65. For more information about these side effects, see section 2. The side effect the most frequently reported in the clinical studies was vaginal discharge. This is likely due to melting of the hard fat added to an expected increase in vaginal secretions due to treatment. Vaginal discharge does not require to stop Intrarosa. The following adverse effects were also reported: − with a common frequency (may affect up to 1 in 10 people): abnormal Pap smear (mostly ASCUS or LGSIL), weight fluctuations (either increase or decrease); − with a uncommon frequency (may affect up to 1 in 100 people): benign cervical or uterine polyps, benign breast mass. The following side effects have been reported with HRT containing estrogens but not with Intrarosa during clinical trials: • gall bladder disease • various skin disorders: - discoloration of the skin especially of the face or neck known as “pregnancy patches” (chloasma); - painful reddish skin nodules (erythema nodosum); - rash with target-shaped reddening or sores (erythema multiforme). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 30 5. How to store Intrarosa Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blisters after EXP. The expiry date refers to the last day of that month. Store below 30 °C. Do not freeze. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Intrarosa contains - The active substance is prasterone. Each pessary contains 6.5 mg of prasterone. - The only other ingredient is the hard fat (adeps solidus). What Intrarosa looks like and contents of the pack Intrarosa is a white to off-white, bullet-shaped pessary approximately 28 mm long and 9 mm in diameter at its widest end. The applicator is made of LDPE and 1% colorant (Titanium dioxide). It is available in blister packs of 28 pessaries with 6 applicators. Marketing Authorisation Holder Endoceutics S.A. Rue Belliard 40 1040 Brussels Belgium Manufacturer Basic Pharma Manufacturing B.V. Burgemeester Lemmensstraat 352 6163 JT Geleen The Netherlands For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien, Luxembourg/Luxemburg, Nederland Theramex Belgium BVBA Tél/Tel: + 32 (0) 28088080 INTRAROSA.Enquiries@theramex.com Deutschland, Österreich Theramex Germany GmbH Tel: + 49 (0) 3088789684 INTRAROSA.Enquiries@theramex.com mailto:INTRAROSA.Enquiries@theramex.com mailto:INTRAROSA.Enquiries@theramex.com 31 España Lacer S.A. Tel: + 34 934 46 53 00 France Theramex France S.A.S. Tél: + 33 (0) 800100350 INTRAROSA.Enquiries@theramex.com Italia Theramex Italy S.r.l. Tel: + 39 (0) 687500626 INTRAROSA.Enquiries@theramex.com Polska Theramex Poland sp. z o.o. Tel.: + 48 (0) 22 30 77 166 INTRAROSA.Enquiries@theramex.com Portugal Tecnimede - Sociedade Técnico-Medicinal, S.A. Tel: + 351 210 414 100 dmed.fv@tecnimede.pt United Kingdom, Ireland, Malta Theramex UK Limited Tel: + 44 (0) 3330096795 INTRAROSA.Enquiries@theramex.com Danmark, Ísland, Norge, Suomi/Finland, Sverige Avia Pharma AB Sverige/Svíþjóð/Ruosti Tlf/Sími/Tlf/Puh/Tel: + 46 (0) 8 544 900 22 България, Česká republika, Eesti, Ελλάδα, Hrvatska, Κύπρο, Latvija, Lietuva, Magyarország, România, Slovenija, Slovenská republika Theramex Ireland Limited Tel/Teл./Τηλ: + 353 (0) 15138855 INTRAROSA.Enquiries@theramex.com This leaflet was last revised in MM/YYYY. Other sources of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu. mailto:INTRAROSA.Enquiries@theramex.com mailto:INTRAROSA.Enquiries@theramex.com mailto:INTRAROSA.Enquiries@theramex.com mailto:dmed.fv@tecnimede.pt mailto:INTRAROSA.Enquiries@theramex.com mailto:INTRAROSA.Enquiries@theramex.com 32 Instructions on how to use Intrarosa How should I use Intrarosa • Insert one prasterone pessary in your vagina once a day at bedtime with an applicator or your finger. Before you start • Empty your bladder and wash your hands before handling the pessary and applicator. • Tear off one wrapped pessary from the 7-pessary strip. A. Using the applicator STEP 1 • 1A. Remove 1 applicator from the package. • 1B. Pull back on the plunger until it stops to activate the applicator. The applicator must be activated before use. Place the applicator on a clean surface. STEP 5 • Select the position for insertion of the pessary that is most comfortable for you. 5a. Lying position STEP 2 • Slowly pull the plastic tabs on the pessary away from each other while keeping the pessary still between your fingers. • Carefully remove the pessary from the plastic wrap. • If a pessary falls on an unsanitary surface, replace it with a new one. 5b. Standing position STEP 3 • Place the flat end of the pessary into the open end of the activated applicator as shown. You are now ready to insert the pessary into your vagina. STEP 6 • Gently slide the pessary end of the applicator into your vagina as far as it will comfortably go. Do not use force. STEP 4 • Hold the applicator between your thumb and middle finger. • Leave your index (pointer) finger free to press the applicator plunger after the applicator is inserted into your vagina. STEP 7 • Press the applicator plunger with your index (pointer) finger to release the pessary. • Remove the applicator. Wash it or throw it away after using for one week (two extra applicators are provided). • To wash the applicator: − Take it to pieces; − Rinse the 2 pieces for 30 seconds under running water; − Wipe with a paper towel and reassemble. Keep it in a clean place. 33 B. Using the finger Follow the above instructions of Step 2, and then insert the pessary into the vagina with your finger as far as it can comfortably go. Do not use force. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what intrarosa is and what it is used for', 'Section_Content': 'intrarosa contains the active substance prasterone. what intrarosa is used for intrarosa is used to treat postmenopausal women having moderate to severe symptoms of vulvar and vaginal atrophy. it is used to relieve menopausal symptoms in the vagina such as dryness or irritation. it is caused by a drop in the levels of oestrogen in your body. this happens naturally after the menopause. how intrarosa works prasterone corrects the symptoms and signs of vulvar and vaginal atrophy by replacing the oestrogens which are normally produced before menopause by the ovaries of women. it is inserted into your vagina, so the hormone is released where it is needed. this may relieve discomfort in the vagina.', 'Entity_Recognition': [{'Text': 'intrarosa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 5, 'BeginOffset': 0, 'EndOffset': 9, 'Score': 0.6486049294471741, 'Text': 'intrarosa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 40, 'EndOffset': 50, 'Score': 0.9843742251396179, 'Text': 'prasterone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5307358503341675}]}, {'Id': 7, 'BeginOffset': 57, 'EndOffset': 66, 'Score': 0.7696083784103394, 'Text': 'intrarosa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 79, 'EndOffset': 88, 'Score': 0.7706685066223145, 'Text': 'intrarosa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'postmenopausal women', 'Type': 'PROBLEM', 'BeginOffset': 106, 'EndOffset': 126}, {'Text': 'moderate to severe symptoms', 'Type': 'PROBLEM', 'BeginOffset': 134, 'EndOffset': 161}, {'Id': 11, 'BeginOffset': 165, 'EndOffset': 191, 'Score': 0.8731752634048462, 'Text': 'vulvar and vaginal atrophy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7951657772064209}]}, {'Text': 'menopausal symptoms in the vagina', 'Type': 'PROBLEM', 'BeginOffset': 215, 'EndOffset': 248}, {'Id': 13, 'BeginOffset': 257, 'EndOffset': 264, 'Score': 0.9894688129425049, 'Text': 'dryness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7323406338691711}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9694943428039551, 'RelationshipScore': 0.9641883373260498, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 0, 'BeginOffset': 242, 'EndOffset': 248, 'Text': 'vagina', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 14, 'BeginOffset': 268, 'EndOffset': 278, 'Score': 0.9862313866615295, 'Text': 'irritation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7343845367431641}]}, {'Id': 15, 'BeginOffset': 298, 'EndOffset': 342, 'Score': 0.32789433002471924, 'Text': 'drop in the levels of oestrogen in your body', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'the menopause', 'Type': 'PROBLEM', 'BeginOffset': 373, 'EndOffset': 386}, {'Text': 'the symptoms', 'Type': 'PROBLEM', 'BeginOffset': 428, 'EndOffset': 440}, {'Id': 17, 'BeginOffset': 454, 'EndOffset': 480, 'Score': 0.765964686870575, 'Text': 'vulvar and vaginal atrophy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7249699234962463}]}, {'Id': 18, 'BeginOffset': 544, 'EndOffset': 553, 'Score': 0.9650244116783142, 'Text': 'menopause', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7744628190994263}]}, {'Id': 2, 'BeginOffset': 561, 'EndOffset': 568, 'Score': 0.8649517297744751, 'Text': 'ovaries', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 3, 'BeginOffset': 604, 'EndOffset': 610, 'Score': 0.9816739559173584, 'Text': 'vagina', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the hormone', 'Type': 'TREATMENT', 'BeginOffset': 615, 'EndOffset': 626}, {'Text': 'discomfort in the vagina', 'Type': 'PROBLEM', 'BeginOffset': 676, 'EndOffset': 700}]}

{'Title': '2. what you need to know before you use intrarosa', 'Section_Content': 'the use of hrt carries risks which need to be considered when deciding whether to start taking it, or whether to carry on taking it. the experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited. if you have a premature menopause the risks of using hrt may be different. please talk to your doctor. before you start (or restart) hrt, your doctor will ask about your own and your family\'s medical history. your doctor may decide to perform a physical examination. this may include an examination of your breasts and/or an internal examination, if necessary. once you have started on intrarosa you should see your doctor for regular check-ups (at least every 6 months). at these check-ups, discuss with your doctor the benefits and risks of continuing with intrarosa. go for regular breast screening, as recommended by your doctor. do not take intrarosa if any of the following applies to you. if you are not sure about any of the points below, talk to your doctor before taking intrarosa, if you have or have ever had breast cancer, or if you are suspected of having it; if you have cancer which is sensitive to oestrogens, such as cancer of the womb lining (endometrium), or if you are suspected of having it; if you have any unexplained vaginal bleeding; if you have excessive thickening of the womb lining (endometrial hyperplasia ) that is not being treated; if you have or have ever had a blood clot in a vein (thrombosis), such as in the legs (deep venous thrombosis) or the lungs (pulmonary embolism); if you have a blood clotting disorder (such as protein c, protein s, or antithrombin deficiency); if you have or recently have had a disease caused by blood clots in the arteries, such as a heart attack, stroke or angina; if you have or have ever had a liver disease and your liver function tests have not returned to normal; if you have a rare blood problem called "porphyria" which is passed down in families (inherited); if you are allergic (hypersensitive) to prasterone or any of the other ingredients of intrarosa (listed in section 6 further information). if any of the above conditions appears for the first time while taking intrarosa, stop taking it at once and consult your doctor immediately. warnings and precautions when to take special care with intrarosa tell your doctor if you have ever had any of the following problems, before you start the treatment, as these may return or become worse during treatment with intrarosa. if so, you should see your doctor more often for check-ups: fibroids inside your womb; growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia); increased risk of developing blood clots (see "blood clots in a vein (thrombosis)"); increased risk of getting a oestrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer); high blood pressure; a liver disorder, such as a benign liver tumour; diabetes; gallstones; migraine or severe headaches; a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, sle); epilepsy; asthma; a disease affecting the eardrum and hearing (otosclerosis); a very high level of fat in your blood (triglycerides); fluid retention due to cardiac or kidney problems. stop taking intrarosa and see a doctor immediately if you notice any of the following when taking hrt: any of the conditions mentioned in the \'do not take intrarosa\' section; yellowing of your skin or the whites of your eyes (jaundice). these may be signs of a liver disease; if you become pregnant; a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness); migraine-like headaches which happen for the first time; if you notice signs of a blood clot, such as: - painful swelling and redness of the legs; - sudden chest pain; - difficulty in breathing. for more information, see \'blood clots in a vein (thrombosis)\' note: intrarosa is not a contraceptive. if it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. speak to your doctor for advice. hrt and cancer intrarosa has not been studied in women with current or history of cancers. excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer) taking oestrogen-only hrt tablets for a long time can increase the risk of developing cancer of the womb lining (the endometrium). intrarosa does not stimulate the endometrium as shown by atrophy of the lining of the womb in all women treated with intrarosa for one year during the clinical trials. it is uncertain whether a risk exists with intrarosa used for long term (more than one year) treatments. however, intrarosa has been shown to have very low absorption into the blood, therefore the addition of a progestagen is not necessary. if you get bleeding or spotting, it\'s usually nothing to worry about, but you should make an appointment to see your doctor. it could be a sign that your endometrium has become thicker. the following risks apply to hrt medicines which circulate in the blood. however intrarosa is for local treatment in the vagina and the absorption into the blood is very low. it is less likely that the conditions mentioned below will get worse or come back during treatment with intrarosa, but you should see your doctor if you are concerned. breast cancer evidence suggests that taking combined oestrogen-progestogen and possibly also oestrogen-only hrt increases the risk of breast cancer. the extra risk depends on how long you take hrt. the additional risk becomes clear within a few years. however, it returns to normal within a few years (at most 5) after stopping treatment. regularly check your breasts. see your doctor if you notice any changes such as: dimpling of the skin; changes in the nipple; any lumps you can see or feel. additionally, you are advised to join mammography screening programs when offered to you. ovarian cancer ovarian cancer is rare - much rarer than breast cancer. the use of oestrogen-only hrt has been associated with a slightly increased risk of ovarian cancer. the risk of ovarian cancer varies with age. for example, in women aged 50 to 54 who are not taking hrt, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period. for women who have been taking hrt for 5 years, there will be about 3 cases per 2000 users (i.e. about 1 extra case). cases of ovarian and breast cancer have rarely been reported in women treated with 6.5 mg of prasterone for 52 weeks. effect of hrt on heart and circulation intrarosa has not been studied in women with history of thromboembolic diseases, uncontrolled hypertension or heart disease. blood clots in a vein (thrombosis) the risk of blood clots in the veins is about 1.3 to 3-times higher in hrt users than in non-users, especially during the first year of taking it. blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death. you are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. inform your doctor if any of these situations applies to you: you are unable to walk for a long time because of major surgery, injury or illness (see also section 3, if you need to have surgery); you are seriously overweight (bmi >30 kg/m2); you have any blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots; if any of your close relatives has ever had a blood clot in the leg, lung or another organ; you have systemic lupus erythematosus (sle); you have cancer. for signs of a blood clot, see "stop taking intrarosa and see a doctor immediately". in clinical trials, no deep vein thrombosis has been observed with intravaginal prasterone while one case of pulmonary embolism which corresponds to an incidence lower with intrarosa than in the placebo group. compare looking at women in their 50s who are not taking hrt, on average, over a 5-year period, 4 to 7 in 1000 would be expected to get a blood clot in a vein. heart disease (heart attack) / hypertension for women taking oestrogen-only therapy there is no increased risk of developing a heart disease. stroke the risk of getting stroke is about 1.5 times higher in hrt users than in non-users. the number of extra cases of stroke due to use of hrt will increase with age. no case of stroke has been observed with intrarosa during clinical trials. compare looking at women in their 50s who are not taking hrt, on average, 8 in 1000 would be expected to have a stroke over a 5-year period. for women in their 50s who are taking hrt, there will be 11 cases in 1000 users, over 5 years (i.e. an extra 3 cases). other conditions hrt will not prevent memory loss. there is some evidence of a higher risk of memory loss in women who start using hrt after the age of 65. speak to your doctor for advice; you may have vaginal discharge due to melting of the \'hard fat base\' which adds to increased vaginal secretions due to treatment. if vaginal discharge occurs, it is not required to stop intrarosa. intrarosa may weaken condoms, diaphragms and cervical caps made of latex. if you have a vaginal infection you will need a course of antibiotics before taking intrarosa. children and adolescents intrarosa is only used in adult women. other medicines and intrarosa tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. no data on efficacy and safety are available in women currently treated with hormonal therapy such as: androgens, hormone replacement therapy (oestrogen alone or combined with progestogens). the use of intraorsa in combination with hormone replacement therapy (oestrogen-only or oestrogen- progestagen combination or androgen treatment) or vaginal oestrogens is not recommended. pregnancy, breast feeding and fertility pregnancy and breast feeding intrarosa is for use in postmenopausal women only. if you become pregnant, stop taking intrarosa and contact your doctor. fertility intrarosa is not meant for women with child-bearing potential. it is not known if this medicine affects fertility. driving and using machines intrarosa does not affect your ability to drive and use machines.', 'Entity_Recognition': [{'Text': 'intrarosa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'hrt carries risks', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 28}, {'Text': 'a premature menopause', 'Type': 'PROBLEM', 'BeginOffset': 171, 'EndOffset': 192}, {'Id': 19, 'BeginOffset': 201, 'EndOffset': 216, 'Score': 0.9702390432357788, 'Text': 'ovarian failure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': 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{'Title': '3. how to use intrarosa', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. your doctor will aim to prescribe the lowest dose to treat your symptom for as short as necessary. speak to your doctor if you think this dose is too strong or not strong enough. how much to use use one pessary once a day, at bedtime. how to use insert the pessary into the vagina with your finger or with an applicator provided in the pack. read the instructions on how to use intrarosa at the end of the leaflet carefully before using this medicine. how long to use after initial use, see your doctor at least every 6 months to check if you need to keep using intrarosa. if you use more intrarosa than you should vaginal douching is recommended. if you forget to use intrarosa if you forget to use a pessary, insert one as soon as you remember. however, if the next dose is due in less than 8 hours, skip the missed pessary. do not use two pessaries to make up for a forgotten dose. if you need to have surgery if you are going to have surgery, tell the surgeon that you are taking intrarosa. you may need to stop taking intrarosa about 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, blood clots in a vein). ask your doctor when you can start taking intrarosa again.', 'Entity_Recognition': [{'Text': 'intrarosa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Text': 'the lowest dose', 'Type': 'TREATMENT', 'BeginOffset': 168, 'EndOffset': 183}, {'Text': 'your symptom', 'Type': 'PROBLEM', 'BeginOffset': 193, 'EndOffset': 205}, {'Text': 'the pessary', 'Type': 'TREATMENT', 'BeginOffset': 387, 'EndOffset': 398}, {'Id': 0, 'BeginOffset': 408, 'EndOffset': 414, 'Score': 0.842574417591095, 'Text': 'vagina', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the following diseases are reported more often in women using hrt medicines which circulate in the blood compared to women not using hrt. these risks apply less to vaginally administered oestrogen treatments: breast cancer; ovarian cancer; blood clots in the veins of the legs or lungs (venous thromboembolism); stroke; probable memory loss if hrt is started over the age of 65. for more information about these side effects, see section 2. the side effect the most frequently reported in the clinical studies was vaginal discharge. this is likely due to melting of the hard fat added to an expected increase in vaginal secretions due to treatment. vaginal discharge does not require to stop intrarosa. the following adverse effects were also reported: − with a common frequency (may affect up to 1 in 10 people): abnormal pap smear (mostly ascus or lgsil), weight fluctuations (either increase or decrease); − with a uncommon frequency (may affect up to 1 in 100 people): benign cervical or uterine polyps, benign breast mass. the following side effects have been reported with hrt containing estrogens but not with intrarosa during clinical trials: gall bladder disease various skin disorders: - discoloration of the skin especially of the face or neck known as "pregnancy patches" (chloasma); - painful reddish skin nodules (erythema nodosum); - rash with target-shaped reddening or sores (erythema multiforme). reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'intrarosa', 'Type': 'PRODUCT_NAME', 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'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6659276485443115}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9829670190811157, 'RelationshipScore': 0.6303657293319702, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 10, 'BeginOffset': 1406, 'EndOffset': 1410, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 48, 'BeginOffset': 1441, 'EndOffset': 1445, 'Score': 0.9934501647949219, 'Text': 'rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.45215362310409546}]}, {'Text': 'shaped reddening', 'Type': 'PROBLEM', 'BeginOffset': 1458, 'EndOffset': 1474}, {'Text': 'sores (erythema multiforme', 'Type': 'PROBLEM', 'BeginOffset': 1478, 'EndOffset': 1504}, {'Id': 52, 'BeginOffset': 1520, 'EndOffset': 1532, 'Score': 0.9391629099845886, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6672715544700623}]}, {'Id': 53, 'BeginOffset': 1548, 'EndOffset': 1560, 'Score': 0.9075103998184204, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6905905604362488}]}, {'Id': 54, 'BeginOffset': 1624, 'EndOffset': 1636, 'Score': 0.9505295753479004, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5946633815765381}]}, {'Id': 55, 'BeginOffset': 1685, 'EndOffset': 1697, 'Score': 0.8508116602897644, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6634889841079712}]}, {'Id': 56, 'BeginOffset': 1751, 'EndOffset': 1762, 'Score': 0.3608551621437073, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5683092474937439}]}, {'Id': 57, 'BeginOffset': 1776, 'EndOffset': 1788, 'Score': 0.85548335313797, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7115870714187622}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1844, 'EndOffset': 1857}]}

{'Title': '5. how to store intrarosa', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and blisters after exp. the expiry date refers to the last day of that month. store below 30 . do not freeze. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'intrarosa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 226, 'EndOffset': 228}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what intrarosa contains - the active substance is prasterone. each pessary contains 6.5 mg of prasterone. - the only other ingredient is the hard fat (adeps solidus). what intrarosa looks like and contents of the pack intrarosa is a white to off-white, bullet-shaped pessary approximately 28 mm long and 9 mm in diameter at its widest end. the applicator is made of ldpe and 1% colorant (titanium dioxide). it is available in blister packs of 28 pessaries with 6 applicators.', 'Entity_Recognition': [{'Text': 'intrarosa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 50, 'EndOffset': 60, 'Score': 0.9751477241516113, 'Text': 'prasterone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'each pessary', 'Type': 'TREATMENT', 'BeginOffset': 62, 'EndOffset': 74}, {'Text': '6.5', 'Type': 'NUMBER', 'BeginOffset': 84, 'EndOffset': 87}, {'Id': 2, 'BeginOffset': 94, 'EndOffset': 104, 'Score': 0.9798380136489868, 'Text': 'prasterone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9242258071899414, 'RelationshipScore': 0.9999991655349731, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 84, 'EndOffset': 90, 'Text': '6.5 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'bullet-shaped pessary', 'Type': 'TREATMENT', 'BeginOffset': 253, 'EndOffset': 274}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 289, 'EndOffset': 291}, {'Text': '9', 'Type': 'NUMBER', 'BeginOffset': 304, 'EndOffset': 305}, {'Text': 'ldpe', 'Type': 'TREATMENT', 'BeginOffset': 366, 'EndOffset': 370}, {'Text': '1% colorant (titanium dioxide', 'Type': 'TREATMENT', 'BeginOffset': 375, 'EndOffset': 404}, {'Text': 'blister packs', 'Type': 'TREATMENT', 'BeginOffset': 426, 'EndOffset': 439}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 443, 'EndOffset': 445}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 461, 'EndOffset': 462}]}

F06CB0C715721E3C777AF60468921DA1

https://www.ema.europa.eu/documents/product-information/pretomanid-fgk-epar-product-information_en.pdf

Pretomanid FGK

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Pretomanid FGK 200 mg tablet 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 200 mg pretomanid. Excipient with known effect Each tablet contains 294 mg lactose (as monohydrate) and 5 mg sodium. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablets. White to off-white oval tablet debossed with M on one side and P200 on the other side. Tablet dimensions: 18 × 9 mm. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Pretomanid FGK is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB), see sections 4.2, 4.4 and 5.1. Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Treatment with pretomanid should be initiated and monitored by a physician experienced in the management of multidrug-resistant tuberculosis. Pretomanid should be administered by directly observed therapy (DOT) or in accordance with local practice. Posology The recommended dosage is 200 mg (one tablet) pretomanid once daily, for 26 weeks. A longer duration of therapy may be considered in patients who have not responded adequately to treatment at 26 weeks on a case by case basis (see section 5.1). 2 Pretomanid should be administered only in combination with bedaquiline (400 mg once daily for 2 weeks followed by 200 mg 3 times per week [with at least 48 hours between doses] orally for a total of 26 weeks) and linezolid (1,200 mg daily orally for up to 26 weeks). The product information for bedaquiline and linezolid should be consulted for additional information on the use of these medicinal products. In addition, see section 4.4 for information on the dose modification of linezolid that was applied during the Nix-TB clinical study and see section 5.1 for details of the study. Discontinuation of the pretomanid-bedaquiline-linezolid treatment regimen (see also sections 4.4, 4.8 and 5.1) • If either bedaquiline or pretomanid is discontinued for any reason, the entire combination regimen should be discontinued. • If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, the entire combination regimen should be discontinued. • If linezolid is discontinued after the initial four weeks of consecutive treatment, the regimen may be continued with only bedaquiline and pretomanid. Missed doses Any missed doses of pretomanid and bedaquiline should be made up at the end of treatment. Doses of linezolid that are missed due to linezolid adverse reactions should not be made up at the end of treatment. Refer to the product information of bedaquiline and linezolid for additional information on these medicinal products. Treatment duration The total duration of treatment with pretomanid in combination with bedaquiline and linezolid is 26 weeks. Data on longer treatment duration is limited. A longer duration of therapy may be considered in patients who have not responded adequately to treatment at 26 weeks on a case by case basis (see section 5.1). Elderly population (≥ 65 years of age) There is limited clinical data on the use of pretomanid in elderly patients. Hence, the safety and efficacy of pretomanid in elderly patients have not been established. Hepatic impairment The safety and efficacy of pretomanid in populations with hepatic impairment have not been established (see section 4.4). Renal impairment The safety and efficacy of pretomanid in populations with renal impairment have not been established. No data are available. Use in patients with renal impairment is not recommended. Paediatric population The safety and efficacy of pretomanid in children and adolescents have not yet been established. No data are available. Method of administration For oral use. Pretomanid should be taken with food (see section 5.2). Tablets should be swallowed with water. 4.3 Contraindications 3 Hypersensitivity to the active substance, other nitroimidazoles, or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Safety and effectiveness of pretomanid have not been established for its use in combination with medicinal products other than bedaquiline and linezolid as part of the recommended dosing regimen, and thus pretomanid should not be used as part of any other regimen. Hepatotoxicity Hepatotoxicity may occur with use of the regimen consisting of pretomanid, bedaquiline and linezolid. Liver-related laboratory tests should be monitored. Alcohol and hepatotoxic medicinal products (including herbal supplements), other than those specified in the indication statement (see section 4.1), should be avoided while on the regimen, especially in patients with impaired hepatic function. Symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) should be addressed throughout treatment. Laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) should be monitored at initiation of treatment, and at a minimum once every week during the first month of treatment, every other week during month 2, and monthly thereafter while on treatment, and as needed. If evidence of new or worsening liver dysfunction occurs, a test for viral hepatitis should be performed and other hepatotoxic medicinal products should be discontinued. Treatment with the entire regimen should be interrupted if: • Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upper limit of normal. • Aminotransferase elevations are greater than 8 times the upper limit of normal. • Aminotransferase elevations are greater than 5 times the upper limit of normal and persist beyond 2 weeks. Treatment may be re-initiated under close surveillance when hepatic enzymes and clinical symptoms normalize. Modification/interruption due to linezolid adverse reactions Modification or interruption of linezolid dosing may be needed during the course of therapy to manage the known linezolid toxicities. The recommendations below reflect the procedures used in the Nix-TB study (section 5.1). Myelosuppression Complete blood counts should be monitored at a minimum at start of treatment, at two weeks, and then monthly in patients receiving linezolid as part of the combination regimen. Haematologic parameters are variable from measurement to measurement, and decreases should be evaluated in the context of the patient’s overall medical condition. Guidelines below may be considered when it is likely that linezolid has caused the decrease in blood count. Consider pausing or reducing the dose of linezolid in the following situations. • Anaemia - if haemoglobin falls below 80 g/l or more than 25% below the start of treatment. • Leukopenia - if the Absolute Neutrophil Count (ANC) falls below 0.75 × 109/l or significantly below baseline. Confirm with a repeat test before making further decisions as ANCs can have diurnal and other variability. • Thrombocytopenia - if platelets fall below 50 × 109/l or significantly below baseline. Ideally confirm with a repeat test before making further decisions. When improvement in the myelosuppression is observed, consider resuming linezolid at the initial dose or at half the initial dose. Peripheral neuropathy and optic neuropathy 4 Peripheral neuropathy associated with linezolid is generally reversible or improved with interruption, dose reduction, or discontinuation of linezolid dosing. When improvement in the peripheral neuropathy is observed, consider resuming linezolid at half the initial dose. In the Nix-TB study (section 5.1), the incidence of interruption/reduction/discontinuation of linezolid due to peripheral neuropathy increased steadily from around 2 months of therapy throughout the completion of therapy. Monitor visual symptoms in all patients receiving the combination regimen of pretomanid, bedaquiline, and linezolid. If a patient experiences symptoms of visual impairment, interrupt linezolid dosing and obtain prompt ophthalmologic examination to evaluate for signs of optic neuropathy. Lactic acidosis Lactic acidosis is a known adverse reaction of linezolid. Patients who develop recurrent nausea or vomiting should receive immediate medical evaluation, including evaluation of bicarbonate and lactic acid levels, and interruption of linezolid should be considered. Linezolid may be reinitiated at a lower dose with close monitoring when signs and symptoms of lactic acidosis resolve. QT prolongation QT prolongation was reported with the combination regimen of pretomanid, bedaquiline, and linezolid. QT prolongation is a known adverse reaction of bedaquiline. Bedaquiline in combination with pretomanid appears to result in a higher QT prolongation than expected with bedaquiline alone. However, the impact of pretomanid has not been fully characterized. An ECG should be obtained before initiation of treatment, and at least monthly during treatment with the combination regimen of pretomanid, bedaquiline, and linezolid. Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Follow-up monitoring of electrolytes should be performed if QT prolongation is detected. The following may increase the risk for QT prolongation: • a history of Torsade de Pointes, • a personal or family history of congenital long QT syndrome, • a history of or ongoing hypothyroidism, • ongoing bradyarrhythmia, • heart failure or known structural heart disease, • QT-interval as corrected by the Fridericia method (QTcF) > 450 ms (confirmed by repeat electrocardiogram) or • serum calcium, magnesium, or potassium levels below the lower limits of normal. The entire regimen of pretomanid, bedaquiline, and linezolid must be discontinued if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG). If syncope occurs, an ECG should be obtained to detect QT prolongation. The QT prolongation risk for the combination regimen has not been established at exposures higher than therapeutic levels. The risk may be increased if the systemic exposure of pretomanid is elevated (see sections 4.5 and 5.2). Excipients Pretomanid FGK contains lactose. Patients with rare hereditary problems such as galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pretomanid FGK contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction Effects of other medicinal products on pretomanid CYP3A4 inducers 5 Pretomanid is metabolized in part by CYP3A4. In consequence, exposure to pretomanid may be reduced during co-administration with inducers of CYP3A4. In interaction studies of multiple-dose pretomanid with multiple-dose rifampicin or efavirenz, the AUC0-24h of pretomanid was reduced by 66% or 35%, respectively. Due to the possibility of a reduction of the therapeutic effect of pretomanid due to a decrease in systemic exposure, co-administration of pretomanid and moderate or strong CYP3A4 inducers (e.g. efavirenz, etravirine, rifamycins including rifampicin, rifapentine and rifabutin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum)) used systemically should be avoided (see section 4.4). In an interaction study of multiple-dose pretomanid with multiple-dose ritonavir-boosted-lopinavir, the AUC0-24h of pretomanid was reduced by 17%. Effects of pretomanid on other medicinal products OAT3 substrates Pretomanid is an inhibitor of the OAT3 transporter in vitro, which could result in increased concentrations of OAT3 substrate medicinal products clinically and may increase the risk of adverse reactions of these medicines. If pretomanid is co-administered with OAT3 substrate medicinal products (e.g., methotrexate, benzylpenicillin, indomethacin, ciprofloxacin), monitoring for OAT3 substrate drug-related adverse reactions should be performed and dosage reductions for OAT3 medicinal product should be considered, if needed (see section 4.4). Substrates of CYP2C8, CYP2C9 and CYP2C19 Pretomanid has been shown to inhibit CYP2C8 and CYP2C19 in a time dependent manner in vitro. Induction of CYP2C8, CYP2C9 and CYP2C19 by pretomanid has not been studied. Therefore, the net effect of pretomanid on CYP2C8 and/or CYP2C19 substrates is unknown. Consequently concomitant treatment with substrates of CYP2C8, CYP2C9 and CYP2C19 should be closely monitored. Substrates of Pgp, OATP1B3, OCT2 and BCRP The potential of pretomanid to inhibit Pgp, OATP1B3, OCT2 and BCRP in vivo is unknown. Caution is recommended for concomitant treatment with pretomanid and transporter substrates with a narrow therapeutic index. 4.6 Fertility, pregnancy and lactation Pregnancy There are very limited amount of data from the use of pretomanid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryo-fetal development (see section 5.3). Pretomanid should be used during pregnancy only if the benefit to the patient is considered to outweigh the potential risk to the foetus. Breast-feeding It is unknown whether pretomanid/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of pretomanid in milk (see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue pretomanid therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Fertility No human data on the effect of pretomanid on fertility are available. Oral administration of pretomanid caused markedly reduced fertility in male rats (see section 5.3). 6 4.7 Effects on ability to drive and use machines Pretomanid may have a minor influence on the ability to drive and use machines. Dizziness has been reported in some patients taking pretomanid and some patients experienced visual impairment. This should be considered when assessing a patient’s ability to drive or operate machinery (see section 4.8). 4.8 Undesirable effects The most frequent adverse drug reactions during treatment with pretomanid in combination with bedaquiline and linezolid were nausea (36%), vomiting (28%) and transaminases increased (21%). 81% and 37% of patients experienced peripheral neuropathy and anaemia, which are known adverse reactions to linezolid, respectively. Nausea, vomiting and transaminases increased are possible adverse reactions to all three medicinal products in the regimen. Refer to the Summary of Product Characteristics of bedaquiline and linezolid for more information on adverse reactions caused by these two medicinal products. Tabulated list of adverse reactions Adverse drug reactions (ADRs) reported from the uncontrolled phase 3 trial in 109 patients treated with pretomanid in combination with bedaquiline and linezolid are summarized in the table below by system organ class and frequency. ADRs considered attributed to linezolid are marked with ∆. System Organ Class Very Common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Infections and infestations Fungal infection, oral candidiasis, oral fungal infection Blood and lymphatic system disorder Anaemia ∆ Leukopenia ∆, neutropenia ∆, thrombocytopenia ∆, Lymphopenia ∆, pancytopenia ∆ Metabolic and nutrition disorders Decreased appetite Hypoglycaemia, lactic acidosis ∆ Acidosis ∆, dehydration, hypocalcaemia, hypovolaemia, hypomagnesaemia Psychiatric disorders Insomnia Anxiety, depression Nervous system disorders Peripheral neuropathy* ∆, headache Dysgeusia, dizziness Eye disorders Visual impairment*, eye irritation, eye pain, optic neuropathy*∆ Lens disorder, dry eye, eye pruritis, eye swelling, papilloedema, presbyopia Ear and labyrinth disorder Deafness Cardiac disorder Palpitations, sinus tachycardia Vascular disorders Hypotension Respiratory, Cough, epistaxis 7 System Organ Class Very Common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 thoracic and mediastinal disorders Gastrointestinal disorders Nausea, vomiting, dyspepsia, abdominal pain* Gastritis*, diarrhoea, constipation, gastrooesophageal reflux disease, pancreatitis* Abdominal distension, glossodynia, haematemesis Hepatobiliary disorders Transaminase increased* Hyperbilirubinaemia Hepatomegaly, jaundice Skin and subcutaneous tissue disorder Acne*, pruritus*, rash* Dry skin, alopecia Dermatitis allergic, skin hyperpigmentation Musculoskeletal and connective tissue disorders Musculoskeletal pain* Muscle spasms Musculoskeletal stiffness Reproductive system and breast disorder Erectile dysfunction, metrorrhagia General disorders and administration site conditions Fatigue, asthenia Malaise Investigations Gamma- glutamyltransferase increased; amylase increased* Electrocardiogram QT prolonged, blood alkaline phosphatase increased, blood creatine phosphokinase increased, blood urea increased, lipase increased* Albumin urine present, blood creatinine increased, blood creatine phosphokinase MB increased, blood uric acid increased, creatinine renal clearance decreased *Selected terms are collapsed as follows: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy); gastritis (gastritis, chronic gastritis); acne (acne, dermatitis acneiform); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity); transaminases increased (alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, liver function test increased, transaminases increased); rash (rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness); visual impairment (vision blurred, visual acuity reduced, visual impairment); amylase increased (amylase increased, hyperamylasaemia); lipase increased (hyperlipasaemia, lipase increased); optic neuropathy (optic neuropathy, optic neuritis); pancreatitis (pancreatitis, haemorrhagic pancreatitis). Description of selected adverse reactions Increased transaminases In the Nix-TB trial in which 109 patients were treated with pretomanid in combination with bedaquiline and linezolid, 21% of patients experienced the ADR of increased transaminases (very common). Except for one patient who died due to pneumonia and sepsis, all patients who experienced 8 increased transaminases were able to continue or resume therapy after interruption, and complete the full course of treatment. ECG QT interval prolongation QT prolongation is a known adverse reaction of bedaquiline. Bedaquiline in combination with pretomanid appears to result in a higher QT prolongation than expected with bedaquiline alone. However, the impact of pretomanid has not been fully characterised. In the Nix-TB trial, 6 patients (5.5%, common) experienced QT prolongation. In the entire Nix-TB trial, no subject was reported to have a treatment emergent QTcF exceeding 480 ms. One subject was reported to have a change from baseline of QTcF exceeding 60 ms. Myelosuppression Myelosuppression is a known adverse reaction of linezolid. In the Nix-TB trial, 37% (very common) of patients experienced anaemia, as the most common ADR of hematopoietic cytopenia attributed to linezolid. The majority of cytopenias began after 2 weeks of treatment. Overall, three patients experienced cytopenias that were considered serious: neutropenia in 1 patient and anaemia in 2 patients. All 3 serious adverse events resulted either in interruption of linezolid or in interruption of pretomanid, bedaquiline, and linezolid, and all resolved. Peripheral neuropathy Peripheral neuropathy is a known ADR of linezolid. In the Nix-TB trial, 81% (very common) of patients experienced peripheral neuropathy. Most of these adverse reactions occurred after 8 weeks of treatment and resulted in dosing interruption, dose reduction, or discontinuation of linezolid. No adverse reactions related to peripheral neuropathy led to a discontinuation of the entire study regimen. Optic neuropathy Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%, common) in the Nix-TB trial developed optic neuropathy, both after 16 weeks of treatment. Both were serious, confirmed on retinal examination as optic neuropathy/neuritis, and resulted in discontinuation of linezolid; both adverse reactions resolved. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose There is no experience of acute overdose with pretomanid. General measures should be taken to support basic vital functions including monitoring of vital signs and ECG in case of deliberate or accidental overdose. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antimycobacterials, drugs for treatment of tuberculosis, ATC code: not yet assigned. Mechanism of action The mechanism of action of pretomanid is thought to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and generation of reactive nitrogen species under anaerobic conditions. Reductive activation of pretomanid by a mycobacterial deazaflavin (F420)-dependent nitro-reductase 9 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc is required for activity under both aerobic and anaerobic conditions (see also mechanism of resistance, below). Resistance The activation of pretomanid, which takes place within the bacterial cell, is dependent on enzymes encoded by 5 genes: a co-factor F420-dependent nitroreductase named Ddn; a glucose-6-phosphate dehydrogenase named Fgd1; and the enzymes of the F420 biosynthetic pathway (FbiA, FbiB, and FbiC). Mutations in the 5 genes encoding these enzymes (ddn, fgd1, fbiA, fbiB, fbiC) have been associated with high level pretomanid resistance in vitro. Not all isolates with increased minimum inhibitory concentrations (MICs) have mutations in these genes, suggesting the existence of at least one other mechanism of resistance. Pretomanid does not show cross-resistance with any currently used anti-tuberculosis drugs, except for delamanid where cross-resistance has been demonstrated in vitro. This is likely to be due to pretomanid and delamanid being activated via the same pathway, see above. Only one case of acquisition of pretomanid resistance has been observed thus far in trials sponsored by TB Alliance. Susceptibility testing breakpoint Based on the limited information available, a critical concentration for pretomanid is provisionally set at 1 μg/ml for testing using the MGIT System. Over 99% of clinical isolates surveyed showed MIC values at or below 1 μg/ml. Conversely, all Mycobacterium tuberculosis isolates with known mechanisms of resistance to pretomanid had MIC values above this concentration Clinical efficacy and safety Pretomanid was evaluated in a multicenter, open-label study conducted in subjects with XDR, treatment-intolerant MDR or non-responsive MDR pulmonary tuberculosis. The subjects received the indicated pretomanid-bedaquiline-linezolid regimen for 6 months (extendable to 9 months) with 24 months of follow-up; linezolid starting dose was either 600 mg twice daily or 1200 mg once daily. A total of 109 patients was treated during the course of the study. The primary efficacy endpoint for the study was treatment failure, defined as the incidence of bacteriologic failure, bacteriological relapse (culture conversion to positive status after completion of therapy with same Mycobacterium tuberculosis strain, after conversion to negative during therapy), or clinical failure through follow-up until 6 months after the End of Treatment. Subjects considered treatment failures were categorised as having an unfavourable outcome. The mean age of the patients was 35.6 years with 48% being female and 52% male. The mean duration since initial TB diagnosis was 24 months. 47%/38% of patients had unilateral/bilateral cavities and 51% of patients were HIV-positive (with a mean CD4 cell count of 396 cells/µl). Outcome of the primary efficacy analysis is presented in the table below. Total XDR TI/NR MDR N 109 71 (65%) 38 (35%) Unassessable 2 1 1 Total Assessable 107 70 37 Favourable 98 (92%) 63 (90%) 35 (95%) Unfavourable 9 (8%) 7 (10%) 2 (5%) XDR: extensively drug resistant TI/NR MDR: treatment-intolerant or nonresponsive multidrug-resistant The outcomes were similar in both HIV negative and HIV positive subjects. Of the 9 unfavourable outcomes, 6 were deaths while receiving treatment. Two additional subjects relapsed in follow-up after the End of Treatment; one of those subjects later died. 10 Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with pretomanid in one or more subsets of the paediatric population in treatment of multi-drug-resistant tuberculosis (see section 4.2 for information on paediatric use). Conditional approval This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary 5.2 Pharmacokinetic properties The pharmacokinetic properties of pretomanid are similar in adult healthy subjects and in adult tuberculosis-infected patients. Absorption The absolute bioavailability of pretomanid has not been established. Two mass balance studies have indicated that the absolute bioavailability is greater than 53% and 64%. The median tmax values range from 4 to 5 hours. Administration of 200 mg pretomanid with a high-fat, high-calorie meal increased mean Cmax by 76% and mean AUC0-inf by 88% as compared with administration in the fasted state. Distribution The binding of pretomanid to human plasma proteins is 86.4%, so the fraction unbound (fu) is 13.6%. Human serum albumin binding was similar (82.7%), indicating that binding to albumin is responsible for the human plasma protein binding of pretomanid. The mean apparent volume of distribution (Vd/F) after a single dose of 200 mg in the fed state was 97 L when the mean weight was 72 kg. Biotransformation The metabolic profile of pretomanid has not been completely elucidated. Pretomanid is extensively metabolised with over 19 metabolites identified through multiple metabolic pathways. In the mass- balance study, pretomanid had a half-life of 16 hours, while that of total radioactivity was 18 days, indicating the presence of partially unidentified long-lived metabolites. In vitro, pretomanid was moderately metabolized by CYP3A4. A role of CYP3A4 was further supported by a clinical drug interaction study with CYP3A4 inducers. Nitro-reduction within Mycobacterium tuberculosis and potentially in gastrointestinal microflora is also involved in the metabolism of pretomanid. Pretomanid is not a substrate of cytochrome P450 (CYP) 2C9, 2C19 or 2D6 in vitro. Elimination The recovery of total radioactivity following a single dose of 14C-preotmanid was approximately 90% with about 53-65% excreted in the urine and 26-38% in faeces. Pretomanid, at clinically relevant concentrations, is not a substrate or inhibitor for the transporters, bile salt export pump (BSEP), multidrug and toxin extrusion protein (MATE)1, MATE2-K, organic anion 11 transporter (OAT)1, OAT1B1 and organic cation transporter (OCT)1. Pretomanid is not a substrate of OAT3, breast cancer resistance protein (BCRP), P-glycoprotein (P gp), OCT2 and organic anion- transporting polypeptide (OATP)1B3. The potential of pretomanid to inhibit P gp, OATP1B3, OCT2 and BCRP has not been investigated at clinically relevant concentrations.. Apparent clearance (CL/F) after a single dose was 7.6 and 3.9 l/h in the fasted and fed states, respectively. The elimination half-life was 17 hours. Non-linearity In the fasted state, bioavailability decreased with increasing doses (50 to 1500 mg/day), with absorption saturation above 1000 mg. In the fed state, there were no significant changes in bioavailability across doses of 50 mg through 200 mg. Special populations Hepatic impairment The pharmacokinetics of pretomanid has not been established in patients with impaired hepatic function. Renal impairment The pharmacokinetics of pretomanid has not been established in patients with impaired renal function. Paediatric population The pharmacokinetics of pretomanid have not been established in the paediatric population. Elderly There is limited clinical data (n=5) on the use of pretomanid in elderly subjects (≥65 years). Race There were no clinically meaningful differences in the pharmacokinetics of pretomanid between Black and Caucasian subjects. The pharmacokinetics of pretomanid have not been established in other racial populations. 5.3 Preclinical safety data Cataracts developed in rats given pretomanid at 300 mg/kg/day for 13 weeks with 7-fold the maximum recommended human dose (MRHD) exposure and at 100 mg/kg/day for 26 weeks with 3-4-fold MRHD exposure. The cataracts were not present at the end of dosing in monkeys given oral pretomanid at 450 mg/kg/day (10.5-fold of MRHD exposure) for 4 weeks and 300 mg/kg/day (5.4-fold MRHD exposure) for 12 more weeks, but observed in 2 of 12 monkeys during the 13-week post treatment recovery period. In a subsequent study in monkeys, cataracts were not observed following 13 weeks treatment with up to 300 mg/kg/day oral pretomanid (5-fold of MRHD exposure) or during the 20 week post treatment recovery period. Additionally, no cataracts were observed in repeat-dose toxicity studies of up to 9 months in monkeys (approximately 2-3-fold of MRHD exposure). Taken together, these studies suggest that the no-effect level for cataracts was 30 mg/kg/day observed in rats (26-week study), which is 2-fold the exposure at the MRHD of 200 mg/day. In repeat dose studies in rats, convulsions were observed at systemic exposures 4- to 10-fold higher than the clinical exposure at the MHRD of 200 mg/day (Cmax = 3.1 µg/ml and AUC0-24 = 57 h×µg/ml). In repeat dose studies in monkeys, convulsions were seen at exposures 2- to 8-fold higher than exposure at the MHRD. In both species, convulsions were observed at lower exposures during the longer duration studies (6-month rat and 9-month monkey). The mechanism of convulsions in nonclinical studies with pretomanid is unknown. The clinical relevance of this finding is unknown. Pretomanid has the potential to affect cardiac repolarisation via blockade of hERG potassium channels and/or other cardiac ion channels including Nav1.5 and KCNQ1/minK. 12 Testicular toxicity was observed in rats and mice without exposure margin to the MRHD. Decreased fertility to complete infertility was observed in male rats treated with oral pretomanid. There were no direct effects of pretomanid on reproductive organs in monkeys given oral pretomanid for 3-months and 9-months. Decreased sperm motility, total sperm count and increased abnormal sperm ratio were observed in monkeys. Based upon the preclinical data, rodents are susceptible to pretomanid-induced testicular injury. Serum levels of the male reproductive hormones are biomarkers that are altered in association with this injury. In the preclinical study of primates, no pretomanid-related alterations in testis or male reproductive hormones were observed. Non-clinical data reveal no special hazard for humans based on conventional studies of embryo-foetal development and peri-postnatal development. Transfer of pretomanid from dam to pup via breast milk was studied in rats. After 14 days dosing of 20 mg/kg/day, the mean maternal plasma concentration 6 hours post dose was 2.84 μg/ml, which is similar to the mean steady state Cmax for 200 mg pretomanid in humans. At the same time, the mean concentration in milk was 4.07 μg/ml, and the mean plasma concentration in rat pups was 0.119 μg/ml. The concentration of pretomanid in rat milk does not necessarily predict the concentration of pretomanid in human milk. No mutagenic or clastogenic effects were detected in conventional genotoxicity studies with pretomanid. A circulating metabolite of pretomanid, M50, was mutagenic in a bacterial reverse mutation assay. No carcinogenic potential was revealed in a 6-month study in transgenic mice where this metabolite is produced. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Microcrystalline cellulose Sodium starch glycolate Magnesium stearate Silica, colloidal Sodium lauryl sulphate Povidone 6.2 Incompatibilities Not applicable. 6.3 Shelf life 24 months 6.4 Special precautions for storage This medicinal product does not require any special temperature storage conditions. 6.5 Nature and contents of container High-density polyethylene (HDPE) bottles with polypropylene screw cap with a pulp liner and an absorbent cotton. Pack size: 26 tablets. 13 PVC/PVdC-Aluminium foil blisters packs. Pack sizes: 14, 14 × 1 (unit dose), 182, 182 × 1 (unit dose) tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER FGK Representative Service GmbH Heimeranstrasse 35 80339 Munich, Germany Phone: +49 (0) 89 893 119-22 Fax: +49 (0) 89 893 119-20 8. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1437/001 EU/1/20/1437/002 EU/1/20/1437/003 EU/1/20/1437/004 EU/1/20/1437/005 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 14 http://www.ema.europa.eu/ ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST- AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION 15 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Mylan Hungary Kft Mylan utca 1. Komarom 2900 Hungary Generics (UK) Limited Station Close Potters Bar, EN6 1TL United Kingdom Mylan UK Healthcare Ltd Building 20, Station Close Potters Bar, EN6 1TL United Kingdom The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c (7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 16 E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION This being a conditional marketing authorisation and pursuant to Article 14-a of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: Description Due date In order to further evaluate the safety, efficacy and tolerability of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary XDR-TB, pre-XDR TB, or treatment intolerant or non-responsive MDR-TB, the marketing authorisation holder should complete and submit results from the ongoing study ZeNix – A Phase 3 Partially-blinded, Randomized Trial Assessing the Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB), Pre-XDR-TB or Treatment Intolerant or Non-responsive Multi- drug Resistant Tuberculosis (MDR-TB) Annual reports to be submitted Final report by Q4 2022 In order to confirm the safety and efficacy of pretomanid the marketing authorisation holder should complete and submit results from the ongoing Phase 3 Open-label Trial Assessing the Safety and Efficacy of Bedaquiline Plus Pretomanid Plus Linezolid (B-Pa- L) in Subjects with Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB) or Treatment Intolerant/Non-responsive Multi-Drug Resistant Tuberculosis (MDR-TB). (NiX) Final report by Q2 2021 17 ANNEX III LABELLING AND PACKAGE LEAFLET 18 A. LABELLING 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON (BLISTER) 1. NAME OF THE MEDICINAL PRODUCT Pretomanid FGK 200 mg tablets pretomanid 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 200 mg pretomanid 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet Blisters: 14 tablets 182 tablets Perforated unit dose blisters: 14 × 1 tablet 182 × 1 tablet 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 20 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER FGK Representative Service GmbH Heimeranstrasse 35 80339 Munich Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1437/001 EU/1/20/1437/002 EU/1/20/1437/004 EU/1/20/1437/005 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Pretomanid FGK 200 mg tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 21 MINIMUM PARTICULARS TO APPEAR ON BLISTERS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Pretomanid FGK 200 mg tablets pretomanid 2. NAME OF THE MARKETING AUTHORISATION HOLDER FGK Representative Services GmbH 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 22 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON (BOTTLE) 1. NAME OF THE MEDICINAL PRODUCT Pretomanid FGK 200 mg tablets pretomanid 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 200 mg pretomanid 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 26 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 23 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER FGK Representative Service GmbH Heimeranstrasse 35 80339 Munich Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1437/003 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Pretomanid FGK 200 mg tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 24 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Pretomanid FGK 200 mg tablets pretomanid 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 200 mg pretomanid. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 26 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 25 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER FGK Representative Service GmbH Heimeranstrasse 35 80339 Munich Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1437/003 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 26 B. PACKAGE LEAFLET 27 Package leaflet: Information for the patient Pretomanid FGK 200 mg tablets pretomanid This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, pharmacist or nurse. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Pretomanid FGK is and what it is used for 2. What you need to know before you take Pretomanid FGK 3. How to take Pretomanid FGK 4. Possible side effects 5. How to store Pretomanid FGK 6. Contents of the pack and other information 1. What Pretomanid FGK is and what it is used for Pretomanid FGK contains the active substance pretomanid, a type of antibiotic. Antibiotics are medicines used to kill bacteria that cause diseases. Pretomanid FGK is used in combination with two other medicines called linezolid and bedaquiline to treat tuberculosis that affects the lungs, when the disease has become resistant to many other antibiotics: • extensively drug resistant tuberculosis or • treatment-intolerant or multidrug-resistant tuberculosis It is used in adults 18 years and over. 2. What you need to know before you take Pretomanid FGK Do not take Pretomanid FGK • if you are allergic to pretomanid, antibiotics of the group called nitroimidazoles, or any of the other ingredients of this medicine (listed in section 6) Since pretomanid must be used in combination with other medicines against tuberculosis – linezolid and bedaquiline – please make sure that you read the “Do not take” section of the package leaflets for these medicines as well. If you are unsure of any information in the package leaflets, please contact your doctor or pharmacist. 28 Warnings and precautions Talk to your doctor, pharmacist or nurse before taking Pretomanid FGK if you: • have reduced liver function • drink alcohol on a regular basis • have reduced kidney function • have or have had disturbances of the heart rhythm, or if someone in your family has a heart rhythm problem • have heart failure • have or have had an underactive thyroid • have reduced blood levels of calcium, magnesium or potassium Liver damage There is a risk of liver damage when you are treated with Pretomanid FGK, linezolid and bedaquiline. Your doctor will therefore monitor you for signs of liver damage and take blood samples before the start of treatment and regularly during treatment. Tell your doctor if you experience symptoms such as: • fatigue • lack or loss of appetite • nausea • yellowing of the skin and eyes • dark urine • abdominal pain The doctor will adjust your treatment if your liver is affected. Reduced number of blood cells Treatment with Pretomanid FGK, linezolid and bedaquiline can severely reduce the number of blood cells, such as blood platelets, red blood cells and white blood cells called neutrophils. Contact your doctor immediately about any signs of bruising, bleeding or infections. Your doctor will monitor complete blood counts before the start of treatment and regularly during treatment. The doctor will adjust your treatment if your blood cell count is reduced. Nerve disorders in hands, feet or eyes Nerve disorders in hands, feet or eyes may occur during treatment. Contact your doctor if you have visual problems, or numbness, tingling or burning in your hands or feet during treatment. Your doctor will adjust your treatment in these cases. If visual problems occur contact a doctor for a prompt eye examination. Increased blood level of lactic acid A disorder of blood over-acidification called lactic acidosis may occur during treatment. Contact your doctor if you have recurrent nausea or vomiting. Your doctor may adjust your treatment in these cases. Heart problems A certain heartbeat abnormality known as QT prolongation may occur during treatment. Your doctor will therefore perform an ECG before the start of treatment and regularly during treatment. Your treatment will be adjusted if heartbeat abnormalities occur. In addition, potassium, calcium and magnesium levels will be monitored and corrected if abnormal. The safety and efficacy of Pretomanid FGK has not been studied in combination with medicines other than linezolid and bedaquiline and therefore it should not be used as part of any other treatment combination. Children and adolescents This medicine is not recommended for children and adolescents under 18 years. This is because it has not been studied in this age group. 29 Other medicines and Pretomanid FGK Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including herbal therapies. These may affect the way Pretomanid FGK works or increase the risk of side effects. Avoid treatment with Pretomanid FGK and any of the following medicines at the same time. These may lower the effect of Pretomanid FGK so your treatment may not work; therefore, inform your doctor immediately about these: • rifampicin, rifamycin, rifapentine, rifabutin: other medicines to treat tuberculosis or certain other infections • efavirenz, etravirine: medicines to treat HIV infection • carbamazipine, phenytoin: medicines to treat epilepsy and certain pain conditions • St John’s wort: a herbal medicine to treat depression and anxiety You should also avoid the use of medicines that may have a damaging effect on your liver (other than bedaquiline and linezolid). Talk to you doctor who will be able to tell you which medicines this applies to. Inform your doctor if you are using: • methotrexate: a medicine to treat severe joint inflammation, cancer and the skin disease psoriasis • benzylpenicillin, ciprofloxacin: medicines to treat bacterial infections • indomethacin: a medicine to treat pain and inflammation • ritonavir: a medicine to treat HIV infection Pretomanid FGK with alcohol Avoid drinking alcohol while being treated with Pretomanid FGK since this increases the risk of serious liver damage. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. • Pregnancy Very limited knowledge exists about the use of Pretomanid FGK during pregnancy. Therefore, Pretomanid FGK is used during pregnancy only if the benefit to the patient outweighs the potential risk to the foetus. Your doctor will decide whether you should be treated with Pretomanid FGK. • Breast-feeding It is not known if pretomanid is passed into human milk. Your doctor has to decide if you should discontinue breast-feeding or avoid treatment with Pretomanid FGK. Driving and using machines You may feel dizzy after taking Pretomanid FGK or you may experience problems with your vision. Do not drive or operate machinery if this happens. 30 Pretomanid FGK contains lactose and sodium If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’. 3. How to take Pretomanid FGK Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Pretomanid FGK is used in combination with linezolid and bedaquiline. Please also read the package leaflets from these medicines. If you have any questions ask your doctor or pharmacist. The recommended dose is • Pretomanid FGK: 1 tablet once daily • linezolid: 1,200 mg daily • bedaquiline: 400 mg once daily for 2 weeks, followed by 200 mg 3 times per week (with at least 48 hours between doses). For example you may take bedaquiline on Monday, Wednesday and Friday every week from week 3 onwards. Method of use Take Pretomanid FGK at the same time as linezolid and bedaquiline. Swallow the tablets with a glass of water and take them with food. The tablets are taken under direct observation of a healthcare professional or in accordance with local practice. Duration of use The duration of treatment with the combination Pretomanid FGK, linezolid and bedaquiline is 26 weeks. Your doctor may decide to expand this period or to interrupt dosing to ensure that the treatment is safe and effective for you. If you take more Pretomanid FGK than you should Contact your doctor straight away and take the medicine pack with you. If you forget to take Pretomanid FGK Do not take a double dose to make up for a forgotten dose. Any missed dose of pretomanid and bedaquiline is recommended to be made up at the end of treatment. Doses of linezolid missed due to linezolid adverse reactions are not recommended to be made up. Talk to your doctor or pharmacist if you have missed a dose and you are not sure what to do. If you stop taking Pretomanid FGK Do not stop taking Pretomanid FGK or its combination medicines linezolid or bedaquiline without your doctor’s permission. Skipping doses or not completing the full course of therapy may make treatment ineffective and your tuberculosis could get worse. In addition, this would increase the chance that bacteria become resistant to these medicines. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 31 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. When Pretomanid FGK is used together with linezolid and bedaquiline the following side effects have been reported: Contact your doctor immediately if you experience any of the following: Very common (may affect more than 1 in 10 people) • reduced number of red blood cells Possible signs are feeling tired, weakness, shortness of breath, loss of consciousness and increased thirst. • increased blood levels of liver enzymes called - gamma GT (indicating how well your liver is working) - transaminase such as ALT, AST Tell your doctor if you experience symptoms such as fatigue, lack or loss of appetite, nausea, yellowing of the skin and eyes, dark urine or abdominal pain. Common (may affect up to 1 in 10 people) • reduced number of white blood cells or platelets Possible signs are bruising, bleeding or infections. • increased blood level of lactic acid Contact your doctor if you have recurrent nausea or vomiting. Other side effects may occur with following frequencies: Very common (may affect more than 1 in 10 people) • headache • nausea, vomiting, indigestion • abdominal pain • acne, itching skin, rash • decreased appetite • nerve problems in the hands or feet, such as pain, burning, abnormal sensation or numbness • muscle and skeleton pain, such as joint pain, back pain, muscle pain • increased blood levels: - amylase - a liver enzyme called gamma GT (indicating how well your liver is working) - liver enzymes called transaminase such as ALT, AST Common (may affect up to 1 in 10 people) • sleeping difficulties • weakness, fatigue • taste disturbance • dizziness • muscle spasm • diarrhoea, constipation • inflammation of stomach lining, pancreas inflammation • reflux of stomach juices in the oesophagus • hair loss, dry skin • irritation or pain of the eye, vision problems • optic nerve damage and/or inflammation with swellings and visual disturbances • abnormal electrical activity of the heart (prolonged electrocardiogram QT interval) • increased blood levels: - bilirubin, which is the yellow breakdown substance of the blood pigment - lipase - alkaline phosphatase - creatine phosphokinase 32 - urea • decreased blood sugar level Uncommon (may affect up to 1 in 100 people) • fungal (including candida yeast fungi) infection in the mouth or throat, which appears as white patches • fungal infection • too much fluid loss, reduced body fluid volume • anxiety, depression • enlarged liver • yellowing of the skin, internal organs and/or the whites of the eyes (jaundice) • eye lens disorder, dry eye • worsening ability to focus clearly on close objects • eye itching, eye swelling • optic disc swelling (leading to loss of vision) • deafness • feeling of increased heartbeat • increased heartbeat • low blood pressure • cough, nosebleed • feeling bloated • burning tongue, enlargement of the small, nipple-like structures on the upper surface of the tongue • eczema, excessive skin pigmentation • muscles and skeleton stiffness • inability to have or maintain an erection • womb bleeding at irregular intervals, particularly between the expected menstrual periods • feeling unwell • abnormal presence of the protein albumin in the urine • vomiting blood • acidity of the blood • decreased elimination of the muscle tissue breakdown product creatinine through kidneys • lack of white and red blood cells, and blood platelets • decreased blood levels: - calcium - magnesium • increased blood levels: - creatinine and creatine phosphokinase - uric acid Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Pretomanid FGK Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton, bottle or blister after “EXP”. The expiry date refers to the last day of that month. 33 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc This medicine does not require any special temperature storage conditions. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 6. Contents of the pack and other information What Pretomanid FGK contains • The active substance is pretomanid. Each tablet contains 200 mg pretomanid. • The other ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, silica colloidal, sodium lauryl sulphate, povidone. What Pretomanid FGK looks like and contents of the pack Pretomanid FGK is a white to off-white oval tablet with “M” debossed on one side and “P200” on the other side. Tablet dimensions: 18 × 9 mm. The tablets are provided in: Blister packs containing 14, 14 × 1, 182 or 182 × 1 tablets Plastic bottles containing 26 tablets Not all pack sizes may be marketed. Marketing Authorisation Holder FGK Representative Service GmbH Heimeranstrasse 35 80339 Munich Germany Manufacturer Mylan Hungary Kft. H-2900, Komárom Mylan utca 1 Hungary Generics [UK] Limited Station Close, Potters Bar Hertfordshire, EN6 1TL United Kingdom Mylan UK Healthcare Ltd Building 20, Station Close Potters Bar, EN6 1TL United Kingdom This leaflet was last revised in {MM/YYYY} This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine. The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary. 34 Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu 35 Annex IV Conclusions on the granting of the conditional marketing authorisation presented by the European Medicines Agency 36 Conclusions presented by the European Medicines Agency on: • Conditional marketing authorisation The CHMP having considered the application is of the opinion that the risk-benefit balance is favourable to recommend the granting of the conditional marketing authorisation as further explained in the European Public Assessment Report. 37 SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION A. LABELLING B. PACKAGE LEAFLET Conclusions on the granting of the conditional marketing authorisation presented by the European Medicines Agency

{'Title': '1. what pretomanid fgk is and what it is used for', 'Section_Content': 'pretomanid fgk contains the active substance pretomanid, a type of antibiotic. antibiotics are medicines used to kill bacteria that cause diseases. pretomanid fgk is used in combination with two other medicines called linezolid and bedaquiline to treat tuberculosis that affects the lungs, when the disease has become resistant to many other antibiotics: extensively drug resistant tuberculosis or treatment-intolerant or multidrug-resistant tuberculosis it is used in adults 18 years and over.', 'Entity_Recognition': [{'Text': 'pretomanid fgk', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 67, 'EndOffset': 77, 'Score': 0.4226691722869873, 'Text': 'antibiotic', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 79, 'EndOffset': 90, 'Score': 0.7600099444389343, 'Text': 'antibiotics', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 95, 'EndOffset': 104}, {'Text': 'kill bacteria', 'Type': 'PROBLEM', 'BeginOffset': 113, 'EndOffset': 126}, {'Text': 'diseases', 'Type': 'PROBLEM', 'BeginOffset': 138, 'EndOffset': 146}, {'Text': 'pretomanid fgk', 'Type': 'TREATMENT', 'BeginOffset': 148, 'EndOffset': 162}, {'Text': 'two other medicines', 'Type': 'TREATMENT', 'BeginOffset': 191, 'EndOffset': 210}, {'Id': 3, 'BeginOffset': 218, 'EndOffset': 227, 'Score': 0.9993176460266113, 'Text': 'linezolid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 232, 'EndOffset': 243, 'Score': 0.9274703860282898, 'Text': 'bedaquiline', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 253, 'EndOffset': 265, 'Score': 0.9695455431938171, 'Text': 'tuberculosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9586454629898071}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.8975540399551392, 'RelationshipScore': 0.9997946619987488, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 0, 'BeginOffset': 283, 'EndOffset': 288, 'Text': 'lungs', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 0, 'BeginOffset': 283, 'EndOffset': 288, 'Score': 0.8975540399551392, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the disease', 'Type': 'PROBLEM', 'BeginOffset': 295, 'EndOffset': 306}, {'Text': 'many other antibiotics', 'Type': 'TREATMENT', 'BeginOffset': 331, 'EndOffset': 353}, {'Text': 'extensively drug resistant tuberculosis', 'Type': 'PROBLEM', 'BeginOffset': 355, 'EndOffset': 394}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 398, 'EndOffset': 407}, {'Id': 7, 'BeginOffset': 408, 'EndOffset': 418, 'Score': 0.32668715715408325, 'Text': 'intolerant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 422, 'EndOffset': 454, 'Score': 0.3513087332248688, 'Text': 'multidrug-resistant tuberculosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9466886520385742}]}, {'Text': '18', 'Type': 'NUMBER', 'BeginOffset': 476, 'EndOffset': 478}]}

{'Title': '2. what you need to know before you take pretomanid fgk', 'Section_Content': 'do not take pretomanid fgk if you are allergic to pretomanid, antibiotics of the group called nitroimidazoles, or any of the other ingredients of this medicine (listed in section 6) since pretomanid must be used in combination with other medicines against tuberculosis linezolid and bedaquiline please make sure that you read the "do not take" section of the package leaflets for these medicines as well. if you are unsure of any information in the package leaflets, please contact your doctor or pharmacist. warnings and precautions talk to your doctor, pharmacist or nurse before taking pretomanid fgk if you: have reduced liver function drink alcohol on a regular basis have reduced kidney function have or have had disturbances of the heart rhythm, or if someone in your family has a heart rhythm problem have heart failure have or have had an underactive thyroid have reduced blood levels of calcium, magnesium or potassium liver damage there is a risk of liver damage when you are treated with pretomanid fgk, linezolid and bedaquiline. your doctor will therefore monitor you for signs of liver damage and take blood samples before the start of treatment and regularly during treatment. tell your doctor if you experience symptoms such as: fatigue lack or loss of appetite nausea yellowing of the skin and eyes dark urine abdominal pain the doctor will adjust your treatment if your liver is affected. reduced number of blood cells treatment with pretomanid fgk, linezolid and bedaquiline can severely reduce the number of blood cells, such as blood platelets, red blood cells and white blood cells called neutrophils. contact your doctor immediately about any signs of bruising, bleeding or infections. your doctor will monitor complete blood counts before the start of treatment and regularly during treatment. the doctor will adjust your treatment if your blood cell count is reduced. nerve disorders in hands, feet or eyes nerve disorders in hands, feet or eyes may occur during treatment. contact your doctor if you have visual problems, or numbness, tingling or burning in your hands or feet during treatment. your doctor will adjust your treatment in these cases. if visual problems occur contact a doctor for a prompt eye examination. increased blood level of lactic acid a disorder of blood over-acidification called lactic acidosis may occur during treatment. contact your doctor if you have recurrent nausea or vomiting. your doctor may adjust your treatment in these cases. heart problems a certain heartbeat abnormality known as qt prolongation may occur during treatment. your doctor will therefore perform an ecg before the start of treatment and regularly during treatment. your treatment will be adjusted if heartbeat abnormalities occur. in addition, potassium, calcium and magnesium levels will be monitored and corrected if abnormal. the safety and efficacy of pretomanid fgk has not been studied in combination with medicines other than linezolid and bedaquiline and therefore it should not be used as part of any other treatment combination. children and adolescents this medicine is not recommended for children and adolescents under 18 years. this is because it has not been studied in this age group. other medicines and pretomanid fgk tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including herbal therapies. these may affect the way pretomanid fgk works or increase the risk of side effects. avoid treatment with pretomanid fgk and any of the following medicines at the same time. these may lower the effect of pretomanid fgk so your treatment may not work; therefore, inform your doctor immediately about these: rifampicin, rifamycin, rifapentine, rifabutin: other medicines to treat tuberculosis or certain other infections efavirenz, etravirine: medicines to treat hiv infection carbamazipine, phenytoin: medicines to treat epilepsy and certain pain conditions st john\'s wort: a herbal medicine to treat depression and anxiety you should also avoid the use of medicines that may have a damaging effect on your liver (other than bedaquiline and linezolid). talk to you doctor who will be able to tell you which medicines this applies to. inform your doctor if you are using: methotrexate: a medicine to treat severe joint inflammation, cancer and the skin disease psoriasis benzylpenicillin, ciprofloxacin: medicines to treat bacterial infections indomethacin: a medicine to treat pain and inflammation ritonavir: a medicine to treat hiv infection pretomanid fgk with alcohol avoid drinking alcohol while being treated with pretomanid fgk since this increases the risk of serious liver damage. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. pregnancy very limited knowledge exists about the use of pretomanid fgk during pregnancy. therefore, pretomanid fgk is used during pregnancy only if the benefit to the patient outweighs the potential risk to the foetus. your doctor will decide whether you should be treated with pretomanid fgk. breast-feeding it is not known if pretomanid is passed into human milk. your doctor has to decide if you should discontinue breast-feeding or avoid treatment with pretomanid fgk. driving and using machines you may feel dizzy after taking pretomanid fgk or you may experience problems with your vision. do not drive or operate machinery if this happens. pretomanid fgk contains lactose and sodium if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. this medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially \'sodium- free\'.', 'Entity_Recognition': [{'Text': 'pretomanid fgk', 'Type': 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{'Title': '3. how to take pretomanid fgk', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. pretomanid fgk is used in combination with linezolid and bedaquiline. please also read the package leaflets from these medicines. if you have any questions ask your doctor or pharmacist. the recommended dose is pretomanid fgk: 1 tablet once daily linezolid: 1,200 mg daily bedaquiline: 400 mg once daily for 2 weeks, followed by 200 mg 3 times per week (with at least 48 hours between doses). for example you may take bedaquiline on monday, wednesday and friday every week from week 3 onwards. method of use take pretomanid fgk at the same time as linezolid and bedaquiline. swallow the tablets with a glass of water and take them with food. the tablets are taken under direct observation of a healthcare professional or in accordance with local practice. duration of use the duration of treatment with the combination pretomanid fgk, linezolid and bedaquiline is 26 weeks. your doctor may decide to expand this period or to interrupt dosing to ensure that the treatment is safe and effective for you. if you take more pretomanid fgk than you should contact your doctor straight away and take the medicine pack with you. if you forget to take pretomanid fgk do not take a double dose to make up for a forgotten dose. any missed dose of pretomanid and bedaquiline is recommended to be made up at the end of treatment. doses of linezolid missed due to linezolid adverse reactions are not recommended to be made up. talk to your doctor or pharmacist if you have missed a dose and you are not sure what to do. if you stop taking pretomanid fgk do not stop taking pretomanid fgk or its combination medicines linezolid or bedaquiline without your doctor's permission. skipping doses or not completing the full course of therapy may make treatment ineffective and your tuberculosis could get worse. in 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. when pretomanid fgk is used together with linezolid and bedaquiline the following side effects have been reported: contact your doctor immediately if you experience any of the following: very common (may affect more than 1 in 10 people) reduced number of red blood cells possible signs are feeling tired, weakness, shortness of breath, loss of consciousness and increased thirst. increased blood levels of liver enzymes called - gamma gt (indicating how well your liver is working) - transaminase such as alt, ast tell your doctor if you experience symptoms such as fatigue, lack or loss of appetite, nausea, yellowing of the skin and eyes, dark urine or abdominal pain. common (may affect up to 1 in 10 people) reduced number of white blood cells or platelets possible signs are bruising, bleeding or infections. increased blood level of lactic acid contact your doctor if you have recurrent nausea or vomiting. other side effects may occur with following frequencies: very common (may affect more than 1 in 10 people) headache nausea, vomiting, indigestion abdominal pain acne, itching skin, rash decreased appetite nerve problems in the hands or feet, such as pain, burning, abnormal sensation or numbness muscle and skeleton pain, such as joint pain, back pain, muscle pain increased blood levels: - amylase - a liver enzyme called gamma gt (indicating how well your liver is working) - liver enzymes called transaminase such as alt, ast common (may affect up to 1 in 10 people) sleeping difficulties weakness, fatigue taste disturbance dizziness muscle spasm diarrhoea, constipation inflammation of stomach lining, pancreas inflammation reflux of stomach juices in the oesophagus hair loss, dry skin irritation or pain of the eye, vision problems optic nerve damage and/or inflammation with swellings and visual disturbances abnormal electrical activity of the heart (prolonged electrocardiogram qt interval) increased blood levels: - bilirubin, which is the yellow breakdown substance of the blood pigment - lipase - alkaline phosphatase - creatine phosphokinase 32 - urea decreased blood sugar level uncommon (may affect up to 1 in 100 people) fungal (including candida yeast fungi) infection in the mouth or throat, which appears as white patches fungal infection too much fluid loss, reduced body fluid volume anxiety, depression enlarged liver yellowing of the skin, internal organs and/or the whites of the eyes (jaundice) eye lens disorder, dry eye worsening ability to focus clearly on close objects eye itching, eye swelling optic disc swelling (leading to loss of vision) deafness feeling of increased heartbeat increased heartbeat low blood pressure cough, nosebleed feeling bloated burning tongue, enlargement of the small, nipple-like structures on the upper surface of the tongue eczema, excessive skin pigmentation muscles and skeleton stiffness inability to have or maintain an erection womb bleeding at irregular intervals, particularly between the expected menstrual periods feeling unwell abnormal presence of the protein albumin in the urine vomiting blood acidity of the blood decreased elimination of the muscle tissue breakdown product creatinine through kidneys lack of white and red blood cells, and blood platelets decreased blood levels: - calcium - magnesium increased blood levels: - creatinine and creatine phosphokinase - uric acid reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'pretomanid fgk', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 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'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'excessive skin pigmentation muscles', 'Type': 'PROBLEM', 'BeginOffset': 2899, 'EndOffset': 2934}, {'Text': 'skeleton stiffness', 'Type': 'PROBLEM', 'BeginOffset': 2939, 'EndOffset': 2957}, {'Id': 157, 'BeginOffset': 2958, 'EndOffset': 2999, 'Score': 0.6991071105003357, 'Text': 'inability to have or maintain an erection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7340244650840759}]}, {'Id': 159, 'BeginOffset': 3072, 'EndOffset': 3089, 'Score': 0.800743818283081, 'Text': 'menstrual periods', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8232710361480713}]}, {'Id': 160, 'BeginOffset': 3090, 'EndOffset': 3113, 'Score': 0.7267443537712097, 'Text': 'feeling unwell abnormal', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.45392435789108276}]}, {'Text': 'the protein 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{'Title': '5. how to store pretomanid fgk', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what pretomanid fgk contains the active substance is pretomanid. each tablet contains 200 mg pretomanid. the other ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, silica colloidal, sodium lauryl sulphate, povidone. what pretomanid fgk looks like and contents of the pack pretomanid fgk is a white to off-white oval tablet with "m" debossed on one side and "p200" on the other side. tablet dimensions: 18 × 9 mm. the tablets are provided in: blister packs containing 14, 14 × 1, 182 or 182 × 1 tablets plastic bottles containing 26 tablets not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'pretomanid fgk', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '200', 'Type': 'NUMBER', 'BeginOffset': 86, 'EndOffset': 89}, {'Id': 1, 'BeginOffset': 131, 'EndOffset': 150, 'Score': 0.7863032221794128, 'Text': 'lactose monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 152, 'EndOffset': 178, 'Score': 0.9944801330566406, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 180, 'EndOffset': 203, 'Score': 0.9984810948371887, 'Text': 'sodium starch glycolate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 205, 'EndOffset': 223, 'Score': 0.9953696131706238, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 225, 'EndOffset': 241, 'Score': 0.9692525863647461, 'Text': 'silica colloidal', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 243, 'EndOffset': 265, 'Score': 0.9989247918128967, 'Text': 'sodium lauryl sulphate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 267, 'EndOffset': 275, 'Score': 0.8410377502441406, 'Text': 'povidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '18', 'Type': 'NUMBER', 'BeginOffset': 463, 'EndOffset': 465}, {'Text': '9', 'Type': 'NUMBER', 'BeginOffset': 468, 'EndOffset': 469}, {'Text': 'the tablets', 'Type': 'TREATMENT', 'BeginOffset': 474, 'EndOffset': 485}, {'Text': 'blister packs', 'Type': 'TREATMENT', 'BeginOffset': 503, 'EndOffset': 516}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 528, 'EndOffset': 530}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 532, 'EndOffset': 534}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 537, 'EndOffset': 538}, {'Text': '182', 'Type': 'NUMBER', 'BeginOffset': 540, 'EndOffset': 543}, {'Text': '182', 'Type': 'NUMBER', 'BeginOffset': 547, 'EndOffset': 550}, {'Text': '1 tablets plastic bottles', 'Type': 'TREATMENT', 'BeginOffset': 553, 'EndOffset': 578}, {'Text': '26', 'Type': 'NUMBER', 'BeginOffset': 590, 'EndOffset': 592}]}

C201632ED6452685184B4EB7A592C624

https://www.ema.europa.eu/documents/product-information/beovu-epar-product-information_en.pdf

Beovu

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Beovu 120 mg/ml solution for injection in pre-filled syringe Beovu 120 mg/ml solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One ml solution for injection contains 120 mg of brolucizumab*. * Brolucizumab is a humanised monoclonal single-chain Fv (scFv) antibody fragment produced in Escherichia coli cells by recombinant DNA technology. Beovu 120 mg/ml solution for injection in pre-filled syringe Each pre-filled syringe contains 19.8 mg brolucizumab in 0.165 ml solution. This provides a usable amount to deliver a single dose of 0.05 ml solution containing 6 mg of brolucizumab. Beovu 120 mg/ml solution for injection Each vial contains 27.6 mg brolucizumab in 0.23 ml solution. This provides a usable amount to deliver a single dose of 0.05 ml solution containing 6 mg of brolucizumab. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection). Clear to slightly opalescent, colourless to slightly brownish-yellow aqueous solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Beovu is indicated in adults for the treatment of neovascular (wet) age-related macular degeneration (AMD). 3 4.2 Posology and method of administration Beovu must be administered by a qualified ophthalmologist experienced in intravitreal injections. Posology The recommended dose is 6 mg brolucizumab (0.05 ml solution) administered by intravitreal injection every 4 weeks (monthly) for the first 3 doses. Thereafter, the physician may individualise treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. A disease activity assessment is suggested 16 weeks (4 months) after treatment start. In patients without disease activity, treatment every 12 weeks (3 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) should be considered. The physician may further individualise treatment intervals based on disease activity. If visual and anatomical outcomes indicate that the patient is not benefiting from continued treatment, Beovu should be discontinued. Special populations Elderly No dosage adjustment is required in patients aged 65 years or above (see section 5.2). Renal impairment No dosage adjustment is required in patients with renal impairment (see section 5.2). Hepatic impairment Brolucizumab has not been studied in patients with hepatic impairment. No dosage adjustment is required in patients with hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of brolucizumab in children and adolescents below 18 years of age have not been established. No data are available. Method of administration Beovu is for intravitreal use only. The solution for injection should be inspected visually prior to administration (see section 6.6). The intravitreal injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Sterile paracentesis equipment should be available as a precautionary measure. The patient’s medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.3). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection. The injection needle should be inserted 3.5 to 4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 ml is then delivered slowly; a different scleral site should be used for subsequent injections. Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, sterile equipment for paracentesis should be available. Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g. eye pain, redness of the eye, photophobia, blurring of vision) without delay. 4 Pre-filled syringe The pre-filled syringe is for single use only. Each pre-filled syringe should only be used for the treatment of a single eye. Since the volume contained in the pre-filled syringe (0.165 ml) is greater than the recommended dose (0.05 ml), a portion of the volume contained in the pre-filled syringe must be discarded prior to administration. Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air bubble along with excess medicinal product, the plunger should be slowly depressed until the edge below the dome of the rubber stopper is aligned with the 0.05 ml dose mark (equivalent to 50 µl, i.e. 6 mg brolucizumab). Vial The vial is for single use only. Each vial should only be used for the treatment of a single eye. Since the volume contained in the vial (0.23 ml) is greater than the recommended dose (0.05 ml), a portion of the volume contained in the vial must be discarded prior to administration. Injecting the entire volume of the vial could result in overdose. To expel the air bubble along with excess medicinal product, the air should be carefully expelled from the syringe and the dose adjusted to the 0.05 ml mark (equivalent to 50 µl, i.e. 6 mg brolucizumab). For instructions on preparation of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with active or suspected ocular or periocular infections. Patients with active intraocular inflammation. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Endophthalmitis, intraocular inflammation, traumatic cataract, retinal detachment, retinal vasculitis, and/or retinal vascular occlusion Intravitreal injections, including those with Beovu, have been associated with endophthalmitis, intraocular inflammation, traumatic cataract and retinal detachment (see section 4.8). Proper aseptic injection techniques must always be used when administering Beovu. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of Beovu (see sections 4.3 and 4.8).In patients developing these events, treatment with Beovu should be discontinued and the events should be promptly managed. Patients should be instructed to report any symptoms suggestive of the above-mentioned events without delay. 5 Intraocular pressure increases Transient increases in intraocular pressure have been seen within 30 minutes of intravitreal injection with vascular endothelial growth factor (VEGF) inhibitors, including brolucizumab (see section 4.8). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Beovu while the intraocular pressure is ≥30 mmHg). Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately. Bilateral treatment The safety and efficacy of brolucizumab administered in both eyes concurrently have not been studied. Immunogenicity As this is a therapeutic protein, there is a potential for immunogenicity with brolucizumab (see section 4.8). Patients should be instructed to inform their physician if they develop symptoms such as eye pain or increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in their vision, or increased sensitivity to light (see section 4.8). Concomitant use of other anti-VEGF There are no data available on the concomitant use of Beovu with other anti-VEGF medicinal products in the same eye. Brolucizumab should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular). Withholding treatment In intravitreal anti-VEGF treatments, the dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:  a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity;  a retinal break;  a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50% of the total lesion area;  performed or planned intraocular surgery within the previous or next 28 days. Retinal pigment epithelial tear Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating brolucizumab therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears. Rhegmatogenous retinal detachment or macular holes Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes. Systemic effects following intravitreal use Systemic adverse events, including non-ocular haemorrhages and arterial thromboembolic events, have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with AMD with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 3 months. Caution should be exercised when treating such patients. 6 Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with brolucizumab and for at least one month after the last dose when stopping treatment.with brolucizumab. Pregnancy There are no or limited amount of data from the use of brolucizumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Although the systemic exposure after ocular administration is very low, brolucizumab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. Breast-feeding It is unknown whether brolucizumab is excreted in human milk. A risk to the breast-fed newborn/infant cannot be excluded. Brolucizumab is not recommended during breast-feeding and breast-feeding should not be started for at least one month after the last dose when stopping treatment with brolucizumab. A decision must be made whether to discontinue breast-feeding or to abstain from brolucizumab therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No reproductive or fertility studies have been conducted. VEGF inhibition has been shown to affect follicular development, corpus luteum function and fertility. Based on the mechanism of action of VEGF inhibitiors, there is a potential risk for female reproduction, and to embryofoetal development. 4.7 Effects on ability to drive and use machines Beovu has a minor influence on the ability to drive and use machines due to possible temporary visual disturbances following the intravitreal injection and the associated eye examination. Patients should not drive or use machines until visual function has recovered sufficiently. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions were reduced visual acuity (7.3%), cataract (7.0%), conjunctival haemorrhage (6.3%) and vitreous floaters (5.1%). The most serious adverse reactions were blindness (0.8%), endophthalmitis (0.7%), retinal artery occlusion (0.8%) and retinal detachment (0.7%). 7 Tabulated list of adverse reactions Adverse reactions (Table 1) are listed according to the MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Frequency categories for each adverse reaction are based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Frequencies of adverse reactions in clinical studies and post-marketing experience MedDRA System organ class Frequency category Immune system disorders Hypersensitivity (including urticaria, rash, pruritus, erythema) Common Eye disorders Visual acuity reduced Common Retinal haemorrhage Common Uveitis Common Iritis Common Vitreous detachment Common Retinal tear Common Cataract Common Conjunctival haemorrhage Common Vitreous floaters Common Eye pain Common Intraocular pressure increase Common Conjunctivitis Common Retinal pigment epithelial tear Common Vision blurred Common Corneal abrasion Common Punctate keratitis Common Blindness Uncommon Endophthalmitis Uncommon Retinal artery occlusion Uncommon Retinal detachment Uncommon Conjunctival hyperaemia Uncommon Lacrimation increased Uncommon Abnormal sensation in eye Uncommon Detachment of retinal pigment epithelium Uncommon Vitritis Uncommon Anterior chamber inflammation Uncommon Iridocyclitis Uncommon Anterior chamber flare Uncommon Corneal oedema Uncommon Vitreous haemorrhage Uncommon Retinal vascular occlusion Not known Retinal vasculitis Not known 8 Description of selected adverse reactions Immunogenicity There is a potential for an immune response in patients treated with Beovu. After dosing with Beovu for 88 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 23–25% of patients. Among patients with treatment-emergent antibodies, a higher number of intraocular inflammation adverse reactions were observed. The clinical significance of anti-brolucizumab antibodies on safety is unclear at this time. Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy. Product-class-related adverse reactions There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the brolucizumab clinical studies in patients with AMD. There were no major notable differences between the groups treated with brolucizumab and comparator. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Overdosing with greater than recommended injection volume may increase intraocular pressure. In the event of overdose, intraocular pressure should therefore be monitored and, if deemed necessary by the treating physician, appropriate treatment should be initiated. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents, ATC code: S01LA06 Mechanism of action Brolucizumab is a humanised monoclonal single chain Fv (scFv) antibody fragment with a molecular weight of ~26 kDa. Increased levels of signalling through the vascular endothelial growth factor A (VEGF-A) pathway are associated with pathological ocular angiogenesis and retinal oedema. Brolucizumab binds with high affinity to VEGF-A isoforms (e.g. VEGF110, VEGF121, and VEGF165), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A binding, brolucizumab suppresses endothelial cell proliferation, thereby reducing pathological neovascularisation and decreasing vascular permeability. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 Pharmacodynamic effects Neovascular (wet) age-related macular degeneration (AMD) is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal thickening or oedema and/or intraretinal/subretinal haemorrhage, resulting in loss of visual acuity. In the HAWK and HARRIER studies, related anatomical parameters were part of the disease activity assessments guiding treatment decisions. Reductions in central subfield thickness (CST) and in presence of intraretinal/subretinal fluid (IRF/SRF) or sub-retinal pigment epithelium (sub-RPE) fluid were observed in patients treated with Beovu as early as 4 weeks after treatment initiation and up to week 48 and week 96. At week 16, the reduction in CST was statistically significant on Beovu versus aflibercept in both studies (HAWK: -161 vs. -134 microns; HARRIER: -174 vs. -134 microns). This decrease from baseline in CST was also statistically significant at week 48 (HAWK: -173 vs. -144 microns; HARRIER: -194 vs. -144 microns), and maintained to the end of each study at week 96 (HAWK: -175 vs. -149 microns; HARRIER: -198 vs. -155 microns). At week 16, the percentage difference in patients with IRF and/or SRF fluid was statistically significant on Beovu versus aflibercept in both studies (HAWK: 34% vs. 52%; HARRIER: 29% vs. 45%). This difference was also statistically significant at week 48 (HAWK: 31% vs. 45%; HARRIER: 26% vs. 44%), and maintained to the end of each study at week 96 (HAWK: 24% vs. 37%; HARRIER: 24% vs. 39%). At week 16, the percentage difference in patients with sub-RPE fluid was statistically significant on Beovu versus aflibercept in both studies (HAWK: 19% vs. 27%; HARRIER: 16% vs. 24%). This difference was also statistically significant at week 48 (HAWK: 14% vs. 22%; HARRIER: 13% vs. 22%), and maintained to the end of each study at week 96 (HAWK: 11% vs. 15%; HARRIER: 17% vs. 22%). In these studies, for patients treated with Beovu, reductions in CNV lesion size were observed as early as 12 weeks, and at weeks 48 and 96 after treatment initiation. Clinical efficacy and safety The efficacy and safety of Beovu were assessed in two randomised, multicentre, double-masked, active-controlled Phase III studies (HAWK and HARRIER) in patients with neovascular (wet) AMD. A total of 1,817 patients were treated in these studies for two years (1,088 on Beovu and 729 on comparator aflibercept). Patient ages ranged from 50 to 97 years, with a mean age of 76 years. In both studies, after the first three monthly doses (weeks 0, 4 and 8), brolucizumab patients were treated every 12 weeks, with the option of adjusting to a dosing interval every 8 weeks based on disease activity. Disease activity was assessed by a physician during the first 12-week interval (at weeks 16 and 20) and at each subsequent scheduled 12-weekly treatment visit. Patients who showed disease activity (e.g. decreased visual acuity, increased CST and/or presence of IRF/SRF or sub-RPE fluid) at any of these visits were adjusted to an 8-weekly treatment interval. The comparator aflibercept was administered every 8 weeks after the first 3 monthly doses. 10 Results The primary efficacy endpoint for the studies was the change from baseline in best corrected visual acuity (BCVA) to week 48, as measured by the early treatment diabetic retinopathy study (ETDRS) letter score, with the primary objective being to demonstrate non-inferiority of Beovu versus aflibercept. In both studies, Beovu (administered in an every 12 weeks or an every 8 weeks regimen) demonstrated non-inferior efficacy to aflibercept 2 mg (administered every 8 weeks). The visual acuity gains observed in the first year were maintained in the second year. Detailed results of both studies are shown in Table 2 and in Figure 1 below. Table 2 Visual acuity outcomes at weeks 48 and 96 in Phase III - HAWK and HARRIER studies HAWK HARRIER Efficacy outcome Week Beovu 6 mg (n=360) Aflibercept 2 mg (n=360) Difference (95% CI) brolucizumab – aflibercept Beovu 6 mg (n=370) Aflibercept 2 mg (n=369) Difference (95% CI) brolucizumab – aflibercept Mean change from baseline in BCVA (measured by ETDRS letters score) 48 6.6 (SE=0.71) 6.8 (SE=0.71) -0.2 (-2.1, 1.8) P<0.0001 a) 6.9 (SE=0.61) 7.6 (SE=0.61) -0.7 (-2.4, 1.0) P <0.0001 a) 36 – 48 b) 6.7 (SE=0.68) 6.7 (SE=0.68) 0.0 (-1.9, 1.9) P<0.0001 a) 6.5 (SE=0.58) 7.7 (SE=0.58) -1.2 (-2.8, 0.4) P=0.0003 a) 96 5.9 (SE=0.78) 5.3 (SE=0.78) 0.5 (-1.6, 2.7) 6.1 (SE=0.73) 6.6 (SE=0.73) -0.4 (-2.5,1.6) % of patients who gained at least 15 letters of vision 48 33.6 25.4 8.2 (2.2, 15.0) 29.3 29.9 -0.6 (-7.1, 5.8) 96 34.2 27.0 7.2 (1.4, 13.8) 29.1 31.5 -2.4 (-8.8, 4.1) % of patients who lost visual acuity (%) (≥15 letters of BCVA loss) 48 6.4 5.5 0.9 (-2.7, 4.3) 3.8 4.8 -1.0 (-3.9, 2.2) 96 8.1 7.4 0.7 (-3.6, 4.6) 7.1 7.5 -0.4 (-3.8, 3.3) BCVA: best corrected visual acuity; missing data are imputed using last observation carried forward (LOCF) method ETDRS: early treatment diabetic retinopathy study a) P-value referring to the non-inferiority hypothesis with a non-interiority margin of 4.0 letters. b) Key secondary endpoint, accounting for differences in timing of Beovu and aflibercept treatments. 11 Figure 1 Mean change in visual acuity from baseline to week 96 in HAWK and HARRIER studies HAWK HARRIER These visual acuity gains were achieved with 56% and 51% of patients treated with Beovu 6 mg on a 12-weekly dosing interval at week 48, and with 45% and 39% of patients at week 96 in HAWK and HARRIER, respectively. Among patients identified as eligible for the 12-weekly regimen during the first 12-week interval, 85% and 82% remained on the 12-weekly dosing interval up to week 48. Of patients on the 12-weekly interval at week 48, 82% and 75% remained on the 12-weekly dosing interval up to week 96. 0 1 2 3 4 5 6 7 8 9 10 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 V A c h an ge f ro m b as el in e (l et te rs ) Time (weeks) Beovu 6 mg (n=360) aflibercept 2 mg (n=360) 0 1 2 3 4 5 6 7 8 9 10 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 V A c h an ge f ro m b as el in e (l et te rs ) Time (weeks) Beovu 6 mg (n=370) aflibercept 2 mg (n=369) 12 Treatment effects in evaluable subgroups (e.g. age, gender, race, baseline visual acuity, baseline retinal thickness, lesion type, lesion size, fluid status) in each study were generally consistent with the results in the overall populations. Disease activity was assessed by changes in visual acuity and/or anatomical parameters, including CST and/or presence of IRF/SRF or sub-RPE. Disease activity was assessed throughout the studies. Anatomical parameters of disease activity were decreased at week 48 and at week 96 for Beovu compared to aflibercept (see “Pharmacodynamic effects”). The percentage difference in patients with disease activity at week 16 was statistically significant on Beovu versus aflibercept (24% vs 35% in HAWK, p=0.0013; 23% vs 32% in HARRIER, p=0.0021). In both studies, Beovu demonstrated clinically meaningful increases from baseline in the pre-specified secondary efficacy endpoint of patient-reported outcomes, reported through the National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in BCVA. Patient-reported outcome benefits were maintained in the second year. No clinically meaningful differences were found between Beovu and aflibercept in changes from baseline to week 48 in NEI VFQ-25 total score and subscales (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, colour vision and peripheral vision). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Beovu in all subsets of the paediatric population in neovascular AMD (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Beovu is administered directly into the vitreous to exert local effects in the eye. Absorption and distribution After intravitreal administration of 6 mg brolucizumab per eye to patients with nAMD, the geometirc mean Cmax of free brolucizumab in the plasma was 49.0 ng/ml (range: 8.97 to 548 ng/ml) and was attained in 1 day. Biotransformation and elimination Brolucizumab is a monoclonal antibody fragment and no metabolism studies have been conducted. As a single-chain antibody fragment, free brolucizumab is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF, passive renal elimination and metabolism via proteolysis. After intravitreal injections, brolucizumab was eliminated with an apparent systemic half-life of 4.4 days. Concentrations were generally near or below the quantitation limit (<0.5 ng/ml) approximately 4 weeks after dosing in most patients. Brolucizumab did not accumulate in the serum when administered intravitreally every 4 weeks. Special populations Elderly There were no relevant differences in systemic pharmacokinetics following intravitreal injection in a study with 22 patients aged 65 to 74 years, 18 patients aged 75 to 84 years and 3 patients aged ≥85 years. 13 Renal impairment The systemic pharmacokinetics of brolucizumab was evaluated in nAMD patients with normal renal function (≥90 ml/min [n=21]), with mild (60 to <90 ml/min [n=22]) or moderate (30 to <60 ml/min [n=7]) renal impairment. While the mean systemic clearance values for patients with mild or moderate renal impairment were generally lower than patients with normal renal function, no significant impact of mild and moderate renal impairment on the overall systemic exposure to brolucizumab was observed. No patients with severe (<30 ml/min) renal impairment were studied. Hepatic impairment Brolucizumab has not been studied in patients with hepatic impairment. Mild to severe hepatic impairment should have no impact on the overall systemic exposure to brolucizumab, because metabolism occurs via proteolysis and does not depend on hepatic function. 5.3 Preclinical safety data No studies have been conducted on the carcinogenic or mutagenic potential of brolucizumab. No animal reproduction studies have been conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium citrate Sucrose Polysorbate 80 Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life Pre-filled syringe: 2 years Vial: 2 years 6.4 Special precautions for storage Pre-filled syringe Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the pre-filled syringe in its sealed blister and in the outer carton in order to protect from light. Prior to use, the unopened blister may be kept at room temperature (below 25°C) for up to 24 hours. Vial Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. Prior to use, the unopened vial may be kept at room temperature (below 25°C) for up to 24 hours. 14 6.5 Nature and contents of container Pre-filled syringe 0.165 ml sterile solution in a pre-filled syringe (type I glass) with a bromobutyl rubber plunger stopper and a syringe cap consisting of a white, tamper-evident rigid seal with a grey bromobutyl rubber tip cap including a Luer lock adapter. The pre-filled syringe has a plunger rod and a purple finger grip, and is packed in a sealed blister. Pack size of 1 pre-filled syringe. Vial 0.230 ml sterile solution in a glass vial with a coated rubber stopper sealed with an aluminium cap with a purple plastic flip-off disk. Pack size of 1 vial and 1 blunt filter needle (18G x 1½″, 1.2 mm x 40 mm, 5 μm). 6.6 Special precautions for disposal and other handling Pre-filled syringe The pre-filled syringe contains more than the recommended dose of 6 mg. The extractable volume of the pre-filled syringe (0.165 ml) is not to be used in total. The excess volume should be expelled prior to injection. Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air bubble along with the excess medicinal product, slowly push the plunger until the edge below the dome of the rubber stopper is aligned with the black dosing line on the syringe (equivalent to 0.05 ml, i.e., 6 mg brolucizumab). The solution should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, the pre-filled syringe must not be used and appropriate replacement procedures followed. The pre-filled syringe is sterile and for single use only. Do not use if the packaging, or pre-filled syringe are damaged or expired. Detailed instructions for use are provided in the package leaflet. Any unused medicinal product or waste material should be disposed of in accordance with local regulations. Vial The vial contains more than the recommended dose of 6 mg. The extractable volume of the vial (0.23 ml) is not to be used in total. The excess volume should be expelled prior to injection. Injecting the entire volume of the vial could result in overdose. The injection dose must be set to the 0.05 ml dose mark, i.e. 6 mg brolucizumab. The solution should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, the vial must not be used, and appropriate replacement procedures must be followed. The content of the vial and the filter needle are sterile and for single use only. Do not use if the packaging, vial and/or filter needle are damaged or expired. Detailed instructions for use are provided in the package leaflet. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 15 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/19/1417/001-002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 13 February 2020 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 16 ANNEX II A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 17 A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) of the biological active substance(s) Sandoz GmbH Biochemiestrasse 10 6250 Kundl Austria Name and address of the manufacturer(s) responsible for batch release S.A. Alcon-Couvreur N.V. Rijksweg 14 2870 Puurs Belgium B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 18  Additional risk minimisation measures Prior to launch in each Member State the MAH shall agree the final educational material with the National Competent Authority. The MAH shall ensure that, following discussions and agreements with the National Competent Authority in each Member State where Beovu is marketed, all ophthalmological clinics where Beovu is expected to be used are provided with a patient guide in written and audio format, including the following key elements:  What is neovascular (wet) age-related macular degeneration  What is Beovu, how does it work, how is it administered and what to expect from the treatment  What are the steps following treatment with Beovu  Description of the risks, including increased intraocular pressure, intraocular inflammation, retinal vasculitis and/or retinal vascular occlusion, retinal detachment & retinal tear and endophthalmitis, and their key signs and symptoms; signs and symptoms of immunogenicity  Recommendations for monitoring and required examinations: Following intravitreal injection: measurement of increased intraocular pressure and perfusion of the optic nerve  When and how to seek urgent attention from the health care provider 19 ANNEX III LABELLING AND PACKAGE LEAFLET 20 A. LABELLING 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON – PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Beovu 120 mg/ml solution for injection in pre-filled syringe brolucizumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled syringe of 0.165 ml solution contains 19.8 mg brolucizmab (120 mg/ml). 3. LIST OF EXCIPIENTS Contains: sodium citrate, sucrose, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1x 0.165 ml pre-filled syringe Delivers a single dose of 6 mg/0.05 ml. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravitreal use For single use only. After opening the sterile sealed blister, proceed under aseptic conditions. Set dose to 0.05 ml dose mark. Excess volume to be expelled prior to injection. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 22 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled syringe in its sealed blister and in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/19/1417/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 23 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PEEL-OFF LABEL AFFIXED TO INNER LID OF CARTON – PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Beovu 2. EXPIRY DATE EXP 3. BATCH NUMBER Lot 24 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER FOIL – PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Beovu 120 mg/ml solution for injection in pre-filled syringe brolucizumab 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 0.165 ml 25 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL – PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Beovu 120 mg/ml injection brolucizumab Intravitreal use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 19.8 mg/0.165 ml 6. OTHER 26 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON – VIAL 1. NAME OF THE MEDICINAL PRODUCT Beovu 120 mg/ml solution for injection brolucizumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial of 0.23 ml solution contains 27.6 mg brolucizmab (120 mg/ml). 3. LIST OF EXCIPIENTS Contains: sodium citrate, sucrose, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1x 0.23 ml vial, 1 filter needle. Delivers a single dose of 6 mg/0.05 ml. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravitreal use For single use only. After opening the vial, proceed under aseptic conditions. Set dose to 0.05 ml. Excess volume to be expelled prior to injection. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 27 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/19/1417/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 28 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL - VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Beovu 120 mg/ml injection brolucizumab Intravitreal use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 27.6 mg/0.23 ml 6. OTHER 29 B. PACKAGE LEAFLET 30 Package leaflet: Information for the patient Beovu 120 mg/ml solution for injection in pre-filled syringe brolucizumab This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you are given this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor. - If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Beovu is and what it is used for 2. What you need to know before you are given Beovu 3. How Beovu is given 4. Possible side effects 5. How to store Beovu 6. Contents of the pack and other information 1. What Beovu is and what it is used for What Beovu is Beovu contains the active substance brolucizumab, which belongs to a group of medicines called antineovascularisation agents. Beovu is injected into the eye by your doctor to treat an eye disorder called neovascular (wet) age-related macular degeneration (AMD). What Beovu is used for Beovu is used to treat neovascular wet AMD in adults, which occurs when abnormal blood vessels form and grow underneath the macula. The macula, which is at the back of the eye, is responsible for clear vision. The abnormal blood vessels may leak fluid or blood into the eye and interfere with the macula’s function, resulting in decreased vision. How Beovu works A substance called vascular endothelial growth factor A (VEGF-A) causes the growth of blood vessels in the eye. By attaching to VEGF-A, Beovu blocks its effect and so reduces the growth of abnormal blood vessels in AMD, which in turn reduces the leakage of fluid or blood in the eye. Beovu may slow down disease progression and thereby maintain, or even improve, your vision. Abnormal blood vessels that leak fluid or blood into the macula 31 2. What you need to know before you are given Beovu You must not be given Beovu: - if you are allergic to brolucizumab or any of the other ingredients of this medicine (listed in section 6). - if you have an active or suspected infection in or around the eye. - if you have pain or redness in your eye (eye inflammation). If any of these applies to you, tell your doctor. You should not be given Beovu. Warnings and precautions Talk to your doctor before you are given Beovu if any of the following applies to you: - if you have glaucoma (an eye condition usually caused by high pressure in the eye). - if you have a history of seeing flashes of light or floaters (dark floating spots) and if you have a sudden increase in the size and number of floaters. - if you have had eye surgery in the last 4 weeks or if eye surgery is planned in the next four weeks. - if you have ever had any eye diseases or eye treatments. Tell your doctor immediately if you: - develop redness of the eye, eye pain, increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in your vision, increased sensitivity to light. - develop sudden vision loss, which could be a sign of retinal vascular occlusion. Furthermore it is important for you to know that: - the safety and efficacy of Beovu when administered to both eyes at the same time has not been studied and use in this way may lead to an increased risk of experiencing side effects. - injections with Beovu may cause an increase in eye pressure (intraocular pressure) in some patients within 30 minutes of the injection. Your doctor will monitor this after each injection. - your doctor will check whether you have other risk factors that may increase the chance of a tear or detachment of one of the layers at the back of the eye (retinal detachment or tear, and retinal pigment epithelial detachment or tear), in which case Beovu must be given with caution. The systemic use of VEGF inhibitors, substances similar to those contained in Beovu, is potentially related to the risk of blood clots blocking blood vessels (arterial thromboembolic events), which may lead to heart attack or stroke. There is a theoretical risk of such events following injection of Beovu into the eye. Children and adolescents Beovu is not used in children and adolescents, because wet AMD occurs only in adults. Other medicines and Beovu Tell your doctor if you are using, have recently used or might use any other medicines. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think that you may be pregnant or are planning to have a baby, ask your doctor for advice before this medicine is given to you. Breast-feeding is not recommended during treatment with Beovu and for at least one month after stopping treatment with Beovu because it is not known whether Beovu passes into human milk. Women who could become pregnant must use an effective method of birth control during treatment and for at least one month after stopping treatment with Beovu. If you become pregnant or think you are pregnant during treatment, tell your doctor right away. 32 Driving and using machines After your injection with Beovu, you may have temporary vision problems (for example blurred vision). Do not drive or use machines as long as these last. Beovu contains sodium The medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 3. How Beovu is given How much and how often Beovu is given The recommended dose is 6 mg brolucizumab. - You will be treated with one injection every month for the first 3 months. - After that, you may get one injection every 3 months. Your doctor will determine your treatment interval based on the condition of your eye; some patients may need treatment every 2 months. Method of administration Beovu is given as an injection into your eye (intravitreal use) by an eye doctor. Before the injection, your doctor will clean your eye carefully, to prevent infection. Your doctor will also give you an eye drop (local anaesthetic) to numb the eye to reduce or prevent pain from the injection. How long does Beovu treatment last for Wet AMD is a chronic disease and it therefore needs long-term treatment with this medicine, possibly continuing for months or years. Your doctor will check that the treatment is working during your regular scheduled visits. Your doctor may also check on your eyes between injections. If you have questions about how long you will receive Beovu, talk to your doctor. Before stopping Beovu treatment Speak with your doctor before stopping treatment. Stopping treatment may increase your risk of vision loss and your vision may worsen. If you have any further questions on the use of this medicine, ask your doctor. For the first Then, 3 months 1 injection per month 1 injection every 3 months or as recommended by your doctor 33 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The side effects with Beovu injection are either from the medicine itself or from the injection procedure and they mostly affect the eye. Some side effects could be serious Get immediate medical help if you have any of the following, which are signs of allergic reactions, inflammations or infections:  a sudden decrease or change in vision  pain, increased discomfort, worsening eye redness If you have any serious side effects, tell your doctor immediately. Other possible side effects Other side effects which may occur after Beovu treatment include those listed below. Most of the side effects are mild to moderate and will generally disappear within a week after each injection. If these side effects become severe, please tell your doctor. Common: may affect up to 1 in every 10 people  inflammation of the middle layer of the eye wall (uveitis)  detachment of the gel-like substance inside the eye (vitreous detachment)  tearing of the retina (the part at the back of the eye that detects light) or one of its layers (retinal pigment epithelial tear)  reduced sharpness of vision (reduced visual acuity)  bleeding in the retina (retinal haemorrhage)  inflammation of the iris, the coloured part of the eye (iritis)  clouding of the lens of the eye (cataract)  bleeding from small blood vessels in the outer layer of the eye (conjunctival haemorrhage)  moving spots in your vision (vitreous floaters)  eye pain  increase in pressure inside the eye (intraocular pressure increase)  redness in the white of the eye (conjunctivitis)  blurred or unclear vision  scratched cornea, damage to the clear layer of the eyeball that covers the iris (corneal abrasion)  damage to the clear layer of the eyeball that covers the iris (punctuate keratitis)  allergic reactions (hypersensitivity) Uncommon: may affect up to 1 in every 100 people  severe inflammation inside the eye (endophthalmitis)  blindness  sudden vision loss due to blockage of an artery in the eye (retinal artery occlusion)  detachment of the retina (retinal detachment)  redness of the eye (conjunctival hyperaemia)  increased tear production (lacrimation increased)  abnormal feeling in the eye  detachment of one of the layers of the retina (detachment of retinal pigment epithelium)  inflammation of the gel-like substance inside the eye (vitritis)  inflammation of the front of the eye (anterior chamber inflammation or flare)  inflammation in the iris and its adjacent tissue in the eye (iridocyclitis)  swelling of the cornea, the clear layer of the eyeball (corneal oedema)  bleeding in the eye (vitreous haemorrhage) 34 Not known: frequency cannot be estimated from the available data  sudden vision loss due to blockage of blood vessels in the back of the eye (retinal vascular occlusion)  inflammation of blood vessels in the back of the eye (retinal vasculitis) Reporting of side effects If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Beovu Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and label after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the pre-filled syringe in the sealed blister and in the outer carton in order to protect from light. Prior to use, the unopened blister with the pre-filled syringe may be kept at room temperature (below 25°C) for up to 24 hours. 6. Contents of the pack and other information What Beovu contains - The active substance is brolucizumab. One ml solution for injection contains 120 mg brolucizumab. Each pre-filled syringe contains 19.8 mg brolucizumab in 0.165 ml solution. This provides a usable amount to deliver a single dose of 0.05 ml solution containing 6 mg of brolucizumab. - The other ingredients are: sodium citrate, sucrose, polysorbate 80, water for injections. What Beovu looks like and contents of the pack Beovu 120 mg/ml solution for injection in a pre-filled syringe (injection) is a clear to slightly opalescent, colourless to slightly brownish-yellow aqueous solution. Pack size of 1 pre-filled syringe for single use only. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer S.A. ALCON-COUVREUR N.V. Rijksweg 14 2870 Puurs Belgium http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 35 For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел.: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 36 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu 37 The following information is intended for healthcare professionals only: Instruction for use of pre-filled syringe Storage and inspection Store Beovu in the refrigerator (2°C - 8°C). Do not freeze. Keep the pre-filled syringe in its sealed blister and the outer carton in order to protect from light. Prior to use, the unopened blister with the pre-filled syringe of Beovu may be kept at room temperature (below 25°C) for up to 24 hours. Make sure that your pack contains a sterile pre-filled syringe in a sealed blister. After opening the blister pack, proceed under aseptic conditions. Beovu is a clear to slightly opalescent and colourless to slightly brownish-yellow aqueous solution. The solution should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, the pre-filled syringe must not be used and appropriate replacement procedures followed. The pre-filled syringe is sterile and for single use only. Do not use if the packaging or pre-filled syringe are damaged or expired. How to prepare and administer Beovu The pre-filled syringe contains more than the recommended dose of 6 mg. The extractable volume of the pre-filled syringe (0.165 ml) is not to be used in total. The excess volume should be expelled prior to injection. Injecting the entire volume of the pre-filled syringe could result in overdose. The intravitreal injection procedure must be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape, a sterile eyelid speculum (or equivalent) and the availability of sterile paracentesis equipment (if required). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection. For intravitreal injection, use a 30G x ½” sterile injection needle. The injection needle is not included in the Beovu pack. Ensure that the injection is given immediately after preparation of the dose (step 5). Note: The dose must be set to 0.05 ml. 38 Injection procedure 1. Peel the lid off the syringe blister and, using aseptic technique, remove the syringe. 2. Snap off (do not turn or twist) the syringe cap. 3. Aseptically and firmly assemble a 30G x ½” injection needle onto the syringe. 4. To check for air bubbles, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top. Carefully remove the needle cap by pulling it straight off. 5. Hold the syringe at eye level and carefully push the plunger until the edge below the dome of the rubber stopper is aligned with the 0.05 ml dose mark. This will expel the air and the excess solution and set the dose to 0.05 ml. The syringe is ready for the injection. 6. Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 ml. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel. Note: Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Syringe cap Finger grip Luer lock 0.05 ml dose mark Rubber stopper Plunger rod 39 Commonly asked questions and answers Q: What if I cannot remove all the air bubbles from the liquid? A: It is important that the liquid is air free. However, tiny air bubbles that are attached to the stopper usually do not detach from the stopper during the injection and therefore do not affect the dose volume. 40 Package leaflet: Information for the patient Beovu 120 mg/ml solution for injection brolucizumab This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you are given this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor. - If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Beovu is and what it is used for 2. What you need to know before you are given Beovu 3. How Beovu is given 4. Possible side effects 5. How to store Beovu 6. Contents of the pack and other information 1. What Beovu is and what it is used for What Beovu is Beovu contains the active substance brolucizumab, which belongs to a group of medicines called antineovascularisation agents. Beovu is injected into the eye by your doctor to treat an eye disorder called neovascular (wet) age-related macular degeneration (AMD). What Beovu is used for Beovu is used to treat neovascular wet AMD in adults, which occurs when abnormal blood vessels form and grow underneath the macula. The macula, which is at the back of the eye, is responsible for clear vision. The abnormal blood vessels may leak fluid or blood into the eye and interfere with the macula’s function, resulting in decreased vision. How Beovu works A substance called vascular endothelial growth factor A (VEGF-A) causes the growth of blood vessels in the eye. By attaching to VEGF-A, Beovu blocks its effect and so reduces the growth of abnormal blood vessels in AMD, which in turn reduces the leakage of fluid or blood in the eye. Beovu may slow down disease progression and thereby maintain, or even improve, your vision. Abnormal blood vessels that leak fluid or blood into the macula 41 2. What you need to know before you are given Beovu You must not be given Beovu: - if you are allergic to brolucizumab or any of the other ingredients of this medicine (listed in section 6). - if you have an active or suspected infection in or around the eye. - if you have pain or redness in your eye (eye inflammation). If any of these applies to you, tell your doctor. You should not be given Beovu. Warnings and precautions Talk to your doctor before you are given Beovu if any of the following applies to you: - if you have glaucoma (an eye condition usually caused by high pressure in the eye). - if you have a history of seeing flashes of light or floaters (dark floating spots) and if you have a sudden increase in the size and number of floaters. - if you have had eye surgery in the last 4 weeks or if eye surgery is planned in the next four weeks. - if you have ever had any eye diseases or eye treatments. Tell your doctor immediately if you: - develop redness of the eye, eye pain, increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in your vision, increased sensitivity to light. - develop sudden vision loss, which could be a sign of retinal vascular occlusion. Furthermore it is important for you to know that: - the safety and efficacy of Beovu when administered to both eyes at the same time has not been studied and use in this way may lead to an increased risk of experiencing side effects. - injections with Beovu may cause an increase in eye pressure (intraocular pressure) in some patients within 30 minutes of the injection. Your doctor will monitor this after each injection. - your doctor will check whether you have other risk factors that may increase the chance of a tear or detachment of one of the layers at the back of the eye (retinal detachment or tear, and retinal pigment epithelial detachment or tear), in which case Beovu must be given with caution. The systemic use of VEGF inhibitors, substances similar to those contained in Beovu, is potentially related to the risk of blood clots blocking blood vessels (arterial thromboembolic events), which may lead to heart attack or stroke. There is a theoretical risk of such events following injection of Beovu into the eye. Children and adolescents Beovu is not used in children and adolescents, because wet AMD occurs only in adults. Other medicines and Beovu Tell your doctor if you are using, have recently used or might use any other medicines. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think that you may be pregnant or are planning to have a baby, ask your doctor for advice before this medicine is given to you. Breast-feeding is not recommended during treatment with Beovu and for at least one month after stopping treatment with Beovu because it is not known whether Beovu passes into human milk. Women who could become pregnant must use an effective method of birth control during treatment and for at least one month after stopping treatment with Beovu. If you become pregnant or think you are pregnant during treatment, tell your doctor right away. 42 Driving and using machines After your injection with Beovu, you may have temporary vision problems (for example blurred vision). Do not drive or use machines as long as these last. Beovu contains sodium The medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 3. How Beovu is given How much and how often Beovu is given The recommended dose is 6 mg brolucizumab. - You will be treated with one injection every month for the first 3 months. - After that, you may get one injection every 3 months. Your doctor will determine your treatment interval based on the condition of your eye; some patients may need treatment every 2 months. Method of administration Beovu is given as an injection into your eye (intravitreal use) by an eye doctor. Before the injection, your doctor will clean your eye carefully, to prevent infection. Your doctor will also give you an eye drop (local anaesthetic) to numb the eye to reduce or prevent pain from the injection. How long does Beovu treatment last for Wet AMD is a chronic disease and it therefore needs long-term treatment with this medicine, possibly continuing for months or years. Your doctor will check that the treatment is working during your regular scheduled visits. Your doctor may also check on your eyes between injections. If you have questions about how long you will receive Beovu, talk to your doctor. Before stopping Beovu treatment Speak with your doctor before stopping treatment. Stopping treatment may increase your risk of vision loss and your vision may worsen. If you have any further questions on the use of this medicine, ask your doctor. For the first Then, 3 months 1 injection per month 1 injection every 3 months or as recommended by your doctor 43 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The side effects with Beovu injection are either from the medicine itself or from the injection procedure and they mostly affect the eye. Some side effects could be serious Get immediate medical help if you have any of the following, which are signs of allergic reactions, inflammations or infections:  a sudden decrease or change in vision  pain, increased discomfort, worsening eye redness If you have any serious side effects, tell your doctor immediately. Other possible side effects Other side effects which may occur after Beovu treatment include those listed below. Most of the side effects are mild to moderate and will generally disappear within a week after each injection. If these side effects become severe, please tell your doctor. Common: may affect up to 1 in every 10 people  inflammation of the middle layer of the eye wall (uveitis)  detachment of the gel-like substance inside the eye (vitreous detachment)  tearing of the retina (the part at the back of the eye that detects light) or one of its layers (retinal pigment epithelial tear)  reduced sharpness of vision (reduced visual acuity)  bleeding in the retina (retinal haemorrhage)  inflammation of the iris, the coloured part of the eye (iritis)  clouding of the lens of the eye (cataract)  bleeding from small blood vessels in the outer layer of the eye (conjunctival haemorrhage)  moving spots in your vision (vitreous floaters)  eye pain  increase in pressure inside the eye (intraocular pressure increase)  redness in the white of the eye (conjunctivitis)  blurred or unclear vision  scratched cornea, damage to the clear layer of the eyeball that covers the iris (corneal abrasion)  damage to the clear layer of the eyeball that covers the iris (punctuate keratitis)  allergic reactions (hypersensitivity) Uncommon: may affect up to 1 in every 100 people  severe inflammation inside the eye (endophthalmitis)  blindness  sudden vision loss due to blockage of an artery in the eye (retinal artery occlusion)  detachment of the retina (retinal detachment)  redness of the eye (conjunctival hyperaemia)  increased tear production (lacrimation increased)  abnormal feeling in the eye  detachment of one of the layers of the retina (detachment of retinal pigment epithelium)  inflammation of the gel-like substance inside the eye (vitritis)  inflammation of the front of the eye (anterior chamber inflammation or flare)  inflammation in the iris and its adjacent tissue in the eye (iridocyclitis)  swelling of the cornea, the clear layer of the eyeball (corneal oedema)  bleeding in the eye (vitreous haemorrhage) 44 Not known: frequency cannot be estimated from the available data  sudden vision loss due to blockage of blood vessels in the back of the eye (retinal vascular occlusion)  inflammation of blood vessels in the back of the eye (retinal vasculitis) Reporting of side effects If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Beovu Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and label after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. Prior to use, the unopened vial may be kept at room temperature (below 25°C) for up to 24 hours. 6. Contents of the pack and other information What Beovu contains - The active substance is brolucizumab. One ml solution for injection contains 120 mg brolucizumab.Each vial contains 27.6 mg brolucizumab in 0.23 ml solution. This provides a usable amount to deliver a single dose of 0.05 ml solution containing 6 mg of brolucizumab. - The other ingredients are: sodium citrate, sucrose, polysorbate 80, water for injections. What Beovu looks like and contents of the pack Beovu 120 mg/ml solution for injection (injection) is a clear to slightly opalescent, colourless to slightly brownish-yellow aqueous solution. Pack size of 1 vial and 1 blunt filter needle (18G x 1½″, 1.2 mm x 40 mm, 5 μm) for single use only. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer S.A. ALCON-COUVREUR N.V. Rijksweg 14 2870 Puurs Belgium http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 45 For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел.: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 46 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu 47 The following information is intended for healthcare professionals only: Instructions for use of vial Storage and inspection Store Beovu in the refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. Prior to use, the unopened vial of Beovu may be kept at room temperature (below 25°C) for up to 24 hours. After opening the vial, proceed under aseptic conditions. Beovu is a clear to slightly opalescent and colourless to slightly brownish-yellow aqueous solution. The solution should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, the vial must not be used and appropriate replacement procedures followed. The contents of the vial and the filter needle are sterile and for single use only. Do not use if the packaging, vial and/or filter needle are damaged or expired. How to prepare and administer Beovu The vial contains more than the recommended dose of 6 mg. The extractable volume of the vial (0.23 ml) is not to be used in total. The excess volume should be expelled prior to injection. Injecting the entire volume of the vial could result in overdose. The intravitreal injection procedure must be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent) and the availability of sterile paracentesis equipment (if required). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection. For preparation and intravitreal injection, the following single-use medical devices are needed:  A 30G x ½” injection needle, sterile.  A 1 ml syringe with a 0.05 ml dose mark, sterile.  The 5 μm blunt filter needle (18G x 1½”, 1.2 mm x 40 mm), sterile. The injection needle and the syringe are not included in the Beovu pack. Ensure that the injection is given immediately after preparation of the dose (step 8). Note: The dose must be set to 0.05 ml. 48 Injection procedure 1. Remove the vial cap and clean the vial septum (e.g. with 70% alcohol swab). 2. Assemble the filter needle onto a 1 ml syringe using aseptic technique. 3. Push the filter needle into the centre of the vial septum until the needle touches the bottom of the vial. 4. To withdraw the liquid, hold the vial slightly inclined and slowly withdraw all the liquid from the vial and filter needle. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. 5. Disconnect the filter needle from the syringe in an aseptic manner and dispose of it. The filter needle is not to be used for intravitreal injection. 6. Aseptically and firmly assemble a 30G x ½” injection needle onto the syringe. 7. To check for air bubbles, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top. 49 8. Hold the syringe at eye level and carefully push the plunger to expel the air along with the excess solution from the syringe and adjust the dose to the 0.05 ml mark. The syringe is ready for the injection. 9. Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 ml. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel. Note: Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Commonly asked questions and answers Q: What if I have difficulty withdrawing sufficient liquid from the vial? A: Do not shake the vial before withdrawal but let the liquid settle to the bottom of the vial. Ensure the vial is in an upright, slightly inclined position. Slowly withdraw the plunger and wait for the liquid to appear in the syringe barrel. Continue to withdraw slowly to completely empty the vial and the filter needle. Q: What if I cannot remove all the air bubbles from the liquid? A: It is important that the liquid is air free. However, tiny air bubbles that are attached to the stopper usually do not detach from the stopper during the injection and therefore do not affect the dose volume. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what beovu is and what it is used for', 'Section_Content': "what beovu is beovu contains the active substance brolucizumab, which belongs to a group of medicines called antineovascularisation agents. beovu is injected into the eye by your doctor to treat an eye disorder called neovascular (wet) age-related macular degeneration (amd). what beovu is used for beovu is used to treat neovascular wet amd in adults, which occurs when abnormal blood vessels form and grow underneath the macula. the macula, which is at the back of the eye, is responsible for clear vision. the abnormal blood vessels may leak fluid or blood into the eye and interfere with the macula's function, resulting in decreased vision. how beovu works a substance called vascular endothelial growth factor a (vegf-a) causes the growth of blood vessels in the eye. by attaching to vegf-a, beovu blocks its effect and so reduces the growth of abnormal blood vessels in amd, which in turn reduces the leakage of fluid or blood in the eye. beovu may slow down disease progression and thereby maintain, or even improve, your vision. abnormal blood vessels that leak fluid or blood into the macula 31", 'Entity_Recognition': [{'Text': 'beovu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 16, 'BeginOffset': 50, 'EndOffset': 62, 'Score': 0.8224484324455261, 'Text': 'brolucizumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a group of medicines', 'Type': 'TREATMENT', 'BeginOffset': 81, 'EndOffset': 101}, {'Text': 'antineovascularisation agents', 'Type': 'TREATMENT', 'BeginOffset': 109, 'EndOffset': 138}, {'Id': 0, 'BeginOffset': 167, 'EndOffset': 170, 'Score': 0.810910165309906, 'Text': 'eye', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'an eye disorder', 'Type': 'PROBLEM', 'BeginOffset': 195, 'EndOffset': 210}, {'Text': 'neovascular (wet) age', 'Type': 'PROBLEM', 'BeginOffset': 218, 'EndOffset': 239}, {'Id': 19, 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{'Title': '2. what you need to know before you are given beovu', 'Section_Content': 'you must not be given beovu: - if you are allergic to brolucizumab or any of the other ingredients of this medicine (listed in section 6). - if you have an active or suspected infection in or around the eye. - if you have pain or redness in your eye (eye inflammation). if any of these applies to you, tell your doctor. you should not be given beovu. warnings and precautions talk to your doctor before you are given beovu if any of the following applies to you: - if you have glaucoma (an eye condition usually caused by high pressure in the eye). - if you have a history of seeing flashes of light or floaters (dark floating spots) and if you have a sudden increase in the size and number of floaters. - if you have had eye surgery in the last 4 weeks or if eye surgery is planned in the next four weeks. - if you have ever had any eye diseases or eye treatments. tell your doctor immediately if you: - develop redness of the eye, eye pain, increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in your vision, increased sensitivity to light. - develop sudden vision loss, which could be a sign of retinal vascular occlusion. furthermore it is important for you to know that: - the safety and efficacy of beovu when administered to both eyes at the same time has not been studied and use in this way may lead to an increased risk of experiencing side effects. - injections with beovu may cause an increase in eye pressure (intraocular pressure) in some patients within 30 minutes of the injection. your doctor will monitor this after each injection. - your doctor will check whether you have other risk factors that may increase the chance of a tear or detachment of one of the layers at the back of the eye (retinal detachment or tear, and retinal pigment epithelial detachment or tear), in which case beovu must be given with caution. the systemic use of vegf inhibitors, substances similar to those contained in beovu, is potentially related to the risk of blood clots blocking blood vessels (arterial thromboembolic events), which may lead to heart attack or stroke. there is a theoretical risk of such events following injection of beovu into the eye. children and adolescents beovu is not used in children and adolescents, because wet amd occurs only in adults. other medicines and beovu tell your doctor if you are using, have recently used or might use any other medicines. pregnancy and breast-feeding if you are pregnant or breast-feeding, think that you may be pregnant or are planning to have a baby, ask your doctor for advice before this medicine is given to you. breast-feeding is not recommended during treatment with beovu and for at least one month after stopping treatment with beovu because it is not known whether beovu passes into human milk. women who could become pregnant must use an effective method of birth control during treatment and for at least one month after stopping treatment with beovu. if you become pregnant or think you are pregnant during treatment, tell your doctor right away. driving and using machines after your injection with beovu, you may have temporary vision problems (for example blurred vision). do not drive or use machines as long as these last. beovu contains sodium the medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially "sodium-free".', 'Entity_Recognition': [{'Text': 'beovu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 42, 'EndOffset': 50}, {'Id': 18, 'BeginOffset': 54, 'EndOffset': 66, 'Score': 0.8939749002456665, 'Text': 'brolucizumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 102, 'EndOffset': 115}, {'Text': 'an active or suspected infection', 'Type': 'PROBLEM', 'BeginOffset': 153, 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{'Title': '3. how beovu is given', 'Section_Content': 'how much and how often beovu is given the recommended dose is 6 mg brolucizumab. - you will be treated with one injection every month for the first 3 months. - after that, you may get one injection every 3 months. your doctor will determine your treatment interval based on the condition of your eye; some patients may need treatment every 2 months. method of administration beovu is given as an injection into your eye (intravitreal use) by an eye doctor. before the injection, your doctor will clean your eye carefully, to prevent infection. your doctor will also give you an eye drop (local anaesthetic) to numb the eye to reduce or prevent pain from the injection. how long does beovu treatment last for wet amd is a chronic disease and it therefore needs long-term treatment with this medicine, possibly continuing for months or years. your doctor will check that the treatment is working during your regular scheduled visits. your doctor may also check on your eyes between injections. if you have questions about how long you will receive beovu, talk to your doctor. before stopping beovu treatment speak with your doctor before stopping treatment. stopping treatment may increase your risk of vision loss and your vision may worsen. if you have any further questions on the use of this medicine, ask your doctor. for the first then, 3 months 1 injection per month 1 injection every 3 months or as recommended by your doctor 33', 'Entity_Recognition': [{'Text': 'beovu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 62, 'EndOffset': 63}, {'Id': 8, 'BeginOffset': 67, 'EndOffset': 79, 'Score': 0.9982324242591858, 'Text': 'brolucizumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9651308059692383, 'RelationshipScore': 0.9999895095825195, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 62, 'EndOffset': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the side effects with beovu injection are either from the medicine itself or from the injection procedure and they mostly affect the eye. some side effects could be serious get immediate medical help if you have any of the following, which are signs of allergic reactions, inflammations or infections: a sudden decrease or change in vision pain, increased discomfort, worsening eye redness if you have any serious side effects, tell your doctor immediately. other possible side effects other side effects which may occur after beovu treatment include those listed below. most of the side effects are mild to moderate and will generally disappear within a week after each injection. if these side effects become severe, please tell your doctor. common: may affect up to 1 in every 10 people inflammation of the middle layer of the eye wall (uveitis) detachment of the gel-like substance inside the eye (vitreous detachment) tearing of the retina (the part at the back of the eye that detects light) or one of its layers (retinal pigment epithelial tear) reduced sharpness of vision (reduced visual acuity) bleeding in the retina (retinal haemorrhage) inflammation of the iris, the coloured part of the eye (iritis) clouding of the lens of the eye (cataract) bleeding from small blood vessels in the outer layer of the eye (conjunctival haemorrhage) moving spots in your vision (vitreous floaters) eye pain increase in pressure inside the eye (intraocular pressure increase) redness in the white of the eye (conjunctivitis) blurred or unclear vision scratched cornea, damage to the clear layer of the eyeball that covers the iris (corneal abrasion) damage to the clear layer of the eyeball that covers the iris (punctuate keratitis) allergic reactions (hypersensitivity) uncommon: may affect up to 1 in every 100 people severe inflammation inside the eye (endophthalmitis) blindness sudden vision loss due to blockage of an artery in the eye (retinal artery occlusion) detachment of the retina (retinal detachment) redness of the eye (conjunctival hyperaemia) increased tear production (lacrimation increased) abnormal feeling in the eye detachment of one of the layers of the retina (detachment of retinal pigment epithelium) inflammation of the gel-like substance inside the eye (vitritis) inflammation of the front of the eye (anterior chamber inflammation or flare) inflammation in the iris and its adjacent tissue in the eye (iridocyclitis) swelling of the cornea, the clear layer of the eyeball (corneal oedema) bleeding in the eye (vitreous haemorrhage) 34 not known: frequency cannot be estimated from the available data sudden vision loss due to blockage of blood vessels in the back of the eye (retinal vascular occlusion) inflammation of blood vessels in the back of the eye (retinal vasculitis) reporting of side effects if you get any 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'RelationshipScore': 0.7963376641273499, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 110, 'BeginOffset': 2872, 'EndOffset': 2875, 'Text': 'eye', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 106, 'BeginOffset': 2790, 'EndOffset': 2793, 'Score': 0.9919347763061523, 'Text': 'eye', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 135, 'BeginOffset': 2795, 'EndOffset': 2821, 'Score': 0.6451123356819153, 'Text': 'retinal vascular occlusion', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7231529951095581}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9270716905593872, 'RelationshipScore': 0.9979275465011597, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 104, 'BeginOffset': 2757, 'EndOffset': 2770, 'Text': 'blood vessels', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'DIRECTION', 'Score': 0.6988710761070251, 'RelationshipScore': 0.891438364982605, 'RelationshipType': 'DIRECTION', 'Id': 105, 'BeginOffset': 2778, 'EndOffset': 2782, 'Text': 'back', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9919347763061523, 'RelationshipScore': 0.9097456336021423, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 106, 'BeginOffset': 2790, 'EndOffset': 2793, 'Text': 'eye', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'inflammation of blood vessels', 'Type': 'PROBLEM', 'BeginOffset': 2823, 'EndOffset': 2852}, {'Id': 110, 'BeginOffset': 2872, 'EndOffset': 2875, 'Score': 0.9907612204551697, 'Text': 'eye', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 137, 'BeginOffset': 2877, 'EndOffset': 2895, 'Score': 0.6421587467193604, 'Text': 'retinal vasculitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.84798264503479}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9342001080513, 'RelationshipScore': 0.9998067021369934, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 108, 'BeginOffset': 2839, 'EndOffset': 2852, 'Text': 'blood vessels', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'DIRECTION', 'Score': 0.6563830375671387, 'RelationshipScore': 0.9963735938072205, 'RelationshipType': 'DIRECTION', 'Id': 109, 'BeginOffset': 2860, 'EndOffset': 2864, 'Text': 'back', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9907612204551697, 'RelationshipScore': 0.9961603879928589, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 110, 'BeginOffset': 2872, 'EndOffset': 2875, 'Text': 'eye', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 138, 'BeginOffset': 2910, 'EndOffset': 2922, 'Score': 0.8803989291191101, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.40941107273101807}]}, {'Id': 139, 'BeginOffset': 2938, 'EndOffset': 2950, 'Score': 0.9030064940452576, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5857420563697815}]}, {'Id': 140, 'BeginOffset': 3000, 'EndOffset': 3012, 'Score': 0.9526463150978088, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5231074094772339}]}, {'Id': 141, 'BeginOffset': 3061, 'EndOffset': 3073, 'Score': 0.8224728107452393, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.566948413848877}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.49475592374801636, 'RelationshipScore': 0.7501680850982666, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 111, 'BeginOffset': 3127, 'EndOffset': 3135, 'Text': 'appendix', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 111, 'BeginOffset': 3127, 'EndOffset': 3135, 'Score': 0.49475592374801636, 'Text': 'appendix', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 142, 'BeginOffset': 3152, 'EndOffset': 3164, 'Score': 0.7058082818984985, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5974693298339844}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 3220, 'EndOffset': 3233}]}

{'Title': '5. how to store beovu', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and label after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 - 8). do not freeze. keep the pre-filled syringe in the sealed blister and in the outer carton in order to protect from light. prior to use, the unopened blister with the pre-filled syringe may be kept at room temperature (below 25) for up to 24 hours.', 'Entity_Recognition': [{'Text': 'beovu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'the pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 264, 'EndOffset': 286}, {'Text': 'the sealed blister', 'Type': 'TREATMENT', 'BeginOffset': 290, 'EndOffset': 308}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 316, 'EndOffset': 332}, {'Text': 'the unopened blister', 'Type': 'PROBLEM', 'BeginOffset': 379, 'EndOffset': 399}, {'Text': 'the pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 405, 'EndOffset': 427}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 467, 'EndOffset': 469}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 481, 'EndOffset': 483}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what beovu contains - the active substance is brolucizumab. one ml solution for injection contains 120 mg brolucizumab. each pre-filled syringe contains 19.8 mg brolucizumab in 0.165 ml solution. this provides a usable amount to deliver a single dose of 0.05 ml solution containing 6 mg of brolucizumab. - the other ingredients are: sodium citrate, sucrose, polysorbate 80, water for injections. what beovu looks like and contents of the pack beovu 120 mg/ml solution for injection in a pre-filled syringe (injection) is a clear to slightly opalescent, colourless to slightly brownish-yellow aqueous solution. pack size of 1 pre-filled syringe for single use only.', 'Entity_Recognition': [{'Text': 'beovu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 46, 'EndOffset': 58, 'Score': 0.9897342920303345, 'Text': 'brolucizumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.7440245151519775, 'RelationshipScore': 0.9999842643737793, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 60, 'EndOffset': 66, 'Text': 'one ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9589861035346985, 'RelationshipScore': 0.9996858835220337, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 67, 'EndOffset': 75, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.7163745164871216, 'RelationshipScore': 0.9956272840499878, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 3, 'BeginOffset': 80, 'EndOffset': 89, 'Text': 'injection', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '120', 'Type': 'NUMBER', 'BeginOffset': 99, 'EndOffset': 102}, {'Id': 5, 'BeginOffset': 106, 'EndOffset': 118, 'Score': 0.9918949007987976, 'Text': 'brolucizumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 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'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 153, 'EndOffset': 160, 'Text': '19.8 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.5983492136001587, 'RelationshipScore': 0.9395988583564758, 'RelationshipType': 'DOSAGE', 'Id': 9, 'BeginOffset': 177, 'EndOffset': 185, 'Text': '0.165 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9563173055648804, 'RelationshipScore': 0.6349589228630066, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 186, 'EndOffset': 194, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.7620590925216675, 'RelationshipScore': 0.8156097531318665, 'RelationshipType': 'DOSAGE', 'Id': 11, 'BeginOffset': 254, 'EndOffset': 261, 'Text': '0.05 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 120, 'EndOffset': 143}, {'Text': '19.8', 'Type': 'NUMBER', 'BeginOffset': 153, 'EndOffset': 157}, {'Id': 8, 'BeginOffset': 161, 'EndOffset': 173, 'Score': 0.9650288820266724, 'Text': 'brolucizumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.5635539293289185, 'RelationshipScore': 0.9494982361793518, 'RelationshipType': 'FORM', 'Id': 6, 'BeginOffset': 125, 'EndOffset': 152, 'Text': 'pre-filled syringe contains', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.959540605545044, 'RelationshipScore': 1.0, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 153, 'EndOffset': 160, 'Text': '19.8 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.5983492136001587, 'RelationshipScore': 0.9974367022514343, 'RelationshipType': 'DOSAGE', 'Id': 9, 'BeginOffset': 177, 'EndOffset': 185, 'Text': '0.165 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9563173055648804, 'RelationshipScore': 0.99623042345047, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 186, 'EndOffset': 194, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.7620590925216675, 'RelationshipScore': 0.8990296125411987, 'RelationshipType': 'DOSAGE', 'Id': 11, 'BeginOffset': 254, 'EndOffset': 261, 'Text': '0.05 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '0.165', 'Type': 'NUMBER', 'BeginOffset': 177, 'EndOffset': 182}, {'Text': 'a single dose of 0.05 ml solution', 'Type': 'TREATMENT', 'BeginOffset': 237, 'EndOffset': 270}, {'Text': '0.05', 'Type': 'NUMBER', 'BeginOffset': 254, 'EndOffset': 258}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 282, 'EndOffset': 283}, {'Id': 14, 'BeginOffset': 290, 'EndOffset': 302, 'Score': 0.9903467297554016, 'Text': 'brolucizumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.9878880381584167, 'RelationshipScore': 0.988926887512207, 'RelationshipType': 'FORM', 'Id': 12, 'BeginOffset': 262, 'EndOffset': 270, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8889325857162476, 'RelationshipScore': 0.9999984502792358, 'RelationshipType': 'DOSAGE', 'Id': 13, 'BeginOffset': 282, 'EndOffset': 286, 'Text': '6 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 15, 'BeginOffset': 333, 'EndOffset': 347, 'Score': 0.9921771883964539, 'Text': 'sodium citrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8889325857162476, 'RelationshipScore': 0.9923793077468872, 'RelationshipType': 'DOSAGE', 'Id': 13, 'BeginOffset': 282, 'EndOffset': 286, 'Text': '6 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.42340806126594543, 'RelationshipScore': 0.8912234902381897, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 18, 'BeginOffset': 384, 'EndOffset': 394, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'sucrose, polysorbate', 'Type': 'TREATMENT', 'BeginOffset': 349, 'EndOffset': 369}, {'Text': '80', 'Type': 'NUMBER', 'BeginOffset': 370, 'EndOffset': 372}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 384, 'EndOffset': 394}, {'Text': 'the pack beovu', 'Type': 'TREATMENT', 'BeginOffset': 434, 'EndOffset': 448}, {'Text': '120', 'Type': 'NUMBER', 'BeginOffset': 449, 'EndOffset': 452}, {'Text': 'a pre-filled syringe (injection', 'Type': 'TREATMENT', 'BeginOffset': 485, 'EndOffset': 516}, {'Text': 'slightly brownish-yellow aqueous solution', 'Type': 'PROBLEM', 'BeginOffset': 567, 'EndOffset': 608}, {'Text': '1 pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 623, 'EndOffset': 643}]}

3E57A488CE288770BB41B0A0DF239588

https://www.ema.europa.eu/documents/product-information/hyqvia-epar-product-information_en.pdf

HyQvia

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT HyQvia 100 mg/ml solution for infusion for subcutaneous use 2. QUALITATIVE AND QUANTITATIVE COMPOSITION HyQvia is a dual vial unit consisting of one vial of human normal immunoglobulin (Immune Globulin 10% or IG 10%) and one vial of recombinant human hyaluronidase (rHuPH20). Human normal immunoglobulin (SCIg) One ml contains: Human normal immunoglobulin. 100 mg (purity of at least 98% IgG) Each vial of 25 ml contains: 2.5 g of human normal immunoglobulin Each vial of 50 ml contains: 5 g of human normal immunoglobulin Each vial of 100 ml contains: 10 g of human normal immunoglobulin Each vial of 200 ml contains: 20 g of human normal immunoglobulin Each vial of 300 ml contains: 30 g of human normal immunoglobulin Distribution of the IgG subclasses (approx. values): IgG1 56.9% IgG2 26.6% IgG3 3.4% IgG4 1.7% The maximum IgA content is 140 micrograms/ml. Produced from the plasma of human donors. Excipients with known effects:  Recombinant human hyaluronidase (rHuPH20) Recombinant human hyaluronidase is a purified glycoprotein of 447 amino acids produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.  Sodium (as chloride and as phosphate) The total sodium content of recombinant human hyaluronidase is 4.03 mg/ml. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for infusion (infusion). IG 10% is a clear or slightly opalescent and colourless or pale yellow solution. Recombinant human hyaluronidase is a clear, colourless solution. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Replacement therapy in adults, children and adolescents (0-18 years) in:  Primary immunodeficiency syndromes with impaired antibody production (see section 4.4).  Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have failed or are contra-indicated.  Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients.  Hypogammaglobulinaemia in patients pre- and post-allogeneic hematopoietic stem cell transplantation (HSCT). 4.2 Posology and method of administration Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency. Posology The dose and dose regimen are dependent on the indication. Replacement therapy The medicinal product should be administered via the subcutaneous route. In replacement therapy the dose may need to be individualized for each patient dependent on the pharmacokinetic and clinical response. The following dosage regimens are given as a guideline. Patients naïve to immunoglobulin therapy The dose required to achieve a trough level of 6 g/l is of the order of 0.4-0.8 g/kg body weight per month. The dosage interval to maintain steady state levels varies from 2-4 weeks. Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels (> 6 g/l). At the initiation of therapy, it is recommended that the treatment intervals for the first infusions be gradually prolonged from a 1-week dose to up to a 3- or 4-week dose. The cumulative monthly dose of IG 10% should be divided into 1-week, 2-week etc. doses according to the planned treatment intervals with HyQvia. Patients previously treated with immunoglobulin administered intravenously For patients switching directly from intravenous administration of immunoglobulin, or who have a previous intravenous dose of immunoglobulin that can be referenced, the medicinal product should be administered at the same dose and at the same frequency as their previous intravenous immunoglobulin treatment. If patients were previously on a 3-week dosing regimen, increasing the interval to 4-weeks can be accomplished by administering the same weekly equivalents. Patients previously treated with immunoglobulin administered subcutaneously For patients currently being administered immunoglobulin subcutaneously, the initial dose of HyQvia is the same as for subcutaneous treatment, but may be adjusted to 3- or 4-weeks interval. The first infusion of HyQvia should be given one week after the last treatment with the previous immunoglobulin. 4 Paediatric population The posology in children and adolescents (0-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned condition. Currently available data are described in sections 4.8, 5.1 and 5.2. Method of administration  The medicinal product is for subcutaneous use only, do not administer intravenously.  Visually inspect both components of HyQvia for discoloration and particulate matter prior to administration.  Allow refrigerated product to come to room temperature before use. Do not use heating devices including microwaves.  Do not shake.  This medicinal product is comprised of two vials. Do not mix the components of this medicinal product. Each vial of IG 10% is supplied with the appropriate corresponding quantity of recombinant human hyaluronidase as stated in the table below. The full contents of the recombinant human hyaluronidase vial should be administered regardless of whether the full content of the IG 10% vial is administered. The two components of the medicinal product must be administered sequentially through the same needle beginning with the recombinant human hyaluronidase followed by IG 10%, as described below. HyQvia administration scheme Recombinant human hyaluronidase Human normal immunoglobulin 10% Volume (ml) Protein (grams) Volume (ml) 1.25 2.5 25 2.5 5 50 5 10 100 10 20 200 15 30 300 Infusion site leakage can occur during or after subcutaneous administration of immunoglobulin, including HyQvia. Consider using longer needles and/or more than one infusion site. Any change of needle size would have to be supervised by the treating physician. In case subcutaneous infusion of HyQvia is used for home treatment, therapy should be initiated and monitored by a physician experienced in the guidance of patients for home treatment. The patient will be instructed in infusion techniques, the use of an infusion pump or syringe driver, the keeping of a treatment diary, recognition of possible severe adverse reactions and measures to be taken in case these occur. HyQvia can be used to administer a full therapeutic dose in one to two sites up to every four weeks. Adjust the frequency and number of infusion sites taking into consideration volume, total infusion time, and tolerability so that the patient receives the same weekly equivalent dose. If a patient misses a dose, administer the missed dose as soon as possible and then resume scheduled treatments as applicable. The IG 10% component should be infused using a pump. The rHuPH20 may be hand-pushed or infused by a pump. A 24 gauge needle may be required to allow patients to infuse at flow rates of 300 mL/hr/infusion site. However, needles with smaller diameters may be used if slower flow rates are acceptable. For the 1.25 mL recombinant human hyaluronidase vial size use a 18-22 gauge needle to withdraw the contents of the vial to prevent stopper push through or coring; for all other vial sizes a needle or needle-less device may be used to withdraw the contents of the vial. 5 The suggested site(s) for the infusion of the medicinal product are the middle to upper abdomen and thighs. If two sites are used, the two infusion sites should be on contra lateral sides of the body. Avoid bony prominences, or scarred areas. The product should not be infused at or around an infected or acutely inflamed area due to the potential risk of spreading a localized infection. It is recommended that the recombinant human hyaluronidase component be administered at a constant rate and that the rate of administration of the IG 10% should not be increased above the recommended rates, particularly when the patient has just started with HyQvia therapy. First, the full dose of recombinant human hyaluronidase solution is infused at a rate of 1 to 2 ml/minute per infusion site or as tolerated. Infuse the full dose per site of IG 10% through the same subcutaneous needle set within 10 minutes of the recombinant human hyaluronidase. The following infusion rates of the IG 10% are recommended per infusion site: Subjects < 40 kg Subjects ≥ 40 kg Interval/Minutes First Two Infusions (ml/hour/infusion site) Subsequent 2-3 Infusions (ml/hour/infusion site) First Two Infusions (ml/hour/infusion site) Subsequent 2 to 3 Infusions (ml/hour/infusion site) 10 minutes 5 10 10 10 10 minutes 10 20 30 30 10 minutes 20 40 60 120 10 minutes 40 80 120 240 Remainder of infusion 80 160 240 300 If the patient tolerates the initial infusions at the full dose per site and maximum rate, an increase in the rate of successive infusions may be considered at the discretion of the physician and the patient. For instructions on how to use the medicinal product, see section 6.6. 4.3 Contraindications HyQvia must not be given intravenously or intramuscularly. Hypersensitivity to the active substance (IgG) or to any of the excipients listed in section 6.1 (see section 4.4). Hypersensitivity to human immunoglobulins, especially in very rare cases of IgA deficiency when the patient has antibodies against IgA. Known systemic hypersensitivity to hyaluronidase or recombinant human hyaluronidase. 4.4 Special warnings and precautions for use If HyQvia is accidentally administered into a blood vessel patients could develop shock. The recommended infusion rate given in section 4.2 should be adhered to. Patients must be closely monitored throughout the infusion period, particularly patients starting with therapy. Certain adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion. 6 Potential complications can often be avoided by:  initially infusing the product slowly (see section 4.2).  ensuring that patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative immunoglobulin product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after the administration.  When treatment is given at home, support from another responsible person should be available for treating adverse reactions or to summon help should a serious adverse reaction occur. Patients on self-home treatment and/or their guardian should also be trained to detect early signs of hypersensitivity reactions. In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction. In case of shock, immediately discontinue the infusion and treat the patient for shock. No chronic changes in the skin were observed in the clinical studies. Patients should be reminded to report any chronic inflammation, nodules or inflammation that occurs at the infusion site and lasts more than a few days. Hypersensitivity to IG 10% True hypersensitivity reactions are rare. They can particularly occur in patients with anti-IgA antibodies who should be treated with particular caution. Patients with anti-IgA antibodies, in whom treatment with subcutaneous IgG products remains the only option, should be treated with HyQvia only under close medical supervision. Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.  If patient is at high risk for any allergic reactions, the product should be administered only where supportive care is available for life threatening reactions.  Patients should be informed of the early signs of anaphylaxis/hypersensitivity (hives, pruritus, generalized urticaria, tightness of the chest, wheezing, and hypotension).  Depending on the severity of associated reaction, and medical practice, pre-medication may prevent this type of reaction.  If known anaphylactic or severe hypersensitivity to human immunoglobulin exists, it should be noted in the patient records. Hypersensitivity to recombinant human hyaluronidase Any suspicion of allergic or anaphylactic like reactions following recombinant human hyaluronidase administration requires immediate discontinuation of the infusion and standard medical treatment should be administered, if necessary. Immunogenicity of recombinant human hyaluronidase Development of non-neutralizing antibodies to the recombinant human hyaluronidase component has been reported in patients receiving HyQvia in clinical studies. The potential exists for such antibodies to cross-react with endogenous PH20, which is known to be expressed in the adult male testes, epididymis, and sperm. It is unknown whether these antibodies may have any clinical significance in humans. 7 Thromboembolism Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Patients should be sufficiently hydrated before use of immunoglobulins. Caution should be exercised in patients with pre-existing risk factors for thromboembolic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilization, severely hypovolemic patients, patients with diseases which increase blood viscosity). Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Thrombosis may also occur in the absence of known risk factors. Patients should be informed about first symptoms of thromboembolic events including shortness of breath, pain and swelling of a limb, focal neurological deficits and chest pain and should be advised to contact their physician immediately upon onset of symptoms. Haemolytic anaemia Immunoglobulin products contain antibodies to blood groups (e.g A, B, D) which may act as haemolysins. These antibodies bind to red blood cells (RBC) epitops (which may be detected as a positive direct antiglobulin test [DAT, (Coombs’ test)] and, rarely, may cause haemolysis. Immunoglobulin product recipients should be monitored for clinical signs and symptoms of haemolysis. Acute renal failure Severe renal adverse reactions have been reported in patients receiving immunoglobulin intravenous treatment, particularly those products containing sucrose (HyQvia does not contain sucrose). Aseptic meningitis syndrome (AMS) Aseptic meningitis syndrome has been reported to occur in association with intravenous and subcutaneous immunoglobulin treatment; the symptoms usually begin within several hours to 2 days following immunoglobulin treatment. Patients should be informed about first symptoms which encompass severe headache, neck stiffness, drowsiness, fever, photophobia, nausea, and vomiting. Discontinuation of immunoglobulin treatment may result in remission of AMS within several days without sequelae. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high-dose (2 g/kg) intravenous immunoglobulin treatment. From post-marketing data no clear correlation of AMS to higher doses was observed. Higher incidences of AMS were seen in women. Important information about some of the ingredients of HyQvia This medicinal product does not contain sugars. The IG 10% component contains trace amounts of sodium. Recombinant human hyaluronidase contains 4.03 mg sodium per ml, with a maximum daily dose of approximately 120 mg. This should be taken into consideration in patients on a controlled sodium diet. Interference with serological testing After infusion of immunoglobulins, the transitory rise of the various passively transferred antibodies in the patient’s blood may result in misleading positive results in serological testing. 8 Passive transmission of antibodies to erythrocyte´s surface antigens, (e.g., A, B, D) may interfere with some serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct Coombs’ test). Infusions of immunoglobulin products may lead to false positive readings in assays that depend on detection of -D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product. Transmissible agents Human normal immunoglobulin and human serum albumin (stabilizer of the recombinant human hyaluronidase) are produced from human plasma. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A (HAV) and parvovirus B19 viruses. There is reassuring clinical evidence regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety. Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Paediatric population The listed warnings and precautions apply both to adults and children. 4.5 Interaction with other medicinal products and other forms of interaction Live attenuated virus vaccines Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked. Paediatric population The listed interactions apply both to adults and children. 9 4.6 Fertility, pregnancy and lactation Pregnancy The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. Immunoglobulin products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected. Development and reproductive toxicology studies have been conducted with recombinant human hyaluronidase in mice and rabbits. No adverse effects on pregnancy and foetal development were associated with anti-rHuPH20 antibodies. In these studies, maternal antibodies to recombinant human hyaluronidase were transferred to offspring in utero. The effects of antibodies to the recombinant human hyaluronidase component of HyQvia on the human embryo or on human foetal development are currently unknown (see section 5.3). If a woman becomes pregnant, the treating physician should encourage her to participate in the pregnancy registry. Breast-feeding Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry. Fertility There are currently no clinical safety data for HyQvia on fertility available. Clinical experience with immunoglobulins suggests that no harmful effects of IG 10% on fertility are to be expected. Animal studies do not indicate direct or indirect harmful effects of recombinant human hyaluronidase with respect to reproductive potential at the doses used for facilitating administration of IG 10% (see section 5.3). 4.7 Effects on ability to drive and use machines The ability to drive and operate machines may be impaired by some adverse reactions associated with HyQvia. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions (ARs) of HyQvia were local reactions. The most frequently reported systemic ARs were headache, fatigue and pyrexia. The majority of these ARs were mild to moderate. Human normal immunoglobulin Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally. Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration. 10 Local reactions at infusion sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash, may frequently occur. Cases of transient aseptic meningitis, transient hemolytic reactions, increase in serum creatinine level and/or acute renal failure have been observed with human normal immunoglobulin, see section 4.4. Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis have been rarely observed with IV and SC administration of immunoglobulin products. Recombinant human hyaluronidase The most frequent adverse reactions reported during post-marketing use of recombinant human hyaluronidase in similar formulations administered subcutaneously for the dispersion and absorption of subcutaneously administered fluids or medicinal products have been mild local infusion site reactions such as erythema and pain. Oedema has been reported most frequently in association with large volume subcutaneous fluid administration. Antibodies against recombinant human hyaluronidase A total of 13 out of 83 subjects who participated in pivotal study developed an antibody capable of binding to recombinant human hyaluronidase (rHuPH20) at least once during the clinical study. These antibodies were not capable of neutralizing recombinant human hyaluronidase. No temporal association between adverse reactions and the presence of anti-rHuPH20 antibodies could be demonstrated. There was no increase in incidence or severity of adverse reactions in patients who developed antibodies to recombinant human hyaluronidase. Tabulated list of adverse reactions The safety of HyQvia was evaluated in 4 clinical studies (160602, 160603, 160902, and 161101) in 124 unique patients with PID receiving 3,202 infusions. The table presented below is according to the MedDRA System Organ Classification (SOC and Preferred Term Level). Frequencies per infusion have been evaluated using the following convention: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from available data). Frequency of Adverse Reactions (ADRs) with HyQvia MedDRA System Organ Class (SOC) Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Gastrointestinal disorders Vomiting, nausea, abdominal pain (including abdominal upper and lower pain and tenderness), diarrhoea Abdominal distension 11 Frequency of Adverse Reactions (ADRs) with HyQvia MedDRA System Organ Class (SOC) Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) General disorders and administration site conditions Local reactions (total) a: Infusion site pain (including discomfort, tenderness, groin pain) Local reactions (total): Infusion site erythema, infusion site swelling (including local swelling and oedema), infusion site pruritus (including vulvovaginal pruritus) Pyrexia, asthenic conditions (including asthenia, fatigue, lethargy, malaise) Local reactions (total): Infusion site discoloration, infusion site bruising (including hematoma, haemorrhage), infusion site mass (including nodule), infusion site warmth, infusion site induration, gravitational oedema/genital swellingb (including genital oedema, scrotal and, vulvovaginal swelling) Oedema (including peripheral, swelling), chills, hyperhidrosis Burning sensation Investigations Direct Coombs’ test positive Musculoskeletal and connective tissue disorders Myalgia, musculoskeletal chest pain Arthralgia, back pain, pain in extremity Nervous system disorders Headache Migraine dizziness Paresthesia Skin and subcutaneous tissue disorders Erythema, rash (including erythematous, papular, maculo-papular), pruritus, urticaria Vascular disorders Hypertension, blood pressure increase Renal and urinary disorders Hemosiderinuria a The following ADRs are not listed but also calculated in the frequency for Local reactions: feeling hot, infusion site paresthesia. b Gravitational oedema/genital swelling was observed subsequent to lower abdominal quadrants administration. In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the post-marketing experience (frequency of these reactions is not known (cannot be estimated from the available data)): Infections and infestations: Meningitis aseptic Immune system disorders: Hypersensitivity General disorders and administration site conditions: Influenza-like illness, infusion site leakage 12 In addition to the adverse reactions listed above, the following additional adverse reactions have been reported for subcutaneously administered immunoglobulin products: Anaphylactic shock, anaphylactic/anaphylactoid reaction, tremor, tachycardia, hypotension, flushing, pallor, peripheral coldness, dyspnea, paraesthesia oral, swelling face, dermatitis allergic, musculoskeletal stiffness, injection site urticaria, injection site rash, alanine aminotransferase increased. Description of selected adverse reactions Local reactions observed during the pivotal clinical study include mild swelling of the site (present in most infusions) due to the large volumes infused, but in general were not considered an adverse reaction unless they caused discomfort. Only two instances of local adverse reactions were severe, infusion site pain and infusion site swelling. There were two instances of transient genital oedema, one considered severe, that resulted from diffusion of the medicinal product from the infusion site in the abdomen. No skin changes were observed that did not resolve during the clinical study. Paediatric population Results of clinical studies indicate similar safety profiles in adults and paediatric population, including the nature, frequency, seriousness and reversibility of adverse reactions. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Consequences of an overdose are not known. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group (human normal immunoglobulin): immune sera and immunoglobulins: immunoglobulins, normal human, ATC code: J06BA01 Mechanism of action The IG 10% component provides the therapeutic effect of this medicinal product. The recombinant human hyaluronidase facilitates the dispersion and absorption of IG 10%. Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of opsonising and neutralizing antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled human plasma from not fewer than 1,000 donations. It has a distribution of IgG subclasses closely proportional to that in native human plasma. Adequate doses of human normal immunoglobulin may restore abnormally low IgG levels to the normal range. Recombinant human hyaluronidase is a soluble recombinant form of human hyaluronidase that increases the permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. Hyaluronan is a polysaccharide found in the intercellular matrix of the connective tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a very fast turnover with half-life of approximately 0.5 days. The recombinant human hyaluronidase of HyQvia acts locally. The effects of 13 the hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours. Clinical efficacy and safety Efficacy and safety of HyQvia was assessed in a phase 3 study (160603) in 83 patients with PID. Patients were treated with HyQvia at either 3- or 4-week treatment intervals for a total of 12 months (following a brief titration period). The dose of HyQvia was based on the previous treatment with intravenous IG 10% (320 to 1,000 mg/kg body weight /4 weeks) and was individually adapted, ensuring adequate IgG levels throughout the study. The results of the study showed a rate of validated, acute, serious bacterial infections per year during HyQvia treatment of 0.025 (upper limit of the one-sided 99% confidence interval 0.046). The overall rate of infections was less during HyQvia administration than during the three months intravenous administration of IG 10%: the point estimate of the annualized rate of all infections was 2.97 (95% CI: 2.51 to 3.47) for HyQvia and 4.51 (95% CI: 3.50 to 5.69) for intravenous IG 10% infusions. Nearly all of the subjects were able to attain the same dose interval with HyQvia as they had for intravenous administration. Seventy eight (78) of 83 (94%) subjects attained the same 3- or 4-week dosing whereas one decreased from 4 to 3 weeks, one from 4 to 2 weeks and one from 3 to 2 weeks (2 subjects withdrew during the titration period). The median number of infusion sites per month for HyQvia was 1.09, which is slightly lower than the median number of intravenous IG 10% infusion sites used in this study (1.34), and considerably lower than the median number of infusion sites in the study of subcutaneous administration of IG 10% (21.43). 66 patients who completed the pivotal phase 3 study participated in an extension study (160902) for the evaluation of long-term safety, tolerability and efficacy of HyQvia in PID. The overall combined exposure of PID patients in both studies was 187.69 patient-years; the longest exposure for adults was 3.8 years and 3.3 years for paediatric patients. Paediatric population HyQvia was evaluated in 24 paediatric patients, including 13 patients between 4 and < 12 years and 11 between 12 and < 18 years, who were treated for up to 3.3 years with an overall safety experience equivalent to 48.66 patient-years (as described in section Clinical efficacy and safety). No appreciable differences in the pharmacodynamic effects or efficacy and safety of HyQvia were observed between paediatric patients and adults. See sections 4.2 and 4.8. The European Medicines Agency has deferred the obligation to submit the results of studies with HyQvia in one or more subsets of the paediatric population in treatment of primary immunodeficiency as model for replacement therapy. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties Following subcutaneous administration of HyQvia, peak serum IgG levels are achieved in the recipient’s circulation after approximately 3 to 5 days. Data from the clinical trials of HyQvia show that serum IgG trough levels can be maintained by dosing regimens of 320 to 1,000 mg/kg body weight/4 weeks given at intervals of 3- or 4-weeks. The pharmacokinetics of HyQvia were evaluated in a clinical study in patients with PID aged 12 years and older. The pharmacokinetic results are presented in the table below, as compared to data for intravenous administration of IG 10% obtained in the same study. 14 IgG and IgG-complexes are broken down in cells of the reticuloendothelial system. Pharmacokinetic Parameters of HyQvia Compared to Intravenous Administration of IG 10% Parameter HyQvia Median (95% Cl) N=60 IVIG 10% Median (95% Cl) N=68 Cmax [g/l] 15.5 (14.5; 17.) 21.9 (20.7; 23.9) Cmin [g/l] 10.4 (9.4 to 11.2) 10.1 (9.5 to 10.9) AUC per week [g*days/l] 90.52 (83.8 to 9) 93.9 (89.1 to 102.1) Tmax [days] 5.0 (3.3 to 5.1) 0.1 (0.1 to 0.1) Apparent clearance or clearance [ml/kg/day] 1.6 (1.4 to 1.79) 1.4 (1.2 to 1.4) Terminal half life [days] 45.3 (41.0 to 60.2) 35.7 (32.4 to 40.4) Paediatric population In the clinical study with HyQvia, no differences in the plasma IgG trough levels were observed between adult and paediatric patients. 5.3 Preclinical safety data Immunoglobulins are normal constituents of the human body. The safety of IG 10% has been demonstrated in several non-clinical studies. Non-clinical data reveal no special risk for humans based on conventional studies of safety pharmacology and toxicity. Studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction in animals are impracticable due to induction of and interference by developing antibodies to heterologous proteins. Long-term animal studies to evaluate the carcinogenic or mutagenic potential of recombinant human hyaluronidase have not been conducted. No adverse effects on fertility were observed in mice, rabbits and cynomolgus monkeys exposed to antibodies that bind to recombinant human hyaluronidase and species-specific hyaluronidase. Reversible infertility has been observed in male and female guinea pigs immunized to produce antibodies to hyaluronidase. However, antibodies to hyaluronidase did not influence reproduction following immunization of mice, rabbits, sheep, or cynomolgus monkeys. The effects of antibodies that bind to recombinant human hyaluronidase on human fertility are unknown. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Human normal immunoglobulin (IG 10%) vial Glycine Water for injections Recombinant human hyaluronidase (rHuPH20) vial Sodium chloride Sodium phosphate dibasic Human albumin Ethylenediaminetetraacetic acid (EDTA) disodium Calcium chloride Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 15 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vials in the outer carton in order to protect from light. 6.5 Nature and contents of container Human normal immunoglobulin (IG 10%) vial 25, 50, 100, 200 or 300 ml of solution in a vial (Type I glass) with a stopper (bromobutyl rubber). Recombinant human hyaluronidase (rHuPH20) vial 1.25, 2.5, 5, 10 or 15 ml of solution in a vial (Type I glass) with a stopper (chlorobutyl rubber). Pack size: One vial of IG 10% and one vial of recombinant human hyaluronidase in a dual vial unit. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The product should be brought to room temperature before use. Do not use heating devices including microwaves. IG 10% is a clear or slightly opalescent and colourless or pale yellow solution. Recombinant human hyaluronidase is a clear, colourless solution. The vials should be inspected visually for particulate matter and discoloration prior to administration. Solutions that are cloudy or have deposits should not be used. Do not shake. Do not mix the components of HyQvia prior to administration. Do not use vented vial access devices to remove recombinant human hyaluronidase from vials. Use aseptic technique when preparing and administering HyQvia. In cases where more than one vial of the medicinal product IG 10% or recombinant human hyaluronidase is required to obtain the required dose of the infusion, the IG 10% and/or recombinant human hyaluronidase should be prepared separately in appropriate solution containers before administration. Partially used vials should be discarded. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Baxalta Innovations GmbH Industriestrasse 67 A-1221 Vienna, Austria 16 8. MARKETING AUTHORISATION NUMBER(S) EU/1/13/840/001 EU/1/13/840/002 EU/1/13/840/003 EU/1/13/840/004 EU/1/13/840/005 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 16 May 2013 Date of renewal: 8 Jan 2018 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 17 ANNEX II A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 18 A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers of the biological active substance(s) Baxalta Belgium Manufacturing SA Boulevard René Branquart 80 B-7860 Lessines Belgium Name and address of the manufacturers responsible for batch release Baxalta Belgium Manufacturing SA Boulevard René Branquart 80 B-7860 Lessines Belgium B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).  Official batch release In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be undertaken by a state laboratory or a laboratory designated for that purpose. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 19 ANNEX III LABELLING AND PACKAGE LEAFLET 20 A. LABELLING 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON (2.5 G, 5 G, 10 G, 20 G AND 30 G) 1. NAME OF THE MEDICINAL PRODUCT HyQvia 100 mg/ml solution for infusion for subcutaneous use human normal immunoglobulin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Human normal immunoglobulin vial: 100 mg/ml, at least 98% is IgG Maximum immunoglobulin A (IgA) content: 140 micrograms/ml. 3. LIST OF EXCIPIENTS Human normal immunoglobulin vial: Glycine, water for injections. Recombinant human hyaluronidase vial: human hyaluronidase. Sodium chloride, sodium phosphate, human albumin, ethylenediaminetetraacetic acid disodium, calcium chloride, water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for infusion for subcutaneous use 1 vial human normal immunoglobulin 2.5 g/25 ml 5 g/50 ml 10 g/100 ml 20 g/200 ml 30 g/300 ml 1 vial recombinant human hyaluronidase 1.25 ml 2.5 ml 5 ml 10 ml 15 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous use only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 22 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake. Do not mix the two vials prior to administration. Infuse first the recombinant human hyaluronidase. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vials in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Baxalta Innovations GmbH A-1221 Vienna, Austria 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/840/001 2.5 g/25 ml EU/1/13/840/002 5 g/50 ml EU/1/13/840/003 10 g/100 ml EU/1/13/840/004 20 g/200 ml EU/1/13/840/005 30 g/300 ml 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 23 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE HyQvia 100 mg/ml 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA National unique code included. 24 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING VIAL LABEL HUMAN NORMAL IMMUNOGLOBULIN (5 G, 10 G, 20 G AND 30 G) 1. NAME OF THE MEDICINAL PRODUCT HyQvia 100 mg/ml infusion for subcutaneous use human normal immunoglobulin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Immunoglobulin: 100 mg/ml, at least 98% is IgG Maximum immunoglobulin A (IgA) content: 140 micrograms/ml. 3. LIST OF EXCIPIENTS Glycine, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Infusion for subcutaneous use. 1 vial 5 g/50 ml 10 g/100 ml 20 g/200 ml 30 g/300 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use only. Infuse 2nd. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 25 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Baxalta Innovations GmbH A-1221 Vienna, Austria 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/840/002 5 g/50 ml EU/1/13/840/003 10 g/100 ml EU/1/13/840/004 20 g/200 ml EU/1/13/840/005 30 g/300 ml 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA National unique code included. 26 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL HUMAN NORMAL IMMUNOGLOBULIN (2.5 G) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION HyQvia 100 mg/ml infusion for subcutaneous use human normal immunoglobulin SC use only. 2. METHOD OF ADMINISTRATION Infuse 2nd. Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2.5 g/25 ml 6. OTHER 27 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL RECOMBINANT HUMAN HYALURONIDASE (2.5 ML, 5 ML, 10 ML, 15 ML) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Infusion for subcutaneous use for HyQvia hyaluronidase Subcutaneous use only. 2. METHOD OF ADMINISTRATION Infuse 1st. Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2.5 ml 5 ml 10 ml 15 ml 6. OTHER 28 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL RECOMBINANT HUMAN HYALURONIDASE (1.25 ML) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Infusion for subcutaneous use for HyQvia hyaluronidase SC use only. 2. METHOD OF ADMINISTRATION Infuse 1st. Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1.25 ml 6. OTHER 29 B. PACKAGE LEAFLET 30 Package leaflet: Information for the user HyQvia 100 mg/ml solution for infusion for subcutaneous use human normal immunoglobulin This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What HyQvia is and what it is used for 2. What you need to know before you use HyQvia 3. How to use HyQvia 4. Possible side effects 5. How to store HyQvia 6. Contents of the pack and other information 1. What HyQvia is and what it is used for What HyQvia is HyQvia contains two solutions for infusion (drip) under the skin (subcutaneous or SC infusion). It is supplied as a package containing one vial of human normal immunoglobulin 10% (the active substance) and one vial of recombinant human hyaluronidase (a substance which helps the human normal immunoglobulin 10% reach your blood). Human normal immunoglobulin 10% belongs to a class of medicines called “human normal immunoglobulins”. Immunoglobulins are also known as antibodies and are found in healthy people’s blood. Antibodies are part of the immune system (the body’s natural defences) and help your body to fight infections. How HyQvia works The vial of immunoglobulins has been prepared from the blood of healthy people. The medicine works in exactly the same way as the immunoglobulins naturally present in the blood. The recombinant human hyaluronidase is a protein that makes it easier for the immunoglobulins to be infused (dripped) under the skin and to reach your blood system. What HyQvia is used for HyQvia is used in patients with a weak immune system, who do not have enough antibodies in their blood and tend to get frequent infections. Regular and sufficient doses of HyQvia can raise abnormally low immunoglobulin levels in your blood to normal levels (replacement therapy). 31 HyQvia is prescribed as replacement therapy to patients who do not have sufficient antibodies, including the following groups:  patients with an inborn inability or reduced ability to produce antibodies (primary immunodeficiencies).  patients with a certain kind of blood cancer (chronic lymphocytic leukaemia) which leads to a lack of antibody production and recurrent infections when preventative antibiotics have failed.  patients with a specific cancer of the bone marrow (multiple myeloma) and lack of antibody production with recurrent infections who have failed to respond to a vaccine against certain bacteria (pneumococci).  patients with low antibody production prior and after transplantation of bone marrow cells from another person. 2. What you need to know before you use HyQvia Do not inject or infuse HyQvia - if you are allergic to immunoglobulins, hyaluronidase, recombinant hyaluronidase or any of the other ingredients of this medicine (listed in section 6, “Contents of the pack and other information”). - if you have antibodies against immunoglobulin A (IgA) in your blood. This may occur if you have IgA deficiency. Since HyQvia contains trace amounts of IgA, you might have an allergic reaction. - into a blood vessel (intravenously). Warnings and precautions The following warnings and precautions should be taken into consideration before you receive or use HyQvia. If you have any questions, talk to your doctor or nurse. Pregnancy, breast-feeding and fertility The effects of long-term use of recombinant human hyaluronidase on pregnancy, breast-feeding and fertility are currently not known. HyQvia should only be used by pregnant and breast-feeding women after discussion with your physician. If you become pregnant when using HyQvia, you should discuss with your doctor the possibility of participating in a pregnancy registry in order to collect data on your pregnancy and the development of the baby. The purpose of such registry is to collect and share data only with the public health authorities responsible for monitoring the safety of this product. Participation in the registry is voluntary. Allergic reactions You may be allergic to immunoglobulins without knowing it. Allergic reactions such as sudden fall in blood pressure or anaphylactic shock (a sharp fall in blood pressure with other symptoms such as swelling of the throat, breathing difficulties and skin rash) are rare but they can occasionally occur even if you have not previously had problems with similar treatments. You are at increased risk of allergic reactions if you have IgA deficiency with anti-IgA antibodies. Signs or symptoms of these rare allergic reactions include: - feeling light-headed, dizzy or faint, - skin rash and itchiness, swelling in the mouth or throat, difficulty breathing, wheezing, - abnormal heart rate, chest pain, blueness of lips or fingers and toes, - blurred vision. 32 Your doctor or nurse will first infuse HyQvia slowly, and carefully monitor you throughout the first infusions so that any allergic reaction can be detected and treated immediately. ► If you notice any of these signs during the infusion, tell your doctor or nurse immediately. He or she will decide whether to slow down the infusion rate or stop the infusion completely. Infusion speed It is very important to infuse the medicine at the correct speed. Your doctor or nurse will advise you on the appropriate infusion speed to use when you are infusing HyQvia at home (see section 3, “How to use HyQvia”). Monitoring during infusion Certain side effects may occur more frequently if: - you are receiving HyQvia for the first time. - you have received another immunoglobulin and have been switched to HyQvia. - there has been a long interval (e.g., more than 2 or 3 infusion intervals) since you last received HyQvia. ► In such cases, you will be closely monitored during your first infusion and for the first hour after your infusion has stopped. In all other cases you should be monitored during the infusion and for at least 20 minutes after you receive HyQvia for the first few infusions. Home treatment Before you start home treatment you should assign a person as guardian. You and your guardian will be trained to detect early signs of side effects, especially allergic reactions. This guardian should help you keep an eye on potential side effects. During the infusion you must look out for first signs of side effects (for further details see section 4, “Possible side effects”). ► If you experience any side effects, you or your guardian must stop the infusion immediately and contact a doctor. ► If you experience a severe side effect, you or your guardian must seek emergency treatment immediately. Spread of localised infections Do not infuse HyQvia into or around an infected or red swollen area on your skin because it may cause the infection to spread. No long-term (chronic) changes in the skin were observed in the clinical studies. Any long-term inflammation, lumps (nodules) or inflammation that occur at the infusion site and last more than a few days should be reported to your physician. Effects on blood tests HyQvia contains many different antibodies, some of which can affect blood tests (serological tests). ► Tell your doctor about your treatment with HyQvia before any blood test. Information on the source material of HyQvia The human normal immunoglobulin 10% of HyQvia and human serum albumin (an ingredient of the recombinant human hyaluronidase) are made from human plasma (the liquid part of blood). When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include: - careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and - the testing of each donation and pools of plasma for signs of viruses/infections. 33 Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are used, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections. The measures taken for the manufacture of HyQvia are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus and for the non-enveloped hepatitis A virus and parvovirus B19. Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly because the antibodies against these infections, which are contained in HyQvia, are protective. It is strongly recommended that every time you use HyQvia, the following data are recorded in your treatment diary: - the date of administration, - the batch number of the medicine, and - the injected volume, flow rate, the number and location of infusion sites. Children and adolescents The same indications, dose and frequency of infusion as for adults apply for children and adolescents (0-18 years). Other medicines and HyQvia Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. Vaccinations HyQvia may reduce the effect of some virus vaccines such as measles, rubella, mumps and chicken pox (live virus vaccines). Therefore, after receiving HyQvia, you may have to wait for up to 3 months before receiving certain vaccines. You may have to wait for up to 1 year after receiving HyQvia before you can receive your measles vaccine. ► Please tell your vaccinating doctor or nurse about your treatment with HyQvia. Driving and using machines Patients may experience side effects (for example dizziness or nausea) during treatment with HyQvia that might affect the ability to drive and use machines. If this happens, you should wait until the reactions have disappeared. HyQvia contains sodium The recombinant human hyaluronidase of HyQvia contains small amounts (4.03 mg per ml) of sodium. This may have to be considered for patients who are on a controlled sodium diet. 3. How to use HyQvia Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. HyQvia has to be infused under the skin (subcutaneous or SC administration). 34 Treatment with HyQvia will be started by your doctor or nurse, but you may be allowed to use the medicine at home once you have received the first few infusions under medical supervision and you (and/or your guardian) have been adequately trained. You and your doctor will decide if you can use HyQvia at home. Do not begin treatment with HyQvia at home until you have received complete instructions. Dosing Your doctor will calculate the correct dose for you based on your body weight, any previous treatment you may have received and your response to treatment. The recommended starting dose is one that supplies 400 to 800 mg of active substance per kg of bodyweight per month. In the beginning you will receive one quarter of this dose at 1 week intervals. This will be increased step-wise to larger doses at 3- to 4-week intervals with the next infusions. Sometimes your doctor may recommend that larger doses are split and given at two sites at once. Your doctor may also adjust your dose depending on your response to treatment. Starting treatment Your treatment will be started by a doctor or nurse experienced in treating patients with a weak immune system and in guiding patients for home treatment. You will be watched carefully throughout the infusion and for at least 1 hour after stopping the infusion to see how well you tolerate the medicine. In the beginning your doctor or nurse will use a slow infusion speed and gradually increase it during the first infusion and in the following infusions. Once the doctor or nurse has found the right dose and speed of infusion for you, you may be allowed to give the treatment to yourself at home. Home treatment You will be instructed in: - Germ-free (aseptic) infusion techniques, - The use of an infusion pump or syringe driver (if needed), - Keeping a treatment diary, and - Measures to be taken in case of severe side effects. You must carefully follow your doctor’s instructions regarding the dose, infusion speed and schedule for infusing HyQvia so that your treatment works for you. Subjects < 40 kg Subjects ≥ 40 kg Interval/Minutes First Two Infusions (ml/hour/infusion site) Subsequent 2-3 Infusions (ml/hour/infusion site) First Two Infusions (ml/hour/infusion site) Subsequent 2 to 3 Infusions (ml/hour/infusion site) 10 minutes 5 10 10 10 10 minutes 10 20 30 30 10 minutes 20 40 60 120 10 minutes 40 80 120 240 Remainder of infusion 80 160 240 300 If you have an infusion site leakage Ask your doctor or pharmacist or nurse if another needle size would be more appropriate for you. Any change of needle size would have to be supervised by the treating physician. If you use more HyQvia than you should If you think that you used more HyQvia than you should, speak to your doctor as soon as possible. 35 If you forget to use HyQvia Do not infuse a double dose of HyQvia to make up for a missed dose. If you think that you have missed a dose speak to your doctor as soon as possible. If you have any further questions on the use of this medicine, ask your doctor, or pharmacist or nurse. Detailed Instructions for Use are provided in the section below. 1. Remove HyQvia from the box:  Allow vials to reach room temperature. This may take up to 60 minutes. Do not use heating devices including microwave.  Do not heat up or shake HyQvia.  Check each vial of HyQvia before using:  Expiration date: Do not use beyond expiration date.  Colour: o The recombinant human hyaluronidase should be clear and colourless. o The human normal immunoglobulin 10% should be clear and colourless or pale yellow. o If either liquid is cloudy or has particles, do not use.  Cap: Protective cap is on the dual vial unit. Do not use the product if it does not have the cap. 2. Gather all supplies: Collect all items for your infusion. Items include: dual vial unit(s) of HyQvia, infusion supplies (subcutaneous needle set, solution container (bag or syringe), sterile clear bandage and tape, pump tubing, transfer devices, syringes, gauze and tape), sharps container, pump, and treatment logbook and other supplies as needed. 3. Prepare a clean work area. 4. Wash hands: Wash your hands thoroughly. Place all gathered supplies and open them as directed by your healthcare professional. 5. Open HyQvia dual vial unit(s):  Remove purple protective caps to expose the vial stoppers.  Prepare to transfer the recombinant human hyaluronidase component of HyQvia by wiping each vial stopper with an alcohol swab, if directed and allow to air dry (at least 30 seconds). 36 6. Prepare recombinant human hyaluronidase vial (HY):  Remove the smaller sterile syringe from package and attach to a non-vented spike or needle (device).  Pull back on the plunger, fill the smaller syringe with air equal to the amount of recombinant human hyaluronidase in the HY vial(s).  Remove the cap of needle/non-vented transfer device.  Insert the tip of the needle/non-vented transfer device into the center of the vial stopper and push straight downward. Push the air into the vial.  Turn the vial upside down, with the needle/non-vented transfer device remaining in the vial. The syringe tip will be pointing upward.  Withdraw the full contents of the recombinant human hyaluronidase into the syringe.  Repeat Step 6, if more than one vial of recombinant human hyaluronidase is needed for your dose.  If possible, combine all of the recombinant human hyaluronidase needed for the entire dose of IgG into the same syringe.  Point the syringe tip up and remove any air bubbles by pointing the syringe tip up and gently tapping the syringe with your finger. Slowly and carefully push the plunger to remove any remaining air. 7. Prepare the needle set with the recombinant human hyaluronidase (HY):  Attach the syringe filled with recombinant human hyaluronidase to the needle set  Push the plunger of smaller syringe to remove the air and fill the needle set up to the needle wings with the recombinant human hyaluronidase.  Note: Your healthcare professional may recommend using a “Y” connector (for more than one site) or other needle set configuration. 8. Prepare human normal immunoglobulin 10% vial:  Prepare to transfer the immunoglobulin 10% component of HyQvia by wiping each vial stopper with an alcohol swab, if directed and allow to air dry (at least 30 seconds).  The human normal immunoglobulin 10% of HyQvia may be infused either o by pooling from the vials either into larger syringe (a) or an infusion bag (b) as directed by your healthcare professional, depending upon the pump to be used; or o directly from the IG vial. Insert the spike of the vented pump tubing or spike and venting needle into human normal immunoglobulin 10% vial(s). Fill the administration pump tubing and set aside until the recombinant human hyaluronidase has been administered.  If more than one vial is required for a full dose, spike subsequent vials after the first vial has been fully administered. (a) (b) 37 9. Prepare the pump: Follow the manufacturer’s instructions for preparing the pump. 10. Prepare the infusion site:  Choose an infusion site(s) in either the middle to upper abdomen or thigh. See image for infusion site locations. o Select sites on the opposite sides of the body if instructed to infuse in two sites for doses above 600 ml.  Avoid bony areas, visible blood vessels, scars and any areas of inflammation or infection.  Rotate infusion sites by choosing opposite sides of the body between future infusions.  If instructed by your health care professional, clean the infusion site(s) with an alcohol swab. Allow to dry (at least 30 seconds). 11. Insert the needle:  Remove the needle cover. Firmly grasp and pinch at least 2 to 2.5 cm of skin between two fingers.  Insert needle completely to the wings of the needle with a rapid motion straight into the skin at a 90-degree angle. Wings of needle should lay flat on the skin.  Secure needle in place with sterile tape.  Repeat this step if you have a second infusion site. 90-degree angle to skin 12. Check for proper needle placement before starting the infusion if instructed by your healthcare professional. 13. Secure the needle to the skin:  Secure the needle(s) in place by putting a sterile clear bandage over the needle.  Check infusion site(s) occasionally throughout the infusion for dislodgement or leaking. 38 14. Administer the recombinant human hyaluronidase infusion first:  Slowly push the plunger of the smaller syringe with the recombinant human hyaluronidase at an initial rate per infusion site to approximately 1 to 2 ml per minute and increase as tolerated.  If using a pump, prepare the pump to infuse the recombinant human hyaluronidase at an initial rate per infusion site of 60 to 120 ml/hour and increase as tolerated. 15. Administer the human normal immunoglobulin 10%: After infusing all of the content of the smaller syringe (recombinant human hyaluronidase), remove the syringe from the hub of the needle set. Attach the pump tubing or, the larger syringe containing human normal immunoglobulin 10% to the needle set. Administer the human normal immunoglobulin 10% with a pump at the rates prescribed by your healthcare professional and start the infusion. 16. Flush the pump tubing when the infusion is complete if instructed by your healthcare professional:  If instructed by your healthcare professional, attach a saline bag to the pump tubing/needle set to push the human normal immunoglobulin 10% up to the needle wings. 17. Remove needle set:  Remove the needle set by loosening the dressing on all edges.  Pull the needle wings straight up and out.  Gently press a small piece of gauze over the needle site and cover with a protective dressing.  Throw away the needle(s) into the sharps container. o Dispose of the sharps container using instructions provided with the container, or contact your healthcare professional. 18. Record the infusion:  Remove the peel-off label from HyQvia vial, which has the product lot number and expiration date, and place the label in your treatment record/log book.  Write down the date, time, dose, site(s) of infusion (to assist in rotating sites) and any reactions after each infusion.  Throw away any unused product in the vial and the disposable supplies as recommended by your healthcare professional.  Follow up with physician as directed. 4. Possible side effects Like all medicines, this medicine can have side effects, although not everybody gets them. Certain side effects, such as headache, chills, or body aches, may be reduced by slowing the infusion rate. Serious side effects Infusions of medicines like HyQvia can occasionally result in serious, but rare, allergic reactions. You may experience a sudden fall in blood pressure and, in isolated cases, anaphylactic shock. Doctors are aware of these possible side effects and will monitor you during and after the initial infusions. 39 Typical signs or symptoms include: feeling light-headed, dizzy or faint, skin rash and itchiness, swelling in the mouth or throat, difficulty breathing, wheezing, abnormal heart rate, chest pain, blueness of lips or fingers and toes, blurred vision.  Tell your doctor or nurse immediately if you notice any of these signs during the infusion.  When using HyQvia at home, you must perform the infusion in the presence of an assigned guardian person who will help you watch out for allergic reactions, stop the infusion, and get help if necessary.  Please also see section 2 of this leaflet about the risk of allergic reactions and using HyQvia at home. Very common side effects (may affect more than 1 in 10 infusions): Infusion site pain, including mild to moderate discomfort and tenderness. These reactions usually go away within a few days. Common side effects (may affect up to 1 in 10 infusions): Reactions at the infusion site: These include redness, swelling, itching, hardening, and rash at the site of infusion. These reactions usually go away within a few days. Headache, tiredness, nausea, vomiting, diarrhoea, abdominal pain, muscle or joint pain, chest pain, fever, feeling weak or unwell. Uncommon side effects (may affect up to 1 in 100 infusions): Chills,migraine, increasedblood pressure, dizziness, abdominal bloating, skin rash/allergic rash/redness, itching, pain in chest, arms and/or legs, genital swelling (resulting from spread of swelling from the infusion site), swelling of the legs, feet and ankles, positive blood tests for antibodies. Frequency not known (cannot be estimated from the available data): Hypersensitivity, influenza-like illness, and infusion site leakage, inflammation of the layers lining the brain (aseptic meningitis). Side effects seen with similar medicines The following side effects have been observed with infusion of medicines like human normal immunoglobulin 10% given under the skin (subcutaneously). Although these side effects have so far not been seen with HyQvia, it is possible that someone using HyQvia may get them: Trembling, oral tingling, fast heart beat, allergic reactions, flushing or pallor, coldness of hand or feet, shortness of breath, swelling of face, excessive sweating, muscle stiffness, change in liver function blood tests (alanine aminotransferase increased). The following rare side effects have been observed in patients using medicines like human normal immunoglobulin 10% given into a vein (intravenously). These reactions have not been seen with HyQvia, but there is a small possibility that someone using HyQvia may get them: Blood clots in blood vessels (thromboembolic reactions) leading to heart attack, stroke, blockage of deep veins, or of blood vessels supplying the lung (pulmonary embolism), kidney disorder or failure, destruction of red blood cells (haemolysis). If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 40 5. How to store HyQvia Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C to 8°C). Do not freeze. Do not shake. Keep the vials in the outer carton in order to protect from light. Do not use this medicine if the solutions are cloudy or have particles or deposits. After opening, dispose of any unused solutions in the vials. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What HyQvia contains HyQvia is a dual vial unit containing: - a solution of recombinant human hyaluronidase (Step 1 of HyQvia/Infuse first) and - a solution of human normal immunoglobulin 10% (Step 2 of HyQvia/Infuse second). The contents of each vial are described below: 1. Recombinant human hyaluronidase This vial contains recombinant human hyaluronidase. The other ingredients are sodium chloride, sodium phosphate, human albumin, ethylenediaminetetraacetic acid (EDTA) disodium, calcium chloride and water for injections (see also section 2, “HyQvia contains sodium”). 2. Human normal immunoglobulin 10% One ml of the solution in this vial contains 100 mg of human normal immunoglobulin, of which at least 98% is immunoglobulin G (IgG). The active substance of HyQvia is human normal immunoglobulin. This medicine contains trace amounts of immunoglobulin A (IgA) (not more than 140 micrograms/ml, 37 micrograms on average). The other ingredients of this vial are glycine and water for injections. What HyQvia looks like and contents of the pack HyQvia is supplied as a pack containing: - one glass vial of recombinant human hyaluronidase, and - one glass vial of human normal immunoglobulin 10%. The recombinant human hyaluronidase is a clear and colourless solution. The human normal immunoglobulin 10% is a clear and colourless or pale yellow solution. 41 The following pack sizes are available: Recombinant human hyaluronidase Human normal immunoglobulin 10% Volume (ml) Protein (grams) Volume (ml) 1.25 2.5 25 2.5 5 50 5 10 100 10 20 200 15 30 300 Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: Baxalta Innovations GmbH Industriestrasse 67 A-1221 Vienna Austria Tel.: +800 66838470 E-mail: medinfoEMEA@shire.com Manufacturer: Baxalta Belgium Manufacturing SA Boulevard René Branquart 80 B-7860 Lessines Belgium This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what hyqvia is and what it is used for', 'Section_Content': 'what hyqvia is hyqvia contains two solutions for infusion (drip) under the skin (subcutaneous or sc infusion). it is supplied as a package containing one vial of human normal immunoglobulin 10% (the active substance) and one vial of recombinant human hyaluronidase (a substance which helps the human normal immunoglobulin 10% reach your blood). human normal immunoglobulin 10% belongs to a class of medicines called "human normal immunoglobulins". immunoglobulins are also known as antibodies and are found in healthy people\'s blood. antibodies are part of the immune system (the body\'s natural defences) and help your body to fight infections. how hyqvia works the vial of immunoglobulins has been prepared from the blood of healthy people. the medicine works in exactly the same way as the immunoglobulins naturally present in the blood. the recombinant human hyaluronidase is a protein that makes it easier for the immunoglobulins to be infused (dripped) under the skin and to reach your blood system. what hyqvia is used for hyqvia is used in patients with a weak immune system, who do not have enough antibodies in their blood and tend to get frequent infections. regular and sufficient doses of hyqvia can raise abnormally low immunoglobulin levels in your blood to normal levels (replacement therapy). hyqvia is prescribed as replacement therapy to patients who do not have sufficient antibodies, including the following groups: patients with an inborn inability or reduced ability to produce antibodies (primary immunodeficiencies). patients with a certain kind of blood cancer (chronic lymphocytic leukaemia) which leads to a lack of antibody production and recurrent infections when preventative antibiotics have failed. patients with a specific cancer of the bone marrow (multiple myeloma) and lack of antibody production with recurrent infections who have failed to respond to a vaccine against certain bacteria (pneumococci). patients with low antibody production prior and after transplantation of bone marrow cells from another person.', 'Entity_Recognition': [{'Text': 'hyqvia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 5, 'BeginOffset': 5, 'EndOffset': 11, 'Score': 0.38094568252563477, 'Text': 'hyqvia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.5647844672203064, 'RelationshipScore': 0.9510037302970886, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 31, 'EndOffset': 44, 'Text': 'two solutions', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.43949779868125916, 'RelationshipScore': 0.9989738464355469, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 8, 'BeginOffset': 49, 'EndOffset': 57, 'Text': 'infusion', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 6, 'BeginOffset': 15, 'EndOffset': 21, 'Score': 0.7681342959403992, 'Text': 'hyqvia', 'Category': 'MEDICATION', 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{'Title': '2. what you need to know before you use hyqvia', 'Section_Content': 'do not inject or infuse hyqvia - if you are allergic to immunoglobulins, hyaluronidase, recombinant hyaluronidase or any of the other ingredients of this medicine (listed in section 6, "contents of the pack and other information"). - if you have antibodies against immunoglobulin a (iga) in your blood. this may occur if you have iga deficiency. since hyqvia contains trace amounts of iga, you might have an allergic reaction. - into a blood vessel (intravenously). warnings and precautions the following warnings and precautions should be taken into consideration before you receive or use hyqvia. if you have any questions, talk to your doctor or nurse. pregnancy, breast-feeding and fertility the effects of long-term use of recombinant human hyaluronidase on pregnancy, breast-feeding and fertility are currently not known. hyqvia should only be used by pregnant and breast-feeding women after discussion with your physician. if you become pregnant when using hyqvia, you should discuss with your doctor the possibility of participating in a pregnancy registry in order to collect data on your pregnancy and the development of the baby. the purpose of such registry is to collect and share data only with the public health authorities responsible for monitoring the safety of this product. participation in the registry is voluntary. allergic reactions you may be allergic to immunoglobulins without knowing it. allergic reactions such as sudden fall in blood pressure or anaphylactic shock (a sharp fall in blood pressure with other symptoms such as swelling of the throat, breathing difficulties and skin rash) are rare but they can occasionally occur even if you have not previously had problems with similar treatments. you are at increased risk of allergic reactions if you have iga deficiency with anti-iga antibodies. signs or symptoms of these rare allergic reactions include: - feeling light-headed, dizzy or faint, - skin rash and itchiness, swelling in the mouth or throat, difficulty breathing, wheezing, - abnormal heart rate, chest pain, blueness of lips or fingers and toes, - blurred vision. your doctor or nurse will first infuse hyqvia slowly, and carefully monitor you throughout the first infusions so that any allergic reaction can be detected and treated immediately. if you notice any of these signs during the infusion, tell your doctor or nurse immediately. he or she will decide whether to slow down the infusion rate or stop the infusion completely. infusion speed it is very important to infuse the medicine at the correct speed. your doctor or nurse will advise you on the appropriate infusion speed to use when you are infusing hyqvia at home (see section 3, "how to use hyqvia"). monitoring during infusion certain side effects may occur more frequently if: - you are receiving hyqvia for the first time. - you have received another immunoglobulin and have been switched to hyqvia. - there has been a long interval (e.g., more than 2 or 3 infusion intervals) since you last received hyqvia. in such cases, you will be closely monitored during your first infusion and for the first hour after your infusion has stopped. in all other cases you should be monitored during the infusion and for at least 20 minutes after you receive hyqvia for the first few infusions. home treatment before you start home treatment you should assign a person as guardian. you and your guardian will be trained to detect early signs of side effects, especially allergic reactions. this guardian should help you keep an eye on potential side effects. during the infusion you must look out for first signs of side effects (for further details see section 4, "possible side effects"). if you experience any side effects, you or your guardian must stop the infusion immediately and contact a doctor. if you experience a severe side effect, you or your guardian must seek emergency treatment immediately. spread of localised infections do not infuse hyqvia into or around an infected or red swollen area on your skin because it may cause the infection to spread. no long-term (chronic) changes in the skin were observed in the clinical studies. any long-term inflammation, lumps (nodules) or inflammation that occur at the infusion site and last more than a few days should be reported to your physician. effects on blood tests hyqvia contains many different antibodies, some of which can affect blood tests (serological tests). tell your doctor about your treatment with hyqvia before any blood test. information on the source material of hyqvia the human normal immunoglobulin 10% of hyqvia and human serum albumin (an ingredient of the recombinant human hyaluronidase) are made from human plasma (the liquid part of blood). when medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. these include: - careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and - the testing of each donation and pools of plasma for signs of viruses/infections. manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. despite these measures, when medicines prepared from human blood or plasma are used, the possibility of passing on infection cannot be totally excluded. this also applies to any unknown or emerging viruses or other types of infections. the measures taken for the manufacture of hyqvia are considered effective for enveloped viruses such as human immunodeficiency virus (hiv), hepatitis b virus and hepatitis c virus and for the non-enveloped hepatitis a virus and parvovirus b19. immunoglobulins have not been associated with hepatitis a or parvovirus b19 infections possibly because the antibodies against these infections, which are contained in hyqvia, are protective. it is strongly recommended that every time you use hyqvia, the following data are recorded in your treatment diary: - the date of administration, - the batch number of the medicine, and - the injected volume, flow rate, the number and location of infusion sites. children and adolescents the same indications, dose and frequency of infusion as for adults apply for children and adolescents (0-18 years). other medicines and hyqvia tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. vaccinations hyqvia may reduce the effect of some virus vaccines such as measles, rubella, mumps and chicken pox (live virus vaccines). therefore, after receiving hyqvia, you may have to wait for up to 3 months before receiving certain vaccines. you may have to wait for up to 1 year after receiving hyqvia before you can receive your measles vaccine. please tell your vaccinating doctor or nurse about your treatment with hyqvia. driving and using machines patients may experience side effects (for example dizziness or nausea) during treatment with hyqvia that might affect the ability to drive and use machines. if this happens, you should wait until the reactions have disappeared. hyqvia contains sodium the recombinant human hyaluronidase of hyqvia contains small amounts (4.03 mg per ml) of sodium. this may have to be considered for patients who are on a controlled sodium diet.', 'Entity_Recognition': [{'Text': 'hyqvia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 11, 'BeginOffset': 24, 'EndOffset': 30, 'Score': 0.5806832313537598, 'Text': 'hyqvia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 44, 'EndOffset': 52}, {'Text': 'immunoglobulins', 'Type': 'TREATMENT', 'BeginOffset': 56, 'EndOffset': 71}, {'Id': 12, 'BeginOffset': 73, 'EndOffset': 86, 'Score': 0.5497332215309143, 'Text': 'hyaluronidase', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can have side effects, although not everybody gets them. certain side effects, such as headache, chills, or body aches, may be reduced by slowing the infusion rate. serious side effects infusions of medicines like hyqvia can occasionally result in serious, but rare, allergic reactions. you may experience a sudden fall in blood pressure and, in isolated cases, anaphylactic shock. doctors are aware of these possible side effects and will monitor you during and after the initial infusions. typical signs or symptoms include: feeling light-headed, dizzy or faint, skin rash and itchiness, swelling in the mouth or throat, difficulty breathing, wheezing, abnormal heart rate, chest pain, blueness of lips or fingers and toes, blurred vision. tell your doctor or nurse immediately if you notice any of these signs during the infusion. when using hyqvia at home, you must perform the infusion in the presence of an assigned guardian person who will help you watch out for allergic reactions, stop the infusion, and get help if necessary. please also see section 2 of this leaflet about the risk of allergic reactions and using hyqvia at home. very common side effects (may affect more than 1 in 10 infusions): infusion site pain, including mild to moderate discomfort and tenderness. these reactions usually go away within a few days. common side effects (may affect up to 1 in 10 infusions): reactions at the infusion site: these include redness, swelling, itching, hardening, and rash at the site of infusion. these reactions usually go away within a few days. headache, tiredness, nausea, vomiting, diarrhoea, abdominal pain, muscle or joint pain, chest pain, fever, feeling weak or unwell. uncommon side effects (may affect up to 1 in 100 infusions): chills,migraine, increasedblood pressure, dizziness, abdominal bloating, skin rash/allergic rash/redness, itching, pain in chest, arms and/or legs, genital swelling (resulting from spread of swelling from the infusion site), swelling of the legs, feet and ankles, positive blood tests for antibodies. frequency not known (cannot be estimated from the available data): hypersensitivity, influenza-like illness, and infusion site leakage, inflammation of the layers lining the brain (aseptic meningitis). side effects seen with similar medicines the following side effects have been observed with infusion of medicines like human normal immunoglobulin 10% given under the skin (subcutaneously). although these side effects have so far not been seen with hyqvia, it is possible that someone using hyqvia may get them: trembling, oral tingling, fast heart beat, allergic reactions, flushing or pallor, coldness of hand or feet, shortness of breath, swelling of face, excessive sweating, muscle stiffness, change in liver function blood tests (alanine aminotransferase increased). the following rare side effects have been observed in patients using medicines like human normal immunoglobulin 10% given into a vein (intravenously). these reactions have not been seen with hyqvia, but there is a small possibility that someone using hyqvia may get them: blood clots in blood vessels (thromboembolic reactions) leading to heart attack, stroke, blockage of deep veins, or of blood vessels supplying the lung (pulmonary embolism), kidney disorder or failure, destruction of red blood cells (haemolysis). if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'hyqvia', 'Type': 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{'Title': '5. how to store hyqvia', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 to 8). do not freeze. do not shake. keep the vials in the outer carton in order to protect from light. do not use this medicine if the solutions are cloudy or have particles or deposits. after opening, dispose of any unused solutions in the vials. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to dispose of medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'hyqvia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'the vials', 'Type': 'TREATMENT', 'BeginOffset': 279, 'EndOffset': 288}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 292, 'EndOffset': 308}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 352, 'EndOffset': 365}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 387, 'EndOffset': 393}, {'Text': 'deposits', 'Type': 'PROBLEM', 'BeginOffset': 415, 'EndOffset': 423}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 591, 'EndOffset': 600}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what hyqvia contains hyqvia is a dual vial unit containing: - a solution of recombinant human hyaluronidase (step 1 of hyqvia/infuse first) and - a solution of human normal immunoglobulin 10% (step 2 of hyqvia/infuse second). the contents of each vial are described below: 1. recombinant human hyaluronidase this vial contains recombinant human hyaluronidase. the other ingredients are sodium chloride, sodium phosphate, human albumin, ethylenediaminetetraacetic acid (edta) disodium, calcium chloride and water for injections (see also section 2, "hyqvia contains sodium"). 2. human normal immunoglobulin 10% one ml of the solution in this vial contains 100 mg of human normal immunoglobulin, of which at least 98% is immunoglobulin g (igg). the active substance of hyqvia is human normal immunoglobulin. this medicine contains trace amounts of immunoglobulin a (iga) (not more than 140 micrograms/ml, 37 micrograms on average). the other ingredients of this vial are glycine and water for injections. what hyqvia looks like and contents of the pack hyqvia is supplied as a pack containing: - one glass vial of recombinant human hyaluronidase, and - one glass vial of human normal immunoglobulin 10%. the recombinant human hyaluronidase is a clear and colourless solution. the human normal immunoglobulin 10% is a clear and colourless or pale yellow solution. the following pack sizes are available: recombinant human hyaluronidase human normal immunoglobulin 10% volume (ml) protein (grams) volume (ml) 1.25 2.5 25 2.5 5 50 5 10 100 10 20 200 15 30 300 not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'hyqvia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a dual vial unit', 'Type': 'TREATMENT', 'BeginOffset': 31, 'EndOffset': 47}, {'Text': 'a solution of recombinant human hyaluronidase', 'Type': 'TREATMENT', 'BeginOffset': 62, 'EndOffset': 107}, {'Text': '1', 'Type': 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5, 'BeginOffset': 386, 'EndOffset': 401, 'Score': 0.9980047345161438, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 403, 'EndOffset': 419, 'Score': 0.9983402490615845, 'Text': 'sodium phosphate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 421, 'EndOffset': 434, 'Score': 0.9912605881690979, 'Text': 'human albumin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ethylenediaminetetraacetic acid (edta) disodium', 'Type': 'TREATMENT', 'BeginOffset': 436, 'EndOffset': 483}, {'Id': 10, 'BeginOffset': 485, 'EndOffset': 501, 'Score': 0.998431384563446, 'Text': 'calcium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.33856844902038574, 'RelationshipScore': 0.9993464350700378, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 11, 'BeginOffset': 516, 'EndOffset': 526, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 516, 'EndOffset': 526}, {'Text': '2.', 'Type': 'NUMBER', 'BeginOffset': 545, 'EndOffset': 547}, {'Text': '2.', 'Type': 'NUMBER', 'BeginOffset': 575, 'EndOffset': 577}, {'Text': 'human normal immunoglobulin', 'Type': 'TREATMENT', 'BeginOffset': 578, 'EndOffset': 605}, {'Text': '1.', 'Type': 'NUMBER', 'BeginOffset': 606, 'EndOffset': 608}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 655, 'EndOffset': 658}, {'Text': 'human normal immunoglobulin', 'Type': 'TREATMENT', 'BeginOffset': 665, 'EndOffset': 692}, {'Text': '98', 'Type': 'NUMBER', 'BeginOffset': 712, 'EndOffset': 714}, {'Id': 13, 'BeginOffset': 767, 'EndOffset': 773, 'Score': 0.34290656447410583, 'Text': 'hyqvia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 806, 'EndOffset': 819}, {'Text': 'immunoglobulin a (iga)', 'Type': 'TREATMENT', 'BeginOffset': 846, 'EndOffset': 868}, {'Text': '140', 'Type': 'NUMBER', 'BeginOffset': 884, 'EndOffset': 887}, {'Text': '37', 'Type': 'NUMBER', 'BeginOffset': 903, 'EndOffset': 905}, {'Text': 'this vial are glycine', 'Type': 'TREATMENT', 'BeginOffset': 955, 'EndOffset': 976}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 991, 'EndOffset': 1001}, {'Id': 14, 'BeginOffset': 1112, 'EndOffset': 1143, 'Score': 0.9002588391304016, 'Text': 'recombinant human hyaluronidase', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.42806679010391235, 'RelationshipScore': 0.8585468530654907, 'RelationshipType': 'DOSAGE', 'Id': 15, 'BeginOffset': 1151, 'EndOffset': 1160, 'Text': 'one glass', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 16, 'BeginOffset': 1169, 'EndOffset': 1196, 'Score': 0.9482147097587585, 'Text': 'human normal immunoglobulin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.42806679010391235, 'RelationshipScore': 0.9875501990318298, 'RelationshipType': 'DOSAGE', 'Id': 15, 'BeginOffset': 1151, 'EndOffset': 1160, 'Text': 'one glass', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'STRENGTH', 'Score': 0.8464503884315491, 'RelationshipScore': 0.9991975426673889, 'RelationshipType': 'STRENGTH', 'Id': 17, 'BeginOffset': 1197, 'EndOffset': 1200, 'Text': '10%', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 1197, 'EndOffset': 1199}, {'Text': 'the recombinant human hyaluronidase', 'Type': 'TREATMENT', 'BeginOffset': 1202, 'EndOffset': 1237}, {'Text': 'the human normal immunoglobulin', 'Type': 'TREATMENT', 'BeginOffset': 1274, 'EndOffset': 1305}, {'Text': '1.', 'Type': 'NUMBER', 'BeginOffset': 1306, 'EndOffset': 1308}, {'Text': 'pale yellow solution', 'Type': 'PROBLEM', 'BeginOffset': 1339, 'EndOffset': 1359}, {'Text': 'the following pack sizes', 'Type': 'TREATMENT', 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182A6C29142B01CD4402579AF2BDA7AE

https://www.ema.europa.eu/documents/product-information/ionsys-epar-product-information_en.pdf

Ionsys

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Me dic ina l p rod uc t n o l on ge r a uth ori se d 2 1. NAME OF THE MEDICINAL PRODUCT IONSYS 40 micrograms per dose transdermal system 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each IONSYS system contains fentanyl hydrochloride equivalent to 9.7 mg of fentanyl and delivers 40 micrograms fentanyl per dose, to a maximum of 80 doses (3.2 mg/24 hours). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Transdermal system IONSYS is composed of an electronic controller and a drug unit with two hydrogels. The controller is white with the identifier ‘IONSYS®’ and has a digital display, a light window, and a recessed dose activation button. The drug unit is blue on the side that connects to the controller and has a red bottom housing containing the hydrogels, one of which contains the fentanyl. The assembled IONSYS product measures 47 mm x 75 mm. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications IONSYS is indicated for the management of acute moderate to severe post-operative pain in adult patients. 4.2 Posology and method of administration IONSYS is restricted to hospital use only. Treatment should be initiated by and remain under the guidance of a physician experienced in the management of opioid therapy. Due to the well-known potential of abuse of fentanyl, physicians should evaluate patients for a history of drug abuse (see section 4.4). Posology Patients should be titrated to an acceptable level of analgesia prior to initiating use of IONSYS (see section 5.1). IONSYS should only be activated by the patient. Each dose of IONSYS delivers 40 micrograms of fentanyl over a 10 minute period, to a maximum of 240 micrograms per hour (6 doses each of 10 minutes duration). IONSYS will operate for 24 hours after the system is assembled or for 80 doses, whichever comes first, and then becomes inoperative. After 24 hours or 80 doses, a new system should be applied if necessary. Each new system should be placed on a new skin site. With each new IONSYS application the patient may use IONSYS more frequently than during the remainder of the 24 hour dosing period, due to a lower absorption of fentanyl from the system for the first few hours (see section 5.2). The maximum treatment duration is 72 hours, although the majority of patients should only need one system. Me dic ina l p rod uc t n o l on ge r a uth ori se d 3 Patients should not wear more than one system at a time. Used systems should not be reapplied to a patient. IONSYS should be removed before the patient is discharged. Elderly patients As with all fentanyl products, the clearance of fentanyl may be reduced in elderly patients, with a consequent increase in half life. No specific dose adjustment is required in elderly patients. However elderly patients should be observed closely for adverse effects of fentanyl (see sections 4.4 and 4.8). Hepatic or renal impairment IONSYS should be administered with caution to patients with moderate or severe hepatic or renal impairment (see section 4.4). Paediatric population The safety and efficacy of IONSYS in children and adolescents younger than 18 years of age has not been established. Currently available data are described in section 4.8, but no recommendation on posology can be made. Method of administration IONSYS is for transdermal use only. Precaution to be taken before manipulating or administering the product Gloves should be worn when manipulating IONSYS. To avoid oral ingestion of the fentanyl- containing hydrogel, which may cause life-threatening hypoventilation or death, the hydrogel must not touch the mouth or other mucosal areas. Patients should not get IONSYS wet. Prolonged contact with water could affect system performance and cause the system to fall off. Preparation of application site IONSYS should be applied to intact, non-irritated and non-irradiated skin. IONSYS should not be placed on abnormal skin sites, such as scars, burns, tattoos, etc. IONSYS should also not be placed on skin on which topical medicines have been applied. Hair at the application site should be clipped (not shaved) before system application. IONSYS should not be applied to a previously used skin site. The application site should be wiped with a standard alcohol swab and the skin should be allowed to dry completely before IONSYS is applied. No soaps, oils, lotions, or any other agents that might irritate the skin or alter its absorption characteristics should be used to clean the application site. Assembly of IONSYS IONSYS should not be used if the seal on the tray or the sachet containing the Drug Unit is broken or damaged. Me dic ina l p rod uc t n o l on ge r a uth ori se d 4 Gloves should be worn during the assembly of IONSYS. The tray is opened by pulling back on the tray lid. The sachet containing the Drug Unit should be opened starting at the pre-cut notch, then by carefully tearing along the top of the sachet. The Drug Unit should be removed from the sachet and the Controller should be snapped on by aligning the shape and firmly pressing the two parts together. When assembled, the digital display of the Controller will complete a short self-test during which there will be an audible beep, the red light will flash once, and the digital display will flash the number 88. At the end of the self-test, the display will show the number 0 and a green light will flash at a slow rate to indicate IONSYS is ready for application. Application of IONSYS The clear plastic film covering the adhesive should be removed and discarded with care taken not to touch the hydrogels. IONSYS should be pressed firmly in place for at least 15 seconds with the sticky side down on the skin of the chest or upper arm of the patient. Pressure should be applied with the fingers around the outer edges to ensure adhesion to the skin site. If at any point during use the system loosens from the skin, a non-allergenic tape may be used to secure the edges to ensure complete contact with the skin. When applying tape, care should be taken not to tape over the light window, the digital display, or the dosing button. The dosing button must not be pressed. For further details, see section 6.6. Dose delivery A recessed dosing button is located on the Controller of IONSYS. To initiate administration of a fentanyl dose, the patient should press and release the dosing button twice within 3 seconds. IONSYS should only be activated by the patient. Upon successful dose initiation, IONSYS will emit a beep indicating the start of delivery. The green light will change from a slow flash rate to a rapid flash rate and the digital display will alternate between a rotating circle and the number of completed doses during the entire 10-minute dose delivery period. The next dose cannot be initiated until the previous 10-minute delivery period is complete. Pressing the button during delivery of a dose will not result in additional fentanyl being administered. After the 10-minute dose has been completely delivered, the green light will return to a slow flash rate, the digital display will show the number of doses that have been delivered, and IONSYS will be ready to be used again by the patient. At the end of 24 hours of use, or after 80 doses have been administered, the green light will switch off and the number of doses delivered will flash on and off. The flashing digital display may be turned off by pressing the dose button for six seconds. Removal IONSYS is removed from the patient by lifting the system at the red tab and peeling it away from the skin site. Gloves must be worn while removing IONSYS from the skin and care should be taken to avoid touching the hydrogels. If the medicinal product contacts the skin during removal, the contact area should be thoroughly rinsed with water without using any soap. IONSYS may be removed at any time. However, once a system has been removed, the same system should not be reapplied. If the patient requires additional treatment for pain, a new system may be applied to a new skin site on the upper outer arm or chest. Special precautions for disposal should be followed (see section 6.6). Me dic ina l p rod uc t n o l on ge r a uth ori se d 5 Troubleshooting Each IONSYS system is designed to deliver up to 80 10-minute doses of fentanyl over a period of 24 hours. The table below represents the different error messages that may occur, together with the probable cause and the action to be taken. Error message/feedback Probable cause Action required • No light • No beeps • No display Low battery or defective system 1. Do not use the system 2. Dispose of system per instructions in Section 6.6 3. Place a new system on a different skin site • Blinking red light for 15 seconds • Beeping for 15 seconds • System is not securely adhered Poor skin contact 1. Secure system to patient’s skin by pressing the edges firmly or by applying non-allergenic tape 2. If system beeps again, then remove and dispose of system, and place a new system on a different skin site. • Continuous blinking red light • Continuous beeping • Steady display number System error 1. Remove system from patient 2. Hold down dosing button until beeping stops and display goes blank 3. Dispose of system per instructions in Section 6.6 4. Place a new system on a different skin site • No light • No beeps • Blinking display number End of use at 24 hours or 80 doses 1. Remove system from patient 2. Hold down dosing button until display goes blank 3. Dispose of system per instructions in Section 6.6 4. Place a new system on a different skin site If device failure or malfunction is suspected by a healthcare professional, IONSYS should be immediately removed from the patient and The Medicines Company contacted straightaway. The healthcare professional must ensure the patient understands that if they suspect a device failure or malfunction, they must immediately inform a healthcare professional. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Severe respiratory depression or cystic fibrosis. 4.4 Special warnings and precautions for use Before any surgery, the healthcare professional should ensure that the patient has been properly informed on how to use IONSYS post-operatively. A potentially dangerous amount of fentanyl remains in the IONSYS system after use. For disposal instructions, see section 6.6. Me dic ina l p rod uc t n o l on ge r a uth ori se d 6 IONSYS should be removed before a magnetic resonance imaging (MRI) procedure, cardioversion, defibrillation, X-ray, CT scan or diathermy is undertaken. Excessive sweating may reduce delivery of fentanyl. Respiratory depression IONSYS should only be activated by the patient, to avoid potential overdosing. Significant respiratory depression may occur with IONSYS; patients must be observed for these effects (see section 4.9). The use of concomitant CNS-active medicinal products may increase the risk of respiratory depression (see section 4.5). Chronic pulmonary disease In patients with chronic obstructive pulmonary disease or patients with conditions pre-disposing them to hypoventilation, more severe adverse reactions may be experienced. In such patients, opioids may decrease respiratory drive and increase airway resistance. Head injuries and increased intracranial pressure Fentanyl should not be used in patients who may be particularly susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head injury. Fentanyl should be used with caution in patients with brain tumours or other significant space occupying lesions of the brain. Cardiac disease Fentanyl may produce bradycardia or hypotension and should, therefore, be administered with caution to patients with bradyarrhythmias or any significant cardiovascular disease. Paralytic ileus IONSYS should be used with caution in patients with paralytic ileus. Abuse potential and dependence Fentanyl has a well-known abuse potential. Patients with a prior history of drug dependence/alcohol abuse are more at risk to develop dependence and abuse in opioid treatment. Physicians should evaluate patients for a history of drug abuse and follow such patients closely. Tolerance, physical dependence, and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is rare. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of IONSYS may result in overdose and/or death. Hepatic disease Fentanyl is metabolised into inactive metabolites in the liver. Hepatic disease may delay elimination. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity. Renal disease Me dic ina l p rod uc t n o l on ge r a uth ori se d 7 Less than 10% of administered fentanyl is excreted unchanged by the kidney. Unlike morphine, no active fentanyl metabolites are eliminated by the kidney. Data obtained with intravenous fentanyl in patients with renal failure suggest that the volume of distribution of fentanyl may be changed by dialysis. This may affect serum concentrations. If patients with renal impairment receive IONSYS, they should be observed carefully for signs of fentanyl toxicity. Elderly patients Elderly patients should be observed carefully for adverse effects of fentanyl during IONSYS administration (see sections 4.2 and 4.8). Obese patients The overall adverse reaction profile for morbidly obese patients (BMI > 40) does not suggest a meaningful difference in safety compared to patients with BMI ≤ 40. However, caution is advised when prescribing IONSYS in morbidly obese patients because they may be at increased risk of other comorbid respiratory conditions (i.e., sleep apnoea) potentially pre-disposing them to hypoventilation or more severe adverse reactions (see section 4.8). Hearing impairment IONSYS should be used with caution in patients with hearing impairment who might not be able to hear the audible signals from the system. Thoracic/chest and upper abdominal surgeries Only limited data are available in patients with thoracic/chest and upper abdominal surgeries. IONSYS should, therefore, be used with caution in these patients. Physical status The safety of IONSYS has not been established in patients with American Society of Anesthesiologists (ASA) physical status classification IV (i.e. patients with a severe systemic disease that is a constant threat to life). Patients with genetic polymorphisms affecting CYP3A4 and CYP3A5 Published literature indicates potential for increased fentanyl exposure in patients with genetic polymorphisms affecting CYP3A4 and CYP3A5, with a small variability in concentrations with transdermal administration; therefore, IONSYS should be used with caution in these patients (see section 5.2) 4.5 Interaction with other medicinal products and other forms of interaction The concomitant use of other central nervous system depressants including other opioids, sedatives or hypnotics, general anaesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages, may produce additive depressant effects. Hypoventilation, hypotension, and profound sedation or coma may occur. Therefore, the use of any of these medicinal products concomitantly with IONSYS requires special patient care and observation. Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4. Itraconazole, a potent CYP3A4 inhibitor, at 200 mg/day orally for 4 days had no significant effect on the pharmacokinetics of intravenous fentanyl. Oral ritonavir, one of the most potent CYP3A4 inhibitors, reduced the clearance of intravenous fentanyl by two thirds. The concomitant use of potent CYP3A4 inhibitors (e.g., as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, and nelfinavir) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) with IONSYS may result in an increase in Me dic ina l p rod uc t n o l on ge r a uth ori se d 8 fentanyl plasma concentrations, which could increase or prolong both the therapeutic effect and adverse reactions, and may cause serious respiratory depression. In this situation, special patient care and observation are appropriate. The concomitant use of ritonavir or other potent or moderate CYP3A4 inhibitors and IONSYS is not recommended unless the patient is closely monitored. The concomitant use of partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependant patients. Serotoninergic medicinal products Co-administration of fentanyl with a serotoninergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition. IONSYS is not recommended for use in patients who have received monoamine oxidase (MAO) inhibitors within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics Interaction studies have only been performed in adults. Topical medicines Application of the IONSYS system on skin on which any topical medicine has been applied should be avoided. An alternative application site should be chosen. 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). IONSYS should not be used in pregnancy unless clearly necessary. Administration during childbirth is not recommended because fentanyl crosses the placenta and the fetal respiratory centre is sensitive to opiates. If IONSYS is administered to the mother during this time, an antidote for the child should be readily available. Following long-term treatment fentanyl may cause withdrawal symptoms in the newborn. Breast-feeding Fentanyl is excreted into human milk. Breast-feeding is not recommended for 24 hours following removal of IONSYS. Fertility There are no clinical data on the effects of fentanyl on fertility. Studies in rats have revealed reduced fertility and enhanced embryo mortality (see section 5.3). 4.7 Effects on ability to drive and use machines Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, or visual disturbance. Me dic ina l p rod uc t n o l on ge r a uth ori se d 9 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions were nausea, vomiting, and application site reactions such as erythema and pruritus. These were mostly of mild to moderate severity. The most serious adverse reactions reported were hypotension and apnoea and all patients should be closely monitored for these. Tabulated list of adverse reactions The following adverse reactions have been reported with IONSYS during clinical studies and post marketing experience. All adverse reactions are listed by System Organ Class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); and rare (≥1/10,000 to <1/1,000). System Organ Class Very Common Common Uncommon Rare Infections and infestations Rhinitis Blood and lymphatic system disorders Anaemia Metabolism and nutrition disorders Decreased appetite Hypocalcaemia Hypoglycaemia Hypokalaemia Psychiatric disorders Insomnia Abnormal dreams Agitation Anxiety Confusional state Hallucination Nervousness Depression Thinking abnormal thoughts Nervous system disorders Dizziness Headache Migraine Paraesthesia Somnolence Syncope Dysgeusia Hypoaesthesia Eye disorders Vision blurred Ear and labyrinth disorders Vertigo Cardiac disorders Tachycardia Bradychardia Vascular disorders Hypotension Hypertension Orthostatic hypotension, Vasodilitation Respiratory, thoracic and mediastinal disorders Hypoxia Apnoea Cough Dyspnoea Hiccups Hypoventilation Lung disorder Gastrointestinal disorders Nausea Vomiting Constipation Abdominal pain Dry mouth Dyspepsia Flatulence Ileus Abdominal distension Diarrhoea Eructation Skin and subcutaneous tissue disorders Pruritus Rash Hyperhidrosis Musculoskeletal and connective tissue Back pain Pain in extremity Hypertonia Myalgia Me dic ina l p rod uc t n o l on ge r a uth ori se d 10 System Organ Class Very Common Common Uncommon Rare disorders Renal and urinary disorders Urinary retention Oliguria Dysuria General disorders and administration site conditions Application site erythema Application site oedema Application site pruritus Application site reaction Application site vesicles Pyrexia Application site pain Application site dryness Application site papules Asthenia Chills Application site reaction Pain Chest pain Malaise Application site paraesthesia Injection site oedema Injection site pain Oedema Injury, poisoning and procedural complications Wound complication Surgical and medical procedures Gastrointestinal disorder therapy Paediatric population Data on IONSYS in paediatrics is limited to information from a single clinical trial. In this study 28 paediatric patients, 6 to 16 years old, were treated with IONSYS fentanyl 40 micrograms after experiencing inadequate analgesia with IONSYS fentanyl 25 micrograms. Among these patients, the incidence of nausea was similar to adult patients; however, vomiting (32.1%) and fever (60.7%) were each reported at a higher incidence in paediatric patients relative to adults. In summary, the limited size of the overall paediatric exposure is insufficient to guide safe and effective dosing of IONSYS in patients younger than 18 years of age. Elderly population Elderly patients (≥ 65 years) made up 28% (499/1763) of the total controlled clinical trial exposure to IONSYS 40 micrograms, with approximately 10% (174/1763) of exposures being in patients ≥ 75 years. No overall differences were observed in the safety of IONSYS fentanyl 40 micrograms in elderly patients (≥ 65 years including a subpopulation ≥ 75 years) and adult patients for all controlled studies. Thus, the adverse reaction profile does not suggest a meaningful difference in safety compared to patients younger than 65 years of age. Obese patients In the controlled clinical trial population, the adverse reaction profile in patients with BMI > 40 (86/1436 or 6%) showed no meaningful difference relative to patients with BMI ≤ 40. However, caution is recommended in these patients (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 11 4.9 Overdose Symptoms The manifestations of fentanyl overdose are an extension of its pharmacologic actions, the most serious effect being respiratory depression (see section 5.2). Treatment For management of respiratory depression, immediate countermeasures include removing the IONSYS system and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone, based on the clinical judgment of the treating health care professional. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. The half-life of the antagonist may be short; therefore, repeated administration or infusion of the antagonist may be necessary. Reversal of the narcotic effect may also result in acute onset of pain and release of catecholamines. If the clinical situation warrants, a patent airway should be established and maintained, possibly with an oropharyngeal airway or endotracheal tube. Oxygen should be administered and respiration assisted or controlled, as appropriate. Adequate body temperature and fluid intake should also be maintained. If severe or persistent hypotension occurs, hypovolaemia should be considered and the condition should be managed with appropriate parenteral fluid therapy or other interventions as needed, based upon the clinical judgment of the treating health care professional. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Analgesics; phenylpiperidine derivatives; ATC code: N02AB03. Mechanism of action Fentanyl is an opioid analgesic, interacting predominantly with the opioid μ-receptor. Pharmacodynamic effects Its primary therapeutic actions are analgesia and sedation. Its secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria (see section 5.2). Clinical efficacy and safety The efficacy and safety of IONSYS for treatment of acute, moderate to severe postoperative pain was evaluated in seven controlled studies in 1763 IONSYS patients: three placebo-controlled studies and four active-controlled studies. The placebo-controlled trials included 791 patients that were predominantly female (72%), Caucasian (82%), with a mean age of 45-54 years (range, 18-90 years), and primarily comprised of surgeries including lower abdominal (including pelvic) and orthopedic bone procedures. Patients were enrolled shortly after major surgery if they were not opioid tolerant, were expected to have an uncomplicated recovery, and required at least 24 hours of parenteral opioid treatment. Long-lasting or any non-opioid analgesics were not permitted. Patients were initially titrated to comfort with intravenous fentanyl or morphine, at which point they were randomized to IONSYS or a matching placebo system. During the first 3 hours post-enrollment, patients could supplement with bolus intravenous fentanyl given, as needed, to achieve comfort. After this point 727 patients remained in the studies using only the IONSYS or control system, and were evaluated for efficacy. Me dic ina l p rod uc t n o l on ge r a uth ori se d 12 The primary endpoint in each placebo-controlled study was the proportion of withdrawals due to inadequate analgesia during the period from 3 to 24-hours after IONSYS application. As illustrated in Table 1 below, IONSYS (fentanyl hydrochloride) was superior to placebo in all studies. Additional analyses suggest that the surgical procedure type did not influence the trends in efficacy endpoints and the efficacy of IONSYS was similar across the range of body mass indices studied (< 25 to > 40 kg/m2 Body Mass Index). Table 1: Placebo-controlled Trials (N=727) Patients Percent (n) of patients who withdrew due to inadequate analgesia Hours 3-24 Study IONSYS n=454 Placebo n=273 p-value C-2001-011 27 % (64/235) 57 % (116/204) <0.0001 C-2000-008 25 % (36/142) 40 % (19/47) 0.049 C-95-016 8 % (6/77) 41 % (9/22) 0.0001 IONSYS was also evaluated in four active-control trials (predominantly female (65%), Caucasian (85%), with a mean age of 55 years (range, 18-91 years), and primarily comprised of surgeries including lower abdominal and orthopedic bone procedures) using a standard intravenous patient controlled analgesia (PCA) morphine regimen as the comparator. In these studies, 1313 patients undergoing major surgery were randomized to PCA with intravenous morphine (1 mg morphine bolus, 5 minute lock-out, total of 10 mg/h) delivered by a pump, and 1288 patients were randomized to IONSYS. Similar to the placebo-controlled studies, in the immediate postoperative period, patients were titrated to comfort with intravenous fentanyl or morphine per hospital protocol. Once comfortable, patients were then randomized to either IONSYS or intravenous PCA morphine treatment. Patients were instructed to use the system for pain relief. These studies evaluated IONSYS vs. intravenous PCA morphine in various surgical procedures commonly seen in clinical practice. Study C-2000-007 evaluated patients after undergoing abdominal, thoracic, or orthopedic surgeries; Study CAPSS-319 evaluated patients after undergoing total hip replacement; Study CAPSS-320 assessed IONSYS in patients following abdominal and pelvic surgeries; and Study FEN-PPA-401 assessed patients following major abdominal or orthopedic surgery. Patients could remain in their respective study up to 72 hours if they required parenteral opioid analgesia for this duration. A new IONSYS system was applied every 24 hours to different skin sites, or earlier if all doses were used. Supplemental intravenous opioid medication (fentanyl or morphine) was only allowed during the first 3 hours of IONSYS or PCA morphine treatment. Concomitant use of analgesics was not allowed after 3 hours in Studies C-2000-007 and CAPSS-320. In Study CAPSS-319, half the patients in each group received rofecoxib perioperatively and in Study FEN-PPA-401 patients were allowed non-opioid analgesics throughout the study period. The primary efficacy endpoint was the patient global assessment of method of pain control at 24 hours used to test equivalence between IONSYS and intravenous PCA morphine using a pre-specified ± 10% equivalence boundary with a 2-sided 95% confidence interval. Each patient and investigator was asked to rate the patient’s method of pain control as either poor, fair, good, or excellent. Efficacy results at the end of 24 hours, are presented in Table 2 below for the evaluable patient population. As shown below, the primary endpoint, proportion of patients reporting “Good or Excellent” ratings for the two methods of pain relief in all four studies demonstrated equivalence, with each 95% confidence interval contained within the prespecified ± 10% equivalence boundaries. Me dic ina l p rod uc t n o l on ge r a uth ori se d 13 Table 2 Active Comparator Trials (n=2569) Evaluable Patients Study No. IONSYS (fentanyl) n=1271 IV-PCA (morphine) n=1298 95% CIa, b Patient Global Assessment of Method of Pain Control -1st 24 hour (% of patients rating good or excellent) C-2000-007 75% (232/310) 78% (246/316) (-9.7%, 3.7%)a, b CAPSS-319 84% (326/389) 83% (331/397) (-4.7%, 5.6%)a, b CAPSS-320 86% (214/250) 85% (212/251) (-5.1%, 7.4%)a, b FEN-PPA- 401 87% (279/322) 88% (293/334) (-6.2%, 4.0%)a, b a 95% Confidence Interval for difference in proportions b The pre-specified equivalence boundary was ± 10% Across the active-controlled studies, dosing with IONSYS was similar to intravenous PCA morphine pump use. The mean amount of supplemental opioid used during this time was also similar among patients treated with IONSYS or PCA morphine i.e. a range across the 4 studies of a mean dose of 5.0 – 7.5 mg morphine in patients treated with IONSYS compared to a mean dose of 5.4 – 7.7mg morphine in patients receiving PCA morphine. . Patients who completed 24 hours of IONSYS treatment in the seven controlled studies used a wide range of the available 80 doses, with a mean of 29.0 doses/patient (range of 0-93 doses) with the majority of patients (56.5%) using between 11 to 50 doses. A single IONSYS system provided a sufficient number of doses for 99% of the studied patients over 24 hours. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with IONSYS in one or more subsets of the paediatric population for the treatment of acute pain. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties Absorption At the initiation of each dose, an electrical current moves a pre-determined amount of fentanyl from the active substance-containing reservoir through the skin and into systemic circulation. IONSYS delivers a nominal dose of 40 micrograms fentanyl over each 10-minute dosing period at steady state. The mean systemic bioavailability is 87%. Upon system removal after the last dose, the decline in serum fentanyl concentration is similar to that of intravenous fentanyl. Absorption of fentanyl from IONSYS is similar whether applied to the upper outer arm or chest. When the system is applied on the lower inner arm, the amount of fentanyl absorbed is approximately 20% lower than at the upper outer arm or chest. Fentanyl pharmacokinetics are similar with both single and multiple 24 hour applications. Systemic absorption of fentanyl increases as a function of time independent of the frequency of dosing, with the initial dose being approximately 16 micrograms. Steady state absorption of the nominal 40 microgram dose is achieved about 12 hours after application, indicating that the skin becomes more permeable to fentanyl during the first 12 hours. The pharmacokinetic absorption profile will repeat with each application to a new skin site, therefore with each new application, Me dic ina l p rod uc t n o l on ge r a uth ori se d 14 absorption will be lower initially. Consequently, the patient may activate IONSYS more frequently to maintain fentanyl blood levels. When IONSYS is applied without activating the electrical current, the average absorption rate of fentanyl over 24 hours was 2.3 micrograms fentanyl/hour, indicating minimal passive delivery. Average serum concentrations observed in post-surgical patients were in the range of 0.4-1.5 ng/ml over a 24 hour dosing period. In general, the maximum serum fentanyl concentration occurs approximately 15 minutes after the initiation of a dose. Following an on-demand dose of fentanyl by IONSYS, fentanyl has an absorption half-life of approximately 15 minutes. Distribution Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent volume of distribution. Fentanyl exhibits three compartment distribution pharmacokinetics. With intravenous administration, the initial distribution half-life is approximately 6 minutes; the second distribution half-life is 1 hour, and the terminal half-life is 13 hours. The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The average volume of distribution for fentanyl at steady state is 6 L/kg, the average clearance is 53 L/h. Biotransformation Fentanyl is metabolised primarily in the liver to norfentanyl by CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal studies. More than 90% of the administered dose of fentanyl is eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Skin does not appear to metabolise fentanyl delivered transdermally. Elimination Around 75% of fentanyl is excreted into the urine, mostly as metabolites, with less than 10% as unchanged active substance. About 9% of the dose is recovered in the faeces, primarily as metabolites. The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h Linearity/non-linearity Dose proportionality has been demonstrated from 25 to 60 micrograms per dose. None of the four demographic factors studied [weight (lean/obese), age, race, or gender] had a significant effect on active substance exposure (AUC) following use of IONSYS. Pharmacokinetic /pharmacodynamic relationship Minimum effective analgesic serum concentrations of fentanyl in opioid-naïve patients treated for acute post-operative pain range from 0.2 to 1.2 ng/ml; undesirable effects increase in frequency at serum levels above 2 ng/ml. Patients with genetic polymorphisms affecting CYP3A4 and CYP3A5 Published literature has indicated that the CYP3A4*22 and CYP3A5*3 single nucleotide polymorphisms influence fentanyl to norfentanyl metabolism with the potential for increased fentanyl exposure in patients with these genetic polymorphs. Literature has shown that the genetic polymorphisms only account for a small amount of variability in concentrations of fentanyl with transdermal administration. Another published article of 52 elderly Japanese post-operative patients Me dic ina l p rod uc t n o l on ge r a uth ori se d 15 receiving continuous intravenous (IV) fentanyl infusion (0.5-1.5 µg/kg/h) showed increased fentanyl exposure in the CYP3A5*3 group (3*/3*) than in the 1* carrier group. Clinical relevance is unknown from these published articles; however, caution should be used if administering IONSYS in patients with genetic polymorphisms of CYP3A4 and CYP3A5 (see section 4.4). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. Standard reproductive and developmental toxicity studies have been carried out using parenteral administration of fentanyl. In a rat study fentanyl did not influence male fertility. Studies with female rats revealed reduced fertility and enhanced embryo mortality. Effects on the embryo were due to maternal toxicity and not to direct effects of the substance on the developing embryo. There was no indication of teratogenic effects in studies in two species (rats and rabbits). In a study on pre- and postnatal development the survival rate of offspring was significantly reduced at doses which slightly reduced maternal weight. This effect could either be due to altered maternal care or a direct effect of fentanyl on the pups. Effects on somatic development and behaviour of the offspring were not observed. Mutagenicity testing in bacteria and in rodents yielded negative results. Fentanyl induced mutagenic effects in mammalian cells in vitro, comparable to other opioid analgesics. A mutagenic risk for the use of therapeutic doses seems unlikely since effects appeared only at high concentrations. A carcinogenicity study (daily subcutaneous injections of fentanyl hydrochloride for two years in Sprague Dawley rats) did not induce any findings indicative of oncogenic potential. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Bottom housing assembly: - bottom housing unit: glycol-modified polyethylene terephthalate - anode hydrogel: polacrilin, purified water, sodium hydroxide, polyvinyl alcohol - cathode hydrogel: purified water, sodium chloride, sodium citrate, polyvinyl alcohol, anhydrous citric acid, cetylpyridinium chloride - anode electrode: layers of silver foil and electrically conductive adhesive tape - cathode electrode: layers of polyisobutylene/silver chloride/carbon black composite material, silver foil, and electrically conductive adhesive tape - skin adhesive: polybutene, polyisobutylene, and rosin ester - protective liner: polyester film coated on one side with silicone. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years Use immediately after opening. 6.4 Special precautions for storage Do not store above 25°C. Do not refrigerate or freeze. Me dic ina l p rod uc t n o l on ge r a uth ori se d 16 6.5 Nature and contents of container Each IONSYS system is packaged in a sealed thermoform tray. The tray contains one Controller and one sachet containing a Drug Unit. The sachet foil is comprised of a lamination of nylon, aluminium foil and a heat seal layer of a copolymer of polyethylene and polymethacrylic acid. Each tray is packaged in a folding cardboard carton. There are 6 systems per carton. 6.6 Special precautions for disposal and other handling Contact with the hydrogel can be harmful to humans. If the fentanyl hydrogel contacts the skin during application or removal, the area should be washed with copious amounts of water. Soap, alcohol, or other solvents should not be used to remove the hydrogel because they may enhance the active substances’ ability to penetrate the skin. Disposal The used IONSYS system contains a dangerous amount of fentanyl within the red hydrogel housing. Gloves must be worn when removing IONSYS from the patient’s skin and during disposal. The used system should be handled carefully by the sides and top. Contact with the hydrogel should be avoided. The design of the system allows separate disposal of the hydrogel housing and the Controller. To dispose of a used IONSYS system: 1. Hold the Controller in one hand and pull the red tab with the other hand to separate the hydrogel housing from the system. 2. Fold the hydrogel housing in half with the sticky side facing in. 3. Dispose of the folded hydrogel housing in accordance with local requirements for opioid medicinal products. 4. Dispose of remainder of the system, containing electronics, according to hospital procedures for battery waste. Local arrangements should be in place to ensure that used systems are returned appropriately (e.g., to hospital pharmacies) for disposal of the residual fentanyl in the hydrogel. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Incline Therapeutics Europe Ltd 21 St. Thomas Street Bristol BS1 6JS United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1050/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Me dic ina l p rod uc t n o l on ge r a uth ori se d 17 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 18 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Me dic ina l p rod uc t n o l on ge r a uth ori se d 19 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Penn Pharmaceutical Services Ltd 23-24 Tafarnaubach Industrial Estate Tredegar Gwent, South Wales NP22 3AA United Kingdom B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to special and restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures Prior to launch of IONSYS in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority. The MAH shall ensure that, following discussions and agreement with the National Competent Authorities in each Member State where IONSYS is launched all healthcare professionals who are expected to prescribe, dispense or administer IONSYS are informed through an information letter on having access to / are provided with the following items: • Summary of Product Characteristics (SmPC) and Package Leaflet • IONSYS Instructions for Use and Disposal Me dic ina l p rod uc t n o l on ge r a uth ori se d 20 • Educational material (including prescriber checklist) for the healthcare professionals The Healthcare provider educational Programme shall contain the following key messages: • Information on the adequate use of the product with regards to medication errors (including accidental exposure), Device malfunction/failure, Product Disposal and Misuse/abuse/diversion/addiction and dependence. • Information highlighting that IONSYS is a patient-controlled device to be used in a hospital setting only and that standard practices for monitoring patients using such devices should be followed by healthcare professionals. • Information to aid healthcare professionals in selecting patients appropriate for treatment with IONSYS. • The importance of the healthcare professional ensuring that the patient understands how to operate the IONSYS system and that only he/she can press the dosing button during use. • The importance of reading the “IONSYS Instructions for Use and Disposal” including the troubleshooting guide and ensuring that the patient understands what to do in the event of a device failure/malfunction. • Checklist for monitoring inadequate product disposal to ensure healthcare professionals understand the dangers of inappropriate handling and accidental exposure to the IONSYS system. Me dic ina l p rod uc t n o l on ge r a uth ori se d 21 ANNEX III LABELLING AND PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 22 A. LABELLING Me dic ina l p rod uc t n o l on ge r a uth ori se d 23 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT IONSYS 40 micrograms per dose transdermal system Fentanyl 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 system contains fentanyl hydrochloride equivalent to 9.7 mg of fentanyl. 1 system delivers 40 micrograms fentanyl per dose, to a maximum of 80 doses (3.2 mg/24 hours). 3. LIST OF EXCIPIENTS Also contains: glycol-modified polyethylene terephthalate, purified water, sodium hydroxide, polacrilin, polyvinyl alcohol, trisodium citrate dihydrate, anhydrous citric acid, cetylpyridinium chloride monohydrate, sodium chloride, silver foil, electrically conductive adhesive tape (ECAT), polyisobutylene/silver chloride/carbon black, polyisobutene, polyisobutylene, rosin ester, siliconised polyester. 4. PHARMACEUTICAL FORM AND CONTENTS 6 transdermal systems 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Transdermal use Do not use if seal on the tray or the sachet containing the drug unit are broken or damaged. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Use immediately after opening. Me dic ina l p rod uc t n o l on ge r a uth ori se d 24 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Do not refrigerate or freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE A potentially dangerous amount of fentanyl remains in the system after use. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Incline Therapeutics Europe Ltd 21 St. Thomas Street Bristol BS1 6JS United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1050/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted Me dic ina l p rod uc t n o l on ge r a uth ori se d 25 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS TRAY LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION IONSYS 40 micrograms per dose transdermal system Fentanyl Transdermal use 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 80 doses This tray contains: 1 Drug Unit, 1 Controller. 6. OTHER Do not use if seal on the tray or the sachet containing the drug unit is broken or damaged. Do not store above 25°C. Do not refrigerate or freeze. See package leaflet for disposal information. Me dic ina l p rod uc t n o l on ge r a uth ori se d 26 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SACHET LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION IONSYS 40 micrograms per dose transdermal system Fentanyl Transdermal use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP Use immediately after opening. 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 80 doses 6. OTHER See package leaflet for disposal information. Tear at notch Me dic ina l p rod uc t n o l on ge r a uth ori se d 27 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS IONSYS DEVICE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION IONSYS Fentanyl 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE 4. BATCH NUMBER 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 28 B. PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 29 Package leaflet: Information for the Patient IONSYS 40 micrograms per dose transdermal system fentanyl Read all of this leaflet carefully before you start using this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, please ask your doctor or your nurse. • This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What IONSYS is and what it is used for 2. Before you use IONSYS 3. How to use IONSYS 4. Possible side effects 5. How to store IONSYS 6. Contents of the pack and other information 1. What IONSYS is and what it is used for What IONSYS is IONSYS is a transdermal system (to be applied on intact skin) that contains a strong analgesic (pain reliever) medicine called fentanyl. What IONSYS is used for IONSYS is used to treat short-term moderate to severe pain in adults after an operation. IONSYS is used in hospital only. How IONSYS works IONSYS is a small device applied to the skin of your upper arm or chest. It works by delivering fentanyl through your skin to relieve your pain. You must talk to a doctor if you do not feel better or if you feel worse. 2. What you need to know before you use IONSYS Do not use IONSYS: • if you are allergic (hypersensitive) to fentanyl, or any of the other ingredients of IONSYS (listed in section 6). • if you suffer from severe breathing problems or cystic fibrosis. Warnings and precautions Talk to your doctor or nurse before using IONSYS if: • you have a severe or persistent lung disease, or any breathing problems • you have a very slow heart rate, low blood pressure, or other serious heart problem • you have problems with your liver or kidneys • you have severe headaches, have had a significant head injury, or have a brain tumour Me dic ina l p rod uc t n o l on ge r a uth ori se d 30 • you have any difficulty hearing as you will need to be able to hear the device’s ‘beep(s)’ to know if it is working properly or if there is a problem • you have abnormally slow bowel movements or severe constipation • you have had a chest or upper abdominal operation • you are severely obese or have a condition called sleep apnoea that causes interrupted breathing during sleep and which can occur in severely obese individuals. Important things to be aware of IONSYS should be removed prior to certain procedures such as cardioversion (electrical current used to restore normal heart rhythm), defibrillation (electric shock given to the heart) or diathermy (electrical current used in physical therapy or surgery). IONSYS should also be removed prior to a magnetic resonance imaging (MRI) procedure, X-ray or CT scan. If you have a history of drug abuse, inform your doctor. If you have a genetic condition (polymorphism) which affects certain enzymes in your body (CYP3A4 and CYP3A5), inform your doctor. If you are an older patient your doctor will monitor you more carefully as IONSYS may affect you more than a younger patient. Children and adolescents IONSYS is not recommended for children and adolescents under 18 years of age due to the lack of data in these patients. Other medicines and IONSYS Tell your doctor or nurse if you are using, have recently used or might use any other medicines. Some medicines can affect the way IONSYS works, or make it more likely that you will have side effects. Tell your doctor or nurse if: • you are taking medicines that might make you sleepy such as sleeping tablets, tranquilisers, medicines for anxiety or medicines for allergies (anti-histamines); • you are taking muscle relaxants (prescribed for back pain), or if you are undergoing general anaesthesia; • you are taking medicines for HIV infection (such as ritonavir, nelfinavir, amprenavir or fosamprenavir); • you are taking medicines for fungal infections (such as ketoconazole, itraconazole or fluconazole); • you are taking medicines for bacterial infections (such as troleandomycin, clarithromycin or erythromycin); • you are taking medicines used to help treat nausea and vomiting (such as aprepitant); • you are taking medicines used for high blood pressure or heart problems (such as diltiazem and verapamil); • you are taking pain killers called partial agonists like buprenorphine, nalbuphine, pentazocine; • you are taking medicines for depression called monoamine-oxidase (MAO) inhibitors. Tell your doctor or nurse if you have taken them within the last 14 days before using IONSYS; • you are using medicines for topical use (i.e. medicines that are applied on the skin). IONSYS with food, drink and alcohol Do not drink alcohol or grapefruit juice whilst you are wearing IONSYS because it can increase the risk of experiencing dangerous side effects. Pregnancy and breast-feeding You must tell your doctor before using IONSYS if you are pregnant or planning to become pregnant. Your doctor will discuss the possible risks and potential benefits of using IONSYS while you are pregnant. Me dic ina l p rod uc t n o l on ge r a uth ori se d 31 IONSYS should not be administered during childbirth. If you are given IONSYS during childbirth your baby may need to be given an antidote when it is born. Prolonged treatment with fentanyl, the active substance in IONSYS, may cause withdrawal symptoms in the newborn baby. Do not use IONSYS if you are breast-feeding. Fentanyl can pass into the breast milk and may cause side effects to the breast-fed child. You should not start breast-feeding until the IONSYS system has been removed for 24 hours. Driving and using machines IONSYS may make you feel sleepy, dizzy or cause blurred vision. Do not drive, operate machines or power tools when you leave hospital if you experience any of these side effects. 3. How to use IONSYS Always use this medicine exactly as your doctor or nurse has told you. Check with your doctor or nurse if you are not sure about how to use IONSYS or forget your instructions. The recommended dose Each dose of IONSYS delivers 40 micrograms of fentanyl. You control your own treatment under the guidance of your doctor or nurse in hospital. IONSYS only delivers the medicine when you activate it, so you control how much medicine you receive. You can take a dose whenever you need it for your pain, or just before you do an activity that may increase your pain (such as physical therapy, getting out of bed, etc.). Each time you are given a new IONSYS you may find you initially need to have more doses to relieve your pain than later on during treatment. Duration of treatment Each IONSYS works for one day (24 hours) and contains 80 doses. IONSYS will stop working after one day (24 hours) or after 80 doses have been delivered, whichever one comes first. The green light will switch off and the number of doses delivered will flash on and off. No more doses can be delivered after this and IONSYS will be removed by your doctor or nurse. Your doctor or nurse will remove the IONSYS system before you leave hospital. After IONSYS has been removed, it may leave small reddish marks at the skin site. This is common, and nothing to worry about. The red area will fade over the next few days to a week. Using IONSYS • Do not let your family or friends start IONSYS for you. Only you know how much pain you are having, and only you should operate IONSYS to start a dose of medicine. To make sure you get the correct amount of medicine, press IONSYS as soon as you start to feel pain. • Do not touch the sticky side of IONSYS. This side of the system contains material called “gels” which you should not normally come into contact with. Swallowing or touching these gels may cause life-threatening breathing difficulties or death, even after you have stopped using the system and it has been removed. Do not let these touch your mouth or eyes. • If you do accidentally touch the gels on the underside of the system: - Alert a nurse or doctor right away - Rinse your hands with large amounts of water - Do not use soap, alcohol, or other solvents to remove the gels because they may increase the medicine’s ability to go through the skin. • The doctor or nurse will put IONSYS on your skin, and take it off or replace it when needed. Only let the doctor or nurse place or remove IONSYS. - Do not take it off or attempt to put it back on yourself. - Do not let the IONSYS system get wet because it could stop working or fall off. Me dic ina l p rod uc t n o l on ge r a uth ori se d 32 How to use IONSYS • The doctor or nurse will get IONSYS ready to use and attach it to your upper outer arm or chest. • The slow blinking green light means IONSYS is ready to dose. • To start a dose from IONSYS, press and release the dosing button twice within 3 seconds. You will know you have started a dose when you hear a beep. - You will know the dose is being delivered when the green light blinks faster. • Each dose will last for 10 minutes. IONSYS will ignore additional button presses during this 10-minute dosing period. • You will know the 10-minute dosing period is complete when the fast blinking green light becomes slow again. The digital display will show the number of doses that have been delivered. • IONSYS is ready to be used again and you may start another dose at any time you need it. However, only press the button when you need pain relief. You will hear IONSYS beep once each time you start a dose. If it beeps at any other time, or more than once, tell your doctor or nurse immediately. They will check that IONSYS is working properly. If you use more IONSYS than you should IONSYS is designed so that you can’t use too much, provided that only you operate it, and that only you use it when you need pain relief. If you do use more IONSYS than you should then you may experience shortness of breath, difficulty breathing, rapid and shallow breathing, or feeling faint. If you experience any of these symptoms then tell your doctor or nurse immediately. If you have any further questions on the use of this medicine, ask your doctor or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. If you feel faint or if you have difficulty in breathing while being treated with IONSYS, tell a doctor or nurse immediately. The following side effects may occur whilst using IONSYS: Very common (may affect more than 1 in 10 people) • feeling sick (nausea) or being sick (vomiting) • reddening of skin at the patch site Common (may affect up to 1 in 10 people) • dizziness • headache • itching skin • low blood pressure • difficulty sleeping • constipation, stomach pain • blue skin colour (lips and finger tips) • swelling, itching, irritation or blistering of skin at the patch site • inability to pass water (urinate) Me dic ina l p rod uc t n o l on ge r a uth ori se d 33 • fever Uncommon (may affect up to 1 in 100 people) • flushing • anaemia (low blood count) • decreased appetite • anxiety • abnormal dreams or hallucinations (seeing or hearing things that are not there) • feeling confused or agitated • severe headache (migraine) • nervousness • pins and needles sensation • sleepiness • blurred vision • looking pale, feeling low in energy or tired • fast or irregular heartbeat • shortness of breath or interruptions in breathing • cough, hiccups • rash • excessive sweating • fainting • dry mouth • passing water (urinating) less frequently than normal • indigestion • passing wind, difficulty passing stools • chills • back pain, pain in arms or legs • pain, bumps, or dry skin at the patch site • high blood pressure • fall in blood pressure when standing up • decreased bowel activity • slow breathing rate • body pain Rare (may affect up to 1 in 1,000 people) • sneezing, itchiness and blocked or runny nose • low calcium/glucose/potassium in blood serum • depression, abnormal thoughts • abnormal sense of taste • reduced sense of touch or sensation • vertigo • slow heart beat • lung disease • swelling of the abdomen, diarrhoea, burping/belching • tightness/tension in muscles, muscle pain • pain when urinating • chest pain, feeling of general discomfort or uneasiness • tingling, prickling, swelling or pain at site of IONSYS application • complications in wound healing • fluid retention/swelling in the body Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Me dic ina l p rod uc t n o l on ge r a uth ori se d 34 Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store IONSYS Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton, or tray or sachet label, after “EXP”. The expiry date refers to the last day of that month. Do not store above 25°C. Do not refrigerate or freeze. The hospital staff will store IONSYS. The used IONSYS will be disposed of by medical staff. 6. Contents of the pack and other information What IONSYS contains The active substance in IONSYS is fentanyl hydrochloride. Each IONSYS system contains fentanyl hydrochloride equivalent to 9.7 mg of fentanyl and delivers 40 micrograms fentanyl per dose, to a maximum of 80 doses (3.2 mg/24 hours). The other ingredients are: bottom housing unit: glycol-modified polyethylene terephthalate anode hydrogel: polacrilin, purified water, sodium hydroxide, polyvinyl alcohol cathode hydrogel: purified water, sodium chloride, sodium citrate, polyvinyl alcohol, anhydrous citric acid, cetylpyridinium chloride anode electrode: layers of silver foil and electrically conductive adhesive tape cathode electrode: layers of polyisobutylene/silver chloride/carbon black composite material, silver foil, and electrically conductive adhesive tape skin adhesive: polybutene, polyisobutylene, and rosin ester protective liner: polyester film coated on one side with silicone. What IONSYS looks like and contents of the pack IONSYS is a transdermal system and is made up of an electronic controller (the top housing) and a drug unit (the red bottom housing). The controller is made of white plastic with the identifier “IONSYS” and has a digital display, a light window, and a dosing button. The drug unit is blue on the side that connects to the controller and has a red bottom housing containing the hydrogels, one of which contains the fentanyl hydrochloride. Each IONSYS carton contains 6 systems. Marketing Authorisation Holder Incline Therapeutics Europe Ltd 21 St. Thomas Street Bristol BS1 6JS United Kingdom Tel: +44 (0)800 587 4149 or +44 (0)203 684 6344 Email: medical.information@themedco.com Manufacturer Penn Pharmaceutical Services Ltd Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 35 23-24 Tafarnaubach Industrial Estate Tredegar Gwent, South Wales NP22 3AA United Kingdom This leaflet was last revised in MM/YYYY Other sources of information Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu/. --------------------------------------------------------------------------------------------------------------------------- Information for the Healthcare Professional: Instructions for use and disposal IONSYS (fentanyl 40 micrograms per dose transdermal system, maximum of 80 doses (3.2 mg/24 hours)). For single use only. IONSYS should not be used if the seal on the tray or the sachet containing the drug unit is broken or damaged. IONSYS will operate for 24 hours after it is applied or for 80 doses, whichever comes first, and will then become inoperative. Refer to the Summary of Product of Characteristics (SmPC) for more information about IONSYS. 1. Preparation of the Application Site • Only 1 IONSYS system should be applied at any given time. • Choose healthy, unbroken skin (non-irritated and non- irradiated skin) site on the chest or upper outer arm ONLY. IONSYS should not be placed on abnormal skin sites, such as scars, burns, and tattoos, or on skin on which topical medicines have been applied. • Excessive hair at the application site should be clipped (not shaved as this can irritate the skin) before application. IONSYS should not be applied to a previously used skin site. • The application site should be wiped with a standard alcohol swab and the skin should be allowed to dry completely before IONSYS is applied. No soaps, oils, lotions, or any other agents that might irritate the skin or alter its absorption characteristics, should be used to clean the application site. • When replacing an IONSYS system, the new system must be applied to a different site on the chest or upper outer arm. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 36 2. Assembly of IONSYS Complete these steps before applying IONSYS to the patient: • Gloves should be worn during the assembly/handling of IONSYS. Open the tray by peeling back the tray lid. Remove the sachet and the controller. Open the sachet containing the drug unit starting at the pre-cut notch and then carefully tearing along the top of the sachet. • Remove the drug unit from the sachet and place on a hard, flat surface. • Align the matching shapes of the controller and the drug unit and firmly press the two parts together at both ends. • Once assembled, the digital display of the controller will complete a short self-test during which there will an audible beep, the red light will flash once, and the digital display will flash the number “88”. At the end of the self-test, the display will show the number “0” and a green light will flash at a slow rate to indicate IONSYS is ready for application. Me dic ina l p rod uc t n o l on ge r a uth ori se d 37 3. Application of IONSYS • Remove and discard the clear plastic liner covering the adhesive. Take care not to touch the hydrogels. • Press IONSYS firmly in place for at least 15 seconds with the sticky side down on the skin of the chest or upper arm of the patient. Apply pressure with the fingers around the outer edges to ensure adhesion to the skin site. Do not press the dosing button. • If at any point during use IONSYS loosens from the skin, a non-allergenic tape may be used to secure the edges to ensure complete contact with the skin. When applying tape, care should be taken not to tape over the light window, the digital display, or the dosing button. • Each IONSYS may be used for 24 hours from the time of assembly or until 80 doses have been administered, whichever comes first. IONSYS will then shut down and will not deliver any further doses. If additional opioid analgesia is required, a new IONSYS should be applied to a different skin site, after removal and disposal of the previous IONSYS. • Patients should not wear more than one IONSYS at the same time. A used IONSYS should not be reapplied to patients. 4. Instructing the patient how to use IONSYS Remember that only the patient may touch the dosing button. Tell your patient the following: • The slow blinking green light means IONSYS is ready to dose. • To start a dose, press and release the dosing button 2 times within 3 seconds. You will hear one single beep upon successful dose initiation. • You will know the dose is being delivered when you see the fast blinking green light. • IONSYS will ignore any button presses during the 10-minute dosing period. • You will know the 10-minute dose is complete when the fast blinking green light returns to a slow blinking green light. • Call your doctor or nurse if you hear additional beeps. Me dic ina l p rod uc t n o l on ge r a uth ori se d 38 5. Removal and disposal of IONSYS See also instructions in SmPC Section 6.6. • Gloves must be worn while removing IONSYS from the skin and care should be taken to avoid touching the hydrogels. If the fentanyl hydrogel contacts the skin during removal, the contact area should be thoroughly rinsed with water without using any soap. • IONSYS may be removed at any time. However, once it has been removed, the same IONSYS should not be reapplied. • At the end of 24 hours of use, or after 80 doses have been delivered, remove IONSYS by gently lifting the red tab and loosening it from the skin application site. If the patient requires additional or continuation of pain relief, a new IONSYS may be applied to a new skin site on the upper outer arm or chest. • Hold the controller in one hand and pull the red tab with the other hand to separate the hydrogel housing from the system. • Fold the hydrogel housing in half with the sticky side facing in. • Dispose of the folded hydrogel housing in accordance with local requirements for opioid medicinal products • Dispose of remainder of the system, containing electronics, according to hospital procedures for battery waste. IONSYS Troubleshooting Each IONSYS is designed to deliver up to 80 10-minute doses of fentanyl over a period of 24 hours. The table below represents the different error messages that may occur, together with the probable cause and the action to be taken. Error message/feedback Probable cause Action required Low battery or defective system 1. Do not use the system. 2. Dispose of system per above Step 5 - Removal and Disposal of IONSYS. 3. Place a new system on a different skin site. Poor skin contact 1. If IONSYS appears to be loose or lifting from the skin, secure it to patient’s skin by pressing the edges firmly or by applying non-allergenic tape. 2. If using tape, apply it along the edges of IONSYS system, do not cover the dosing button or display. 3. If system beeps again, then remove and Me dic ina l p rod uc t n o l on ge r a uth ori se d 39 dispose of system, and place a new system on a different skin site. System error 1. Remove system from patient. 2. Hold down dosing button until beeping stops and display goes blank. 3. Dispose of system per above Step 5 - Removal and Disposal of IONSYS. 4. Place a new system on a different skin site. End of use at 24 hours or 80 doses 1. Remove system from patient. 2. Hold down dosing button until display goes blank. 3. Dispose of system per above Step 5 - Removal and Disposal of IONSYS. 4. Place a new system on a different skin site. If device failure or malfunction is suspected by a healthcare professional, IONSYS should be immediately removed from the patient and The Medicines Company contacted straightaway. The healthcare professional must ensure the patient understands that if they suspect a device failure or malfunction, they must inform a healthcare professional immediately. Me dic ina l p rod uc t n o l on ge r a uth ori se d SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what ionsys is and what it is used for', 'Section_Content': 'what ionsys is ionsys is a transdermal system (to be applied on intact skin) that contains a strong analgesic (pain reliever) medicine called fentanyl. what ionsys is used for ionsys is used to treat short-term moderate to severe pain in adults after an operation. ionsys is used in hospital only. how ionsys works ionsys is a small device applied to the skin of your upper arm or chest. it works by delivering fentanyl through your skin to relieve your pain. you must talk to a doctor if you do not feel better or if you feel worse.', 'Entity_Recognition': [{'Text': 'ionsys', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a transdermal system', 'Type': 'TREATMENT', 'BeginOffset': 25, 'EndOffset': 45}, {'Id': 0, 'BeginOffset': 71, 'EndOffset': 75, 'Score': 0.946945309638977, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a strong analgesic (pain reliever', 'Type': 'TREATMENT', 'BeginOffset': 91, 'EndOffset': 124}, {'Id': 6, 'BeginOffset': 142, 'EndOffset': 150, 'Score': 0.9988995790481567, 'Text': 'fentanyl', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ionsys', 'Type': 'TREATMENT', 'BeginOffset': 176, 'EndOffset': 182}, {'Text': 'short-term moderate to severe pain', 'Type': 'PROBLEM', 'BeginOffset': 200, 'EndOffset': 234}, {'Text': 'an operation', 'Type': 'TREATMENT', 'BeginOffset': 251, 'EndOffset': 263}, {'Text': 'a small device', 'Type': 'TREATMENT', 'BeginOffset': 325, 'EndOffset': 339}, {'Id': 1, 'BeginOffset': 355, 'EndOffset': 359, 'Score': 0.967990517616272, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 3, 'BeginOffset': 374, 'EndOffset': 377, 'Score': 0.9948634505271912, 'Text': 'arm', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 4, 'BeginOffset': 381, 'EndOffset': 386, 'Score': 0.9935176372528076, 'Text': 'chest', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 7, 'BeginOffset': 411, 'EndOffset': 419, 'Score': 0.997289776802063, 'Text': 'fentanyl', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 433, 'EndOffset': 437, 'Score': 0.9788309931755066, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your pain', 'Type': 'PROBLEM', 'BeginOffset': 449, 'EndOffset': 458}, {'Id': 11, 'BeginOffset': 522, 'EndOffset': 532, 'Score': 0.355691522359848, 'Text': 'feel worse', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8459420204162598}]}]}

{'Title': '2. before you use ionsys', 'Section_Content': "do not use ionsys: if you are allergic (hypersensitive) to fentanyl, or any of the other ingredients of ionsys (listed in section 6). if you suffer from severe breathing problems or cystic fibrosis. warnings and precautions talk to your doctor or nurse before using ionsys if: you have a severe or persistent lung disease, or any breathing problems you have a very slow heart rate, low blood pressure, or other serious heart problem you have problems with your liver or kidneys you have severe headaches, have had a significant head injury, or have a brain tumour 30 you have any difficulty hearing as you will need to be able to hear the device's 'beep(s)' to know if it is working properly or if there is a problem you have abnormally slow bowel movements or severe constipation you have had a chest or upper abdominal operation you are severely obese or have a condition called sleep apnoea that causes interrupted breathing during sleep and which can occur in severely obese individuals. important things to be aware of ionsys should be removed prior to certain procedures such as cardioversion (electrical current used to restore normal heart rhythm), defibrillation (electric shock given to the heart) or diathermy (electrical current used in physical therapy or surgery). ionsys should also be removed prior to a magnetic resonance imaging (mri) procedure, x-ray or ct scan. if you have a history of drug abuse, inform your doctor. if you have a genetic condition (polymorphism) which affects certain enzymes in your body (cyp3a4 and cyp3a5), inform your doctor. if you are an older patient your doctor will monitor you more carefully as ionsys may affect you more than a younger patient. children and adolescents ionsys is not recommended for children and adolescents under 18 years of age due to the lack of data in these patients. other medicines and ionsys tell your doctor or nurse if you are using, have recently used or might use any other medicines. some medicines can affect the way ionsys works, or make it more likely that you will have side effects. tell your doctor or nurse if: you are taking medicines that might make you sleepy such as sleeping tablets, tranquilisers, medicines for anxiety or medicines for allergies (anti-histamines); you are taking muscle relaxants (prescribed for back pain), or if you are undergoing general anaesthesia; you are taking medicines for hiv infection (such as ritonavir, nelfinavir, amprenavir or fosamprenavir); you are taking medicines for fungal infections (such as ketoconazole, itraconazole or fluconazole); you are taking medicines for bacterial infections (such as troleandomycin, clarithromycin or erythromycin); you are taking medicines used to help treat nausea and vomiting (such as aprepitant); you are taking medicines used for high blood pressure or heart problems (such as diltiazem and verapamil); you are taking pain killers called partial agonists like buprenorphine, nalbuphine, pentazocine; you are taking medicines for depression called monoamine-oxidase (mao) inhibitors. tell your doctor or nurse if you have taken them within the last 14 days before using ionsys; you are using medicines for topical use (i.e. medicines that are applied on the skin). ionsys with food, drink and alcohol do not drink alcohol or grapefruit juice whilst you are wearing ionsys because it can increase the risk of experiencing dangerous side effects. pregnancy and breast-feeding you must tell your doctor before using ionsys if you are pregnant or planning to become pregnant. your doctor will discuss the possible risks and potential benefits of using ionsys while you are pregnant. ionsys should not be administered during childbirth. if you are given ionsys during childbirth your baby may need to be given an antidote when it is born. prolonged treatment with fentanyl, the active substance in ionsys, may cause withdrawal symptoms in the newborn baby. do not use ionsys if you are breast-feeding. fentanyl can pass into the breast milk and may cause side effects to the breast-fed child. you should not start breast-feeding until the ionsys system has been removed for 24 hours. driving and using machines ionsys may make you feel sleepy, dizzy or cause blurred vision. do not drive, operate machines or power tools when you leave hospital if you experience any of these side effects.", 'Entity_Recognition': [{'Text': 'ionsys', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 30, 'EndOffset': 38}, {'Id': 13, 'BeginOffset': 40, 'EndOffset': 54, 'Score': 0.7425245046615601, 'Text': 'hypersensitive', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 59, 'EndOffset': 67, 'Score': 0.997685432434082, 'Text': 'fentanyl', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'severe breathing problems', 'Type': 'PROBLEM', 'BeginOffset': 153, 'EndOffset': 178}, {'Id': 15, 'BeginOffset': 182, 'EndOffset': 197, 'Score': 0.8861908316612244, 'Text': 'cystic fibrosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7348476648330688}]}, {'Text': 'a severe or persistent lung disease', 'Type': 'PROBLEM', 'BeginOffset': 286, 'EndOffset': 321}, {'Text': 'any breathing problems', 'Type': 'PROBLEM', 'BeginOffset': 326, 'EndOffset': 348}, {'Text': 'a very slow heart rate', 'Type': 'PROBLEM', 'BeginOffset': 358, 'EndOffset': 380}, {'Id': 20, 'BeginOffset': 382, 'EndOffset': 400, 'Score': 0.7638998627662659, 'Text': 'low blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8067878484725952}], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.8319775462150574, 'RelationshipScore': 0.5293042063713074, 'RelationshipType': 'ACUITY', 'Id': 16, 'BeginOffset': 298, 'EndOffset': 308, 'Text': 'persistent', 'Category': 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{'Title': '3. how to use ionsys', 'Section_Content': 'always use this medicine exactly as your doctor or nurse has told you. check with your doctor or nurse if you are not sure about how to use ionsys or forget your instructions. the recommended dose each dose of ionsys delivers 40 micrograms of fentanyl. you control your own treatment under the guidance of your doctor or nurse in hospital. ionsys only delivers the medicine when you activate it, so you control how much medicine you receive. you can take a dose whenever you need it for your pain, or just before you do an activity that may increase your pain (such as physical therapy, getting out of bed, etc.). each time you are given a new ionsys you may find you initially need to have more doses to relieve your pain than later on during treatment. duration of treatment each ionsys works for one day (24 hours) and contains 80 doses. ionsys will stop working after one day (24 hours) or after 80 doses have been delivered, whichever one comes first. the green light will switch off and the number of doses delivered will flash on and off. no more doses can be delivered after this and ionsys will be removed by your doctor or nurse. your doctor or nurse will remove the ionsys system before you leave hospital. after ionsys has been removed, it may leave small reddish marks at the skin site. this is common, and nothing to worry about. the red area will fade over the next few days to a week. using ionsys do not let your family or friends start ionsys for you. only you know how much pain you are having, and only you should operate ionsys to start a dose of medicine. to make sure you get the correct amount of medicine, press ionsys as soon as you start to feel pain. do not touch the sticky side of ionsys. this side of the system contains material called "gels" which you should not normally come into contact with. swallowing or touching these gels may cause life-threatening breathing difficulties or death, even after you have stopped using the system and it has been removed. do not let these touch your mouth or eyes. if you do accidentally touch the gels on the underside of the system: - alert a nurse or doctor right away - rinse your hands with large amounts of water - do not use soap, alcohol, or other solvents to remove the gels because they may increase the medicine\'s ability to go through the skin. the doctor or nurse will put ionsys on your skin, and take it off or replace it when needed. only let the doctor or nurse place or remove ionsys. - do not take it off or attempt to put it back on yourself. - do not let the ionsys system get wet because it could stop working or fall off. how to use ionsys the doctor or nurse will get ionsys ready to use and attach it to your upper outer arm or chest. the slow blinking green light means ionsys is ready to dose. to start a dose from ionsys, press and release the dosing button twice within 3 seconds. you will know you have started a dose when you hear a beep. - you will know the dose is being delivered when the green light blinks faster. each dose will last for 10 minutes. ionsys will ignore additional button presses during this 10-minute dosing period. you will know the 10-minute dosing period is complete when the fast blinking green light becomes slow again. the digital display will show the number of doses that have been delivered. ionsys is ready to be used again and you may start another dose at any time you need it. however, only press the button when you need pain relief. you will hear ionsys beep once each time you start a dose. if it beeps at any other time, or more than once, tell your doctor or nurse immediately. they will check that ionsys is working properly. if you use more ionsys than you should ionsys is designed so that you can\'t use too much, provided that only you operate it, and that only you use it when you need pain relief. if you do use more ionsys than you should then you may experience shortness of breath, difficulty 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. if you feel faint or if you have difficulty in breathing while being treated with ionsys, tell a doctor or nurse immediately. the following side effects may occur whilst using ionsys: very common (may affect more than 1 in 10 people) feeling sick (nausea) or being sick (vomiting) reddening of skin at the patch site common (may affect up to 1 in 10 people) dizziness headache itching skin low blood pressure difficulty sleeping constipation, stomach pain blue skin colour (lips and finger tips) swelling, itching, irritation or blistering of skin at the patch site inability to pass water (urinate) 33 fever uncommon (may affect up to 1 in 100 people) flushing anaemia (low blood count) decreased appetite anxiety abnormal dreams or hallucinations (seeing or hearing things that are not there) feeling confused or agitated severe headache (migraine) nervousness pins and needles sensation sleepiness blurred vision looking pale, feeling low in energy or tired fast or irregular heartbeat shortness of breath or interruptions in breathing cough, hiccups rash excessive sweating fainting dry mouth passing water (urinating) less frequently than normal indigestion passing wind, difficulty passing stools chills back pain, pain in arms or legs pain, bumps, or dry skin at the patch site high blood pressure fall in blood pressure when standing up decreased bowel activity slow breathing rate body pain rare (may affect up to 1 in 1,000 people) sneezing, itchiness and blocked or runny nose low calcium/glucose/potassium in blood serum depression, abnormal thoughts abnormal sense of taste reduced sense of touch or sensation vertigo slow heart beat lung disease swelling of the abdomen, diarrhoea, burping/belching tightness/tension in muscles, muscle pain pain when urinating chest pain, feeling of general discomfort or uneasiness tingling, prickling, swelling or pain at site of ionsys application complications in wound healing fluid retention/swelling in the body reporting of side effects if you get any side effects, talk to your doctor or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in 34 appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'ionsys', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 24, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9652129411697388, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7992855906486511}]}, {'Id': 25, 'BeginOffset': 99, 'EndOffset': 109, 'Score': 0.4953838884830475, 'Text': 'feel faint', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9313424825668335}]}, {'Id': 26, 'BeginOffset': 125, 'EndOffset': 148, 'Score': 0.9880678653717041, 'Text': 'difficulty in breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9422386884689331}]}, {'Id': 27, 'BeginOffset': 232, 'EndOffset': 244, 'Score': 0.8702688217163086, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8537691235542297}]}, {'Id': 28, 'BeginOffset': 293, 'EndOffset': 299, 'Score': 0.3474710285663605, 'Text': 'affect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 310, 'EndOffset': 311}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 315, 'EndOffset': 317}, {'Id': 29, 'BeginOffset': 326, 'EndOffset': 338, 'Score': 0.6749899387359619, 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0.9814963936805725, 'Text': 'sneezing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9817388653755188}]}, {'Id': 96, 'BeginOffset': 1544, 'EndOffset': 1553, 'Score': 0.9962129592895508, 'Text': 'itchiness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9788819551467896}]}, {'Id': 97, 'BeginOffset': 1558, 'EndOffset': 1565, 'Score': 0.6641970276832581, 'Text': 'blocked', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7271815538406372}]}, {'Id': 98, 'BeginOffset': 1569, 'EndOffset': 1579, 'Score': 0.9157959222793579, 'Text': 'runny nose', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 99, 'BeginOffset': 1592, 'EndOffset': 1624, 'Score': 0.4302210807800293, 'Text': 'glucose/potassium in blood serum', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4885767996311188}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.8598213791847229, 'RelationshipScore': 0.4293201267719269, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 16, 'BeginOffset': 1575, 'EndOffset': 1579, 'Text': 'nose', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'abnormal thoughts abnormal sense of taste', 'Type': 'PROBLEM', 'BeginOffset': 1637, 'EndOffset': 1678}, {'Id': 103, 'BeginOffset': 1687, 'EndOffset': 1714, 'Score': 0.942351222038269, 'Text': 'sense of touch or sensation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9905250668525696}]}, {'Text': 'slow heart beat lung disease swelling of the abdomen', 'Type': 'PROBLEM', 'BeginOffset': 1723, 'EndOffset': 1775}, {'Id': 108, 'BeginOffset': 1777, 'EndOffset': 1786, 'Score': 0.9950395226478577, 'Text': 'diarrhoea', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9684816002845764}]}, {'Id': 109, 'BeginOffset': 1788, 'EndOffset': 1795, 'Score': 0.9943087697029114, 'Text': 'burping', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9855889678001404}]}, {'Text': 'belching tightness', 'Type': 'PROBLEM', 'BeginOffset': 1796, 'EndOffset': 1814}, {'Text': 'tension in muscles', 'Type': 'PROBLEM', 'BeginOffset': 1815, 'EndOffset': 1833}, {'Text': 'muscle pain pain', 'Type': 'PROBLEM', 'BeginOffset': 1835, 'EndOffset': 1851}, {'Id': 115, 'BeginOffset': 1867, 'EndOffset': 1877, 'Score': 0.7286356687545776, 'Text': 'chest pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9758314490318298}]}, {'Id': 116, 'BeginOffset': 1879, 'EndOffset': 1908, 'Score': 0.6952670812606812, 'Text': 'feeling of general discomfort', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9881401062011719}]}, {'Id': 117, 'BeginOffset': 1912, 'EndOffset': 1922, 'Score': 0.8740739822387695, 'Text': 'uneasiness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9680987000465393}]}, {'Id': 118, 'BeginOffset': 1923, 'EndOffset': 1931, 'Score': 0.9957701563835144, 'Text': 'tingling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9698373079299927}]}, {'Id': 119, 'BeginOffset': 1933, 'EndOffset': 1942, 'Score': 0.9890015125274658, 'Text': 'prickling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9679173827171326}]}, {'Id': 120, 'BeginOffset': 1944, 'EndOffset': 1952, 'Score': 0.9990904331207275, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9834150671958923}]}, {'Id': 121, 'BeginOffset': 1956, 'EndOffset': 1960, 'Score': 0.9989683628082275, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9385315179824829}]}, {'Text': 'application complications', 'Type': 'PROBLEM', 'BeginOffset': 1979, 'EndOffset': 2004}, {'Text': 'wound healing', 'Type': 'PROBLEM', 'BeginOffset': 2008, 'EndOffset': 2021}, {'Id': 123, 'BeginOffset': 2022, 'EndOffset': 2037, 'Score': 0.8652437925338745, 'Text': 'fluid retention', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9182403683662415}]}, {'Id': 124, 'BeginOffset': 2038, 'EndOffset': 2046, 'Score': 0.9944567680358887, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.932616651058197}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.615882396697998, 'RelationshipScore': 0.9994543194770813, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 23, 'BeginOffset': 2054, 'EndOffset': 2058, 'Text': 'body', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 23, 'BeginOffset': 2054, 'EndOffset': 2058, 'Score': 0.615882396697998, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 125, 'BeginOffset': 2072, 'EndOffset': 2084, 'Score': 0.7644838094711304, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8549026846885681}]}, {'Id': 127, 'BeginOffset': 2100, 'EndOffset': 2112, 'Score': 0.7707457542419434, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4829976260662079}]}, {'Id': 128, 'BeginOffset': 2171, 'EndOffset': 2183, 'Score': 0.959983766078949, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.606188178062439}, {'Name': 'DIAGNOSIS', 'Score': 0.4205651581287384}]}, {'Id': 129, 'BeginOffset': 2232, 'EndOffset': 2244, 'Score': 0.8538393378257751, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6915053129196167}]}, {'Text': '34', 'Type': 'NUMBER', 'BeginOffset': 2298, 'EndOffset': 2300}, {'Id': 130, 'BeginOffset': 2326, 'EndOffset': 2338, 'Score': 0.8061902523040771, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6854099631309509}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2394, 'EndOffset': 2407}]}

{'Title': '5. how to store ionsys', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton, or tray or sachet label, after "exp". the expiry date refers to the last day of that month. do not store above 25. do not refrigerate or freeze. the hospital staff will store ionsys. the used ionsys will be disposed of by medical staff.', 'Entity_Recognition': [{'Text': 'ionsys', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '25.', 'Type': 'NUMBER', 'BeginOffset': 248, 'EndOffset': 251}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what ionsys contains the active substance in ionsys is fentanyl hydrochloride. each ionsys system contains fentanyl hydrochloride equivalent to 9.7 mg of fentanyl and delivers 40 micrograms fentanyl per dose, to a maximum of 80 doses (3.2 mg/24 hours). the other ingredients are: bottom housing unit: glycol-modified polyethylene terephthalate anode hydrogel: polacrilin, purified water, sodium hydroxide, polyvinyl alcohol cathode hydrogel: purified water, sodium chloride, sodium citrate, polyvinyl alcohol, anhydrous citric acid, cetylpyridinium chloride anode electrode: layers of silver foil and electrically conductive adhesive tape cathode electrode: layers of polyisobutylene/silver chloride/carbon black composite material, silver foil, and electrically conductive adhesive tape skin adhesive: polybutene, polyisobutylene, and rosin ester protective liner: polyester film coated on one side with silicone. what ionsys looks like and contents of the pack ionsys is a transdermal system and is made up of an electronic controller (the top housing) and a drug unit (the red bottom housing). the controller is made of white plastic with the identifier "ionsys" and has a digital display, a light window, and a dosing button. the drug unit is blue on the side that connects to the controller and has a red bottom housing containing the hydrogels, one of which contains the fentanyl hydrochloride. each ionsys carton contains 6 systems.', 'Entity_Recognition': [{'Text': 'ionsys', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 55, 'EndOffset': 77, 'Score': 0.9073413014411926, 'Text': 'fentanyl hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 107, 'EndOffset': 129, 'Score': 0.9269043803215027, 'Text': 'fentanyl hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9731289744377136, 'RelationshipScore': 0.7860292792320251, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 144, 'EndOffset': 150, 'Text': '9.7 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '9.7', 'Type': 'NUMBER', 'BeginOffset': 144, 'EndOffset': 147}, {'Id': 4, 'BeginOffset': 154, 'EndOffset': 162, 'Score': 0.9984851479530334, 'Text': 'fentanyl', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9731289744377136, 'RelationshipScore': 0.9999969005584717, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 144, 'EndOffset': 150, 'Text': '9.7 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 167, 'EndOffset': 175, 'Score': 0.19152463972568512, 'Text': 'delivers', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.347123384475708, 'RelationshipScore': 0.7091169357299805, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 225, 'EndOffset': 233, 'Text': '80 doses', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '40', 'Type': 'NUMBER', 'BeginOffset': 176, 'EndOffset': 178}, {'Id': 7, 'BeginOffset': 190, 'EndOffset': 198, 'Score': 0.9997469782829285, 'Text': 'fentanyl', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9211909770965576, 'RelationshipScore': 0.9999755620956421, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 176, 'EndOffset': 189, 'Text': '40 micrograms', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.347123384475708, 'RelationshipScore': 0.9997275471687317, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 225, 'EndOffset': 233, 'Text': '80 doses', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9084597229957581, 'RelationshipScore': 0.9997027516365051, 'RelationshipType': 'DOSAGE', 'Id': 9, 'BeginOffset': 235, 'EndOffset': 241, 'Text': '3.2 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '80', 'Type': 'NUMBER', 'BeginOffset': 225, 'EndOffset': 227}, {'Id': 10, 'BeginOffset': 301, 'EndOffset': 358, 'Score': 0.662411630153656, 'Text': 'glycol-modified polyethylene terephthalate anode hydrogel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 360, 'EndOffset': 370, 'Score': 0.9635166525840759, 'Text': 'polacrilin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 372, 'EndOffset': 386, 'Score': 0.9905027151107788, 'Text': 'purified water', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 388, 'EndOffset': 404, 'Score': 0.9989938139915466, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 406, 'EndOffset': 440, 'Score': 0.9462997913360596, 'Text': 'polyvinyl alcohol cathode hydrogel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 442, 'EndOffset': 456, 'Score': 0.9817997217178345, 'Text': 'purified water', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 458, 'EndOffset': 473, 'Score': 0.9995444416999817, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 475, 'EndOffset': 489, 'Score': 0.999019980430603, 'Text': 'sodium citrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 18, 'BeginOffset': 491, 'EndOffset': 508, 'Score': 0.9489664435386658, 'Text': 'polyvinyl alcohol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 19, 'BeginOffset': 510, 'EndOffset': 531, 'Score': 0.7817935347557068, 'Text': 'anhydrous citric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'cetylpyridinium chloride anode electrode', 'Type': 'TREATMENT', 'BeginOffset': 533, 'EndOffset': 573}, {'Text': 'layers of silver foil and electrically conductive adhesive tape cathode electrode', 'Type': 'TREATMENT', 'BeginOffset': 575, 'EndOffset': 656}, {'Text': 'polyisobutylene/silver chloride/carbon black composite material', 'Type': 'TREATMENT', 'BeginOffset': 668, 'EndOffset': 731}, {'Text': 'silver foil', 'Type': 'TREATMENT', 'BeginOffset': 733, 'EndOffset': 744}, {'Text': 'electrically conductive adhesive tape skin adhesive', 'Type': 'TREATMENT', 'BeginOffset': 750, 'EndOffset': 801}, {'Id': 21, 'BeginOffset': 803, 'EndOffset': 813, 'Score': 0.6419329643249512, 'Text': 'polybutene', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 22, 'BeginOffset': 815, 'EndOffset': 830, 'Score': 0.9717088341712952, 'Text': 'polyisobutylene', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'rosin ester protective liner', 'Type': 'TREATMENT', 'BeginOffset': 836, 'EndOffset': 864}, {'Text': 'polyester film coated', 'Type': 'TREATMENT', 'BeginOffset': 866, 'EndOffset': 887}, {'Id': 23, 'BeginOffset': 905, 'EndOffset': 913, 'Score': 0.5764039754867554, 'Text': 'silicone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a transdermal system', 'Type': 'TREATMENT', 'BeginOffset': 973, 'EndOffset': 993}, {'Text': 'a drug unit (the red bottom housing', 'Type': 'TREATMENT', 'BeginOffset': 1059, 'EndOffset': 1094}, {'Text': 'a light window', 'Type': 'TREATMENT', 'BeginOffset': 1193, 'EndOffset': 1207}, {'Text': 'a dosing button', 'Type': 'TREATMENT', 'BeginOffset': 1213, 'EndOffset': 1228}, {'Text': 'a red bottom housing', 'Type': 'TREATMENT', 'BeginOffset': 1304, 'EndOffset': 1324}, {'Text': 'the hydrogels', 'Type': 'TREATMENT', 'BeginOffset': 1336, 'EndOffset': 1349}, {'Text': 'the fentanyl hydrochloride', 'Type': 'TREATMENT', 'BeginOffset': 1373, 'EndOffset': 1399}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 1429, 'EndOffset': 1430}]}

7283A4BA0162D5172DA35B90FFE48B36

https://www.ema.europa.eu/documents/product-information/zyprexa-velotab-epar-product-information_en.pdf

Zyprexa Velotab

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 5 mg orodispersible tablets ZYPREXA VELOTAB 10 mg orodispersible tablets ZYPREXA VELOTAB 15 mg orodispersible tablets ZYPREXA VELOTAB 20 mg orodispersible tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ZYPREXA VELOTAB 5 mg orodispersible tablets Each orodispersible tablet contains 5 mg olanzapine. Excipients with known effect: Each orodispersible tablet contains 0.60 mg aspartame, 0.1125 mg sodium methyl parahydroxybenzoate, 0.0375 mg sodium propyl parahydroxybenzoate. ZYPREXA VELOTAB 10 mg orodispersible tablets Each orodispersible tablet contains 10 mg olanzapine. Excipients with known effect: Each orodispersible tablet contains 0.80 mg aspartame, 0.15 mg sodium methyl parahydroxybenzoate, 0.05 mg sodium propyl parahydroxybenzoate. ZYPREXA VELOTAB 15 mg orodispersible tablets Each orodispersible tablet contains 15 mg olanzapine. Excipients with known effect: Each orodispersible tablet contains 1.20 mg aspartame, 0.225 mg sodium methyl parahydroxybenzoate, 0.075 mg sodium propyl parahydroxybenzoate. ZYPREXA VELOTAB 20 mg orodispersible tablets Each orodispersible tablet contains 20 mg olanzapine. Excipients with known effect: Each orodispersible tablet contains 1.60 mg aspartame, 0.30 mg sodium methyl parahydroxybenzoate, 0.10 mg sodium propyl parahydroxybenzoate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Orodispersible tablet Yellow, round, freeze dried, rapid-dispersing preparation to be placed in the mouth or alternatively to be dispersed in water or other suitable beverage for administration. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adults Olanzapine is indicated for the treatment of schizophrenia. Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response. Olanzapine is indicated for the treatment of moderate to severe manic episode. In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder (see section 5.1). 4.2 Posology and method of administration Adults Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day. Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in combination therapy (see section 5.1). Preventing recurrence in bipolar disorder: The recommended starting dose is 10 mg/day. For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence at the same dose. If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimisation as needed), with supplementary therapy to treat mood symptoms, as clinically indicated. During treatment for schizophrenia, manic episode and recurrence prevention in bipolar disorder, daily dosage may subsequently be adjusted on the basis of individual clinical status within the range 5- 20 mg/day. An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours. Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual tapering of the dose should be considered when discontinuing olanzapine. ZYPREXA VELOTAB orodispersible tablet should be placed in the mouth, where it will rapidly disperse in saliva, so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately before administration. Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. It has the same dosage and frequency of administration as olanzapine coated tablets. Olanzapine orodispersible tablets may be used as an alternative to olanzapine coated tablets. Special populations Elderly A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant (see section 4.4). 4 Renal and/or hepatic impairment A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh Class A or B), the starting dose should be 5 mg and only increased with caution. Smokers The starting dose and dose range need not be routinely altered for non-smokers relative to smokers. The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.5). When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients. In cases where dose increments of 2.5 mg are considered necessary, ZYPREXA coated tablets should be used. (See sections 4.5 and 5.2.) Paediatric population Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterations has been reported in short term studies of adolescent patients than in studies of adult patients (see sections 4.4, 4.8, 5.1 and 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with known risk of narrow-angle glaucoma. 4.4 Special warnings and precautions for use During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period. Dementia-related psychosis and/or behavioural disturbances Olanzapine is not recommended for use in patients with dementia-related psychosis and/or behavioural disturbances because of an increase in mortality and the risk of cerebrovascular accident. In placebo- controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementia- related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5 %, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of these risk factors. In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3 % vs. 0.4 %, respectively). All olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials. 5 Parkinson's disease The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti- Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement. Neuroleptic Malignant Syndrome (NMS) NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued. Hyperglycaemia and diabetes Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported uncommonly, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic medicines, including ZYPREXA VELOTAB, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter. Lipid alterations Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo- controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipids disorders. Patients treated with any antipsychotic medicines, including ZYPREXA VELOTAB, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter. Anticholinergic activity While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions. Hepatic function Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic medicines. In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued. 6 Neutropenia Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see section 4.8). Discontinuation of treatment Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported rarely ( ≥ 0.01 % and < 0.1 %) when olanzapine is stopped abruptly. QT interval In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ≥ 500 milliseconds [msec] at any time post baseline in patients with baseline QTcF < 500 msec) were uncommon (0.1 % to 1 %) in patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. However, caution should be exercised when olanzapine is prescribed with medicines known to increase QTc interval, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia. Thromboembolism Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism all possible risk factors of VTE e.g. immobilisation of patients, should be identified and preventive measures undertaken. General CNS activity Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists. Seizures Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported. Tardive Dyskinesia In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment. Postural hypotension Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. It is recommended that blood pressure is measured periodically in patients over 65 years. Sudden cardiac death In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis. 7 Paediatric population Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels(see sections 4.8 and 5.1). Phenylalanine ZYPREXA VELOTAB orodispersible tablet contains aspartame, which is a source of phenylalanine. May be harmful for people with phenylketonuria. Mannitol ZYPREXA VELOTAB orodispersible tablet contains mannitol. Sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate Olanzapine orodispersible tablet contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate. These preservatives are known to cause urticaria. Generally, delayed type reactions such as contact dermatitis may occur, but rarely immediate reactions with bronchospasm may occur. 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults. Potential interactions affecting olanzapine Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine. Induction of CYP1A2 The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.2). Inhibition of CYP1A2 Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54 % in female non- smokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 % respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated. Decreased bioavailability Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60 % and should be taken at least 2 hours before or after olanzapine. Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine. Potential for olanzapine to affect other medicinal products Olanzapine may antagonise the effects of direct and indirect dopamine agonists. Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19). 8 Olanzapine showed no interaction when co-administered with lithium or biperiden. Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine. General CNS activity Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression. The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4). QTc interval Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4). 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. New born infants exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. Breast-feeding In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8 % of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed an infant if they are taking olanzapine. Fertility Effects on fertility are unknown (see section 5.3 for preclinical information). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Because olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles. 4.8 Undesirable effects Summary of the safety profile Adults The most frequently (seen in ≥ 1% of patients ) reported adverse reactions associated with the use of olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin, cholesterol, glucose and triglyceride levels (see section 4.4), glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema. 9 Tabulated list of adverse reactions The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the data available). Very common Common Uncommon Rare Not known Blood and the lymphatic system disorders Eosinophilia Leukopenia10 Neutropenia10 Thrombocytopenia11 Immune system disorders Hypersensitivity11 Metabolism and nutrition disorders Weight gain1 Elevated cholesterol levels2,3 Elevated glucose levels4 Elevated triglyceride levels2,5 Glucosuria Increased appetite Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4) 11 Hypothermia12 Nervous system disorders Somnolence Dizziness Akathisia6 Parkinsonism6 Dyskinesia6 Seizures where in most cases a history of seizures or risk factors for seizures were reported11 Dystonia (including oculogyration) 11 Tardive dyskinesia11 Amnesia 9 Dysarthria Stuttering11 Restless Legs Syndrome11 Neuroleptic malignant syndrome (see section 4.4)12 Discontinuation symptoms7, 12 Cardiac disorders Bradycardia QTc prolongation (see section 4.4) Ventricular tachycardia/fibrillation, sudden death (see section 4.4)11 Vascular disorders Orthostatic hypotension10 Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section 4.4) 10 Respiratory, thoracic and mediastinal disorders Epistaxis9 Gastrointestinal disorders Mild, transient anticholinergic effects including constipation and dry mouth Abdominal distension9 Salivary hypersecretion11 Pancreatitis11 Hepatobiliary disorders Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment (see section 4.4) Hepatitis (including hepatocellular, cholestatic or mixed liver injury)11 Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Musculoskeletal and connective tissue disorders Arthralgia9 Rhabdomyolysis11 Renal and urinary disorders Urinary incontinence, urinary retention Urinary hesitation11 Pregnancy, puerperium and perinatal conditions Drug withdrawal syndrome neonatal (see section 4.6) Reproductive system and breast disorders Erectile dysfunction in males Decreased libido in males and females Amenorrhea Breast enlargement Galactorrhea in females Gynaecomastia/breast enlargement in males Priapism12 General disorders and administration site conditions Asthenia Fatigue Oedema Pyrexia10 11 Investigations Elevated plasma prolactin levels8 Increased alkaline phosphatase10 High creatine phosphokinase11 High Gamma Glutamyltransferase 10 High uric acid 10 Increased total bilirubin 1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and 12.3 % respectively). 2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline. 3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common. 4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l). Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were very common. 5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high (≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - < 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common. 6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes. 7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly. 8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin value. In the majority of these patients the elevations were generally mild, and remained below two times the upper limit of normal range. 9 Adverse event identified from clinical trials in the Olanzapine Integrated Database. 10 As assessed by measured values from clinical trials in the Olanzapine Integrated Database. 11 Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database. 12 Adverse event identified from spontaneous post-marketing reporting with frequency estimated at the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database. 12 Long-term exposure (at least 48 weeks) The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months. Additional information on special populations In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see section 4.4). Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly. In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson’s disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo. In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (≥ 10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was also reported commonly. During treatment with olanzapine in combination with lithium or divalproex, an increase of ≥ 7% from baseline body weight occurred in 17.4% of patients during acute treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with bipolar disorder was associated with an increase of ≥ 7% from baseline body weight in 39.9% of patients. Paediatric population Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years. Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials. The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (≥ 7%) appears to occur more frequently in the adolescent population compared to adults with comparable exposures. The magnitude of weight gain and the proportion of adolescent patients who had clinically significant weight gain were greater with long-term exposure (at least 24 weeks) than with short-term exposure. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10). Metabolism and nutrition disorders Very common: Weight gain13, elevated triglyceride levels14, increased appetite. Common: Elevated cholesterol levels15 Nervous system disorders Very common: Sedation (including: hypersomnia, lethargy, somnolence). Gastrointestinal disorders Common: Dry mouth Hepatobiliary disorders Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). Investigations Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 13 13 Following short term treatment (median duration 22 days), weight gain ≥ 7% of baseline body weight (kg) was very common (40.6 %), ≥ 15% of baseline body weight was common (7.1 %) and ≥ 25 % was common (2.5 %). With long-term exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3 % gained ≥ 15 % and 29.1 % gained ≥ 25% of their baseline body weight. 14 Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high (≥ 1.467 mmol/l) and changes in fasting triglycerides from borderline at baseline (≥ 1.016 mmol/l - < 1.467 mmol/l) to high (≥ 1.467 mmol/l). 15 Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high (≥ 5.17 mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline at baseline (≥ 4.39 - < 5.17 mmol/l) to high (≥ 5.17 mmol/l) were very common. 16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Signs and symptoms Very common symptoms in overdose (> 10 % incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Other medically significant sequelae of overdose include delirium, convulsion, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (< 2 % of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine. Management There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated (i.e. gastric lavage, administration of activated charcoal). The concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50 to 60 %. Symptomatic treatment and monitoring of vital organ function should be instituted according to clinical presentation, including treatment of hypotension and circulatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta- agonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATC code N05A H03. 14 Pharmacodynamic effects Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems. In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki < 100 nM) for serotonin 5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5 HT2 than D2 activity in vivo models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an “anxiolytic” test. In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced a higher 5 HT2A than dopamine D2 receptor occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients. Clinical efficacy In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms. In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p= 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1). In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks. In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression. In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055). In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria. 15 Paediatric population Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data. 5.2 Pharmacokinetic properties Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine coated tablets. Absorption Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous administration has not been determined. Distribution The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1000 ng/ml. Olanzapine is bound predominantly to albumin and α1-acid-glycoprotein. Biotransformation Olanzapine is metabolized in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450- CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent olanzapine. Elimination After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender. In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 hr) and the clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44 patients with schizophrenia > 65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events. In female versus male subjects the mean elimination half life was somewhat prolonged (36.7 versus 32.3 hrs) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n=467) as in male patients (n=869). Renal impairment In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hr) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabelled olanzapine appeared in urine, principally as metabolites. Hepatic impairment A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of 16 orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic dysfunction had slightly increased systemic clearance and faster elimination half-time compared to subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis (4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %). Smoking In non-smoking versus smoking subjects (males and females) the mean elimination half-life was prolonged (38.6 versus 30.4 hr) and the clearance was reduced (18.6 versus 27.7 l/hr). The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals. In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations. Paediatric population Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents. 5.3 Preclinical safety data Acute (single-dose) toxicity Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness. Repeated-dose toxicity In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland. Haematologic toxicity: Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [area under the curve] is 12- to 15-fold greater than that of a man given a 12-mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow. Reproductive toxicity Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen. 17 Mutagenicity Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests. Carcinogenicity Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Gelatin Mannitol (E421) Aspartame (E951) Sodium methyl parahydroxybenzoate (E219) Sodium propyl parahydroxybenzoate (E217) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store in the original package in order to protect from light and moisture. 6.5 Nature and contents of container Aluminium blister strips in cartons of 28, 35, 56, 70 or 98 orodispersible tablets per carton. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands. 8. MARKETING AUTHORISATION NUMBER(S) EU/1/99/125/001 EU/1/99/125/002 EU/1/99/125/003 EU/1/99/125/004 EU/1/99/125/005 EU/1/99/125/006 EU/1/99/125/007 EU/1/99/125/008 18 EU/1/99/125/009 EU/1/99/125/010 EU/1/99/125/011 EU/1/99/125/012 EU/1/99/125/013 EU/1/99/125/014 EU/1/99/125/015 EU/1/99/125/016 EU/1/99/125/017 EU/1/99/125/018 EU/1/99/125/019 EU/1/99/125/020 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 3 February 2000 Date of latest renewal: 12 September 2006 10. DATE OF REVISION OF THE TEXT {MM/YYYY} Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 19 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 20 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorization holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached 21 ANNEX III LABELLING AND PACKAGE LEAFLET 22 A. LABELLING 23 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF ZYPREXA VELOTAB 5 mg ORODISPERSIBLE TABLETS 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 5 mg orodispersible tablets Olanzapine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each orodispersible tablet contains 5 mg olanzapine 3. LIST OF EXCIPIENTS Other ingredients: gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate (E219), sodium propyl parahydroxybenzoate (E217). 4. PHARMACEUTICAL FORM AND CONTENTS 28 orodispersible tablets 35 orodispersible tablets 56 orodispersible tablets 70 orodispersible tablets 98 orodispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use Oral use 1. Separate one blister cell from the strip. 2. Carefully peel off the backing. 3. Gently push the tablet out. 4. Put the tablet in your mouth 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 24 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands. 12. MARKETING AUTHORISATION NUMBER (S) EU/1/99/125/001 28 orodispersible tablets EU/1/99/125/009 35 orodispersible tablets EU/1/99/125/005 56 orodispersible tablets EU/1/99/125/013 70 orodispersible tablets EU/1/99/125/017 98 orodispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ZYPREXA VELOTAB 5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 25 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 26 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS ZYPREXA VELOTAB 5 mg ORODISPERSIBLE TABLETS: BLISTER FOIL LABEL 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 5 mg orodispersible tablets Olanzapine 2. NAME OF THE MARKETING AUTHORISATION HOLDER Lilly 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 27 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF ZYPREXA VELOTAB 10 mg ORODISPERSIBLE TABLETS 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 10 mg orodispersible tablets Olanzapine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each orodispersible tablet contains 10 mg olanzapine 3. LIST OF EXCIPIENTS Other ingredients: gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate (E219), sodium propyl parahydroxybenzoate (E217). 4. PHARMACEUTICAL FORM AND CONTENTS 28 orodispersible tablets 35 orodispersible tablets 56 orodispersible tablets 70 orodispersible tablets 98 orodispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use Oral use 1. Separate one blister cell from the strip. 2. Carefully peel off the backing. 3. Gently push the tablet out. 4. Put the tablet in your mouth 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 28 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands. 12. MARKETING AUTHORISATION NUMBER (S) EU/1/99/125/002 28 orodispersible tablets EU/1/99/125/010 35 orodispersible tablets EU/1/99/125/006 56 orodispersible tablets EU/1/99/125/014 70 orodispersible tablets EU/1/99/125/018 98 orodispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ZYPREXA VELOTAB 10 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 29 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 30 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS ZYPREXA VELOTAB 10 mg ORODISPERSIBLE TABLETS: BLISTER FOIL LABEL 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 10 mg orodispersible tablets Olanzapine 2. NAME OF THE MARKETING AUTHORISATION HOLDER Lilly 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 31 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF ZYPREXA VELOTAB 15 mg ORODISPERSIBLE TABLETS 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 15 mg orodispersible tablets Olanzapine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each orodispersible tablet contains 15 mg olanzapine 3. LIST OF EXCIPIENTS Other ingredients: gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate (E219), sodium propyl parahydroxybenzoate (E217). 4. PHARMACEUTICAL FORM AND CONTENTS 28 orodispersible tablets 35 orodispersible tablets 56 orodispersible tablets 70 orodispersible tablets 98 orodispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use Oral use 1. Separate one blister cell from the strip. 2. Carefully peel off the backing. 3. Gently push the tablet out. 4. Put the tablet in your mouth 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 32 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands. 12. MARKETING AUTHORISATION NUMBER (S) EU/1/99/125/003 28 orodispersible tablets EU/1/99/125/011 35 orodispersible tablets EU/1/99/125/007 56 orodispersible tablets EU/1/99/125/015 70 orodispersible tablets EU/1/99/125/019 98 orodispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ZYPREXA VELOTAB 15 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 33 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 34 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS ZYPREXA VELOTAB 15 mg ORODISPERSIBLE TABLETS: BLISTER FOIL LABEL 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 15 mg orodispersible tablets Olanzapine 2. NAME OF THE MARKETING AUTHORISATION HOLDER Lilly 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 35 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF ZYPREXA VELOTAB 20 mg ORODISPERSIBLE TABLETS 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 20 mg orodispersible tablets Olanzapine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each orodispersible tablet contains 20 mg olanzapine 3. LIST OF EXCIPIENTS Other ingredients: gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate (E219), sodium propyl parahydroxybenzoate (E217). 4. PHARMACEUTICAL FORM AND CONTENTS 28 orodispersible tablets 35 orodispersible tablets 56 orodispersible tablets 70 orodispersible tablets 98 orodispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 1. Separate one blister cell from the strip. 2. Carefully peel off the backing. 3. Gently push the tablet out. 4. Put the tablet in your mouth 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 36 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands. 12. MARKETING AUTHORISATION NUMBER (S) EU/1/99/125/004 28 orodispersible tablets EU/1/99/125/012 35 orodispersible tablets EU/1/99/125/008 56 orodispersible tablets EU/1/99/125/016 70 orodispersible tablets EU/1/99/125/020 98 orodispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ZYPREXA VELOTAB 20 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 37 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 38 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS ZYPREXA VELOTAB 20 mg ORODISPERSIBLE TABLETS: BLISTER FOIL LABEL 1. NAME OF THE MEDICINAL PRODUCT ZYPREXA VELOTAB 20 mg orodispersible tablets Olanzapine 2. NAME OF THE MARKETING AUTHORISATION HOLDER Lilly 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 39 B. PACKAGE LEAFLET 40 Package leaflet: Information for the user ZYPREXA VELOTAB 5 mg orodispersible tablets ZYPREXA VELOTAB 10 mg orodispersible tablets ZYPREXA VELOTAB 15 mg orodispersible tablets ZYPREXA VELOTAB 20 mg orodispersible tablets Olanzapine Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What ZYPREXA VELOTAB is and what it is used for 2. What you need to know before you take ZYPREXA VELOTAB 3. How to take ZYPREXA VELOTAB 4. Possible side effects 5. How to store ZYPREXA VELOTAB 6. Contents of the pack and other information 1. What ZYPREXA VELOTAB is and what it is used for ZYPREXA VELOTAB contains the active substance olanzapine. ZYPREXA VELOTAB belongs to a group of medicines called antipsychotics and is used to treat the following conditions: • Schizophrenia, a disease with symptoms such as hearing, seeing or sensing things which are not there, mistaken beliefs, unusual suspiciousness, and becoming withdrawn. People with this disease may also feel depressed, anxious or tense. • Moderate to severe manic episodes, a condition with symptoms of excitement or euphoria. ZYPREXA VELOTAB has been shown to prevent recurrence of these symptoms in patients with bipolar disorder whose manic episode has responded to olanzapine treatment. 2. What you need to know before you take ZYPREXA VELOTAB Do not take ZYPREXA VELOTAB • If you are allergic (hypersensitive) to olanzapine or any of the other ingredients of this medicine (listed in section 6). An allergic reaction may be recognised as a rash, itching, a swollen face, swollen lips or shortness of breath. If this has happened to you, tell your doctor. • If you have been previously diagnosed with eye problems such as certain kinds of glaucoma (increased pressure in the eye). Warnings and precautions Talk to your doctor or pharmacist before you take ZYPREXA VELOTAB • The use of ZYPREXA VELOTAB in elderly patients with dementia is not recommended as it may have serious side effects. • Medicines of this type may cause unusual movements mainly of the face or tongue. If this happens after you have been given ZYPREXA VELOTAB tell your doctor. 41 • Very rarely, medicines of this type cause a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness. If this happens, contact your doctor at once. • Weight gain has been seen in patients taking ZYPREXA VELOTAB. You and your doctor should check your weight regularly. Consider referral to a dietician or help with a diet plan if necessary. • High blood sugar and high levels of fat (triglycerides and cholesterol) have been seen in patients taking ZYPREXA VELOTAB. Your doctor should do blood tests to check blood sugar and certain fat levels before you start taking ZYPREXA VELOTAB and regularly during treatment. • Tell the doctor if you or someone else in your family has a history of blood clots, as medicines like these have been associated with the formation of blood clots. If you suffer from any of the following illnesses tell your doctor as soon as possible: • Stroke or “mini” stroke (temporary symptoms of stroke) • Parkinson’s disease • Prostate problems • A blocked intestine (Paralytic ileus) • Liver or kidney disease • Blood disorders • Heart disease • Diabetes • Seizures • If you know that you may have salt depletion as a result of prolonged severe diarrhoea and vomiting (being sick) or usage of diuretics (water tablets) If you suffer from dementia, you or your carer/relative should tell your doctor if you have ever had a stroke or “mini” stroke. As a routine precaution, if you are over 65 years your blood pressure may be monitored by your doctor. Children and adolescents ZYPREXA VELOTAB is not for patients who are under 18 years. Other medicines and ZYPREXA VELOTAB Only take other medicines while you are on ZYPREXA VELOTAB if your doctor tells you that you can. You might feel drowsy if ZYPREXA VELOTAB is taken in combination with antidepressants or medicines taken for anxiety or to help you sleep (tranquillisers). Tell your doctor if you are taking, have recently taken or might take any other medicines In particular, tell your doctor if you are taking: • medicines for Parkinson’s disease. • carbamazepine (an anti-epileptic and mood stabiliser), fluvoxamine (an antidepressant) or ciprofloxacin (an antibiotic) - it may be necessary to change your ZYPREXA VELOTAB dose. ZYPREXA VELOTAB with alcohol Do not drink any alcohol if you have been given ZYPREXA VELOTAB as together with alcohol it may make you feel drowsy. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. You should not be given this medicine when breast-feeding, as small amounts of ZYPREXA VELOTAB can pass into breast milk. 42 The following symptoms may occur in newborn babies, of mothers that have used ZYPREXA VELOTAB in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms you may need to contact your doctor. Driving and using machines There is a risk of feeling drowsy when you are given ZYPREXA VELOTAB. If this happens do not drive or operate any tools or machines. Tell your doctor. ZYPREXA VELOTAB contains aspartame, mannitol and sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate Patients who cannot take phenylalanine should note that ZYPREXA VELOTAB contains aspartame, which is a source of phenylalanine. May be harmful for people with phenylketonuria. Patients who cannot take mannitol should note that ZYPREXA VELOTAB contains mannitol. ZYPREXA VELOTAB contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate, which may cause an allergic reaction in some people. An allergic reaction may be recognised as a rash, itching or shortness of breath. This may occur immediately or some time after you take ZYPREXA VELOTAB. 3. How to take ZYPREXA VELOTAB Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Your doctor will tell you how many ZYPREXA VELOTAB tablets to take and how long you should continue to take them. The daily dose of ZYPREXA VELOTAB is between 5 mg and 20 mg. Consult your doctor if your symptoms return but do not stop taking ZYPREXA VELOTAB unless your doctor tells you to. You should take your ZYPREXA VELOTAB tablets once a day following the advice of your doctor. Try to take your tablets at the same time each day. It does not matter whether you take them with or without food. ZYPREXA VELOTAB orodispersible tablets are for oral use. ZYPREXA VELOTAB tablets break easily, so you should handle the tablets carefully. Do not handle the tablets with wet hands as the tablets may break up. 1. Hold the blister strip at the edges and separate one blister cell from the rest of the strip by gently tearing along the perforations around it. 2. Carefully peel off the backing. 3. Gently push the tablet out. 4. Put the tablet in your mouth. It will dissolve directly in your mouth, so that it can be easily swallowed. You can also place the tablet in a full glass or cup of water, orange juice, apple juice, milk or coffee, and stir. With some drinks, the mixture may change colour and possibly become cloudy. Drink it straight away. If you take more ZYPREXA VELOTAB than you should Patients who have taken more ZYPREXA VELOTAB than they should have experienced the following symptoms: rapid beating of the heart, agitation/aggressiveness, problems with speech, 43 unusual movements (especially of the face or tongue) and reduced level of consciousness. Other symptoms may be: acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness, slowing of the breathing rate, aspiration, high blood pressure or low blood pressure, abnormal rhythms of the heart. Contact your doctor or hospital straight away if you experience any of the above symptoms. Show the doctor your pack of tablets. If you forget to take ZYPREXA VELOTAB Take your tablets as soon as you remember. Do not take two doses in one day. If you stop taking ZYPREXA VELOTAB Do not stop taking your tablets just because you feel better. It is important that you carry on taking ZYPREXA VELOTAB for as long as your doctor tells you. If you suddenly stop taking ZYPREXA VELOTAB, symptoms such as sweating, unable to sleep, tremor, anxiety or nausea and vomiting might occur. Your doctor may suggest you to reduce the dose gradually before stopping treatment. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor immediately if you have: • unusual movement (a common side effect that may affect up to 1 in 10 people) mainly of the face or tongue; • blood clots in the veins (an uncommon side effect that may affect up to 1 in 100 people) especially in the legs (symptoms include swelling, pain, and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any of these symptoms seek medical advice immediately; • a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness (the frequency of this side effect cannot be estimated from the available data). Very common side effects (may affect more than 1 in 10 people) include weight gain; sleepiness; and increases in levels of prolactin in the blood. In the early stages of treatment, some people may feel dizzy or faint (with a slow heart rate), especially when getting up from a lying or sitting position. This will usually pass on its own but if it does not, tell your doctor. Common side effects (may affect up to 1 in 10 people) include changes in the levels of some blood cells, circulating fats and early in treatment, temporary increases in liver enzymes ; increases in the level of sugars in the blood and urine; increases in levels of uric acid and creatine phosphokinase in the blood; feeling more hungry; dizziness; restlessness; tremor; unusual movements (dyskinesias); constipation; dry mouth; rash; loss of strength; extreme tiredness; water retention leading to swelling of the hands, ankles or feet; fever, joint pain and sexual dysfunctions such as decreased libido in males and females or erectile dysfunction in males. Uncommon side effects (may affect up to 1 in 100 people) include hypersensitivity (e.g. swelling in the mouth and throat, itching, rash); diabetes or the worsening of diabetes, occasionally associated with ketoacidosis (ketones in the blood and urine) or coma; seizures, usually associated with a history of seizures (epilepsy); muscle stiffness or spasms ( including eye movements); restless legs syndrome; problems with speech; stuttering; slow heart rate; sensitivity to sunlight; bleeding from the nose; abdominal distension; drooling; memory loss or forgetfulness; urinary incontinence; lack of ability to urinate; hair loss; absence or decrease in menstrual periods; and changes in breasts in males and females such as an abnormal production of breast milk or abnormal growth. 44 Rare side effects (may affect up to 1 in 1000 people) include lowering of normal body temperature; abnormal rhythms of the heart; sudden unexplained death; inflammation of the pancreas causing severe stomach pain, fever and sickness; liver disease appearing as yellowing of the skin and white parts of the eyes; muscle disease presenting as unexplained aches and pains; and prolonged and/or painful erection. Very rare side effects include serious allergic reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). DRESS appears initially as flu-like symptoms with a rash on the face and then with an extended rash, high temperature, enlarged lymph nodes, increased levels of liver enzymes seen on blood tests and an increase in a type of white blood cells (eosinophilia). While taking olanzapine, elderly patients with dementia may suffer from stroke, pneumonia, urinary incontinence, falls, extreme tiredness, visual hallucinations, a rise in body temperature, redness of the skin and have trouble walking. Some fatal cases have been reported in this particular group of patients. In patients with Parkinson's disease ZYPREXA VELOTAB may worsen the symptoms. Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store ZYPREXA VELOTAB Keep this medicine out of sight and reach of children. Do not use this medicine after the expiry date, which is stated on the carton. ZYPREXA VELOTAB should be stored in its original pack in order to protect from light and moisture. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What ZYPREXA VELOTAB contains • The active substance is olanzapine. Each ZYPREXA VELOTAB orodispersible tablet contains either 5 mg, 10 mg, 15 mg or 20 mg of the active substance. The exact amount is shown on your ZYPREXA VELOTAB pack. • The other ingredients are - gelatin, mannitol (E421), aspartame (E951), sodium methyl parahydroxybenzoate (E219) and sodium propyl parahydroxybenzoate (E217). What ZYPREXA VELOTAB looks like and contents of the pack ZYPREXA VELOTAB 5 mg, 10 mg, 15 mg and 20 mg are yellow orodispersible tablets. Orodispersible tablet is the technical name for a tablet which dissolves directly in your mouth, so that it can be easily swallowed. ZYPREXA VELOTAB is available in packs containing 28, 35, 56, 70 or 98 tablets. Not all pack sizes may be marketed. 45 Marketing Authorisation Holder Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands. Manufacturer Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain. For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Eli Lilly Benelux S.A./N.V. Tél/Tel: + 32 (0)2 548 84 84 Lietuva Eli Lilly Lietuva Tel: + 370 (5) 2649600 България ТП "Ели Лили Недерланд" Б.В. - България Тел : + 359 2 491 41 40 Luxembourg/Luxemburg Eli Lilly Benelux S.A./N.V. Tél/Tel: + 32 (0)2 548 84 84 Česká republika Eli Lilly ČR, s.r.o. Tel: + 420 234 664 111 Magyarország Lilly Hungária Kft. Tel: + 36 1 328 5100 Danmark Eli Lilly Danmark A/S Tlf.: + 45 45 26 60 00 Malta Charles de Giorgio Ltd. Tel: + 356 25600 500 Deutschland Lilly Deutschland GmbH Tel: + 49 (0) 6172 273 2222 Nederland Eli Lilly Nederland B.V. Tel: + 31(0)30 6025800 Eesti Eli Lilly Nederland B.V. Tel: + 372 6817 280 Norge Eli Lilly Norge A.S Tlf: + 47 22 88 18 00 Ελλάδa ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε. Τηλ: + 30 210 629 4600 Österreich Eli Lilly Ges. m.b.H. Tel: + 43 (0) 1 711 780 España Lilly S.A. Tel: + 34 91 663 50 00 Polska Eli Lilly Polska Sp. z o.o. Tel: + 48 22 440 33 00 France Lilly France SAS Tél: + 33 (0) 1 55 49 34 34 Portugal Lilly Portugal Produtos Farmacêuticos, Lda Tel: + 351 21 412 66 00 Hrvatska Eli Lilly Hrvatska d.o.o. Tel: +385 1 2350 999 România Eli Lilly România S.R.L. Tel: + 40 21 4023000 Ireland Eli Lilly and Company (Ireland) Limited Tel: + 353 (0) 1 661 4377 Slovenija Eli Lilly farmacevtska družba, d.o.o Tel: + 386 (0)1 580 00 10 Ísland Icepharma hf. Sími: + 354 540 8000 Slovenská republika Eli Lilly Slovakia s.r.o. Tel: + 421 220 663 111 Italia Eli Lilly Italia S.p.A. Tel: + 39 055 42571 Suomi/Finland Oy Eli Lilly Finland Ab Puh/Tel: + 358 (0)9 8545 250 Κύπρος Phadisco Ltd Τηλ: + 357 22 715000 Sverige Eli Lilly Sweden AB Tel: + 46 (0)8 7378800 Latvija Eli Lilly (Suisse) S.A Pārstāvniecība Latvijā Tel: + 371 67364000 United Kingdom Eli Lilly and Company Limited Tel: + 44 (0) 1256 315000 46 This leaflet was last revised in {month XXXX} Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu http://www.ema.europa.eu/ http://www.ema.europa.eu/ 47 Annex IV Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s) 48 Scientific conclusions Taking into account the PRAC Assessment Report on the PSUR(s) for olanzapine, the scientific conclusions of CHMP are as follows: Following the review of case reports in the UK Sentinel database, the EudraVigilance database, and the literature, a signal for salivary hypersecretion with olanzapine was identified on 14 February 2019 by the Medicines and Healthcare products Regulatory Agency (MHRA) and validated by the PRAC. Based on signal analysis presented by the MAH including mechanistic plausibility, number of dechallenge/rechallenge cases and strong temporal relationship, the PRAC agrees that salivary hypersecretion may be associated with olanzapine and the adverse reaction salivary hypersecretion should be added to the product information. The CHMP agrees with the scientific conclusions made by the PRAC. Grounds for the variation to the terms of the marketing authorisation(s) On the basis of the scientific conclusions for olanzapine the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing olanzapine is unchanged subject to the proposed changes to the product information The CHMP recommends that the terms of the marketing authorisation(s) should be varied. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)

{'Title': '1. what zyprexa velotab is and what it is used for', 'Section_Content': 'zyprexa velotab contains the active substance olanzapine. zyprexa velotab belongs to a group of medicines called antipsychotics and is used to treat the following conditions: schizophrenia, a disease with symptoms such as hearing, seeing or sensing things which are not there, mistaken beliefs, unusual suspiciousness, and becoming withdrawn. people with this disease may also feel depressed, anxious or tense. moderate to severe manic episodes, a condition with symptoms of excitement or euphoria. zyprexa velotab has been shown to prevent recurrence of these symptoms in patients with bipolar disorder whose manic episode has responded to olanzapine treatment.', 'Entity_Recognition': [{'Text': 'zyprexa velotab', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'zyprexa velotab', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 15}, {'Text': 'the active substance olanzapine', 'Type': 'TREATMENT', 'BeginOffset': 25, 'EndOffset': 56}, {'Id': 3, 'BeginOffset': 58, 'EndOffset': 65, 'Score': 0.9626833200454712, 'Text': 'zyprexa', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 96, 'EndOffset': 105}, {'Id': 17, 'BeginOffset': 113, 'EndOffset': 127, 'Score': 0.3431752920150757, 'Text': 'antipsychotics', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 175, 'EndOffset': 188, 'Score': 0.9969890713691711, 'Text': 'schizophrenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9518405795097351}]}, {'Id': 7, 'BeginOffset': 192, 'EndOffset': 213, 'Score': 0.4736754894256592, 'Text': 'disease with symptoms', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.44585731625556946}]}, {'Text': 'hearing', 'Type': 'PROBLEM', 'BeginOffset': 222, 'EndOffset': 229}, {'Text': 'this disease', 'Type': 'PROBLEM', 'BeginOffset': 355, 'EndOffset': 367}, {'Id': 8, 'BeginOffset': 382, 'EndOffset': 391, 'Score': 0.9785290956497192, 'Text': 'depressed', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9083225727081299}]}, {'Id': 9, 'BeginOffset': 393, 'EndOffset': 400, 'Score': 0.9938285946846008, 'Text': 'anxious', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8700447082519531}]}, {'Id': 10, 'BeginOffset': 404, 'EndOffset': 409, 'Score': 0.8358750343322754, 'Text': 'tense', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8592584133148193}]}, {'Text': 'moderate to severe manic episodes', 'Type': 'PROBLEM', 'BeginOffset': 411, 'EndOffset': 444}, {'Text': 'symptoms', 'Type': 'PROBLEM', 'BeginOffset': 463, 'EndOffset': 471}, {'Id': 12, 'BeginOffset': 475, 'EndOffset': 485, 'Score': 0.9088391661643982, 'Text': 'excitement', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.769029438495636}]}, {'Id': 13, 'BeginOffset': 489, 'EndOffset': 497, 'Score': 0.957571268081665, 'Text': 'euphoria', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7654320597648621}]}, {'Text': 'zyprexa velotab', 'Type': 'TREATMENT', 'BeginOffset': 499, 'EndOffset': 514}, {'Id': 14, 'BeginOffset': 541, 'EndOffset': 551, 'Score': 0.2935267984867096, 'Text': 'recurrence', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'these symptoms', 'Type': 'PROBLEM', 'BeginOffset': 555, 'EndOffset': 569}, {'Id': 15, 'BeginOffset': 587, 'EndOffset': 603, 'Score': 0.9808521866798401, 'Text': 'bipolar disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9557281732559204}]}, {'Id': 16, 'BeginOffset': 610, 'EndOffset': 623, 'Score': 0.8829721212387085, 'Text': 'manic episode', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.642870306968689}]}, {'Text': 'olanzapine treatment', 'Type': 'TREATMENT', 'BeginOffset': 641, 'EndOffset': 661}]}

{'Title': '2. what you need to know before you take zyprexa velotab', 'Section_Content': 'do not take zyprexa velotab if you are allergic (hypersensitive) to olanzapine or any of the other ingredients of this medicine (listed in section 6). an allergic reaction may be recognised as a rash, itching, a swollen face, swollen lips or shortness of breath. if this has happened to you, tell your doctor. if you have been previously diagnosed with eye problems such as certain kinds of glaucoma (increased pressure in the eye). warnings and precautions talk to your doctor or pharmacist before you take zyprexa velotab the use of zyprexa velotab in elderly patients with dementia is not recommended as it may have serious side effects. medicines of this type may cause unusual movements mainly of the face or tongue. if this happens after you have been given zyprexa velotab tell your doctor. very rarely, medicines of this type cause a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness. if this happens, contact your doctor at once. weight gain has been seen in patients taking zyprexa velotab. you and your doctor should check your weight regularly. consider referral to a dietician or help with a diet plan if necessary. high blood sugar and high levels of fat (triglycerides and cholesterol) have been seen in patients taking zyprexa velotab. your doctor should do blood tests to check blood sugar and certain fat levels before you start taking zyprexa velotab and regularly during treatment. tell the doctor if you or someone else in your family has a history of blood clots, as medicines like these have been associated with the formation of blood clots. if you suffer from any of the following illnesses tell your doctor as soon as possible: stroke or "mini" stroke (temporary symptoms of stroke) parkinson\'s disease prostate problems a blocked intestine (paralytic ileus) liver or kidney disease blood disorders heart disease diabetes seizures if you know that you may have salt depletion as a result of prolonged severe diarrhoea and vomiting (being sick) or usage of diuretics (water tablets) if you suffer from dementia, you or your carer/relative should tell your doctor if you have ever had a stroke or "mini" stroke. as a routine precaution, if you are over 65 years your blood pressure may be monitored by your doctor. children and adolescents zyprexa velotab is not for patients who are under 18 years. other medicines and zyprexa velotab only take other medicines while you are on zyprexa velotab if your doctor tells you that you can. you might feel drowsy if zyprexa velotab is taken in combination with antidepressants or medicines taken for anxiety or to help you sleep (tranquillisers). tell your doctor if you are taking, have recently taken or might take any other medicines in particular, tell your doctor if you are taking: medicines for parkinson\'s disease. carbamazepine (an anti-epileptic and mood stabiliser), fluvoxamine (an antidepressant) or ciprofloxacin (an antibiotic) - it may be necessary to change your zyprexa velotab dose. zyprexa velotab with alcohol do not drink any alcohol if you have been given zyprexa velotab as together with alcohol it may make you feel drowsy. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. you should not be given this medicine when breast-feeding, as small amounts of zyprexa velotab can pass into breast milk. the following symptoms may occur in newborn babies, of mothers that have used zyprexa velotab in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. if your baby develops any of these symptoms you may need to contact your doctor. driving and using machines there is a risk of feeling drowsy when you are given zyprexa velotab. if this happens do not drive or operate any tools or machines. tell your doctor. zyprexa velotab contains aspartame, mannitol and sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate patients who cannot take phenylalanine should note that zyprexa velotab contains aspartame, which is a source of phenylalanine. may be harmful for people with phenylketonuria. patients who cannot take mannitol should note that zyprexa velotab contains mannitol. zyprexa velotab contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate, which may cause an allergic reaction in some people. an allergic reaction may be recognised as a rash, itching or shortness of breath. this may occur immediately or some time after you take zyprexa velotab.', 'Entity_Recognition': [{'Text': 'zyprexa velotab', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 12, 'BeginOffset': 12, 'EndOffset': 19, 'Score': 0.8831237554550171, 'Text': 'zyprexa', 'Category': 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'Type': 'TREATMENT', 'BeginOffset': 1400, 'EndOffset': 1415}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 1437, 'EndOffset': 1446}, {'Id': 49, 'BeginOffset': 1519, 'EndOffset': 1530, 'Score': 0.982100784778595, 'Text': 'blood clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8984231948852539}]}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 1535, 'EndOffset': 1544}, {'Id': 50, 'BeginOffset': 1599, 'EndOffset': 1610, 'Score': 0.9832426905632019, 'Text': 'blood clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8523439168930054}]}, {'Id': 51, 'BeginOffset': 1652, 'EndOffset': 1661, 'Score': 0.5931496024131775, 'Text': 'illnesses', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 52, 'BeginOffset': 1700, 'EndOffset': 1706, 'Score': 0.9902305006980896, 'Text': 'stroke', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': 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{'Title': '3. how to take zyprexa velotab', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. your doctor will tell you how many zyprexa velotab tablets to take and how long you should continue to take them. the daily dose of zyprexa velotab is between 5 mg and 20 mg. consult your doctor if your symptoms return but do not stop taking zyprexa velotab unless your doctor tells you to. you should take your zyprexa velotab tablets once a day following the advice of your doctor. try to take your tablets at the same time each day. it does not matter whether you take them with or without food. zyprexa velotab orodispersible tablets are for oral use. zyprexa velotab tablets break easily, so you should handle the tablets carefully. do not handle the tablets with wet hands as the tablets may break up. 1. hold the blister strip at the edges and separate one blister cell from the rest of the strip by gently tearing along the perforations around it. 2. carefully peel off the backing. 3. gently push the tablet out. 4. put the tablet in your mouth. it will dissolve directly in your mouth, so that it can be easily swallowed. you can also place the tablet in a full glass or cup of water, orange juice, apple juice, milk or coffee, and stir. with some drinks, the mixture may change colour and possibly become cloudy. drink it straight away. if you take more zyprexa velotab than you should patients who have taken more zyprexa velotab than they should have experienced the following symptoms: rapid beating of the heart, agitation/aggressiveness, problems with speech, 43 unusual movements (especially of the face or tongue) and reduced level of consciousness. other symptoms may be: acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness, slowing of the breathing rate, aspiration, high blood pressure or low blood pressure, abnormal rhythms of the heart. contact your doctor or hospital straight away if you experience any of the above symptoms. show the doctor your pack of tablets. if you forget to take zyprexa velotab take your tablets as soon as you remember. do not take two doses in one day. if you stop taking zyprexa velotab do not stop taking your tablets just because you feel better. it is important that you carry on taking zyprexa velotab for as long as your doctor tells you. if you suddenly stop taking zyprexa velotab, symptoms such as sweating, unable to sleep, tremor, anxiety or nausea and vomiting might occur. your doctor may suggest you to reduce the dose gradually before stopping treatment. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'zyprexa velotab', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor immediately if you have: unusual movement (a common side effect that may affect up to 1 in 10 people) mainly of the face or tongue; blood clots in the veins (an uncommon side effect that may affect up to 1 in 100 people) especially in the legs (symptoms include swelling, pain, and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing. if you notice any of these symptoms seek medical advice immediately; a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness (the frequency of this side effect cannot be estimated from the available data). very common side effects (may affect more than 1 in 10 people) include weight gain; sleepiness; and increases in levels of prolactin in the blood. in the early stages of treatment, some people may feel dizzy or faint (with a slow heart rate), especially when getting up from a lying or sitting position. this will usually pass on its own but if it does not, tell your doctor. common side effects (may affect up to 1 in 10 people) include changes in the levels of some blood cells, circulating fats and early in treatment, temporary increases in liver enzymes ; increases in the level of sugars in the blood and urine; increases in levels of uric acid and creatine phosphokinase in the blood; feeling more hungry; dizziness; restlessness; tremor; unusual movements (dyskinesias); constipation; dry mouth; rash; loss of strength; extreme tiredness; water retention leading to swelling of the hands, ankles or feet; fever, joint pain and sexual dysfunctions such as decreased libido in males and females or erectile dysfunction in males. uncommon side effects (may affect up to 1 in 100 people) include hypersensitivity (e.g. swelling in the mouth and throat, itching, rash); diabetes or the worsening of diabetes, occasionally associated with ketoacidosis (ketones in the blood and urine) or coma; seizures, usually associated with a history of seizures (epilepsy); muscle stiffness or spasms ( including eye movements); restless legs syndrome; problems with speech; stuttering; slow heart rate; sensitivity to sunlight; bleeding from the nose; abdominal distension; drooling; memory loss or forgetfulness; urinary incontinence; lack of ability to urinate; hair loss; absence or decrease in menstrual periods; and changes in breasts in males and females such as an abnormal production of breast milk or abnormal growth. rare side effects (may affect up to 1 in 1000 people) include lowering of normal body temperature; abnormal rhythms of the heart; sudden unexplained death; inflammation of the pancreas causing severe stomach pain, fever and sickness; liver disease appearing as yellowing of the skin and white parts of the eyes; muscle disease presenting as unexplained aches and pains; and prolonged and/or painful erection. very rare side effects include serious allergic reactions such as drug reaction with eosinophilia and systemic symptoms (dress). dress appears initially as flu-like symptoms with a rash on the face and then with an extended rash, high temperature, enlarged lymph nodes, increased levels of liver enzymes seen on blood tests and an increase in a type of white blood cells (eosinophilia). while taking olanzapine, elderly patients with dementia may suffer from stroke, pneumonia, urinary incontinence, falls, extreme tiredness, visual hallucinations, a rise in body temperature, redness of the skin and have trouble walking. some fatal cases have been reported in this particular group of patients. in patients with parkinson's disease zyprexa velotab may worsen the symptoms. reporting of side effects if you get any side effects, talk to your doctor or nurse. this includes any possible side effects not listed in this leaflet. you can also report side 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'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}, {'Type': 'TEST_VALUE', 'Score': 0.4315536320209503, 'RelationshipScore': 0.9999822378158569, 'RelationshipType': 'TEST_VALUE', 'Id': 170, 'BeginOffset': 3318, 'EndOffset': 3326, 'Text': 'increase', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'white blood cells', 'Type': 'TEST', 'BeginOffset': 3340, 'EndOffset': 3357}, {'Id': 148, 'BeginOffset': 3359, 'EndOffset': 3371, 'Score': 0.9065421223640442, 'Text': 'eosinophilia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8700203895568848}]}, {'Id': 91, 'BeginOffset': 3387, 'EndOffset': 3397, 'Score': 0.9974244832992554, 'Text': 'olanzapine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 149, 'BeginOffset': 3421, 'EndOffset': 3429, 'Score': 0.9939975738525391, 'Text': 'dementia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 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{'Title': '5. how to store zyprexa velotab', 'Section_Content': 'keep this medicine out of sight and reach of children. do not use this medicine after the expiry date, which is stated on the carton. zyprexa velotab should be stored in its original pack in order to protect from light and moisture. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'zyprexa velotab', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 66, 'EndOffset': 79}, {'Text': 'zyprexa velotab', 'Type': 'TREATMENT', 'BeginOffset': 134, 'EndOffset': 149}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 367, 'EndOffset': 381}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what zyprexa velotab contains the active substance is olanzapine. each zyprexa velotab orodispersible tablet contains either 5 mg, 10 mg, 15 mg or 20 mg of the active substance. the exact amount is shown on your zyprexa velotab pack. the other ingredients are - gelatin, mannitol (e421), aspartame (e951), sodium methyl parahydroxybenzoate (e219) and sodium propyl parahydroxybenzoate (e217). what zyprexa velotab looks like and contents of the pack zyprexa velotab 5 mg, 10 mg, 15 mg and 20 mg are yellow orodispersible tablets. orodispersible tablet is the technical name for a tablet which dissolves directly in your mouth, so that it can be easily swallowed. zyprexa velotab is available in packs containing 28, 35, 56, 70 or 98 tablets. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'zyprexa velotab', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'zyprexa velotab', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 20}, {'Id': 3, 'BeginOffset': 54, 'EndOffset': 64, 'Score': 0.9984174966812134, 'Text': 'olanzapine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9417210221290588, 'RelationshipScore': 0.5458140969276428, 'RelationshipType': 'DOSAGE', 'Id': 9, 'BeginOffset': 147, 'EndOffset': 152, 'Text': '20 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each zyprexa velotab orodispersible tablet', 'Type': 'TREATMENT', 'BeginOffset': 66, 'EndOffset': 108}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 125, 'EndOffset': 126}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 131, 'EndOffset': 133}, {'Text': '15', 'Type': 'NUMBER', 'BeginOffset': 138, 'EndOffset': 140}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 147, 'EndOffset': 149}, {'Text': 'your zyprexa velotab pack', 'Type': 'TREATMENT', 'BeginOffset': 207, 'EndOffset': 232}, {'Text': 'gelatin', 'Type': 'TREATMENT', 'BeginOffset': 262, 'EndOffset': 269}, {'Id': 11, 'BeginOffset': 271, 'EndOffset': 279, 'Score': 0.5669428706169128, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'aspartame', 'Type': 'TREATMENT', 'BeginOffset': 288, 'EndOffset': 297}, {'Id': 12, 'BeginOffset': 306, 'EndOffset': 339, 'Score': 0.9947502017021179, 'Text': 'sodium methyl parahydroxybenzoate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 351, 'EndOffset': 384, 'Score': 0.9916908740997314, 'Text': 'sodium propyl parahydroxybenzoate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'zyprexa velotab', 'Type': 'TREATMENT', 'BeginOffset': 398, 'EndOffset': 413}, {'Text': 'the pack zyprexa velotab', 'Type': 'TREATMENT', 'BeginOffset': 441, 'EndOffset': 465}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 466, 'EndOffset': 467}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 472, 'EndOffset': 474}, {'Text': '15', 'Type': 'NUMBER', 'BeginOffset': 479, 'EndOffset': 481}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 489, 'EndOffset': 491}, {'Id': 0, 'BeginOffset': 620, 'EndOffset': 625, 'Score': 0.4199739396572113, 'Text': 'mouth', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'zyprexa velotab', 'Type': 'TREATMENT', 'BeginOffset': 663, 'EndOffset': 678}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 712, 'EndOffset': 714}, {'Text': '35', 'Type': 'NUMBER', 'BeginOffset': 716, 'EndOffset': 718}, {'Text': '56', 'Type': 'NUMBER', 'BeginOffset': 720, 'EndOffset': 722}, {'Text': '70', 'Type': 'NUMBER', 'BeginOffset': 724, 'EndOffset': 726}, {'Text': '98', 'Type': 'NUMBER', 'BeginOffset': 730, 'EndOffset': 732}]}

C18EFFA40A73A83A1C1FBDB12BC03949

https://www.ema.europa.eu/documents/product-information/azarga-epar-product-information_en.pdf

Azarga

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One ml of suspension contains 10 mg brinzolamide and 5 mg timolol (as timolol maleate). Excipient with known effect: One ml of suspension contains 0.10 mg benzalkonium chloride. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Eye drops, suspension (eye drops) White to off-white uniform suspension, pH 7.2 (approximately). 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Decrease of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP reduction (see section 5.1). 4.2 Posology and method of administration Posology Use in adults, including the elderly The dose is one drop of AZARGA in the conjunctival sac of the affected eye(s) twice daily. When using nasolacrimal occlusion or closing the eyelids, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity (see section 4.4). If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed one drop in the affected eye (s) twice daily. When substituting another ophthalmic antiglaucoma medicinal product with AZARGA, the other medicinal product should be discontinued and AZARGA should be started the following day. Special populations Paediatric population The safety and efficacy of AZARGA in children and adolescents aged 0 to 18 years have not yet been established. No data are available. Hepatic and renal impairment No studies have been conducted with AZARGA or with timolol 5 mg/ml eye drops in patients with hepatic or renal impairment. No dosage adjustment is necessary in patients with hepatic impairment or in patients with mild to moderate renal impairment. 3 AZARGA has not been studied in patients with severe renal impairment (creatinine clearance <30 ml/min) or in patients with hyperchloraemic acidosis (see section 4.3). Since brinzolamide and its main metabolite are excreted predominantly by the kidney, AZARGA is therefore contraindicated in patients with severe renal impairment (see section 4.3). AZARGA should be used with caution in patients with severe hepatic impairment (see section 4.4). Method of administration For ocular use. Patients should be instructed to shake the bottle well before use. After cap is removed, if tamper evident snap collar is loose, remove before using product. To prevent contamination of the dropper tip and the suspension, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Instruct patients to keep the bottle tightly closed when not in use. If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered at least 5 minutes apart. Eye ointments should be administered last. 4.3 Contraindications  Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.  Hypersensitivity to other beta-blockers.  Hypersensitivity to sulphonamides (see section 4.4).  Reactive airway disease including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease.  Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock.  Severe allergic rhinitis  Hyperchloraemic acidosis (see section 4.2).  Severe renal impairment. 4.4 Special warnings and precautions for use Systemic effects  Brinzolamide and timolol are absorbed systemically. Due to the beta-adrenergic blocking component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.  Hypersensitivity reactions common to all sulphonamide derivates can occur in patients receiving AZARGA as it is absorbed systemically. Cardiac disorders In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions. Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block. 4 Vascular disorders Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution. Hyperthyroidism Beta-blockers may also mask the signs of hyperthyroidism. Muscle weakness Beta-adrenergic blocking medicinal products have been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis and generalised weakness). Respiratory disorders Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers. AZARGA should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk. Hypoglycaemia/diabetes Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia. Acid/base disturbances AZARGA contains brinzolamide, a sulphonamide. The same types of adverse reactions that are attributable to sulphonamides may occur with topical administration. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. This medicinal product should be used with caution in patients with risk of renal impairment because of the possible risk of metabolic acidosis. If signs of serious reactions or hypersensitivity occur, discontinue the use of this medicinal product. Mental alertness Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination. AZARGA is absorbed systemically and therefore this may occur with topical administration. Anaphylactic reactions While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions. Choroidal detachment Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures. Surgical anaesthesia Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol. 5 Concomitant therapy The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents or two local carbonic anhydrase inhibitors is not recommended (see section 4.5). There is potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and AZARGA. The concomitant administration of AZARGA and oral carbonic anhydrase inhibitors has not been studied and is not recommended (see section 4.5). Ocular effects There is limited experience with AZARGA in the treatment of patients with pseudoexfoliative glaucoma or pigmentary glaucoma. Caution should be utilised in treating these patients and close monitoring of IOP is recommended. AZARGA has not been studied in patients with narrow-angle glaucoma and its use is not recommended in these patients. Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution. The possible role of brinzolamide on corneal endothelial function has not been investigated in patients with compromised corneas (particularly in patients with low endothelial cell count). Specifically, patients wearing contact lenses have not been studied and careful monitoring of these patients when using brinzolamide is recommended, since carbonic anhydrase inhibitors may affect corneal hydration. This may lead to a corneal decompensation and oedema and wearing contact lenses might increase the risk for the cornea. Careful monitoring of patients with compromised corneas, such as patients with diabetes mellitus or corneal dystrophies, is recommended. AZARGA may be used while wearing contact lenses with careful monitoring (see below under ‘Benzalkonium chloride’). Benzalkonium chloride AZARGA contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided. Patients must be instructed to remove contact lenses prior to the application of AZARGA and wait 15 minutes after instillation of the dose before reinsertion. Benzalkonium chloride has also been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Close monitoring is required with frequent or prolonged use. Hepatic impairment AZARGA should be used with caution in patients with severe hepatic impairment. 4.5 Interaction with other medicinal products and other forms of interaction No specific drug interaction studies have been performed with AZARGA. AZARGA contains brinzolamide, a carbonic anhydrase inhibitor and, although administered topically, is absorbed systemically. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. The potential for interactions must be considered in patients receiving AZARGA. 6 There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide eye drops. The concomitant administration of eye drops containing brinzolamide and oral carbonic anhydrase inhibitors is not recommended. The cytochrome P-450 isozymes responsible for metabolism of brinzolamide include CYP3A4 (main), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. It is expected that inhibitors of CYP3A4 such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin will inhibit the metabolism of brinzolamide by CYP3A4. Caution is advised if CYP3A4 inhibitors are given concomitantly. However, accumulation of brinzolamide is unlikely as renal elimination is the major route. Brinzolamide is not an inhibitor of cytochrome P-450 isozymes. There is a potential for additive effects resulting in hypotension and/or marked bradycardia when an ophthalmic beta-blocker solution is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine. Beta blockers can decrease the response to adrenaline used to treat anaphylactic reactions. Special caution should be exercised in patients with a history of atopy or anaphylaxis (see section 4.4). The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta- blockers. Caution is recommended in the concomitant use of this medicinal product with clonidine. Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol. Caution is recommended. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4). Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally. 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate data regarding the use of ophthalmic brinzolamide and timolol in pregnant women. Studies in animals with brinzolamide have shown reproductive toxicity following systemic administration, see section 5.3. AZARGA should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If AZARGA is administered until delivery, the neonate should be carefully monitored during the first days of life. Breast-feeding It is not known whether ophthalmic brinzolamide is excreted in human breast milk. Studies in animals have shown that following oral administration brinzolamide is excreted in breast milk, see section 5.3. Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see section 4.2. 7 However, a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from AZARGA therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Studies have not been performed to evaluate the effect of topical ocular administration of Azarga on human fertility. Non clinical data do not show any effects of either brinzolamide or timolol on male or female fertility following oral dosing. No effects on male or female fertility are anticipated from the use of AZARGA. 4.7 Effects on ability to drive and use machines AZARGA has minor influence on the ability to drive and use machines. Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machines. Carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination (see section 4.4). 4.8 Undesirable effects Summary of the safety profile In clinical trials, the most common adverse reactions were blurred vision, eye irritation and eye pain, occurring in approximately 2% to 7% of patients. Tabulated summary of adverse reactions The following adverse reactions have been reported during clinical studies and post-marketing surveillance with AZARGA and the individual components brinzolamide and timolol. They are classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. System Organ Classification MedDRA Preferred Term (v. 18.0) Infections and infestations Not known: nasopharyngitis3, pharyngitis3, sinusitis3, rhinitis3 Blood and lymphatic system disorders Uncommon: white blood cell count decreased1 Not known: decreased red blood cell count3, increased blood chloride3 Immune system disorders Not known: anaphylaxis2, anaphylactic shock1, systemic allergic reactions including angioedema, 2 localised and generalised rash2, hypersensitivity1, urticaria2, pruritus2 Metabolism and nutrition disorders Not known: hypoglycaemia2 Psychiatric disorders Rare: insomnia1 Not known: hallucinations2, depression1, memory loss2, apathy3, depressed mood3, decreased libido3, nightmare2,3, nervousness3 8 Nervous system disorders Common: dysgeusia1 Not known: cerebral ischaemia2, cerebrovascular accident2, syncope2, increases in the signs and symptoms of myasthenia gravis2, somnolence3, motor dysfunction3, amnesia3, memory impairment3, paraesthesia2,3, tremor3, hypoaesthesia3, ageusia3, dizziness1, headache1 Eye disorders Common: punctate keratitis1, blurred vision1, eye pain1, eye irritation1 Uncommon: keratitis1,2,3, dry eye1, vital dye staining cornea present1, eye discharge1, eye pruritus1, foreign body sensation in eyes1, ocular hyperaemia1, conjunctival hyperaemia1 Rare: corneal erosion1, anterior chamber flare1, photophobia1, lacrimation increased1, scleral hyperaemia1, erythema of eyelid1, eyelid margin crusting1 Not known: increased optic nerve cup/disc ratio3, choroidal detachment following filtration surgery2 (see section 4.4 Special warnings and precautions for use), keratopathy3, corneal epithelium defect3, corneal epithelium disorder3, increased intraocular pressure3, eye deposit3, corneal staining3, corneal oedema3, decreased corneal sensitivity2, conjunctivitis3, meibomianitis3, diplopia2, 3, glare3, photopsia3, reduced visual acuity3, visual impairment1, pterygium3, ocular discomfort3, keratoconjunctivitis sicca3, hypoaesthesia of the eye3, scleral pigmentation3, subconjunctival cyst3, visual disturbance3, eye swelling3, eye allergy3, madarosis3, eyelid disorder3, eyelid oedema1, ptosis2 Ear and labyrinth disorders Not known: vertigo3, tinnitus3 Cardiac disorders Common: heart rate decreased1 Not known: cardiac arrest2, cardiac failure2, congestive heart failure2, atrioventricular block2, cardio-respiratory distress3, angina pectoris3, bradycardia2,3, irregular heart rate3, arrhythmia2,3, palpitations2,3, tachycardia3, increased heart rate3, chest pain2, oedema2 Vascular disorders Uncommon: decreased blood pressure1 Not known: hypotension2, hypertension3, blood pressure increased1, Raynaud’s phenomenon2, cold hands and feet2 Respiratory, thoracic and mediastinal disorders Uncommon: cough1 Rare: oropharyngeal pain1, rhinorrhoea1 Not known: bronchospasm2 (predominantly in patients with pre- existing bronchospastic disease), dyspnoea1, asthma3, epistaxis1, bronchial hyperactivity3, throat irritation3, nasal congestion3, upper respiratory tract congestion3, postnasal drip3, sneezing3, nasal dryness3 Gastrointestinal disorders Not known: vomiting2,3, abdominal pain upper1, abdominal pain2, diarrhoea1, dry mouth1, nausea1, oesophagitis3, dyspepsia2,3, abdominal discomfort3, stomach discomfort3, frequent bowel movements3, gastrointestinal disorder3, oral hypoaesthesia3, oral paraesthesia3, flatulence3 Hepatobiliary disorders Not known: abnormal liver function test3 Skin and subcutaneous tissue disorders Not known: urticaria3, maculo-papular rash3, generalised pruritus3, skin tightness3, dermatitis3, alopecia1, psoriasiform rash or exacerbation of psoriasis2, rash1, erythema1 Musculoskeletal and connective tissue disorders Not known: myalgia1, muscle spasms3, arthralgia3, back pain3, pain in extremity3 Renal and urinary disorders Uncommon: blood urine present1 Not known: renal pain3, pollakiuria3 Reproductive system and breast disorders Not known: erectile dysfunction3, sexual dysfunction2, decreased libido2 9 General disorders and administration site conditions Uncommon: malaise1,3 Not known: chest pain1, pain3, fatigue1, asthenia2,3, chest discomfort3, feeling jittery3, irritability3, peripheral oedema3, medication residue3 Investigations Uncommon: blood potassium increase1, blood lactate dehydrogenase increased1 1 adverse reactions observed for Azarga 2 additional adverse reactions observed with timolol monotherapy 3 additional adverse reactions observed with brinzolamide monotherapy Description of selected adverse reactions Dysgeusia (bitter or unusual taste in the mouth following instillation) was a frequently reported systemic adverse reaction associated with the use of AZARGA during clinical trials. It is likely to be caused by passage of the eye drops in the nasopharynx via the nasolacrimal canal and is attributable to brinzolamide. Nasolacrimal occlusion or gently closing the eyelid after instillation may help reduce the occurrence of this effect (see section 4.2). AZARGA contains brinzolamide which is a sulphonamide inhibitor of carbonic anhydrase with systemic absorption. Gastrointestinal, nervous system, haematological, renal and metabolic effects are generally associated with systemic carbonic anhydrase inhibitors. The same type of adverse reactions attributable to oral carbonic anhydrase inhibitors may occur with topical administration. Timolol is absorbed into the systemic circulation. This may cause similar adverse reactions as seen with systemic beta-blocking medicinal products. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers. Additional adverse reactions associated with the use of the individual components that may potentially occur with AZARGA are included in the table above. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2. Paediatric population AZARGA is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In case of accidental ingestion, symptoms of overdose from beta blockade may include bradycardia, hypotension, cardiac failure and bronchospasm. If overdose with AZARGA eye drops occurs, treatment should be symptomatic and supportive. Due to brinzolamide, electrolyte imbalance, development of an acidotic state, and possibly central nervous system effects may occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol does not dialyse readily. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 10 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Ophthalmologicals, Antiglaucoma preparation and miotics ATC code: S01ED51 Mechanism of action AZARGA contains two active substances: brinzolamide and timolol maleate. These two components decrease elevated IOP primarily by reducing aqueous humour secretion, but do so by different mechanisms of action. The combined effect of these two active substances results in additional IOP reduction compared to either compound alone. Brinzolamide is a potent inhibitor of human carbonic anhydrase II (CA-II), the predominant iso- enzyme in the eye. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humour secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol is a non-selective adrenergic-blocking agent that has no intrinsic sympathomimetic, direct myocardial depressant or membrane-stabilising activity. Tonography and fluorophotometry studies in man suggest that its predominant action is related to reduced aqueous humour formation and a slight increase in outflow facility. Pharmacodynamic effects Clinical effects: In a twelve-month, controlled clinical trial in patients with open-angle glaucoma or ocular hypertension who, in the investigator’s opinion could benefit from a combination therapy, and who had baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of AZARGA dosed twice daily was 7 to 9 mmHg. The non-inferiority of AZARGA as compared to dorzolamide 20 mg/ml + timolol 5 mg/ml in the mean IOP reduction was demonstrated across all time-points at all visits. In a six-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of AZARGA dosed twice daily was 7 to 9 mmHg, and was up to 3 mmHg greater than that of brinzolamide 10 mg/ml dosed twice daily and up to 2 mmHg greater than that of timolol 5 mg/ml dosed twice daily. A statistically superior reduction in mean IOP was observed compared to both brinzolamide and timolol at all time- points and visits throughout the study. In three controlled clinical trials, the ocular discomfort upon instillation of AZARGA was significantly lower than that of dorzolamide 20 mg/ml + timolol 5 mg/ml. 11 5.2 Pharmacokinetic properties Absorption Following topical ocular administration, brinzolamide and timolol are absorbed through the cornea and into the systemic circulation. In a pharmacokinetic study, healthy subjects received oral brinzolamide (1 mg) twice daily for 2 weeks to shorten the time to reach steady-state prior to starting AZARGA administration. Following twice daily dosing of AZARGA for 13 weeks, red blood cell (RBC) concentrations of brinzolamide averaged 18.8  3.29 µM, 18.1  2.68 µM and 18.4  3.01 µM at weeks 4, 10 and 15, respectively, indicating that steady-state RBC concentrations of brinzolamide were maintained At steady state, following administration of AZARGA, the mean plasma Cmax and AUC0-12h of timolol were 27% and 28% lower (Cmax: 0.824 ± 0.453 ng/ml; AUC0-12h: 4.71 ± 4.29 ng·h/ml), respectively, in comparison to the administration of timolol 5 mg/ml (Cmax: 1.13 ± 0.494 ng/ml; AUC0-12h: 6.58 ± 3.18 ng·h/ml). The lower systemic exposure to timolol following AZARGA administration is not clinically relevant. Following administration of AZARGA, mean Cmax of timolol was reached at 0.79 ± 0.45 hours. Distribution Plasma protein binding of brinzolamide is moderate (about 60%). Brinzolamide is sequestered in RBCs due to its high affinity binding to CA-II and to a lesser extent to CA-I. Its active N-desethyl metabolite also accumulates in RBCs where it binds primarily to CA-I. The affinity of brinzolamide and metabolite to RBC and tissue CA results in low plasma concentrations. Ocular tissue distribution data in rabbits showed that timolol can be measured in aqueous humour up to 48 hours after administration of AZARGA. At steady-state, timolol is detected in human plasma for up to 12 hours after administration of AZARGA. Biotransformation The metabolic pathways for the metabolism of brinzolamide involve N-dealkylation, O-dealkylation and oxidation of its N-propyl side chain. N-desethyl brinzolamide is a major metabolite of brinzolamide formed in humans, which also binds to CA-I in the presence of brinzolamide and accumulates in RBCs. In vitro studies show that the metabolism of brinzolamide mainly involves CYP3A4 as well as at least four other isozymes (CYP2A6, CYP2B6, CYP2C8 and CYP2C9). Timolol is metabolised by two pathways. One route yields an ethanolamine side chain on the thiadiazole ring and the other giving an ethanolic side chain on the morpholine nitrogen and a second similar side chain with a carbonyl group adjacent to the nitrogen. Timolol metabolism is mediated primarily by CYP2D6. Elimination Brinzolamide is eliminated primarily by renal excretion (approximately 60%). About 20% of the dose has been accounted for in urine as metabolite. Brinzolamide and N-desethyl-brinzolamide are the predominant components found in the urine along with trace levels (<1%) of the N-desmethoxypropyl and O-desmethyl metabolites. Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of a timolol dose is excreted in the urine unchanged and the remainder excreted in urine as metabolites. The plasma t1/2 of timolol is 4.8 hours after administration of AZARGA. 12 5.3 Preclinical safety data Brinzolamide Non-clinical data reveal no special hazard for humans with brinzolamide based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Developmental toxicity studies in rabbits with oral doses of brinzolamide of up to 6 mg/kg/day (214 times the recommended daily clinical dose of 28 µg/kg/day) revealed no effect on foetal development despite significant maternal toxicity. Similar studies in rats resulted in slightly reduced ossification of skull and sternebrae of foetuses of dams receiving brinzolamide at doses of 18 mg/kg/day (642 times the recommended daily clinical dose), but not 6 mg/kg/day. These findings occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased foetal weights. Dose-related decreases in foetal weights were observed in pups of dams receiving brinzolamide orally ranging from a slight decrease (about 5-6%) at 2 mg/kg/day to nearly 14% at 18 mg/kg/day. During lactation, the no adverse effect level in the offspring was 5 mg/kg/day. Timolol Non-clinical data reveal no special hazard for humans with timolol based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Reproduction toxicity studies with timolol showed delayed foetal ossification in rats with no adverse effects on postnatal development (at 50 mg/kg/day or 3,500 times the daily clinical dose of 14 g/kg/day) and increased foetal resorptions in rabbits (at 90 mg/kg/day or 6,400 times the daily clinical dose). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Benzalkonium chloride Mannitol (E421) Carbopol 974P Tyloxapol Disodium edetate Sodium chloride Hydrochloric acid and/or sodium hydroxide (for pH adjustment) Purified water 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 4 weeks after first opening. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 13 6.5 Nature and contents of container 5 ml round opaque low density polyethylene bottles with a dispensing plug and white polypropylene screw cap (DROP-TAINER) containing 5 ml suspension. Cartons containing 1 or 3 bottles. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/08/482/001-002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first Authorisation: 25 November 2008 Date of latest renewal: 26 August 2013 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/ 14 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 15 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release S.A. Alcon-Couvreur N.V. Rijksweg 14 B-2870 Puurs Belgium or Alcon Cusí, S.A. Camil Fabra 58 08320 El Masnou Barcelona Spain The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 16 ANNEX III LABELLING AND PACKAGE LEAFLET 17 A. LABELLING 18 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON FOR SINGLE BOTTLE 5 ml + CARTON FOR 3 x 5 ml BOTTLES 1. NAME OF THE MEDICINAL PRODUCT AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension brinzolamide/timolol 2. STATEMENT OF ACTIVE SUBSTANCE 1 ml of suspension contains 10 mg brinzolamide and 5 mg timolol (as timolol maleate). 3. LIST OF EXCIPIENTS Contains: benzalkonium chloride, mannitol (E421), carbopol 974P, tyloxapol, disodium edetate, sodium chloride, hydrochloric acid and/or sodium hydroxide (to adjust pH), purified water. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Eye drops, suspension 1 x 5 ml 3 x 5 ml 5. METHOD AND ROUTE OF ADMINISTRATION Shake well before use. Read the package leaflet before use. Ocular use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Discard 4 weeks after first opening. Opened: 19 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBERS EU/1/08/482/001 1 x 5 ml EU/1/08/482/002 3 x 5 ml 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE azarga 17. UNIQUE IDENTIFIER-2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 20 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION AZARGA 10 mg/ml + 5 mg/ml eye drops brinzolamide/timolol Ocular use 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP Discard 4 weeks after first opening. Opened: 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 5 ml 6 OTHER 21 B. PACKAGE LEAFLET 22 Package leaflet: Information for the user AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension brinzolamide/timolol Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them even if their signs of illnesses are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What AZARGA is and what it is used for 2. What you need to know before you use AZARGA 3. How to use AZARGA 4. Possible side effects 5. How to store AZARGA 6. Contents of the pack and other information 1. What AZARGA is and what it is used for AZARGA contains two active substances, brinzolamide and timolol, which work together to reduce pressure within the eye. AZARGA is used to treat high pressure in the eyes, also called glaucoma or ocular hypertension, in adult patients that are more than 18 years of age and in whom high pressure in the eyes cannot be controlled effectively by one medicine alone. 2. What you need to know before you use AZARGA Do not use AZARGA  If you are allergic to brinzolamide, medicines called sulphonamides (examples include medicines used to treat diabetes, infections and also diuretics (water tablets)), timolol, beta- blockers (medicines used to lower blood pressure or to treat heart disease) or any of the other ingredients of this medicine (listed in section 6).  If you have now or have had in the past respiratory problems such as asthma, severe long lasting obstructive bronchitis (severe lung condition which may cause wheezing, difficulty in breathing and/or long standing cough) or other types of breathing problems.  If you have severe hay fever  If you have a slow heart beat, heart failure or disorders of heart rhythm (irregular heartbeats).  If you have too much acidity in your blood (a condition called hyperchloraemic acidosis).  If you have severe kidney problems. 23 Warnings and precautions Only use AZARGA for dropping in your eye(s). If signs of serious reactions or hypersensitivity occur, discontinue the use of this product and talk to your doctor. Talk to your doctor or pharmacist before using AZARGA if you have or have had in the past:  coronary heart disease (symptoms can include chest pain or tightness, breathlessness or choking), heart failure, low blood pressure  disturbances of heart rate such as slow heart beat  breathing problems, asthma or chronic obstructive pulmonary disease  poor blood circulation disease (such as Raynaud’s disease or Raynaud’s syndrome)  diabetes as timolol may mask signs and symptoms of low blood sugar  overactivity of the thyroid gland as timolol may mask signs and symptoms of thyroid disease  muscular weakness (myasthenia gravis)  tell your doctor before you have an operation that you are using AZARGA as timolol may change effects of some medicines used during anaesthesia.  if you have a history of atopy (a tendency to develop an allergic reaction) and severe allergic reactions you may be more sensitive to developing an allergic reaction whilst using AZARGA and adrenaline may not be as effective to treat an allergic reaction. When receiving any other treatment please tell the doctor or nurse that you are taking AZARGA.  if you have liver problems.  if you have dry eyes or cornea problems.  if you have problems with your kidneys. Children and adolescents AZARGA is not recommended for children and adolescents under 18 years. Other medicines and AZARGA Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. AZARGA can affect, or be affected by, other medicines you are taking, including other eye drops for the treatment of glaucoma. Tell your doctor if you are taking or intent to take medicines to lower blood pressure like parasympathomimetics and guanetidine, or other heart medicines including quinidine (used to treat heart conditions and some types of malaria), amiodarone or other medicines to treat heart rhythm disorders and glycosides to treat heart insufficiency. Also tell your doctor if you are taking or intend to take medicines to treat diabetes, or to treat gastric ulcers, antifungal, antiviral or antibiotic medicines, or antidepressants such as fluoxetine and paroxetine. If you are taking another carbonic anhydrase inhibitor (acetazolamide or dorzolamide), talk to your doctor. Increase in pupil size when taking Azarga and adrenaline (epinephrine) together has been reported occasionally. Pregnancy and breast-feeding You should not use AZARGA if you are pregnant or might get pregnant, unless your doctor considers it necessary. Talk to your doctor before you use AZARGA. Do not use AZARGA if you are breast feeding, timolol may get into your milk. Ask your doctor for advice before taking any medicine during breastfeeding. Driving and using machines Do not drive or use machines until your vision is clear. You may find that your vision is blurred for some time just after using AZARGA. 24 One of the active ingredients may impair the ability to perform tasks requiring mental alertness and/or physical coordination. If affected take care when driving or using machines. AZARGA contains benzalkonium chloride This medicine contains 3.34 µg benzalkonium chloride per drop (= 1 dose) which is equivalent to 0.01% or 0.1 mg/ml. AZARGA contains a preservative (benzalkonium chloride) which may be absorbed by soft contact lenses and may change the colour of the contact lenses. You should remove contact lenses before using this medicine and put them back 15 minutes afterwards. Benzalkonium chloride may also cause eye irritation, especially if you have dry eyes or disorders of the cornea (the clear layer at the front of the eye). If you feel abnormal eye sensation, stinging or pain in the eye after using this medicine, talk to your doctor. 3. How to use AZARGA Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. If you are changing from another eye drop medicine used to treat glaucoma to AZARGA, you should stop using the other medicine and start using AZARGA the following day. Check with your doctor or pharmacist if you are not sure To prevent contamination of the dropper tip and the suspension, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip. Keep the bottle tightly closed when not in use. The following measure is useful to limit the amount of medicine that will come into the blood after application of eye drops: - Keep the eyelid closed, while simultaneously applying gentle pressure to the corner of the eye next to the nose with a finger for at least 2 minutes. The recommended dose is One drop in the affected eye or eyes, twice a day. Only use AZARGA in both eyes if your doctor told you to. Take it for as long as your doctor told you to. How to use 1 2 3  Get the AZARGA bottle and a mirror.  Wash your hands.  Shake well before use.  Twist off the bottle cap. After the cap is removed, if the tamper evident snap collar is loose, remove before using product.  Hold the bottle, pointing down, between your thumb and fingers.  Tilt your head back. Pull down your eyelid with a clean finger, until there is a ‘pocket’ between the eyelid and your eye. The drop will go in here (picture 1).  Bring the bottle tip close to the eye. Use the mirror if it helps. 25  Do not touch your eye or eyelid, surrounding areas or other surfaces with the dropper. It could infect the drops.  Gently press on the base of the bottle to release one drop of AZARGA at a time.  Do not squeeze the bottle: it is designed so that a gentle press on the bottom is all that it needs (picture 2).  After using AZARGA, press a finger into the corner of your eye, by the nose for 2 minutes (picture 3). This helps to stop AZARGA getting into the rest of the body.  If you use drops in both eyes, repeat the steps for your other eye.  Close the bottle cap firmly immediately after use.  Use up one bottle before opening the next bottle. If a drop misses your eye, try again. If you are using other eye drop or eye ointment medicines leave at least 5 minutes between each medicine. Eye ointments should be administered last. If you use more AZARGA than you should, rinse your eye with warm water. Do not put in any more drops until it is time for your next regular dose. You may experience a decreased heart rate, decreased blood pressure, heart failure, difficulty breathing and your nervous system may be affected If you forget to use AZARGA, continue with the next dose as planned. Do not use a double dose to make up for the forgotten dose. Do not use more than one drop in the affected eye(s) twice daily. If you stop using AZARGA without speaking to your doctor, the pressure in your eye will not be controlled which could lead to loss of sight. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects although not everybody gets them. Stop using this medicine and contact your doctor immediately if you develop skin rash, severe skin reaction, or severe redness and itching of the eye. These could be the signs of an allergic reaction (frequency is not known). You can usually carry on taking the drops, unless the effects are serious. If you are worried, talk to your doctor or pharmacist. Do not stop using Azarga without speaking to your doctor first. Common side effects (may affect up to 1 in 10 people)  Effects in the eye: eye surface inflammation, blurred vision, signs and symptoms of eye irritation (e.g. burning, stinging, itching, tearing, redness), eye pain.  General side effects: heart rate decreased, taste disturbances. Uncommon side effects (may affect up to 1 in 100 people)  Effects in the eye:corneal erosion (damage to the front layer of the eyeball), Eye surface inflammation with surface damage, inflammation inside the eye, corneal staining, abnormal sensation in the eyes, eye discharge, dry eye, tired eyes, itchy eye, eye redness, eyelid redness.  General side effects: decrease in white blood cell count, decreased blood pressure, cough, blood in urine, body weakness. 26 Rare side effects (may affect up to 1 in 1,000 people)  Effects in the eye: corneal disorder, sensitivity to light, increased tear production, eyelid crusting  General side effects: difficulty sleeping (insomnia), throat pain, running nose Not known (frequency cannot be estimated from the available data)  Effects in the eye: eye allergy, disturbance of vision, damage to the optic nerve, increased pressure in eye, deposits on the eye surface, decreased eye sensation, inflammation or infection of the conjunctiva (white of the eye), abnormal, double or reduced vision, increased pigmentation of the eye, growth on surface of eye, eye swelling, sensitivity to light, decreased growth or number of eyelashes, drooping of the upper eyelids (making the eye stay half closed), inflammation of the eyelid and eye lid glands, inflammation in the cornea and detachment of the layer below the retina that contains blood vessels following filtration surgery which may cause visual disturbances, decreased corneal sensitivity.  Heart and circulation: changes in rhythm or rate of the heartbeat, slow heart rate, palpitations, a type of heart rhythm disorder, abnormal increase in heart rate, chest pain, reduced heart function, heart attack, increased blood pressure, reduced blood supply to the brain, stroke, oedema (fluid build up), congestive heart failure (heart disease with shortness of breath and swelling of the feet and legs due to fluid build up), swelling of the extremities, low blood pressure, discoloration of the fingers, toes, and occasionally other areas of the body (Raynaud’s phenomenon), cold hands and feet.  Respiratory: Constriction of the airways in the lungs (predominantly in patients with pre- existing disease) shortness of breath or difficulty breathing, cold symptoms, chest congestion, sinus infection, sneezing, stuffy nose, dry nose, nose bleeds, asthma, throat irritation.  Nervous system and general disorders: hallucinations, depression, nightmares, memory loss, headache, nervousness, irritability, tiredness, shaking, feeling abnormal, fainting, dizziness, drowsiness, generalised or severe weakness, unusual sensations like pins and needles.  Gastric: nausea, vomiting, diarrhoea, intestinal gas or abdominal discomfort, inflammation of the throat, dry or abnormal sensation in mouth, indigestion, stomach ache.  Blood: abnormal liver function values, increased blood chlorine levels, or decreased red blood cell count as seen in a blood test.  Allergy: increased allergic symptoms, generalised allergic reactions including swelling beneath the skin that can occur in areas such as the face and limbs and can obstruct the airway which may cause difficulty swallowing or breathing, hives, localised and generalised rash, itchiness, severe sudden life-threatening allergic reaction.  Ear: ringing in the ears, sensation of spinning or dizziness.  Skin: rash, skin redness or inflammation, abnormal or decreased skin sensation, hair loss, rash with white silvery coloured appearance (psoriasiform rash) or worsening of psoriasis.  Muscular: generalised back, joint, or muscle pain not caused by exercise, muscle spasms, pain in extremities, muscle weakness/tiredness, increases in the signs and symptoms of myasthenia gravis (muscle disorder).  Kidney: kidney pain such as lower back pain, frequent urination.  Reproduction: sexual dysfunction, decreased libido, male sexual difficulty.  Metabolism: low blood sugar levels. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 27 5. How to store AZARGA Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the bottle and the carton after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Throw away the bottle 4 weeks after first opening to prevent infections, and use a new bottle. Write down the date of opening on the bottle label and carton label in the space provided. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What AZARGA contains  The active substances are brinzolamide and timolol. One ml of suspension contains 10 mg of brinzolamide and 5 mg of timolol (as maleate).  The other ingredients are benzalkonium chloride (see section 2 ‘AZARGA contains benzalkonium’), carbopol 974P, disodium edetate, mannitol (E421), purified water, sodium chloride, tyloxapol, hydrochloric acid and/or sodium hydroxide. Tiny amounts of hydrochloric acid and/or sodium hydroxide are added to keep acidity levels (pH levels) normal. What AZARGA looks like and contents of the pack AZARGA is a liquid (white to off-white uniform suspension) supplied in a pack containing one 5 ml plastic bottle with a screw cap or in a pack containing three 5 ml bottles. Not all pack sizes may be marketed. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer S.A. Alcon-Couvreur N.V. Rijksweg 14 B-2870 Puurs Belgium or Alcon Cusí, S.A., Camil Fabra 58, 08320 El Masnou, Barcelona, Spain 28 For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел.: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: + 421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 29 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you use azarga', 'Section_Content': "do not use azarga if you are allergic to brinzolamide, medicines called sulphonamides (examples include medicines used to treat diabetes, infections and also diuretics (water tablets)), timolol, beta- blockers (medicines used to lower blood pressure or to treat heart disease) or any of the other ingredients of this medicine (listed in section 6). if you have now or have had in the past respiratory problems such as asthma, severe long lasting obstructive bronchitis (severe lung condition which may cause wheezing, difficulty in breathing and/or long standing cough) or other types of breathing problems. if you have severe hay fever if you have a slow heart beat, heart failure or disorders of heart rhythm (irregular heartbeats). if you have too much acidity in your blood (a condition called hyperchloraemic acidosis). if you have severe kidney problems. warnings and precautions only use azarga for dropping in 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{'Title': '3. how to use azarga', 'Section_Content': "always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. if you are changing from another eye drop medicine used to treat glaucoma to azarga, you should stop using the other medicine and start using azarga the following day. check with your doctor or pharmacist if you are not sure to prevent contamination of the dropper tip and the suspension, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip. keep the bottle tightly closed when not in use. the following measure is useful to limit the amount of medicine that will come into the blood after application of eye drops: - keep the eyelid closed, while simultaneously applying gentle pressure to the corner of the eye next to the nose with a finger for at least 2 minutes. the recommended dose is one drop in the affected eye or eyes, twice a day. only use azarga in both eyes if your doctor told you to. take it for as long as your doctor told you to. how to use 1 2 3 get the azarga bottle and a mirror. wash your hands. shake well before use. twist off the bottle cap. after the cap is removed, if the tamper evident snap collar is loose, remove before using product. hold the bottle, pointing down, between your thumb and fingers. tilt your head back. pull down your eyelid with a clean finger, until there is a 'pocket' between the eyelid and your eye. the drop will go in here (picture 1). bring the bottle tip close to the eye. use the mirror if it helps. do not touch your eye or eyelid, surrounding areas or other surfaces with the dropper. it could infect the drops. gently press on the base of the bottle to release one drop of azarga at a time. do not squeeze the bottle: it is designed so that a gentle press on the bottom is all that it needs (picture 2). after using azarga, press a finger into the corner of your eye, by the nose for 2 minutes (picture 3). this helps to stop azarga getting into the rest of the body. if you use drops in both eyes, repeat the steps for your other eye. close the bottle cap firmly immediately after use. use up one bottle before opening the next bottle. if a drop misses your eye, try again. if you are using other eye drop or eye ointment medicines leave at least 5 minutes between each medicine. eye ointments should be administered last. if you use more azarga than you should, rinse your eye with warm water. do not put in any more drops until it is time for your next regular dose. you may experience a decreased heart rate, decreased blood pressure, heart failure, difficulty breathing and your nervous system may be affected if you forget to use azarga, continue with the next dose as planned. do not use a double dose to make up for the forgotten dose. do not use more than one drop in the affected eye(s) twice daily. if you stop using azarga without speaking to your doctor, the pressure in your eye 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects although not everybody gets them. stop using this medicine and contact your doctor immediately if you develop skin rash, severe skin reaction, or severe redness and itching of the eye. these could be the signs of an allergic reaction (frequency is not known). you can usually carry on taking the drops, unless the effects are serious. if you are worried, talk to your doctor or pharmacist. do not stop using azarga without speaking to your doctor first. common side effects (may affect up to 1 in 10 people) effects in the eye: eye surface inflammation, blurred vision, signs and symptoms of eye irritation (e.g. burning, stinging, itching, tearing, redness), eye pain. general side effects: heart rate decreased, taste disturbances. uncommon side effects (may affect up to 1 in 100 people) effects in the eye:corneal erosion (damage to the front layer of the eyeball), eye surface inflammation with surface damage, inflammation inside the eye, corneal staining, abnormal sensation in the eyes, eye discharge, dry eye, tired eyes, itchy eye, eye redness, eyelid redness. general side effects: decrease in white blood cell count, decreased blood pressure, cough, blood in urine, body weakness. rare side effects (may affect up to 1 in 1,000 people) effects in the eye: corneal disorder, sensitivity to light, increased tear production, eyelid crusting general side effects: difficulty sleeping (insomnia), throat pain, running nose not known (frequency cannot be estimated from the available data) effects in the eye: eye allergy, disturbance of vision, damage to the optic nerve, increased pressure in eye, deposits on the eye surface, decreased eye sensation, inflammation or infection of the conjunctiva (white of the eye), abnormal, double or reduced vision, increased pigmentation of the eye, growth on surface of eye, eye swelling, sensitivity to light, decreased growth or number of eyelashes, drooping of the upper eyelids (making the eye stay half closed), inflammation of the eyelid and eye lid glands, inflammation in the cornea and detachment of the layer below the retina that contains blood vessels following filtration surgery which may cause visual disturbances, decreased corneal sensitivity. heart and circulation: changes in rhythm or rate of the heartbeat, slow heart rate, palpitations, a type of heart rhythm disorder, abnormal increase in heart rate, chest pain, reduced heart function, heart attack, increased blood pressure, reduced blood supply to the brain, stroke, oedema (fluid build up), congestive heart failure (heart disease with shortness of breath and swelling of the feet and legs due to fluid build up), swelling of the extremities, low blood pressure, discoloration of the fingers, toes, and occasionally other areas of the body (raynaud's phenomenon), cold hands and feet. respiratory: constriction of the airways in the lungs (predominantly in patients with pre- existing disease) shortness of breath or difficulty breathing, cold symptoms, chest congestion, sinus infection, sneezing, stuffy nose, dry nose, nose bleeds, asthma, throat irritation. nervous system and general disorders: hallucinations, depression, nightmares, memory loss, headache, nervousness, irritability, tiredness, shaking, feeling abnormal, fainting, dizziness, drowsiness, generalised or severe weakness, unusual sensations like pins and needles. gastric: nausea, vomiting, diarrhoea, intestinal gas or abdominal discomfort, inflammation of the throat, dry or abnormal sensation in mouth, indigestion, stomach ache. blood: abnormal liver function values, increased blood chlorine levels, or decreased red blood cell count as seen in a blood test. allergy: increased allergic symptoms, generalised allergic reactions including swelling beneath the skin that can occur in areas such as the face and limbs and can obstruct the airway which may cause difficulty swallowing or breathing, hives, localised and generalised rash, itchiness, severe sudden life-threatening allergic reaction. ear: ringing in the ears, sensation of spinning or dizziness. skin: rash, skin redness or inflammation, abnormal or decreased skin sensation, hair loss, rash with white silvery coloured appearance (psoriasiform rash) or worsening of psoriasis. muscular: generalised back, joint, or muscle pain not caused by exercise, muscle spasms, pain in extremities, muscle weakness/tiredness, increases in the signs and symptoms of myasthenia gravis (muscle disorder). kidney: kidney pain such as lower back pain, frequent urination. reproduction: sexual dysfunction, decreased libido, male sexual difficulty. metabolism: low blood sugar levels. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed 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0.9920932650566101, 'Text': 'tiredness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.933085560798645}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.39434003829956055, 'RelationshipScore': 0.5729111433029175, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 242, 'BeginOffset': 4298, 'EndOffset': 4306, 'Text': 'muscular', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the signs and symptoms', 'Type': 'PROBLEM', 'BeginOffset': 4448, 'EndOffset': 4470}, {'Text': 'myasthenia gravis (muscle disorder', 'Type': 'PROBLEM', 'BeginOffset': 4474, 'EndOffset': 4508}, {'Id': 250, 'BeginOffset': 4511, 'EndOffset': 4517, 'Score': 0.997965931892395, 'Text': 'kidney', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 278, 'BeginOffset': 4519, 'EndOffset': 4530, 'Score': 0.9607910513877869, 'Text': 'kidney pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 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'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9019791483879089}]}, {'Id': 281, 'BeginOffset': 4590, 'EndOffset': 4608, 'Score': 0.9616572260856628, 'Text': 'sexual dysfunction', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8096187710762024}]}, {'Id': 282, 'BeginOffset': 4610, 'EndOffset': 4626, 'Score': 0.9700709581375122, 'Text': 'decreased libido', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8949229717254639}]}, {'Id': 283, 'BeginOffset': 4633, 'EndOffset': 4650, 'Score': 0.8839178681373596, 'Text': 'sexual difficulty', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7596940398216248}]}, {'Id': 284, 'BeginOffset': 4652, 'EndOffset': 4662, 'Score': 0.5490817427635193, 'Text': 'metabolism', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 285, 'BeginOffset': 4664, 'EndOffset': 4686, 'Score': 0.7510830163955688, 'Text': 'low blood sugar levels', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6205162405967712}]}, {'Id': 293, 'BeginOffset': 4668, 'EndOffset': 4679, 'Score': 0.9978474378585815, 'Text': 'blood sugar', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.6230716705322266, 'RelationshipScore': 0.9999995231628418, 'RelationshipType': 'TEST_VALUE', 'Id': 292, 'BeginOffset': 4664, 'EndOffset': 4667, 'Text': 'low', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 286, 'BeginOffset': 4701, 'EndOffset': 4713, 'Score': 0.9577354192733765, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7883523106575012}]}, {'Id': 287, 'BeginOffset': 4729, 'EndOffset': 4741, 'Score': 0.9241843819618225, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7706053256988525}]}, {'Id': 288, 'BeginOffset': 4805, 'EndOffset': 4817, 'Score': 0.9564308524131775, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6745410561561584}]}, {'Id': 289, 'BeginOffset': 4866, 'EndOffset': 4878, 'Score': 0.8677140474319458, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7119624614715576}]}, {'Id': 290, 'BeginOffset': 4932, 'EndOffset': 4943, 'Score': 0.3894020617008209, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6257548332214355}]}, {'Id': 291, 'BeginOffset': 4957, 'EndOffset': 4969, 'Score': 0.860832929611206, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7444343566894531}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 5025, 'EndOffset': 5038}]}

{'Title': '5. how to store azarga', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle and the carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. throw away the bottle 4 weeks after first opening to prevent infections, and use a new bottle. write down the date of opening on the bottle label and carton label in the space provided. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what azarga contains the active substances are brinzolamide and timolol. one ml of suspension contains 10 mg of brinzolamide and 5 mg of timolol (as maleate). the other ingredients are benzalkonium chloride (see section 2 'azarga contains benzalkonium'), carbopol 974p, disodium edetate, mannitol (e421), purified water, sodium chloride, tyloxapol, hydrochloric acid and/or sodium hydroxide. tiny amounts of hydrochloric acid and/or sodium hydroxide are added to keep acidity levels (ph levels) normal. what azarga looks like and contents of the pack azarga is a liquid (white to off-white uniform suspension) supplied in a pack containing one 5 ml plastic bottle with a screw cap or in a pack containing three 5 ml bottles. not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'azarga', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 11, 'Score': 0.37979766726493835, 'Text': 'azarga', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 47, 'EndOffset': 59, 'Score': 0.9953165054321289, 'Text': 'brinzolamide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 64, 'EndOffset': 71, 'Score': 0.9963213205337524, 'Text': 'timolol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9647300839424133, 'RelationshipScore': 0.8960998058319092, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 73, 'EndOffset': 79, 'Text': 'one ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.8663648366928101, 'RelationshipScore': 0.9609482288360596, 'RelationshipType': 'FORM', 'Id': 4, 'BeginOffset': 83, 'EndOffset': 93, 'Text': 'suspension', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'suspension', 'Type': 'TREATMENT', 'BeginOffset': 83, 'EndOffset': 93}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 103, 'EndOffset': 105}, {'Id': 6, 'BeginOffset': 112, 'EndOffset': 124, 'Score': 0.9987285733222961, 'Text': 'brinzolamide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9647300839424133, 'RelationshipScore': 0.9755481481552124, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 73, 'EndOffset': 79, 'Text': 'one ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.8663648366928101, 'RelationshipScore': 0.866624653339386, 'RelationshipType': 'FORM', 'Id': 4, 'BeginOffset': 83, 'EndOffset': 93, 'Text': 'suspension', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8855811357498169, 'RelationshipScore': 0.9988241791725159, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 103, 'EndOffset': 108, 'Text': '10 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 129, 'EndOffset': 130}, {'Id': 8, 'BeginOffset': 137, 'EndOffset': 144, 'Score': 0.9732924103736877, 'Text': 'timolol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.7821664810180664, 'RelationshipScore': 0.9968587160110474, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 129, 'EndOffset': 133, 'Text': '5 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 9, 'BeginOffset': 149, 'EndOffset': 156, 'Score': 0.5537223815917969, 'Text': 'maleate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 185, 'EndOffset': 206, 'Score': 0.9963511228561401, 'Text': 'benzalkonium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 220, 'EndOffset': 221}, {'Id': 11, 'BeginOffset': 223, 'EndOffset': 229, 'Score': 0.7168176770210266, 'Text': 'azarga', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 239, 'EndOffset': 253, 'Score': 0.6283045411109924, 'Text': "benzalkonium')", 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 255, 'EndOffset': 263, 'Score': 0.6224609613418579, 'Text': 'carbopol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.49320435523986816, 'RelationshipScore': 0.9913911819458008, 'RelationshipType': 'STRENGTH', 'Id': 14, 'BeginOffset': 264, 'EndOffset': 268, 'Text': '974p', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 15, 'BeginOffset': 270, 'EndOffset': 286, 'Score': 0.9663904309272766, 'Text': 'disodium edetate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 288, 'EndOffset': 296, 'Score': 0.8798372149467468, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 305, 'EndOffset': 319, 'Score': 0.9903387427330017, 'Text': 'purified water', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 18, 'BeginOffset': 321, 'EndOffset': 336, 'Score': 0.9996870756149292, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 19, 'BeginOffset': 338, 'EndOffset': 347, 'Score': 0.9610293507575989, 'Text': 'tyloxapol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 20, 'BeginOffset': 349, 'EndOffset': 366, 'Score': 0.9972035884857178, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 21, 'BeginOffset': 374, 'EndOffset': 390, 'Score': 0.9989499449729919, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 22, 'BeginOffset': 408, 'EndOffset': 425, 'Score': 0.9961572289466858, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 23, 'BeginOffset': 433, 'EndOffset': 449, 'Score': 0.9971217513084412, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'acidity levels', 'Type': 'TEST', 'BeginOffset': 468, 'EndOffset': 482}, {'Text': 'ph levels', 'Type': 'TEST', 'BeginOffset': 484, 'EndOffset': 493}, {'Text': 'the pack azarga', 'Type': 'TREATMENT', 'BeginOffset': 542, 'EndOffset': 557}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 644, 'EndOffset': 645}, {'Text': 'a screw cap', 'Type': 'TREATMENT', 'BeginOffset': 669, 'EndOffset': 680}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 711, 'EndOffset': 712}]}

9A41613B51C2B72D58D71772D83A306A

https://www.ema.europa.eu/documents/product-information/aripiprazole-zentiva-epar-product-information_en.pdf

Aripiprazole Zentiva

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 5 mg tablets Aripiprazole Zentiva 10 mg tablets Aripiprazole Zentiva 15 mg tablets Aripiprazole Zentiva 30 mg tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Aripiprazole Zentiva 5 mg tablets Each tablet contains 5 mg of aripiprazole. Excipient with known effect Each tablet contains 33 mg of lactose (as monohydrate). Aripiprazole Zentiva 10 mg tablets Each tablet contains 10 mg of aripiprazole. Excipient with known effect Each tablet contains 66 mg of lactose (as monohydrate). Aripiprazole Zentiva 15 mg tablets Each tablet contains 15 mg of aripiprazole. Excipient with known effect Each tablet contains 99 mg of lactose (as monohydrate). Aripiprazole Zentiva 30 mg tablets Each tablet contains 30 mg of aripiprazole. Excipient with known effect Each tablet contains 198 mg of lactose (as monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablet Aripiprazole Zentiva 5 mg tablets White to off-white round flat bevel edged uncoated tablets with ‘5’ debossed on one side and plain on the other side with diameter approx. 6 mm. 3 Aripiprazole Zentiva 10 mg tablets White to off-white round uncoated tablets with ‘10’ debossed on one side and snap tab breakline on the other side with diameter approx. 8 mm. The score line is not intended for breaking the tablet. Aripiprazole Zentiva 15 mg tablets White to off-white round flat bevel edged uncoated tablets with ‘15’ debossed on one side and plain on the other side with diameter approx. 8.8 mm. Aripiprazole Zentiva 30 mg tablets White to off-white capsule shaped uncoated tablets with ‘30’ debossed on one side and snap tab breakline on the other side with dimensions approx. 15.5 x 8 mm. The score line is not intended for breaking the tablet. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aripiprazole Zentiva is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and older. Aripiprazole Zentiva is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1). Aripiprazole Zentiva is indicated for the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older (see section 5.1). 4.2 Posology and method of administration Posology Adults Schizophrenia The recommended starting dose for Aripiprazole Zentiva is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole Zentiva is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg. Manic episodes in Bipolar I Disorder The recommended starting dose for Aripiprazole Zentiva is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see section 5.1). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg. 4 Recurrence prevention of manic episodes in Bipolar I Disorder For preventing recurrence of manic episodes in patients, who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status. Paediatric population Schizophrenia in adolescents aged 15 years and older The recommended dose for Aripiprazole Zentiva is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section 5.1). Aripiprazole Zentiva is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose. Aripiprazole Zentiva is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy (see sections 4.8 and 5.1). Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older The recommended dose for Aripiprazole Zentiva is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain (see section 4.8). Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring (see sections 4.4, 4.8 and 5.1). Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Aripiprazole Zentiva is not recommended for use in patients below 13 years of age (see sections 4.8 and 5.1). Irritability associated with autistic disorder The safety and efficacy of aripiprazole in children and adolescents aged below 18 years have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Tics associated with Tourette’s disorder The safety and efficacy of aripiprazole in children and adolescents 6 to 18 years of age have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. 5 Special populations Hepatic impairment No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section 5.2). Renal impairment No dosage adjustment is required in patients with renal impairment. Elderly The safety and efficacy of aripiprazole in the treatment of schizophrenia or manic episodes in Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant (see section 4.4). Gender No dosage adjustment is required for female patients as compared to male patients (see section 5.2). Smoking status According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers (see section 4.5). Dose adjustments due to interactions When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5). When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see section 4.5). Method of administration Aripiprazole Zentiva is for oral use. Orodispersible tablets may be used as an alternative to Aripiprazole Zentiva tablets for patients who have difficulty swallowing Aripiprazole Zentiva tablets (see section 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use During antipsychotic treatment, improvement in the patient’s clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period. 6 Suicidality The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic treatment. Cardiovascular disorders Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken. QT prolongation In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation (see section 4.8). Tardive dyskinesia In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered (see section 4.8). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. Other extrapyramidal symptoms In paediatric clinical trials of aripiprazole akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered. Neuroleptic Malignant Syndrome (NMS) NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued. 7 Seizure In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures (see section 4.8). Elderly patients with dementia-related psychosis Increased mortality In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56 – 99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimerʼs disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in aripiprazole- treated patients was 3.5% compared to 1.7% in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature (see section 4.8). Cerebrovascular adverse reactions In the same trials, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78 – 88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole (see section 4.8). Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis. Hyperglycaemia and diabetes mellitus Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotic, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8). Hypersensitivity Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). Weight gain Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically 8 relevant weight gain in adults (see section 5.1). In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section 4.8). Dysphagia Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia. Pathological gambling and other impulse control disorders Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole (see section 4.8). Patients with attention deficit hyperactivity disorder (ADHD) comorbidity Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered. Falls Aripiprazole may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g., elderly or debilitated patients; see section 4.2). Lactose Aripiprazole Zentiva tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Sodium This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’. 4.5 Interaction with other medicinal products and other forms of interaction Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products. 9 Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. Potential for other medicinal products to affect aripiprazole A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant. Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers. Quinidine and other CYP2D6 inhibitors In a clinical trial in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107%, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32% and 47%, respectively. Aripiprazole dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of aripiprazole with quinidine occurs. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied. Ketoconazole and other CYP3A4 inhibitors In a clinical trial in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and Cmax by 63% and 37%, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77% and 43%, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers. When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconazole with aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors, may be expected to have similar effects and similar dose reductions should therefore be applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be increased to the level prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly with aripiprazole, modest increases in plasma aripiprazole concentrations may be expected. Carbamazepine and other CYP3A4 inducers Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC for aripiprazole were 68% and 73% lower, respectively, compared to when aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69% and 71% lower, respectively, than those following treatment with aripiprazole alone. Aripiprazole dose should be doubled when concomitant administration of aripiprazole occurs with carbamazepine. Concomitant administration of aripiprazole and other inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John’s 10 Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of strong CYP3A4 inducers, the dosage of aripiprazole should be reduced to the recommended dose. Valproate and lithium When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations and therefore no dose adjustment is necessary when either valproate or lithium is administered with aripiprazole. Potential for aripiprazole to affect other medicinal products In clinical studies, 10 – 30 mg/day doses of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydro- aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, aripiprazole is unlikely to cause clinically important medicinal product interactions mediated by these enzymes. When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations. Serotonin syndrome Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as selective serotonin reuptake inhibitor/selective serotonin noradrenalin reuptake inhibitor (SSRI/SNRI), or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8). 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole. Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus. Newborn infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborn infants should be monitored carefully (see section 4.8). Breast-feeding Aripiprazole/metabolites are excreted in human milk.A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from aripiprazole therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. 11 Fertility Aripiprazole did not impair fertility based on data from reproductive toxicity studies. 4.7 Effects on ability to drive and use machines Aripiprazole has minor to moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions in placebo-controlled trials were akathisia and nausea each occurring in more than 3% of patients treated with oral aripiprazole. Tabulated list of adverse reactions The incidences of the Adverse Drug Reactions (ADRs) associated with aripiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials and/or post- marketing use. All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as “not known”. Common Uncommon Not known Blood and lymphatic system disorders Leukopenia Neutropenia Thrombocytopenia Immune system disorders Allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus allergic, or urticaria) Endocrine disorders Hyperprolactinaemia Diabetic hyperosmolar coma Diabetic ketoacidosis Metabolism and nutrition disorders Diabetes mellitus Hyperglycaemia Hyponatremia Anorexia Psychiatric disorders Insomnia Anxiety Restlessness Depression Hypersexuality Suicide attempt, suicidal ideation and completed suicide (see section 4.4) Pathological gambling Impulse-control disorders Binge eating 12 Common Uncommon Not known Compulsive shopping Poriomania Aggression Agitation Nervousness Nervous system disorders Akathisia Extrapyramidal disorder Tremor Headache Sedation Somnolence Dizziness Tardive dyskinesia Dystonia Neuroleptic Malignant Syndrome Grand mal convulsion Serotonin syndrome Speech disorder Eye disorders Vision blurred Diplopia Photophobia Oculogyric crisis Cardiac disorders Tachycardia Sudden unexplained death Torsades de pointes Ventricular arrhythmias Cardiac arrest Bradycardia Vascular disorders Orthostatic hypotension Venous thromboembolism (including pulmonary embolism and deep vein thrombosis) Hypertension Syncope Respiratory, thoracic and mediastinal disorders Hiccups Aspiration pneumonia Laryngospasm Oropharyngeal spasm Gastrointestinal disorders Constipation Dyspepsia Nausea Salivary hypersecretion Vomiting Pancreatitis Dysphagia Diarrhoea Abdominal discomfort Stomach discomfort Hepatobiliary disorders Hepatic failure Hepatitis Jaundice Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Hyperhidrosis Musculoskeletal and connective tissue disorders Rhabdomyolysis Myalgia Stiffness Renal and urinary disorders Urinary incontinence Urinary retention Pregnancy, puerperium and perinatal conditions Drug withdrawal syndrome neonatal (see section 4.6) 13 Common Uncommon Not known Reproductive system and breast disorders Priapism General disorders and administration site conditions Fatigue Temperature regulation disorder (e.g. hypothermia, pyrexia) Chest pain Peripheral oedema Investigations Weight decreased Weight gain Alanine Aminotransferase increased Aspartate Aminotransferase increased Gamma-glutamyltransferase increased Alkaline phosphatase increased QT prolonged Blood glucose increased Glycosylated haemoglobin increased Blood glucose fluctuation Creatine phosphokinase increased Description of selected adverse reactions Adults Extrapyramidal symptoms (EPS) Schizophrenia – in a long term 52-week controlled trial, aripiprazole-treated patients had an overall- lower incidence (25.8%) of EPS including Parkinsonism, akathisia, dystonia and dyskinesia compared with those treated with haloperidol (57.3%). In a long term 26-week placebo-controlled trial, the incidence of EPS was 19% for aripiprazole-treated patients and 13.1% for placebo-treated patients. In another long-term 26-week controlled trial, the incidence of EPS was 14.8% for aripiprazole-treated patients and 15.1% for olanzapine-treated patients. Manic episodes in Bipolar I Disorder – in a 12-week controlled trial, the incidence of EPS was 23.5% for aripiprazole-treated patients and 53.3% for haloperidol-treated patients. In another 12-week trial, the incidence of EPS was 26.6% for patients treated with aripiprazole and 17.6% for those treated with lithium. In the long term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2% for aripiprazole-treated patients and 15.7% for placebo-treated patients. Akathisia In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1% with aripiprazole and 3.2% with placebo. In schizophrenia patients the incidence of akathisia was 6.2% with aripiprazole and 3.0% with placebo. Dystonia Class effect – Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of 14 the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups. Prolactin In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (see section 5.1). Laboratory parameters Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo. Paediatric population Schizophrenia in adolescents aged 15 years and older In a short-term placebo-controlled clinical trial involving 302 adolescents (13 – 17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults except for the following reactions that were reported more frequently in adolescents receiving aripiprazole than in adults receiving aripiprazole (and more frequently than placebo): Somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite, and orthostatic hypotension were reported commonly (≥ 1/100, < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short- term, placebo-controlled trial. The safety profile of a long-term, double-blind placebo controlled trial was also similar except for the following reactions that were reported more frequently than paediatric patients taking placebo: weight decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (≥ 1/100, < 1/10). In the pooled adolescent schizophrenia population (13 – 17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 29.5% and 48.3%, respectively. In the adolescent (13 – 17 years) schizophrenia population with aripiprazole exposure of 5 to 30 mg up to 72 months, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 25.6% and 45.0%, respectively. In two long term trials with adolescent (13 – 17 years) schizophrenia and bipolar patients treated with aripiprazole, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 37.0% and 59.4%, respectively. Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older The frequency and type of adverse reactions in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (≥ 1/10) somnolence (23.0%), extrapyramidal disorder (18.4%), akathisia (16.0%), and fatigue (11.8%); and commonly (≥ 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia. The following adverse reactions had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1%, 30 mg, 28.8%, placebo, 1.7%,); and akathisia (incidences were 10 mg, 12.1%, 30 mg, 20.3%, placebo, 1.7%). 15 Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively. In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia. In the paediatric bipolar population (10 – 17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 28.0% and 53.3%, respectively. Pathological gambling and other impulse control disorders Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating can occur in patients treated with aripiprazole (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Signs and symptoms In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities. The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms. Management of overdose Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers. Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax by about 41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of overdose. Haemodialysis Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 16 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12 Mechanism of action It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism of serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole. Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography. Clinical efficacy and safety Adults Schizophrenia In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. Aripiprazole is effective in maintaining the clinical improvement during continuation therapy in adult patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (aripiprazole 77% and haloperidol 73%). The overall completion rate was significantly higher for patients on aripiprazole (43%) than for haloperidol (30%). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale (MADRS) showed a significant improvement over haloperidol. In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34% in aripiprazole group and 57% in placebo. Weight gain In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain. In a 26- week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 adult patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on aripiprazole (n = 18, or 13% of evaluable patients), compared to olanzapine (n = 45, or 33% of evaluable patients). 17 Lipid parameters In a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, High Density Lipoprotein (HDL) and Low Density Lipoprotein (LDL). Prolactin Prolactin levels were evaluated in all trials of all doses of aripiprazole (n = 28,242). The incidence of hyperprolactinaemia or increased serum prolactin in patients treated with aripiprazole (0.3%) was similar to that of placebo (0.2%). For patients receiving aripiprazole, the median time to onset was 42 days and median duration was 34 days. The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazole was 0.4%, compared with 0.02% for patients treated with placebo. For patients receiving aripiprazole, the median time to onset was 30 days and median duration was 194 days. Manic episodes in Bipolar I Disorder In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction of manic symptoms over 3 weeks. These trials included patients with or without psychotic features and with or without a rapid-cycling course. In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo. In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12. Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium or haloperidol at week 12. In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy. In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomisation, aripiprazole demonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence into depression. In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I Disorder who achieved sustained remission (Young Mania Rating Scale [YMRS] and MADRS with total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated superiority over placebo with a 46% decreased risk (hazard ratio of 0.54) in preventing bipolar recurrence and a 65% decreased risk (hazard ratio of 0.35) in preventing recurrence into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure in Clinical Global Impression - Bipolar version (CGI-BP) Severity of Illness (SOI; mania) scores. 18 In this trial, patients were assigned by investigators with either open-label lithium or valproate monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer. Stabilized patients were then randomised to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16% in aripiprazole + lithium and 18% in aripiprazole + valproate compared to 45% in placebo + lithium and 19% in placebo + valproate. Paediatric population Schizophrenia in adolescents In a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13 – 17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. In a 60- to 89-week, randomised, double-blind, placebo-controlled trial in adolescent subjects (n = 146; ages 13 – 17 years) with schizophrenia, there was a statistically significant difference in the rate of relapse of psychotic symptoms between the aripiprazole (19.39%) and placebo (37.50%) groups. The point estimate of the hazard ratio (HR) was 0.461 (95% confidence interval, 0.242 – 0.879) in the full population. In subgroup analyses the point estimate of the HR was 0.495 for subjects 13 to 14 years of age compared to 0.454 for subjects 15 to 17 years of age. However, the estimation of the HR for the younger (13 – 14 years) group was not precise, reflecting the smaller number of subjects in that group (aripiprazole, n = 29; placebo, n = 12), and the confidence interval for this estimation (ranging from 0.151 to 1.628) did not allow conclusions to be drawn on the presence of a treatment effect. In contrast the 95% confidence interval for the HR in the older subgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242 to 0.879 and hence a treatment effect could be concluded in the older patients. Manic episodes in Bipolar I Disorder in children and adolescents Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children and adolescents (10 – 17 years), who met DSM-IV criteria (Diagnostic and Statistical Manual of Mental Disorders) for Bipolar I Disorder with manic or mixed episodes with or without psychotic features and had a YMRS score ≥ 20 at baseline. Among the patients included in the primary efficacy analysis, 139 patients had a current comorbid diagnosis of ADHD. Aripiprazole was superior to placebo in change from baseline at week 4 and at week 12 on the Y-MRS total score. In a post-hoc analysis, the improvement over placebo was more pronounced in the patients with associated comorbidity of ADHD compared to the group without ADHD, where there was no difference from placebo. Recurrence prevention was not established. The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidal disorder (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with placebo. 19 Irritability associated with autistic disorder in paediatric patients (see section 4.2) Aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2 – 15 mg/day) and one fixed-dose (5, 10, or 15 mg/day)] and in one 52-week open- label trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly increments to the target dose. Over 75% of patients were less than 13 years of age. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the Aberrant Behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In the pooled trials, the incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) in aripiprazole-treated patients was 27/46 (58.7%) and 258/298 (86.6%), respectively. In the placebo- controlled trials, the mean weight gain was 0.4 kg for placebo and 1.6 kg for aripiprazole. Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial. After a 13 - 26 week stabilisation on aripiprazole (2 – 15 mg/day) patients with a stable response were either maintained on aripiprazole or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo; the hazard ratio for relapse within 16 weeks (aripiprazole/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26 weeks) on aripiprazole was 3.2 kg, and a further mean increase of 2.2 kg for aripiprazole as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17% of patients, with tremor accounting for 6.5%. Tics associated with Tourette’s disorder in paediatric patients (see section 4.2) The efficacy of aripiprazole was studied in paediatric subjects with Tourette’s disorder (aripiprazole: n = 99, placebo: n = 44) in a randomised, double-blind, placebo controlled, 8 week study using a fixed dose weight-based treatment group design over the dose range of 5 mg/day to 20 mg/day and a starting dose of 2 mg. Patients were 7 – 17 years of age and presented an average score of 30 on Total Tic Score on the Yale Global Tic Severity Scale (TTS-YGTSS) at baseline. Aripiprazole showed an improvement on TTS-YGTSS change from baseline to week 8 of 13.35 for the low dose group (5 mg or 10 mg) and 16.94 for the high dose group (10 mg or 20 mg) as compared with an improvement of 7.09 in the placebo group. The efficacy of aripiprazole in paediatric subjects with Tourette’s syndrome (aripiprazole: n = 32, placebo: n = 29) was also evaluated over a flexible dose range of 2 mg/day to 20 mg/day and a starting dose of 2 mg, in a 10 week, randomised, double blind, placebo-controlled study conducted in South- Korea. Patients were 6 – 18 years and presented an average score of 29 on TTS-YGTSS at baseline. Aripiprazole group showed an improvement of 14.97 on TTS-YGTSS change from baseline to week 10 as compared with an improvement of 9.62 in the placebo group. In both of these short term trials, the clinical relevance of the efficacy findings has not been established, considering the magnitude of treatment effect compared to the large placebo effect and the unclear effects regarding psycho-social functioning. No long term data are available with regard to the efficacy and the safety of aripiprazole in this fluctuating disorder. The European Medicines Agency has deferred the obligation to submit the results of studies with the reference medicinal product containing aripiprazole in one or more subsets of the paediatric population in the treatment of schizophrenia and in the treatment of bipolar affective disorder (see section 4.2 for information on paediatric use). 20 5.2 Pharmacokinetic properties Absorption Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3 – 5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole. Distribution Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin. Biotransformation Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. Elimination The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6. The total body clearance of aripiprazole is 0.7 ml/min/kg, which is primarily hepatic. Following a single oral dose of [14C]-labelled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces. Paediatric population The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of age were similar to those in adults after correcting for the differences in body weights. Pharmacokinetics in special patient groups Elderly There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients. Gender There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients. 21 Smoking Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from smoking on the pharmacokinetics of aripiprazole. Race Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole. Renal impairment The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects. Hepatic impairment A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC at the maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose. An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 to 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m2). However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) their limits of in vitro solubility. In repeat-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse reactions on development. Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non- genotoxic. Aripiprazole did not impair fertility in reproductive toxicity studies. Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity. 22 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Microcrystalline cellulose Crospovidone Hydroxypropyl cellulose Silica colloidal anhydrous Croscarmellose sodium Magnesium stearate 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container OPA/Alu/PVC/Alu foil blisters (Alu-Alu blister), carton box. Pack size: 14, 28, 49, 56, or 98 tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 23 8. MARKETING AUTHORISATION NUMBER(S) Aripiprazole Zentiva 5 mg tablets EU/1/15/1009/001 EU/1/15/1009/002 EU/1/15/1009/003 EU/1/15/1009/004 EU/1/15/1009/005 Aripiprazole Zentiva 10 mg tablets EU/1/15/1009/006 EU/1/15/1009/007 EU/1/15/1009/008 EU/1/15/1009/009 EU/1/15/1009/010 Aripiprazole Zentiva 15 mg tablets EU/1/15/1009/011 EU/1/15/1009/012 EU/1/15/1009/013 EU/1/15/1009/014 EU/1/15/1009/015 Aripiprazole Zentiva 30 mg tablets EU/1/15/1009/016 EU/1/15/1009/017 EU/1/15/1009/018 EU/1/15/1009/019 EU/1/15/1009/020 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 25 June 2015 Date of latest renewal: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 24 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 10 mg orodispersible tablets Aripiprazole Zentiva 15 mg orodispersible tablets Aripiprazole Zentiva 30 mg orodispersible tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Aripiprazole Zentiva 10 mg orodispersible tablets Each orodispersible tablet contains 10 mg of aripiprazole. Excipient with known effect Each orodispersible tablet contains 37 mg of lactose (as monohydrate). Aripiprazole Zentiva 15 mg orodispersible tablets Each orodispersible tablet contains 15 mg of aripiprazole. Excipient with known effect Each orodispersible tablet contains 55.5 mg of lactose (as monohydrate). Aripiprazole Zentiva 30 mg orodispersible tablets Each orodispersible tablet contains 30 mg of aripiprazole. Excipient with known effect Each orodispersible tablet contains 111 mg of lactose (as monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Orodispersible tablet Aripiprazole Zentiva 10 mg orodispersible tablets White to off-white round tablets debossed ‘10’ on one side and snap break line on other side with diameter approx. 7 mm. The score line is not intended for breaking the tablet. Aripiprazole Zentiva 15 mg orodispersible tablets White to off-white round flat bevel edged tablets debossed ‘15’ on one side and plain on the other side with diameter approx. 8 mm. Aripiprazole Zentiva 30 mg orodispersible tablets 25 White to off-white round tablets debossed ‘30’ on one side and snap break line on the other side with diameter approx. 10.2 mm. The score line is not intended for breaking the tablet. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aripiprazole Zentiva is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and older. Aripiprazole Zentiva is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1). Aripiprazole Zentiva is indicated for the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older (see section 5.1). 4.2 Posology and method of administration Posology Adults Schizophrenia The recommended starting dose for Aripiprazole Zentiva is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole Zentiva is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg. Manic episodes in Bipolar I Disorder The recommended starting dose for Aripiprazole Zentiva is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see section 5.1). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg. Recurrence prevention of manic episodes in Bipolar I Disorder For preventing recurrence of manic episodes in patients who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status. Paediatric population Schizophrenia in adolescents aged 15 years and older The recommended dose for Aripiprazole Zentiva is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section 5.1). 26 Aripiprazole Zentiva is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose. Aripiprazole Zentiva is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy (see sections 4.8 and 5.1). Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older The recommended dose for Aripiprazole Zentiva is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain (see section 4.8). Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring (see sections 4.4, 4.8 and 5.1). Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Aripiprazole Zentiva is not recommended for use in patients below 13 years of age (see sections 4.8 and 5.1). Irritability associated with autistic disorder The safety and efficacy of aripiprazole in children and adolescents aged below 18 years have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Tics associated with Tourette’s disorder The safety and efficacy of aripiprazole in children and adolescents 6 to 18 years of age have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Special populations Hepatic impairment No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section 5.2). Renal impairment No dosage adjustment is required in patients with renal impairment. Elderly The safety and efficacy of aripiprazole in the treatment of schizophrenia or manic episodes in Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant (see section 4.4). 27 Gender No dosage adjustment is required for female patients as compared to male patients (see section 5.2). Smoking status According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers (see section 4.5). Dose adjustments due to interactions When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5). When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see section 4.5). Method of administration Aripiprazole Zentiva is for oral use. The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly disperse in saliva. It can be taken with or without liquid. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, disperse the tablet in water and drink the resulting suspension. The orodispersible tablets may be used as an alternative to Aripiprazole Zentiva tablets for patients who have difficulty swallowing Aripiprazole Zentiva tablets (see section 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use During antipsychotic treatment, improvement in the patient’s clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period. Suicidality The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Cardiovascular disorders Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant. 28 Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken. QT prolongation In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation (see section 4.8). Tardive dyskinesia In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered (see section 4.8). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. Other extrapyramidal symptoms In paediatric clinical trials of aripiprazole akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered. Neuroleptic Malignant Syndrome (NMS) NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued. Seizure In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures (see section 4.8). Elderly patients with dementia-related psychosis Increased mortality In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56 – 99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimer’s disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in aripiprazole- treated patients was 3.5% compared to 1.7% in the placebo group. Although the causes of deaths were 29 varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature (see section 4.8). Cerebrovascular adverse reactions In the same trials, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78 – 88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6% of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole (see section 4.8). Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis. Hyperglycaemia and diabetes mellitus Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotics, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8). Hypersensitivity Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). Weight gain Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain in adults (see section 5.1). In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section 4.8). Dysphagia Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia. 30 Pathological gambling and other impulse control disorders Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole (see section 4.8). Patients with attention deficit hyperactivity disorder (ADHD) comorbidity Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered. Falls Aripiprazole may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g., elderly or debilitated patients; see section 4.2). Lactose Aripiprazole Zentiva orodispersible tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Sodium This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’. 4.5 Interaction with other medicinal products and other forms of interaction Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products. Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. Potential for other medicinal products to affect aripiprazole A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant. 31 Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers. Quinidine and other CYP2D6 inhibitors In a clinical trial in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107%, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32% and 47%, respectively. Aripiprazole dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of aripiprazole with quinidine occurs. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied. Ketoconazole and other CYP3A4 inhibitors In a clinical trial in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and Cmax by 63% and 37%, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77% and 43%, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers. When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconazole with aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should therefore be applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be increased to the level prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly with aripiprazole, modest increases in plasma aripiprazole concentrations may be expected. Carbamazepine and other CYP3A4 inducers Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC for aripiprazole were 68% and 73% lower, respectively, compared to when aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69% and 71% lower, respectively, than those following treatment with aripiprazole alone. Aripiprazole dose should be doubled when concomitant administration of aripiprazole occurs with carbamazepine. Concomitant administration of aripiprazole and other inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John’s Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of strong CYP3A4 inducers, the dosage of aripiprazole should be reduced to the recommended dose. Valproate and lithium When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations and therefore no dose adjustment is necessary when either valproate or lithium is administered with aripiprazole. 32 Potential for aripiprazole to affect other medicinal products In clinical studies, 10 – 30 mg/day doses of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydro- aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, aripiprazole is unlikely to cause clinically important medicinal product interactions mediated by these enzymes. When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations. Serotonin syndrome Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as selective serotonin reuptake inhibitor/selective serotonin noradrenalin reuptake inhibitor (SSRI/SNRI), or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8). 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole. Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus. Newborn infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborn infants should be monitored carefully (see section 4.8). Breast-feeding Aripiprazole/metabolites are excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from aripiprazole therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Aripiprazole did not impair fertility based on data from reproductive toxicity studies. 4.7 Effects on ability to drive and use machines Aripiprazole has minor to moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia (see section 4.8). 33 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions in placebo-controlled trials were akathisia and nausea each occurring in more than 3% of patients treated with oral aripiprazole. Tabulated list of adverse reactions The incidences of the Adverse Drug Reactions (ADRs) associated with aripiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials and/or post- marketing use. All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as “not known”. Common Uncommon Not known Blood and lymphatic system disorders Leukopenia Neutropenia Thrombocytopenia Immune system disorders Allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus allergic, or urticaria) Endocrine disorders Hyperprolactinaemia Diabetic hyperosmolar coma Diabetic ketoacidosis Metabolism and nutrition disorders Diabetes mellitus Hyperglycaemia Hyponatremia Anorexia Psychiatric disorders Insomnia Anxiety Restlessness Depression Hypersexuality Suicide attempt, suicidal ideation and completed suicide (see section 4.4) Pathological gambling Impulse-control disorders Binge eating Compulsive shopping Poriomania Aggression Agitation Nervousness Nervous system disorders Akathisia Extrapyramidal disorder Tremor Tardive dyskinesia Dystonia Neuroleptic Malignant Syndrome Grand mal convulsion Serotonin syndrome 34 Common Uncommon Not known Headache Sedation Somnolence Dizziness Speech disorder Eye disorders Vision blurred Diplopia Photophobia Oculogyric crisis Cardiac disorders Tachycardia Sudden death unexplained Torsades de pointes Ventricular arrhythmias Cardiac arrest Bradycardia Vascular disorders Orthostatic hypotension Venous thromboembolism (including pulmonary embolism and deep vein thrombosis) Hypertension Syncope Respiratory, thoracic and mediastinal disorders Hiccups Aspiration pneumonia Laryngospasm Oropharyngeal spasm Gastrointestinal disorders Constipation Dyspepsia Nausea Salivary hypersecretion Vomiting Pancreatitis Dysphagia Diarrhoea Abdominal discomfort Stomach discomfort Hepatobiliary disorders Hepatic failure Hepatitis Jaundice Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Hyperhidrosis Musculoskeletal and connective tissue disorders Rhabdomyolysis Myalgia Stiffness Renal and urinary disorders Urinary incontinence Urinary retention Pregnancy, puerperium and perinatal conditions Drug withdrawal syndrome neonatal (see section 4.6) Reproductive system and breast disorders Priapism General disorders and administration site conditions Fatigue Temperature regulation disorder (e.g. hypothermia, pyrexia) Chest pain Peripheral oedema Investigations Weight decreased Weight gain 35 Common Uncommon Not known Alanine Aminotransferase increased Aspartate Aminotransferase increased Gamma-glutamyltransferase increased Alkaline phosphatase increased QT prolonged Blood glucose increased Glycosylated haemoglobin increased Blood glucose fluctuation Creatine phosphokinase increased Description of selected adverse reactions Adults Extrapyramidal symptoms (EPS) Schizophrenia – in a long term 52-week controlled trial, aripiprazole-treated patients had an overall- lower incidence (25.8%) of EPS including Parkinsonism, akathisia, dystonia and dyskinesia compared with those treated with haloperidol (57.3%). In a long term 26-week placebo-controlled trial, the incidence of EPS was 19% for aripiprazole-treated patients and 13.1% for placebo-treated patients. In another long-term 26-week controlled trial, the incidence of EPS was 14.8% for aripiprazole-treated patients and 15.1% for olanzapine-treated patients. Manic episodes in Bipolar I Disorder – in a 12-week controlled trial, the incidence of EPS was 23.5% for aripiprazole-treated patients and 53.3% for haloperidol-treated patients. In another 12-week trial, the incidence of EPS was 26.6% for patients treated with aripiprazole and 17.6% for those treated with lithium. In the long term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2% for aripiprazole-treated patients and 15.7% for placebo-treated patients. Akathisia In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1% with aripiprazole and 3.2% with placebo. In schizophrenia patients the incidence of akathisia was 6.2% with aripiprazole and 3.0% with placebo. Dystonia Class effect – Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups. Prolactin In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (see section 5.1). 36 Laboratory parameters Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo. Paediatric population Schizophrenia in adolescents aged 15 years and older In a short-term placebo-controlled clinical trial involving 302 adolescents (13 – 17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults except for the following reactions that were reported more frequently in adolescents receiving aripiprazole than in adults receiving aripiprazole (and more frequently than placebo): Somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite, and orthostatic hypotension were reported commonly (≥ 1/100, < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short- term, placebo-controlled trial. The safety profile of a long-term, double-blind placebo controlled trial was also similar except for the following reactions that were reported more frequently than paediatric patients taking placebo: weight decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (≥ 1/100, < 1/10). In the pooled adolescent schizophrenia population (13 – 17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 29.5% and 48.3%, respectively. In the adolescent (13 – 17 years) schizophrenia population with aripiprazole exposure of 5 to 30 mg up to 72 months, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 25.6% and 45.0%, respectively. In two long term trials with adolescent (13 – 17 years) schizophrenia and bipolar patients treated with aripiprazole, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 37.0 % and 59.4 %, respectively. Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older The frequency and type of adverse reactions in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (≥ 1/10) somnolence (23.0%), extrapyramidal disorder (18.4%), akathisia (16.0%), and fatigue (11.8%); and commonly (≥ 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia. The following adverse reactions had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1%, 30 mg, 28.8%, placebo, 1.7%,); and akathisia (incidences were 10 mg, 12.1%, 30 mg, 20.3%, placebo, 1.7%). Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively. In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia. In the paediatric bipolar population (10 – 17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 28.0% and 53.3%, respectively. 37 Pathological gambling and other impulse control disorders Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating can occur in patients treated with aripiprazole (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Signs and symptoms In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities. The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms. Management of overdose Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers. Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax by about 41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of overdose. Haemodialysis Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 38 Mechanism of action It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism of serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole. Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography. Clinical efficacy and safety Adults Schizophrenia In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. Aripiprazole is effective in maintaining the clinical improvement during continuation therapy in adult patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (aripiprazole 77% and haloperidol 73%). The overall completion rate was significantly higher for patients on aripiprazole (43%) than for haloperidol (30%). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale (MADRS) showed a significant improvement over haloperidol. In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34% in aripiprazole group and 57% in placebo. Weight gain In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain. In a 26- week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 adult patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on aripiprazole (N = 18, or 13% of evaluable patients), compared to olanzapine (N = 45, or 33% of evaluable patients). Lipid parameters In a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, High Density Lipoprotein (HDL) and Low Density Lipoprotein (LDL). 39 Prolactin Prolactin levels were evaluated in all trials of all doses of aripiprazole (n = 28,242). The incidence of hyperprolactinaemia or increased serum prolactin in patients treated with aripiprazole (0.3%) was similar to that of placebo (0.2%). For patients receiving aripiprazole, the median time to onset was 42 days and median duration was 34 days. The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazole was 0.4%, compared with 0.02% for patients treated with placebo. For patients receiving aripiprazole, the median time to onset was 30 days and median duration was 194 days. Manic episodes in Bipolar I Disorder In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction of manic symptoms over 3 weeks. These trials included patients with or without psychotic features and with or without a rapid-cycling course. In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo. In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12. Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium or haloperidol at week 12. In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy. In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomisation, aripiprazole demonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence into depression. In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I Disorder who achieved sustained remission (Young Mania Rating Scale [YMRS] and MADRS with total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated superiority over placebo with a 46% decreased risk (hazard ratio of 0.54) in preventing bipolar recurrence and a 65% decreased risk (hazard ratio of 0.35) in preventing recurrence into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure in Clinical Global Impression - Bipolar version (CGI-BP) Severity of Illness (SOI; mania) score . In this trial, patients were assigned by investigators with either open-label lithium or valproate monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer. Stabilized patients were then randomised to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. 40 The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16% in aripiprazole + lithium and 18% in aripiprazole + valproate compared to 45% in placebo + lithium and 19% in placebo + valproate. Paediatric population Schizophrenia in adolescents In a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13 – 17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. In a 60- to 89-week, randomised, double-blind, placebo-controlled trial in adolescent subjects (n = 146; ages 13 – 17 years) with schizophrenia, there was a statistically significant difference in the rate of relapse of psychotic symptoms between the aripiprazole (19.39%) and placebo (37.50%) groups. The point estimate of the hazard ratio (HR) was 0.461 (95% confidence interval, 0.242 – 0.879) in the full population. In subgroup analyses the point estimate of the HR was 0.495 for subjects 13 to 14 years of age compared to 0.454 for subjects 15 to 17 years of age. However, the estimation of the HR for the younger (13 – 14 years) group was not precise, reflecting the smaller number of subjects in that group (aripiprazole, n = 29; placebo, n = 12), and the confidence interval for this estimation (ranging from 0.151 to 1.628) did not allow conclusions to be drawn on the presence of a treatment effect. In contrast the 95% confidence interval for the HR in the older subgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242 to 0.879 and hence a treatment effect could be concluded in the older patients. Manic episodes in Bipolar I Disorder in children and adolescents Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children and adolescents (10 – 17 years), who met DSM-IV criteria (Diagnostic and Statistical Manual of Mental Disorders) for Bipolar I Disorder with manic or mixed episodes with or without psychotic features and had a Y-MRS score ≥ 20 at baseline. Among the patients included in the primary efficacy analysis, 139 patients had a current co-morbid diagnosis of ADHD. Aripiprazole was superior to placebo in change from baseline at week 4 and at week 12 on the Y-MRS total score. In a post-hoc analysis, the improvement over placebo was more pronounced in the patients with associated co-morbidity of ADHD compared to the group without ADHD, where there was no difference from placebo. Recurrence prevention was not established. The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidal disorder (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with placebo. Irritability associated with autistic disorder in paediatric patients (see section 4.2) Aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2 – 15 mg/day) and one fixed-dose (5, 10, or 15 mg/day)] and in one 52-week open- label trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly increments to the target dose. Over 75% of patients were less than 13 years of age. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the Aberrant Behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In the pooled trials, 41 the incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) in aripiprazole-treated patients was 27/46 (58.7%) and 258/298 (86.6%), respectively. In the placebo- controlled trials, the mean weight gain was 0.4 kg for placebo and 1.6 kg for aripiprazole. Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial. After a 13 - 26 week stabilisation on aripiprazole (2 – 15 mg/day) patients with a stable response were either maintained on aripiprazole or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo; the hazard ratio for relapse within 16 weeks (aripiprazole/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26 weeks) on aripiprazole was 3.2 kg, and a further mean increase of 2.2 kg for aripiprazole as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17% of patients, with tremor accounting for 6.5%. Tics associated with Tourette’s disorder in paediatric patients (see section 4.2) The efficacy of aripiprazole was studied in paediatric subjects with Tourette’s disorder (aripiprazole: n = 99, placebo: n = 44) in a randomised, double-blind, placebo controlled, 8 week study using a fixed dose weight-based treatment group design over the dose range of 5 mg/day to 20 mg/day and a starting dose of 2 mg. Patients were 7 – 17 years of age and presented an average score of 30 on Total Tic Score on the Yale Global Tic Severity Scale (TTS-YGTSS) at baseline. Aripiprazole showed an improvement on TTS-YGTSS change from baseline to week 8 of 13.35 for the low dose group (5 mg or 10 mg) and 16.94 for the high dose group (10 mg or 20 mg) as compared with an improvement of 7.09 in the placebo group. The efficacy of aripiprazole in paediatric subjects with Tourette’s syndrome (aripiprazole: n = 32, placebo: n = 29) was also evaluated over a flexible dose range of 2 mg/day to 20 mg/day and a starting dose of 2 mg, in a 10 week, randomised, double blind, placebo-controlled study conducted in South- Korea. Patients were 6 - 18 years and presented an average score of 29 on TTS-YGTSS at baseline. Aripiprazole group showed an improvement of 14.97 on TTS-YGTSS change from baseline to week 10 as compared with an improvement of 9.62 in the placebo group. In both of these short term trials, the clinical relevance of the efficacy findings has not been established, considering the magnitude of treatment effect compared to the large placebo effect and the unclear effects regarding psycho-social functioning. No long term data are available with regard to the efficacy and the safety of aripiprazole in this fluctuating disorder. The European Medicines Agency has deferred the obligation to submit the results of studies with the reference medicinal product containing aripiprazole in one or more subsets of the paediatric population in the treatment of schizophrenia and in the treatment of bipolar affective disorder (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3 – 5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole. 42 Distribution Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin. Biotransformation Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. Elimination The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6. The total body clearance of aripiprazole is 0.7 ml/min/kg, which is primarily hepatic. Following a single oral dose of [14C]-labelled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces. Paediatric population The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of age were similar to those in adults after correcting for the differences in body weights. Pharmacokinetics in special patient groups Elderly There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients. Gender There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients. Smoking Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from smoking on the pharmacokinetics of aripiprazole. Race Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole. 43 Renal impairment The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects. Hepatic impairment A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC at the maximum recommended human dose). The highest non-tumorigenic exposure in female rats was 7 times the human exposure at the recommended dose. An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 to 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m2). However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) their limits of in vitro solubility. In repeat-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse reactions on development. Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non- genotoxic. Aripiprazole did not impair fertility in reproductive toxicity studies. Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Microcrystalline cellulose Crospovidone 44 Hydroxypropyl cellulose Silica colloidal anhydrous Croscarmellose sodium Acesulfame potassium Mango flavour Magnesium stearate 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container OPA/Alu/PVC/Alu foil blisters (Alu-Alu blister), carton box. Pack size: 14, 28 or 49 orodispersible tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 8. MARKETING AUTHORISATION NUMBER(S) Aripiprazole Zentiva 10 mg orodispersible tablets EU/1/15/1009/021 EU/1/15/1009/022 EU/1/15/1009/023 Aripiprazole Zentiva 15 mg orodispersible tablets EU/1/15/1009/024 EU/1/15/1009/025 EU/1/15/1009/026 45 Aripiprazole Zentiva 30 mg orodispersible tablets EU/1/15/1009/027 EU/1/15/1009/028 EU/1/15/1009/029 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 25 June 2015 Date of latest renewal: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 46 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 47 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Zentiva SA 50 Theodor Pallady Blvd. District 3, 032266 Bucuresti Romania B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 48 ANNEX III LABELLING AND PACKAGE LEAFLET 49 A. LABELLING 50 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 5 mg tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 5 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet 14 tablets 28 tablets 49 tablets 56 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 51 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1009/001 EU/1/15/1009/002 EU/1/15/1009/003 EU/1/15/1009/004 EU/1/15/1009/005 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Zentiva 5 mg tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 52 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 53 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 5 mg tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Zentiva logo 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 54 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 10 mg tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 10 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet 14 tablets 28 tablets 49 tablets 56 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 55 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1009/006 EU/1/15/1009/007 EU/1/15/1009/008 EU/1/15/1009/009 EU/1/15/1009/010 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Zentiva 10 mg tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 56 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 57 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 10 mg tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Zentiva logo 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 58 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 15 mg tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 15 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet 14 tablets 28 tablets 49 tablets 56 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 59 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1009/011 EU/1/15/1009/012 EU/1/15/1009/013 EU/1/15/1009/014 EU/1/15/1009/015 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Zentiva 15 mg tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 60 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 61 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 15 mg tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Zentiva logo 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 62 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 30 mg tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 30 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet 14 tablets 28 tablets 49 tablets 56 tablets 98 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 63 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1009/016 EU/1/15/1009/017 EU/1/15/1009/018 EU/1/15/1009/019 EU/1/15/1009/020 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Zentiva 30 mg tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 64 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 65 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 30 mg tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Zentiva logo 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 66 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 10 mg orodispersible tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each orodipersible tablet contains 10 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Orodispersible tablet 14 orodispersible tablets 28 orodispersible tablets 49 orodispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 67 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1009/021 EU/1/15/1009/022 EU/1/15/1009/023 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Zentiva 10 mg orodispersible tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 68 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 10 mg orodispersible tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Zentiva logo 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 69 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 15 mg orodispersible tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each orodipersible tablet contains 15 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Orodispersible tablet 14 orodispersible tablets 28 orodispersible tablets 49 orodispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 70 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1009/024 EU/1/15/1009/025 EU/1/15/1009/026 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Zentiva 15 mg orodispersible tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 71 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 15 mg orodispersible tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Zentiva logo 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 72 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 30 mg orodispersible tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each orodipersible tablet contains 30 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Orodispersible tablet 14 orodispersible tablets 28 orodispersible tablets 49 orodispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 73 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1009/027 EU/1/15/1009/028 EU/1/15/1009/029 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Zentiva 30 mg orodispersible tablets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 74 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Zentiva 30 mg orodispersible tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Zentiva logo 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 75 B. PACKAGE LEAFLET 76 Package leaflet: Information for the user Aripiprazole Zentiva 5 mg tablets Aripiprazole Zentiva 10 mg tablets Aripiprazole Zentiva 15 mg tablets Aripiprazole Zentiva 30 mg tablets aripiprazole Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aripiprazole Zentiva is and what it is used for 2. What you need to know before you take Aripiprazole Zentiva 3. How to take Aripiprazole Zentiva 4. Possible side effects 5. How to store Aripiprazole Zentiva 6. Contents of the pack and other information 1. What Aripiprazole Zentiva is and what it is used for Aripiprazole Zentiva contains the active substance aripiprazole and belong to a group of medicines called antipsychotics. It is used to treat adults and adolescents aged 15 years and older who suffer from a disease characterised by symptoms such as hearing, seeing or sensing things which are not there, suspiciousness, mistaken beliefs, incoherent speech and behaviour and emotional flatness. People with this condition may also feel depressed, guilty, anxious or tense. Aripiprazole Zentiva is used to treat adults and adolescents aged 13 years and older who suffer from a condition with symptoms such as feeling “high”, having excessive amounts of energy, needing much less sleep than usual, talking very quickly with racing ideas and sometimes severe irritability. In adults it also prevents this condition from returning in patients who have responded to the treatment with Aripiprazole Zentiva. 2. What you need to know before you take Aripiprazole Zentiva Do not take Aripiprazole Zentiva • if you are allergic to aripiprazole or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor before taking Aripiprazole Zentiva. Suicidal thoughts and behaviours have been reported during aripiprazole treatment. Tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. 77 Before treatment with Aripiprazole Zentiva, tell your doctor if you suffer from • high blood sugar (characterised by symptoms such as excessive thirst, passing of large amounts of urine, increase in appetite and feeling weak) or family history of diabetes • fits (seizures) since your doctor may want to monitor you more closely • involuntary, irregular muscle movements, especially in the face • cardiovascular diseases (diseases of the heart and circulation), family history of cardiovascular disease, stroke or “mini” stroke, abnormal blood pressure • blood clots, or family history of blood clots, as antipsychotics have been associated with formation of blood clots • past experience with excessive gambling. If you notice you are gaining weight, develop unusual movements, experience somnolence that interferes with normal daily activities, any difficulty in swallowing or allergic symptoms, please tell your doctor. If you are an elderly patient suffering from dementia (loss of memory and other mental abilities), you or your carer/relative should tell your doctor if you have ever had a stroke or “mini” stroke. Tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. Suicidal thoughts and behaviours have been reported during aripiprazole treatment. Tell your doctor immediately if you suffer from muscle stiffness or inflexibility with high fever, sweating, altered mental status, or very rapid or irregular heart beat. Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or preoccupation with an increase in sexual thoughts or feelings. Your doctor may need to adjust or stop your dose. Aripiprazole may cause sleepiness, fall in blood pressure when standing up, dizziness and changes in your ability to move and balance, which may lead to falls. Caution should be taken, particularly if you are an elderly patient or have some debility. Children and adolescents Do not use this medicine in children and adolescents under 13 years of age. It is not known if it is safe and effective in these patients. Other medicines and Aripiprazole Zentiva Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. Blood pressure-lowering medicines: Aripiprazole Zentiva may increase the effect of medicines used to lower the blood pressure. Be sure to tell your doctor if you take a medicine to keep your blood pressure under control. Taking Aripiprazole Zentiva with some medicines may mean the doctor will need to change your dose of Aripiprazole Zentiva or the other medicines. It is especially important to mention the following to your doctor: • Medicines to correct heart rhythm (such as quinidine, amiodarone, flecainide) 78 • Antidepressants or herbal remedy used to treat depression and anxiety (such as fluoxetine, paroxetine, venlafaxine, St. Johnʼs Wort) • Antifungal medicines (such as ketoconazole, itraconazole) • Certain medicines to treat HIV infection (such as efavirenz, nevirapine, an protease inhibitors e.g. indinavir, ritonavir) • Anticonvulsants used to treat epilepsy (such as carbamazepine, phenytoin, phenobarbital) • Certain antibiotics used to treat tuberculosis (rifabutin, rifampicin) These medicines may increase the risk of side effects or reduce the effect of Aripiprazole Zentiva; if you get any unusual symptom taking any of these medicines together with Aripiprazole Zentiva, you should see your doctor. Medicines that increase the level of serotonin are typically used in conditions including depression, generalised anxiety disorder, obsessive-compulsive disorder (OCD) and social phobia as well as migraine and pain: • Triptans, tramadol and tryptophan used for conditions including depression, generalised anxiety disorder, obsessive compulsive disorder (OCD) and social phobia as well as migraine and pain • Selective-serotonin-reuptake-inhibitors (SSRIs) (such as paroxetine and fluoxetine) used for depression, OCD, panic and anxiety • Other anti-depressants (such as venlafaxine and tryptophan) used in major depression • Tricyclic’s (such as clomipramine and amitriptyline) used for depressive illness • St John’s Wort (Hypericum perforatum) used as a herbal remedy for mild depression • Pain killers (such as tramadol and pethidine) used for pain relief • Triptans (such as sumatriptan and zolmitripitan) used for treating migraine These medicines may increase the risk of side effects; if you get any unusual symptom taking any of these medicines together with Aripiprazole Zentiva, you should see your doctor. Aripiprazole Zentiva with food, drink and alcohol This medicine can be taken regardless of meals. Alcohol should be avoided. Pregnancy, breast-feeding and fertility If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. The following symptoms may occur in newborn babies, of mothers that have used Aripiprazole Zentiva in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms you may need to contact your doctor. If you are taking Aripiprazole Zentiva, your doctor will discuss with you whether you should breast feed considering the benefit to you of your therapy and the benefit to your baby of breast feeding. You should not do both. Talk to your doctor about the best way to feed your baby if you are taking this medicine. Driving and using machines Dizziness and vision problems may occur during treatment with this medicine (see section 4). This should be considered in cases where full alertness is required, e.g. when driving a car or handling machines. Aripiprazole Zentiva contains lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. http://en.wikipedia.org/wiki/Major_depressive_disorder http://en.wikipedia.org/wiki/Generalized_anxiety_disorder http://en.wikipedia.org/wiki/Social_anxiety_disorder 79 Aripiprazole Zentiva contains sodium This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’. 3. How to take Aripiprazole Zentiva Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The recommended dose for adults is 15 mg once a day. However your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. Use in children and adolescents This medicinal product may be started at a low dose with the oral solution (liquid) form. The dose may be gradually increased to the recommended dose for adolescents of 10 mg once a day. However your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. If you have the impression that the effect of Aripiprazole Zentiva is too strong or too weak, talk to your doctor or pharmacist. Try to take Aripiprazole Zentiva at the same time each day. It does not matter whether you take it with or without food. Always take the tablet with water and swallow it whole. Even if you feel better, do not alter or discontinue the daily dose of Aripiprazole Zentiva without first consulting your doctor. Aripiprazole Zentiva 10 mg, 30 mg tablets: The score line is not intended for breaking the tablet. If you take more Aripiprazole Zentiva than you should If you realise you have taken more Aripiprazole Zentiva than your doctor has recommended (or if someone else has taken some of your Aripiprazole Zentiva), contact your doctor right away. If you cannot reach your doctor, go to the nearest hospital and take the pack with you. Patients who have taken too much aripiprazole have experienced the following symptoms: • Rapid heartbeat, agitation/aggressiveness, problems with speech. • Unusual movements (especially of the face or tongue) and reduced level of consciousness. Other symptoms may include: • Acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, • Muscle stiffness, and drowsiness or sleepiness, slower breathing, choking, high or low blood pressure, abnormal rhythms of the heart. Contact your doctor or hospital immediately if you experience any of the above. If you forget to take Aripiprazole Zentiva If you miss a dose, take the missed dose as soon as you remember but do not take two doses in one day. If you stop taking Aripiprazole Zentiva Do not stop your treatment just because you feel better. It is important that you carry on taking Aripiprazole Zentiva for as long as your doctor has told you to. 80 If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Common side effects (may affect up to 1 in 10 people): • diabetes mellitus, • difficulty sleeping, • feeling anxious, • feeling restless and unable to keep still, difficulty sitting still, • uncontrollable twitching, jerking or writhing movements, restless legs, • trembling, • headache, • tiredness, • sleepiness, • light-headedness, • shaking and blurred vision, • decreased number of or difficulty making bowel movements, • indigestion, • feeling sick, • more saliva in mouth than normal, • vomiting, • feeling tired. Uncommon side effects (may affect up to 1 in 100 people): • increased blood levels of the hormone prolactin, • too much sugar in the blood, • depression, • altered or increased sexual interest, • uncontrollable movements of mouth, tongue and limbs (tardive dyskinesia), • muscle disorder causing twisting movements (dystonia), • double vision, • eye sensitivity to light, • fast heart beat, • a fall in blood pressure on standing up which causes dizziness, light-headedness or fainting, • hiccups. The following side effects have been reported since the marketing of oral aripiprazole but the frequency for them to occur is not known: • low levels of white blood cells, • low levels of blood platelets, • allergic reaction (e.g. swelling in the mouth, tongue, face and throat, itching, hives), • onset or worsening of diabetes, ketoacidosis (ketones in the blood and urine) or coma, • high blood sugar, • not enough sodium in the blood, • loss of appetite (anorexia), • weight loss, • weight gain, 81 • thoughts of suicide, suicide attempt and suicide; • feeling aggressive, • agitation, • nervousness, • combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness and sudden changes in blood pressure and heart rate, fainting (neuroleptic malignant syndrome), • seizure, • serotonin syndrome (a reaction which may cause feelings of great happiness, drowsiness, clumsiness, restlessness, feeling of being drunk, fever, sweating or rigid muscles), • speech disorder, • fixation of the eyeballs in one position, • sudden unexplained death, • life-threatening irregular heart beat, • heart attack, • slower heart beat, • blood clots in the veins, especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek medical advice immediately), • high blood pressure, • fainting, • accidental inhalation of food with risk of pneumonia (lung infection), • spasm of the muscles around the voice box, • inflammation of the pancreas, • difficulty swallowing, • diarrhoea, • abdominal discomfort, • stomach discomfort, • liver failure, • inflammation of the liver, • yellowing of the skin and white part of eyes, • reports of abnormal liver tests values; • skin rash, • skin sensitivity to light, • baldness, • excessive sweating, • abnormal muscle breakdown which can lead to kidney problems, • muscle pain, • stiffness, • involuntary loss of urine (incontinence), • difficulty in passing urine; • withdrawal symptoms in newborn babies in case of exposure during pregnancy, • prolonged and/or painful erection, • difficulty controlling core body temperature or overheating, • chest pain, • swelling of hands, ankles or feet, • in blood tests: increased or fluctuating blood sugar, increased glycosylated haemoglobin. • inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include: - strong impulse to gamble excessively despite serious personal or family consequences - altered or increased sexual interest and behaviour of significant concern to you or to 82 others, for example, an increased sexual drive - uncontrollable excessive shopping - binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger) - a tendency to wander away. Tell your doctor if you experience any of these behaviours; he/she will discuss ways of managing or reducing the symptoms. In elderly patients with dementia, more fatal cases have been reported while taking aripiprazole. In addition, cases of stroke or “mini” stroke have been reported. Additional side effects in children and adolescents Adolescents aged 13 years and older experienced side effects that were similar in frequency and type to those in adults except that sleepiness, uncontrollable twitching or jerking movements, restlessness, and tiredness were very common (greater than 1 in 10 patients) and upper abdominal pain, dry mouth, increased heart rate, weight gain, increased appetite, muscle twitching, uncontrolled movements of the limbs, and feeling dizzy, especially when getting up from a lying or sitting position, were common (greater than 1 in 100 patients). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aripiprazole Zentiva Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aripiprazole Zentiva contains The active substance is aripiprazole. Each tablet contains 5 mg/10 mg/15 mg/30 mg of aripiprazole. The other ingredients are lactose monohydrate, microcrystalline cellulose, crospovidone, hydroxypropyl cellulose, silica colloidal anhydrous, croscarmellose sodium, magnesium stearate. What Aripiprazole Zentiva looks like and contents of the pack Aripiprazole Zentiva 5 mg are white to off-white round flat bevel edged uncoated tablets with ‘5’ debossed on one side and plain on the other side with diameter approx. 6 mm. Aripiprazole Zentiva 10 mg tablets are white to off-white round uncoated tablets with ‘10’ debossed on one side and snap tab breakline on the other side with diameter approx. 8 mm. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 83 Aripiprazole Zentiva 15 mg tablets are white to off-white round flat bevel edged uncoated tablets with ‘15’ debossed on one side and plain on the other side with diameter approx. 8.8 mm. Aripiprazole Zentiva 30 mg tablets are white to off-white capsule shaped uncoated tablets with ‘30’ debossed on one side and snap tab breakline on the other side with dimensions approx. 15.5 x 8 mm. Pack size: 14, 28, 49, 56, or 98 tablets Not all pack sizes may be marketed. Marketing Authorisation Holder Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic Manufacturer S.C. Zentiva S.A. 50 Theodor Pallady Blvd. Bucharest 032266 Romania For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Zentiva, k.s. Tél/Tel: +32 280 86 420 PV-Belgium@zentiva.com Lietuva Zentiva, k.s. Tel: +370 52152025 PV-Lithuania@zentiva.com България Zentiva, k.s. Тел: + 359 2 805 72 08 PV-Bulgaria@zentiva.com Luxembourg/Luxemburg Zentiva, k.s. Tél/Tel: +352 208 82330 PV-Luxembourg@zentiva.com Česká republika Zentiva, k.s. Tel: +420 267 241 111 PV-Czech-Republic@zentiva.com Magyarország Zentiva, k.s. Tel.: +36 165 55 722 PV-Hungary@zentiva.com Danmark Zentiva, k.s. Tlf: +45 787 68 400 PV-Denmark@zentiva.com Malta Zentiva, k.s. Tel: +356 277 82 052 PV-Malta@zentiva.com Deutschland Zentiva Pharma GmbH Tel: +49 (0) 800 53 53 010 PV-Germany@zentiva.com Nederland Zentiva, k.s. Tel: +31 202 253 638 PV-Netherlands@zentiva.com Eesti Zentiva, k.s. Tel: +372 52 70308 PV-Estonia@zentiva.com Norge Zentiva, k.s. Tlf: +47 219 66 203 PV-Norway@zentiva.com 84 Ελλάδα Zentiva, k.s. Τηλ: +30 211 198 7510 PV-Greece@zentiva.com Österreich Zentiva, k.s. Tel: +43 720 778 877 PV-Austria@zentiva.com España Zentiva, k.s. Tel: +34 931 815 250 PV-Spain@zentiva.com Polska Zentiva Polska Sp. z o.o. Tel: + 48 22 375 92 00 PV-Poland@zentiva.com France Zentiva France Tél: +33 (0) 800 089 219 PV-France@zentiva.com Portugal Zentiva Portugal, Lda Tel: +351210601360 PV-Portugal@zentiva.com Hrvatska Zentiva, k.s. Tel: +385 155 17 772 PV-Croatia@zentiva.com România ZENTIVA S.A. Tel: +40 021.304.7597 zentivaRO@zentiva.com Ireland Zentiva, k.s. Tel: +353 766 803 944 PV-Ireland@zentiva.com Slovenija Zentiva, k.s. Tel: +386 360 00 408 PV-Slovenia@zentiva.com Ísland Zentiva, k.s. Sími: +354 539 0650 PV-Iceland@zentiva.com Slovenská republika Zentiva, a.s. Tel: +421 2 3918 3010 PV-Slovakia@zentiva.com Italia Zentiva Italia S.r.l. Tel: +39-02-38598801 PV-Italy@zentiva.com Suomi/Finland Zentiva, k.s. Puh/Tel: +358 942 598 648 PV-Finland@zentiva.com Κύπρος Zentiva, k.s. Τηλ: +357 240 30 144 PV-Cyprus@zentiva.com Sverige Zentiva, k.s. Tel: +46 840 838 822 PV-Sweden@zentiva.com Latvija Zentiva, k.s. Tel: +371 67893939 PV-Latvia@zentiva.com United Kingdom Zentiva Pharma UK Limited Tel: +44 (0) 845 372 7101 PV-United-Kingdom@zentiva.com This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ 85 Package leaflet: Information for the user Aripiprazole Zentiva 10 mg orodispersible tablets Aripiprazole Zentiva 15 mg orodispersible tablets Aripiprazole Zentiva 30 mg orodispersible tablets aripiprazole Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aripiprazole Zentiva is and what they are used for 2. What you need to know before you take Aripiprazole Zentiva 3. How to take Aripiprazole Zentiva 4. Possible side effects 5. How to store Aripiprazole Zentiva 6. Contents of the pack and other information 1. What Aripiprazole Zentiva is and what it is used for Aripiprazole Zentiva contains the active substance aripiprazole and belong to a group of medicines called antipsychotics. It is used to treat adults and adolescents aged 15 years and older who suffer from a disease characterised by symptoms such as hearing, seeing or sensing things which are not there, suspiciousness, mistaken beliefs, incoherent speech and behaviour and emotional flatness. People with this condition may also feel depressed, guilty, anxious or tense. Aripiprazole Zentiva is used to treat adults and adolescents aged 13 years and older who suffer from a condition with symptoms such as feeling “high”, having excessive amounts of energy, needing much less sleep than usual, talking very quickly with racing ideas and sometimes severe irritability. In adults it also prevents this condition from returning in patients who have responded to the treatment with Aripiprazole Zentiva. 2. What you need to know before you take Aripiprazole Zentiva Do not take Aripiprazole Zentiva • if you are allergic to aripiprazole or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor before taking Aripiprazole Zentiva. Suicidal thoughts and behaviours have been reported during aripiprazole treatment. Tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. 86 Before treatment with Aripiprazole Zentiva, tell your doctor if you suffer from • high blood sugar (characterised by symptoms such as excessive thirst, passing of large amounts of urine, increase in appetite and feeling weak) or family history of diabetes • fits (seizures) since your doctor may want to monitor you more closely • involuntary, irregular muscle movements, especially in the face • cardiovascular diseases (diseases of the heart and circulation), family history of cardiovascular disease, stroke or “mini” stroke, abnormal blood pressure • blood clots, or family history of blood clots, as antipsychotics have been associated with formation of blood clots • past experience with excessive gambling If you notice you are gaining weight, develop unusual movements, experience somnolence that interferes with normal daily activities, any difficulty in swallowing or allergic symptoms, please tell your doctor. If you are an elderly patient suffering from dementia (loss of memory and other mental abilities), you or your carer/relative should tell your doctor if you have ever had a stroke or “mini” stroke. Tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. Suicidal thoughts and behaviours have been reported during aripiprazole treatment. Tell your doctor immediately if you suffer from muscle stiffness or inflexibility with high fever, sweating, altered mental status, or very rapid or irregular heart beat. Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or preoccupation with an increase in sexual thoughts or feelings. Your doctor may need to adjust or stop your dose. Aripiprazole may cause sleepiness, fall in blood pressure when standing up, dizziness and changes in your ability to move and balance, which may lead to falls. Caution should be taken, particularly if you are an elderly patient or have some debility. Children and adolescents Do not use this medicine in children and adolescents under 13 years of age. It is not known if it is safe and effective in these patients. Other medicines and Aripiprazole Zentiva Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. Blood pressure-lowering medicines: Aripiprazole Zentiva may increase the effect of medicines used to lower the blood pressure. Be sure to tell your doctor if you take a medicine to keep your blood pressure under control. Taking Aripiprazole Zentiva with some medicines may mean the doctor will need to change your dose of Aripiprazole Zentiva or the other medicines. It is especially important to mention the following to your doctor: • Medicines to correct heart rhythm (such as quinidine, amiodarone, flecainide) • Antidepressants or herbal remedy used to treat depression and anxiety (such as fluoxetine, paroxetine, venlafaxine, St. Johnʼs Wort) 87 • Antifungal medicines (such as ketoconazole, itraconazole) • Certain medicines to treat HIV infection (such as efavirenz, nevirapine, an protease inhibitors e.g. indinavir, ritonavir) • Anticonvulsants used to treat epilepsy (such as carbamazepine, phenytoin, phenobarbital) • Certain antibiotics used to treat tuberculosis (rifabutin, rifampicin) These medicines may increase the risk of side effects or reduce the effect of Aripiprazole Zentiva; if you get any unusual symptom taking any of these medicines together with Aripiprazole Zentiva tablets, you should see your doctor. Medicines that increase the level of serotonin are typically used in conditions including depression, generalised anxiety disorder, obsessive-compulsive disorder (OCD) and social phobia as well as migraine and pain: • Triptans, tramadol and tryptophan used for conditions including depression, generalised anxiety disorder, obsessive compulsive disorder (OCD) and social phobia as well as migraine and pain • Selective-serotonin-reuptake-inhibitors (SSRIs) (such as paroxetine and fluoxetine) used for depression, OCD, panic and anxiety • Other anti-depressants (such as venlafaxine and tryptophan) used in major depression • Tricyclic’s (such as clomipramine and amitriptyline) used for depressive illness • St John’s Wort (Hypericum perforatum) used as a herbal remedy for mild depression • Pain killers (such as tramadol and pethidine) used for pain relief • Triptans (such as sumatriptan and zolmitripitan) used for treating migraine These medicines may increase the risk of side effects; if you get any unusual symptom taking any of these medicines together with Aripiprazole Zentiva, you should see your doctor. Aripiprazole Zentiva with food, drink and alcohol This medicine can be taken regardless of meals. Alcohol should be avoided. Pregnancy, breast-feeding and fertility If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. The following symptoms may occur in newborn babies, of mothers that have used Aripiprazole Zentiva in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms you may need to contact your doctor. If you are taking Aripiprazole Zentiva, your doctor will discuss with you whether you should breast feed considering the benefit to you of your therapy and the benefit to your baby of breast feeding. You should not do both. Talk to your doctor about the best way to feed your baby if you are taking this medicine. Driving and using machines Dizziness and vision problems may occur during treatment with this medicine (see section 4). This should be considered in cases where full alertness is required, e.g., when driving a car or handling machines. Aripiprazole Zentiva contains lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. 88 Aripiprazole Zentiva contains sodium This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’. 3. How to take Aripiprazole Zentiva Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The recommended dose for adults is 15 mg once a day. However your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. Use in children and adolescents This medicinal product may be started at a low dose with the oral solution (liquid) form. The dose may be gradually increased to the recommended dose for adolescents of 10 mg once a day. However your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. If you have the impression that the effect of Aripiprazole Zentiva is too strong or too weak, talk to your doctor or pharmacist. Try to take Aripiprazole Zentiva at the same time each day. It does not matter whether you take it with or without food. Do not open the blister until ready to administer. Immediately upon opening the blister, using dry hands, remove the tablet and place the entire orodispersible tablet on the tongue. Tablet disintegration occurs rapidly in saliva. The orodispersible tablet can be taken with or without liquid. Alternatively, disperse the tablet in water and drink the resulting suspension. Even if you feel better, do not alter or discontinue the daily dose of Aripiprazole Zentiva without first consulting your doctor. Aripiprazole Zentiva 10 mg, 30 mg orodispersible tablets: The score line is not intended for breaking the tablet. If you take more Aripiprazole Zentiva than you should If you realise you have taken more Aripiprazole Zentiva than your doctor has recommended (or if someone else has taken some of your Aripiprazole Zentiva), contact your doctor right away. If you cannot reach your doctor, go to the nearest hospital and take the pack with you. Patients who have taken too much aripiprazole have experienced the following symptoms: • Rapid heartbeat, agitation/aggressiveness, problems with speech. • Unusual movements (especially of the face or tongue) and reduced level of consciousness. Other symptoms may include: • Acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, • Muscle stiffness, and drowsiness or sleepiness, slower breathing, choking, high or low blood pressure, abnormal rhythms of the heart. Contact your doctor or hospital immediately if you experience any of the above. 89 If you forget to take Aripiprazole Zentiva If you miss a dose, take the missed dose as soon as you remember but do not take two doses in one day. If you stop taking Aripiprazole Zentiva Do not stop your treatment just because you feel better. It is important that you carry on taking Aripiprazole Zentiva orodispersible tablets for as long as your doctor has told you to. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Common side effects (may affect up to 1 in 10 people): • diabetes mellitus, • difficulty sleeping, • feeling anxious, • feeling restless and unable to keep still, difficulty sitting still, • uncontrollable twitching, jerking or writhing movements, restless legs, • trembling, • headache, • tiredness, • sleepiness, • light-headedness, • shaking and blurred vision, • decreased number of or difficulty making bowel movements, • indigestion, • feeling sick, • more saliva in mouth than normal, • vomiting, • feeling tired. Uncommon side effects (may affect up to 1 in 100 people): • increased blood levels of the hormone prolactin, • too much sugar in the blood, • depression, • altered or increased sexual interest, • uncontrollable movements of mouth, tongue and limbs (tardive dyskinesia), • muscle disorder causing twisting movements (dystonia), • double vision, • eye sensitivity to light, • fast heart beat, • a fall in blood pressure on standing up which causes dizziness, light-headedness or fainting, • hiccups. The following side effects have been reported since the marketing of oral aripiprazole but the frequency for them to occur is not known: • low levels of white blood cells; • low levels of blood platelets, 90 • allergic reaction (e.g. swelling in the mouth, tongue, face and throat, itching, hives), • onset or worsening of diabetes, ketoacidosis (ketones in the blood and urine) or coma, • high blood sugar, • not enough sodium in the blood, • loss of appetite (anorexia), • weight loss, • weight gain, • thoughts of suicide, suicide attempt and suicide; • feeling aggressive, • agitation, • nervousness, • combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness and sudden changes in blood pressure and heart rate, fainting (neuroleptic malignant syndrome), • seizure, • serotonin syndrome (a reaction which may cause feelings of great happiness, drowsiness, clumsiness, restlessness, feeling of being drunk, fever, sweating or rigid muscles), • speech disorder, • fixation of the eyeballs in one position, • sudden unexplained death, • life-threatening irregular heart beat, • heart attack, • slower heart beat, • blood clots in the veins, especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek medical advice immediately), • high blood pressure, • fainting, • accidental inhalation of food with risk of pneumonia (lung infection), • spasm of the muscles around the voice box, • inflammation of the pancreas, • difficulty swallowing, • diarrhoea, • abdominal discomfort, • stomach discomfort, • liver failure, • inflammation of the liver, • yellowing of the skin and white part of eyes, • reports of abnormal liver test values, • skin rash, • skin sensitivity to light, • baldness, • excessive sweating, • abnormal muscle breakdown which can lead to kidney problems, • muscle pain, • stiffness, • involuntary loss of urine (incontinence), • difficulty in passing urine, • withdrawal symptoms in newborn babies in case of exposure during pregnancy, • prolonged and/or painful erection, • difficulty controlling core body temperature or overheating, 91 • chest pain, • swelling of hands, ankles or feet, • in blood tests: increased or fluctuating blood sugar, increased glycosylated haemoglobin. • inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include: - strong impulse to gamble excessively despite serious personal or family consequences - altered or increased sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive - uncontrollable excessive shopping - binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger) - a tendency to wander away. Tell your doctor if you experience any of these behaviours; he/she will discuss ways of managing or reducing the symptoms. In elderly patients with dementia, more fatal cases have been reported while taking aripiprazole. In addition, cases of stroke or “mini” stroke have been reported. Additional side effects in children and adolescents Adolescents aged 13 years and older experienced side effects that were similar in frequency and type to those in adults except that sleepiness, uncontrollable twitching or jerking movements, restlessness, and tiredness were very common (greater than 1 in 10 patients) and upper abdominal pain, dry mouth, increased heart rate, weight gain, increased appetite, muscle twitching, uncontrolled movements of the limbs, and feeling dizzy, especially when getting up from a lying or sitting position, were common (greater than 1 in 100 patient). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aripiprazole Zentiva Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aripiprazole Zentiva contains The active substance is aripiprazole. Each orodispersible tablet contains 10 mg/15 mg/30 mg of aripiprazole. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 92 The other ingredients are lactose monohydrate, microcrystalline cellulose, crospovidone, hydroxypropyl cellulose, silica colloidal anhydrous, croscarmellose sodium, acesulfame potassium, mango flavour, magnesium stearate. What Aripiprazole Zentiva looks like and contents of the pack Aripiprazole Zentiva 10 mg orodispersible tablets are white to off-white round tablets debossed ‘10’ on one side and snap break line on other side with diameter approx. 7 mm. Aripiprazole Zentiva 15 mg orodispersible tablets are white to off-white round flat bevel edged tablets debossed ‘15’ on one side and plain on the other side with diameter approx. 8 mm. Aripiprazole Zentiva 30 mg orodispersible tablets are white to off-white round tablets debossed ‘30’ on one side and snap break line on the other side with diameter approx. 10.2 mm. Pack size: 14, 28 or 49 orodispersible tablets Not all pack sizes may be marketed. Marketing Authorisation Holder Zentiva, k.s. U Kabelovny 130 102 37 Prague 10 Czech Republic Manufacturer S.C. Zentiva S.A. 50 Theodor Pallady Blvd. Bucharest 032266 Romania For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Zentiva, k.s. Tél/Tel: +32 280 86 420 PV-Belgium@zentiva.com Lietuva Zentiva, k.s. Tel: +370 52152025 PV-Lithuania@zentiva.com България Zentiva, k.s. Тел: + 359 2 805 72 08 PV-Bulgaria@zentiva.com Luxembourg/Luxemburg Zentiva, k.s. Tél/Tel: +352 208 82330 PV-Luxembourg@zentiva.com Česká republika Zentiva, k.s. Tel: +420 267 241 111 PV-Czech-Republic@zentiva.com Magyarország Zentiva, k.s. Tel.: +36 165 55 722 PV-Hungary@zentiva.com Danmark Zentiva, k.s. Tlf: +45 787 68 400 PV-Denmark@zentiva.com Malta Zentiva, k.s. Tel: +356 277 82 052 PV-Malta@zentiva.com 93 Deutschland Zentiva Pharma GmbH Tel: +49 (0) 800 53 53 010 PV-Germany@zentiva.com Nederland Zentiva, k.s. Tel: +31 202 253 638 PV-Netherlands@zentiva.com Eesti Zentiva, k.s. Tel: +372 52 70308 PV-Estonia@zentiva.com Norge Zentiva, k.s. Tlf: +47 219 66 203 PV-Norway@zentiva.com Ελλάδα Zentiva, k.s. Τηλ: +30 211 198 7510 PV-Greece@zentiva.com Österreich Zentiva, k.s. Tel: +43 720 778 877 PV-Austria@zentiva.com España Zentiva, k.s. Tel: +34 931 815 250 PV-Spain@zentiva.com Polska Zentiva Polska Sp. z o.o. Tel: + 48 22 375 92 00 PV-Poland@zentiva.com France Zentiva France Tél: +33 (0) 800 089 219 PV-France@zentiva.com Portugal Zentiva Portugal, Lda Tel: +351210601360 PV-Portugal@zentiva.com Hrvatska Zentiva, k.s. Tel: +385 155 17 772 PV-Croatia@zentiva.com România ZENTIVA S.A. Tel: +40 021.304.7597 zentivaRO@zentiva.com Ireland Zentiva, k.s. Tel: +353 766 803 944 PV-Ireland@zentiva.com Slovenija Zentiva, k.s. Tel: +386 360 00 408 PV-Slovenia@zentiva.com Ísland Zentiva, k.s. Sími: +354 539 0650 PV-Iceland@zentiva.com Slovenská republika Zentiva, a.s. Tel: +421 2 3918 3010 PV-Slovakia@zentiva.com Italia Zentiva Italia S.r.l. Tel: +39-02-38598801 PV-Italy@zentiva.com Suomi/Finland Zentiva, k.s. Puh/Tel: +358 942 598 648 PV-Finland@zentiva.com Κύπρος Zentiva, k.s. Τηλ: +357 240 30 144 PV-Cyprus@zentiva.com Sverige Zentiva, k.s. Tel: +46 840 838 822 PV-Sweden@zentiva.com Latvija Zentiva, k.s. Tel: +371 67893939 PV-Latvia@zentiva.com United Kingdom Zentiva Pharma UK Limited Tel: +44 (0) 845 372 7101 PV-United-Kingdom@zentiva.com 94 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take aripiprazole zentiva', 'Section_Content': 'do not take aripiprazole zentiva if you are allergic to aripiprazole or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor before taking aripiprazole zentiva. suicidal thoughts and behaviours have been reported during aripiprazole treatment. tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. before treatment with aripiprazole zentiva, tell your doctor if you suffer from high blood sugar (characterised by symptoms such as excessive thirst, passing of large amounts of urine, increase in appetite and feeling weak) or family history of diabetes fits (seizures) since your doctor may want to monitor you more closely involuntary, irregular muscle movements, especially in the face cardiovascular diseases (diseases of the heart and circulation), family history of cardiovascular disease, stroke or "mini" stroke, abnormal blood pressure blood clots, or family history of blood clots, as antipsychotics have been associated with formation of blood clots past experience with excessive gambling. if you notice you are gaining weight, develop unusual movements, experience somnolence that interferes with normal daily activities, any difficulty in swallowing or allergic symptoms, please tell your doctor. if you are an elderly patient suffering from dementia (loss of memory and other mental abilities), you or your carer/relative should tell your doctor if you have ever had a stroke or "mini" stroke. tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. suicidal thoughts and behaviours have been reported during aripiprazole treatment. tell your doctor immediately if you suffer from muscle stiffness or inflexibility with high fever, sweating, altered mental status, or very rapid or irregular heart beat. tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. these are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or preoccupation with an increase in sexual thoughts or feelings. your doctor may need to adjust or stop your dose. aripiprazole may cause sleepiness, fall in blood pressure when standing up, dizziness and changes in your ability to move and balance, which may lead to falls. caution should be taken, particularly if you are an elderly patient or have some debility. children and adolescents do not use this medicine in children and adolescents under 13 years of age. it is not known if it is safe and effective in these patients. other medicines and aripiprazole zentiva tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. blood pressure-lowering medicines: aripiprazole zentiva may increase the effect of medicines used to lower the blood pressure. be sure to tell your doctor if you take a medicine to keep your blood pressure under control. taking aripiprazole zentiva with some medicines may mean the doctor will need to change your dose of aripiprazole zentiva or the other medicines. it is especially important to mention the following to your doctor: medicines to correct heart rhythm (such as quinidine, amiodarone, flecainide) 78 antidepressants or herbal remedy used to treat depression and anxiety (such as fluoxetine, paroxetine, venlafaxine, st. johnʼs wort) antifungal medicines (such as ketoconazole, itraconazole) certain medicines to treat hiv infection (such as efavirenz, nevirapine, an protease inhibitors e.g. indinavir, ritonavir) anticonvulsants used to treat epilepsy (such as carbamazepine, phenytoin, phenobarbital) certain antibiotics used to treat tuberculosis (rifabutin, rifampicin) these medicines may increase the risk of side effects or reduce the effect of aripiprazole zentiva; if you get any unusual symptom taking any of these medicines together with aripiprazole zentiva, you should see your doctor. medicines that increase the level of serotonin are typically used in conditions including depression, generalised anxiety disorder, obsessive-compulsive disorder (ocd) and social phobia as well as migraine and pain: triptans, tramadol and tryptophan used for conditions including depression, generalised anxiety disorder, obsessive compulsive disorder (ocd) and social phobia as well as migraine and pain selective-serotonin-reuptake-inhibitors (ssris) (such as paroxetine and fluoxetine) used for depression, ocd, panic and anxiety other anti-depressants (such as venlafaxine and tryptophan) used in major depression tricyclic\'s (such as clomipramine and amitriptyline) used for depressive illness st john\'s wort (hypericum perforatum) used as a herbal remedy for mild depression pain killers (such as tramadol and pethidine) used for pain relief triptans (such as sumatriptan and zolmitripitan) used for treating migraine these medicines may increase the risk of side effects; if you get any unusual symptom taking any of these medicines together with aripiprazole zentiva, you should see your doctor. aripiprazole zentiva with food, drink and alcohol this medicine can be taken regardless of meals. alcohol should be avoided. pregnancy, breast-feeding and fertility if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. the following symptoms may occur in newborn babies, of mothers that have used aripiprazole zentiva in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. if your baby develops any of these symptoms you may need to contact your doctor. if you are taking aripiprazole zentiva, your doctor will discuss with you whether you should breast feed considering the benefit to you of your therapy and the benefit to your baby of breast feeding. you should not do both. talk to your doctor about the best way to feed your baby if you are taking this medicine. driving and using machines dizziness and vision problems may occur during treatment with this medicine (see section 4). this should be considered in cases where full alertness is required, e.g. when driving a car or handling machines. aripiprazole zentiva contains lactose if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. aripiprazole zentiva contains sodium this medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially \'sodium- free\'.', 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{'Title': '3. how to take aripiprazole zentiva', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose for adults is 15 mg once a day. however your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. use in children and adolescents this medicinal product may be started at a low dose with the oral solution (liquid) form. the dose may be gradually increased to the recommended dose for adolescents of 10 mg once a day. however your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. if you have the impression that the effect of aripiprazole zentiva is too strong or too weak, talk to your doctor or pharmacist. try to take aripiprazole zentiva at the same time each day. it does not matter whether you take it with or without food. always take the tablet with water and swallow it whole. even if you feel better, do not alter or discontinue the daily dose of aripiprazole zentiva without first consulting your doctor. aripiprazole zentiva 10 mg, 30 mg tablets: the score line is not intended for breaking the tablet. if you take more aripiprazole zentiva than you should if you realise you have taken more aripiprazole zentiva than your doctor has recommended (or if someone else has taken some of your aripiprazole zentiva), contact your doctor right away. if you cannot reach your doctor, go to the nearest hospital and take the pack with you. patients who have taken too much aripiprazole have experienced the following symptoms: rapid heartbeat, agitation/aggressiveness, problems with speech. unusual movements (especially of the face or tongue) and reduced level of consciousness. other symptoms may include: acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, muscle stiffness, and drowsiness or sleepiness, slower breathing, choking, high or low blood pressure, abnormal rhythms of the heart. contact your doctor or hospital immediately if you experience any of the above. if you forget to take aripiprazole zentiva if you miss a dose, take the missed dose as soon as you remember but do not take two doses in one day. if you stop taking aripiprazole zentiva do not stop your treatment just because you feel better. it is important that you carry on taking aripiprazole zentiva for as long as your doctor has told you to. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'aripiprazole zentiva', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': '15', 'Type': 'NUMBER', 'BeginOffset': 170, 'EndOffset': 172}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 261, 'EndOffset': 263}, {'Text': 'this medicinal product', 'Type': 'TREATMENT', 'BeginOffset': 311, 'EndOffset': 333}, 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. common side effects (may affect up to 1 in 10 people): diabetes mellitus, difficulty sleeping, feeling anxious, feeling restless and unable to keep still, difficulty sitting still, uncontrollable twitching, jerking or writhing movements, restless legs, trembling, headache, tiredness, sleepiness, light-headedness, shaking and blurred vision, decreased number of or difficulty making bowel movements, indigestion, feeling sick, more saliva in mouth than normal, vomiting, feeling tired. uncommon side effects (may affect up to 1 in 100 people): increased blood levels of the hormone prolactin, too much sugar in the blood, depression, altered or increased sexual interest, uncontrollable movements of mouth, tongue and limbs (tardive dyskinesia), muscle disorder causing twisting movements (dystonia), double vision, eye sensitivity to light, fast heart beat, a fall in blood pressure on standing up which causes dizziness, light-headedness or fainting, hiccups. the following side effects have been reported since the marketing of oral aripiprazole but the frequency for them to occur is not known: low levels of white blood cells, low levels of blood platelets, allergic reaction (e.g. swelling in the mouth, tongue, face and throat, itching, hives), onset or worsening of diabetes, ketoacidosis (ketones in the blood and urine) or coma, high blood sugar, not enough sodium in the blood, loss of appetite (anorexia), weight loss, weight gain, 81 thoughts of suicide, suicide attempt and suicide; feeling aggressive, agitation, nervousness, combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness and sudden changes in blood pressure and heart rate, fainting (neuroleptic malignant syndrome), seizure, serotonin syndrome (a reaction which may cause feelings of great happiness, drowsiness, clumsiness, restlessness, feeling of being drunk, fever, sweating or rigid muscles), speech disorder, fixation of the eyeballs in one position, sudden unexplained death, life-threatening irregular heart beat, heart attack, slower heart beat, blood clots in the veins, especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek medical advice immediately), high blood pressure, fainting, accidental inhalation of food with risk of pneumonia (lung infection), spasm of the muscles around the voice box, inflammation of the pancreas, difficulty swallowing, diarrhoea, abdominal discomfort, stomach discomfort, liver failure, inflammation of the liver, yellowing of the skin and white part of eyes, reports of abnormal liver tests values; skin rash, skin sensitivity to light, baldness, excessive sweating, abnormal muscle breakdown which can lead to kidney problems, muscle pain, stiffness, involuntary loss of urine (incontinence), difficulty in passing urine; withdrawal symptoms in newborn babies in case of exposure during pregnancy, prolonged and/or painful erection, difficulty controlling core body temperature or overheating, chest pain, swelling of hands, ankles or feet, in blood tests: increased or fluctuating blood sugar, increased glycosylated haemoglobin. inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include: - strong impulse to gamble excessively despite serious personal or family consequences - altered or increased sexual interest and behaviour of significant concern to you or to 82 others, for example, an increased sexual drive - uncontrollable excessive shopping - binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger) - a tendency to wander away. tell your doctor if you experience any of these behaviours; he/she will discuss ways of managing or reducing the symptoms. in elderly patients with dementia, more fatal cases have been reported while taking aripiprazole. in addition, cases of stroke or "mini" stroke have been reported. additional side effects in children and adolescents adolescents aged 13 years and older experienced side effects that were similar in frequency and type to those in adults except that sleepiness, uncontrollable twitching or jerking movements, restlessness, and tiredness were very common (greater than 1 in 10 patients) and upper abdominal pain, dry mouth, increased heart rate, weight gain, increased appetite, muscle twitching, uncontrolled movements of the limbs, and feeling dizzy, especially when getting up from a lying or sitting position, were common (greater than 1 in 100 patients). reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any 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{'Title': '5. how to store aripiprazole zentiva', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what aripiprazole zentiva contains the active substance is aripiprazole. each tablet contains 5 mg/10 mg/15 mg/30 mg of aripiprazole. the other ingredients are lactose monohydrate, microcrystalline cellulose, crospovidone, hydroxypropyl cellulose, silica colloidal anhydrous, croscarmellose sodium, magnesium stearate. what aripiprazole zentiva looks like and contents of the pack aripiprazole zentiva 5 mg are white to off-white round flat bevel edged uncoated tablets with '5' debossed on one side and plain on the other side with diameter approx. 6 mm. aripiprazole zentiva 10 mg tablets are white to off-white round uncoated tablets with '10' debossed on one side and snap tab breakline on the other side with diameter approx. 8 mm. aripiprazole zentiva 15 mg tablets are white to off-white round flat bevel edged uncoated tablets with '15' debossed on one side and plain on the other side with diameter approx. 8.8 mm. aripiprazole zentiva 30 mg tablets are white to off-white capsule shaped uncoated tablets with '30' debossed on one side and snap tab breakline on the other side with dimensions approx. 15.5 x 8 mm. pack size: 14, 28, 49, 56, or 98 tablets not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'aripiprazole zentiva', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'aripiprazole zentiva', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 25}, {'Id': 2, 'BeginOffset': 59, 'EndOffset': 71, 'Score': 0.9988968372344971, 'Text': 'aripiprazole', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8679715991020203, 'RelationshipScore': 0.9617905020713806, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 78, 'EndOffset': 84, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'STRENGTH', 'Score': 0.7280531525611877, 'RelationshipScore': 0.7043834924697876, 'RelationshipType': 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EDCEDBE56018CE371FD5D66B4DDE9CC8

https://www.ema.europa.eu/documents/product-information/xermelo-epar-product-information_en.pdf

Xermelo

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Xermelo 250 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains telotristat etiprate equivalent to 250 mg telotristat ethyl. Excipient with known effect Each tablet contains 168 mg of lactose (as anhydrous). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. White to off-white film-coated oval tablets (approximately 17 mm long by 7.5 mm wide) with ‘T-E’ debossed on one side and ‘250’ debossed on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Xermelo is indicated for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy. 4.2 Posology and method of administration Posology The recommended dose is 250 mg three times daily (tid). Available data suggest that clinical response is usually achieved within 12 weeks of treatment. It is recommended to reassess the benefit of continued therapy in a patient not responding within this time period. Based on the high inter-subject variability observed, accumulation in a subset of patients with carcinoid syndrome cannot be excluded. Therefore, intake of higher doses is not recommended (see section 5.2). Missed doses In the event of a missed dose, patients should take their subsequent dose at the next scheduled time point. Patients should not take a double dose to make up for a missed dose. Elderly (65 years of age and above) No specific dose recommendations are available for elderly patients (see section 5.2). 3 Renal impairment No change in dose is required in patients with mild, moderate or severe renal impairment; who are not requiring dialysis (see section 5.2). As a precautionary measure, it is recommended that patients with severe renal impairment will be monitored for signs of reduced tolerability. The use of Xermelo is not recommended in patients with end-stage renal disease requiring dialysis (eGFR < 15 mL/min requiring dialysis) because efficacy and safety of Xermelo in these patients has not been established. Hepatic impairment In patients with mild hepatic impairment (Child Pugh score A), it may be necessary to reduce the dose to 250 mg twice daily according to tolerability. In patients with moderate hepatic impairment (Child Pugh score B), it may be necessary to reduce the dose to 250 mg once daily according to tolerability. The use of telotristat is not recommended in patients with severe hepatic impairment (Child Pugh score C) (see section 5.2). Paediatric population There is no relevant use of telotristat in the paediatric population in the indication of carcinoid syndrome. Method of administration Oral use Xermelo should be taken with food (see sections 5.1 and 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Hepatic enzymes elevations Elevations in hepatic enzymes were observed in clinical trials (see section 4.8). Laboratory monitoring of hepatic enzymes prior to and during telotristat therapy is recommended as clinically indicated. In patients with hepatic impairment, continuous monitoring for adverse events and worsening of liver function is recommended. Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes tested and telotristat should be discontinued if liver injury is suspected. Therapy with telotristat should not be resumed unless the liver injury can be explained by another cause. Constipation Telotristat reduces bowel movement (BM) frequency. Constipation was reported in patients using a higher dose (500 mg). Patients should be monitored for signs and symptoms of constipation. If constipation develops, the use of telotristat and other concomitant therapies affecting bowel motility should be re-evaluated. Depressive disorders Depression, depressed mood and decreased interest have been reported in clinical trials and from post- marketing in some patients treated with telotristat (see section 4.8). Patients should be advised to report any symptoms of depression, depressed mood and decreased interest to their physicians. Lactose intolerance Xermelo contains anhydrous lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction 4 Effect of other medicinal products on Xermelo Short acting octreotide Concomitant administration of short-acting octreotide with Xermelo significantly decreased the systemic exposure of telotristat ethyl and telotristat, the active metabolite (see section 5.2). Short- acting octreotide should be administered at least 30 minutes after administration of Xermelo if treatment with short-acting octreotide is needed in combination with Xermelo. Carboxylesterase 2 (CES2) inhibitors The IC50 of the inhibition of loperamide on the metabolism of telotristat ethyl by CES2 was 5.2 µM (see section 5.2). In phase 3 clinical trials, telotristat was routinely combined with loperamide with no evidence of safety concerns. Effect of Xermelo on other medicinal products CYP2B6 substrates Telotristat induced CYP2B6 in vitro (see section 5.2). Concomitant use of Xermelo may decrease the efficacy of medicinal products that are CYP2B6 substrates (e.g. valproic acid, bupropion, sertraline) by decreasing their systemic exposure. Monitoring for suboptimal efficacy is recommended. CYP3A4 substrates Concomitant use of Xermelo may decrease the efficacy of medicinal products that are CYP3A4 substrates (e.g. midazolam, everolimus, sunitinib, simvastatin, ethinyloestradiol, amlodipine, cyclosporine…) by decreasing their systemic exposure (see section 5.2). Monitoring for suboptimal efficacy is recommended. Carboxylesterase 2 (CES2) substrates Concomitant use of Xermelo may change the exposure of medicinal products that are CES2 substrates (e.g. prasugrel, irinotecan, capecitabine and flutamide) (see section 5.2). If co-administration is unavoidable, monitor for suboptimal efficacy and safety events. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential should be advised to use adequate contraception during treatment with telotristat. Pregnancy There are no data from the use of telotristat in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Xermelo is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether telotristat ethyl and its metabolite are excreted in human breast milk. A risk to newborns/infants cannot be excluded. Patients should not breast-feed during telotristat treatment. Fertility No studies on the effect of telotristat on human fertility have been conducted. Telotristat had no effect on fertility in animal studies (see section 5.3). 4.7 Effects on ability to drive and use machines Telotristat has minor influence on the ability to drive and use machines. Fatigue may occur following administration of telotristat (see section 4.8). 4.8 Undesirable effects Summary of the safety profile 5 The most commonly reported adverse reactions in patients treated with telotristat were abdominal pain (26%), gamma-glutamyl transferase increased (11%) and fatigue (10%). They were generally of mild or moderate intensity. The most frequently reported adverse reaction leading to discontinuation of telotristat was abdominal pain in 7.1% of patients (5/70). Tabulated list of adverse reactions Adverse reactions reported in a pooled safety dataset of 70 patients with carcinoid syndrome receiving telotristat ethyl 250 mg tid in combination with SSA therapy in placebo-controlled clinical trials are listed in Table 1. Adverse reactions are listed by MedDRA body system organ class and by frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness Table 1 - Adverse reactions reported in patients treated with Xermelo System organ class Very common Common Uncommon Metabolism and nutrition disorders Decreased appetite Psychiatric disorders Depression, depressed mood Nervous system disorders Headache Gastrointestinal disorders Abdominal paina, nausea Abdominal distension, Constipation, Flatulence Faecalomac, intestinal obstruction Hepatobiliary disorders Gamma- glutamyltransferase increasedb Alanine aminotransferase increased (ALT), Aspartate aminotransferase increased (AST), Blood alkaline phosphatase increased (ALP) General disorders and administration site conditions Fatigue Oedema peripheral, Pyrexia a Abdominal pain (including upper and lower abdominal pain) b Gamma-glutamyl transferase increased (including preferred terms of gamma-glutamyl transferase increased, gamma-glutamyl transferase, and liver function test abnormal / hepatic enzyme increased for which gamma-glutamyl transferase was increased). c Faecaloma has only been observed in a clinical study at a dosage of 500mg tid (twice the recommended dose). Description of selected adverse reactions Hepatic enzymes elevations Elevations in ALT >3 × upper limit of normal (ULN) or ALP>2 ULN have been reported in patients receiving therapy with telotristat, most cases being reported at a higher dose (500 mg). These have not been associated with concomitant elevations in total serum bilirubin. The increases were largely reversible on dose interruption or reduction, or recovered whilst maintaining treatment at the same dose. For clinical management of elevated hepatic enzymes, see section 4.4. Gastrointestinal disorders The most frequently reported adverse event in patients receiving telotristat ethyl 250 mg tid was abdominal pain (25.7%; 18/70) versus placebo (19.7%; 14/71). Abdominal distension was reported in 7.1% of patients (5/70) receiving telotristat ethyl 250 mg tid, versus 4.2% in the placebo group (3/71). Flatulence was seen in 5.7% of patients (4/70) and 1.4% (1/71) in the telotristat ethyl 250 mg and placebo groups, respectively. Most events were mild or moderate and did not limit study treatment. 6 Constipation was reported in 5.7% of patients (4/70) in the telotristat ethyl 250 mg group and in 4.2% of patients (3/71) in the placebo group. Serious constipation was observed in 3 patients treated with a higher dose (500 mg) in the overall safety population (239 patients). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Symptoms There is limited clinical experience with telotristat overdose in humans. Gastrointestinal disorders including nausea, diarrhoea, abdominal pain and vomiting have been reported in healthy subjects taking a single dose of 1,500 mg in a phase 1 study. Management Treatment of an overdose should include general symptomatic management. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other alimentary tract and metabolism products: Various alimentary tract and metabolism products, ATC code: A16AX15 Mechanism of action Both the prodrug (telotristat ethyl) and its active metabolite (telotristat) are inhibitors of L-tryptophan hydroxylases (TPH1 and TPH2, the rate limiting steps in serotonin biosynthesis). Serotonin plays a critical role in regulating several major physiological processes, including secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-secreted in patients with carcinoid syndrome. Through inhibition of peripheral TPH1, telotristat reduces the production of serotonin, thus alleviating symptoms associated with carcinoid syndrome. Pharmacodynamic effects In Phase 1 studies, dosing with telotristat ethyl in healthy subjects (dose range: 100 mg once daily to 500 mg tid) produced statistically significant reductions from baseline in whole blood serotonin and 24-hour urinary 5-hydroxyindoleacetic acid (u5-HIAA) compared with placebo. In patients with carcinoid syndrome, telotristat resulted in reductions in u5-HIAA (refer to Table 3 for TELESTAR and information provided for TELECAST). Statistically significant reductions in u5-HIAA were seen for telotristat ethyl 250 mg tid compared with placebo in both Phase 3 studies. Clinical efficacy and safety The efficacy and safety of telotristat for the treatment of carcinoid syndrome in patients with metastatic neuroendocrine tumours who were receiving SSA therapy was established in a 12-week double-blind, placebo-controlled, randomised, multicentre phase 3 trial in adult patients, which included a 36-week extension during which all patients were treated with open-label telotristat (TELESTAR Study). A total of 135 patients were evaluated for efficacy. The mean age was 64 years (range 37 to 88 years), 52% were male and 90% were white. All patients had well-differentiated metastatic neuroendocrine tumours and carcinoid syndrome. They were on SSA therapy and had ≥4 daily BM. The study included a 12-week double-blind treatment (DBT) period, in which patients initially received placebo (n=45), telotristat ethyl 250 mg (n=45) or a higher dose (telotristat ethyl 500 mg; http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 7 n=45) tid. During the study, patients were allowed to use rescue medication (short-acting SSA therapy) and anti-diarrhoeals for symptomatic relief but were required to be on stable-dose long-acting SSA therapy for the duration of the DBT period. Xermelo was taken within 15 minutes before, or within 1 hour after food. Table 2: BM response (TELESTAR Study) Parameter Placebo Telotristat ethyl 250 mg tid BMs/day at baseline Number of patients 45 45 Baseline mean (SD) 5.2 (1.35) 6.1 (2.07) Primary endpoint: change from baseline in BMs/day averaged over 12 weeks Number of patients 45 45 Change averaged over 12 weeks: mean (SD) ˗0.6 (0.83) ˗1.4 (1.37) ANCOVAa Least Square mean difference --- -0.6 97.5% CL for difference --- -1.16, -0.06 p value --- 0.01 Percentage of patients with durable responseb Number of patients 45 45 Responder, n (%) 9 (20.0) 20 (44.4)c BM = bowel movement; CL=confidence limit; tid=three times daily; SD=standard deviation. a. Analysis of covariance including treatment group and urinary 5-HIAA stratification at randomisation as fixed effects, and the baseline number of BM as a fixed covariate. b. Defined as the proportion of responders with ≥30% reduction in daily number of BMs for ≥50% of time over the DBT period. c. p=0.01 When the full effect of telotristat is observed (during the last 6 weeks of the DBT period) the proportion of responders with at least 30% BM reduction was 51% (23/45) in the 250 mg group versus 22% (10/45) in the placebo group (post-hoc analysis). In the 12-week DBT period of the study, average weekly reductions in BM frequency on telotristat were observed as early as 3 weeks, with the greatest reductions occurring during the last 6 weeks of the DBT period, compared with placebo (refer to Figure 1). 8 Figure 1 – Mean change from baseline in BMs by study week during the DBT period, Intent-to- Treat Population The proportions of patients reporting reductions from baseline in daily BM frequency (averaged over 12 weeks) were: - Patients with a mean reduction of at least 1 BM per day: 66.7% (telotristat ethyl 250 mg) and 31.1% (placebo); - Patients with a mean reduction of at least 1.5 BM per day: 46.7% (telotristat ethyl 250 mg) and 20.0% (placebo); - Patients with a mean reduction of at least 2 BM per day: 33.3% (telotristat ethyl 250 mg) and 4.4% (placebo). Table 3: u5-HIAA excretion at baseline and week 12 (TELESTAR Study) Parameter Placebo Telotristat ethyl 250 mg tid u5-HIAA excretion (mg/24 hours) at baseline Number of Patients 44 42 Baseline Meana (SD) 81.0 (161.01) 92.6 (114.90) Percent change from baseline in u5-HIAA excretion (mg/24 hours) at week 12 Number of Patients 28 32 Percent Change at Week 12: Mean (SD) 14.4 (57.80) -42.3 (41.96) Estimate of Treatment Difference (95% CL)b --- -53.4 c (-69.32, -38.79) CL=confidence limit; tid=three times daily; SD=standard deviation; u5-HIAA = urinary 5--hydroxyindoleacetic acid. a. Baseline data based on all patients with data at baseline. b. Statistical tests used a blocked 2-sample Wilcoxon Rank Sum statistic (van Elteren test) stratified by the u5-HIAA stratification at randomization. CLs were based on the Hodges- Lehmann estimator of the median paired difference. c. p<0.001 There was no significant difference between treatment groups for the endpoints of flushing and abdominal pain. A post-hoc analysis showed that the average number of daily short-acting SSA injections used for rescue therapy over the 12-week DBT period was 0.3 and 0.7 in the telotristat ethyl 250 mg and placebo groups, respectively. 0 1 2 3 4 5 6 7 8 9 10 11 12 Study week -2.50 -2.25 -2.00 -1.75 -1.50 -1.25 -1.00 -0.75 -0.50 -0.25 0.00 in B ow el M ov em en ts (c ou nt s/ da y) M ea n C ha ng e fr om B as el in e (a nd 9 5% C L) Telotristat Ethyl 250mgPlacebo , p Note: This figure plots the arithmetic mean and 95% confidence limits (CL) (based on normal approximation) of the change from Baseline in the number of daily bowel movements (counts/day) averaged at each week. 9 A pre-specified patient exit interview substudy was conducted to assess relevance and clinical meaningfulness of symptom improvements in 35 patients. Questions were asked to blinded participants to further characterise the degree of change experienced during the trial. There were 12 patients who were “very satisfied”, and all of them were on telotristat. The proportions of patients who were “very satisfied” were 0/9 (0%) on placebo, 5/9 (56%) on telotristat ethyl 250 mg tid and 7/15 (47%) on a higher dose of telotristat ethyl. Overall, 18 patients (13.2%) prematurely discontinued from the study during the DBT Period, 7 patients in the placebo group, 3 in the telotristat ethyl 250 mg group and 8 in the higher dose group. At the conclusion of the 12-week DBT period, 115 patients (85.2%) entered the 36-week open-label extension period, where all patients were titrated to receive a higher dose of telotristat ethyl (500 mg) tid. In a phase 3 study of similar design (TELECAST), a total of 76 patients were evaluated for efficacy. The mean age was 63 years (range 35 to 84 years), 55% were male and 97% were white. All patients had well-differentiated metastatic neuroendocrine tumour with carcinoid syndrome. Most patients (92.1%) had fewer than 4 BM per day and all except 9 were treated by SSA therapy. The primary endpoint was the percent change from Baseline in u5-HIAA at Week 12. The mean u5-HIAA excretion at baseline was 69.1 mg/24hours in the 250 mg group (n=17) and 84.8 mg/24 hours in the placebo group (n=22). The percent change from baseline in u5-HIAA excretion at week 12 was +97.7% in the placebo group versus -33.2% in the 250 mg group. The mean number of daily BM at baseline was 2.2 and 2.5 respectively in the placebo (n=25) and 250 mg group (n=25). The change from baseline in daily BM averaged over 12 weeks was +0.1 and -0.5 in the placebo and 250 mg groups respectively. Telotristat ethyl 250 mg showed that stool consistency, as measured by Bristol Stool Form Scale, was improved compared with placebo. There were 40% patients (10/25) with durable response (as defined in Table2) in the telotristat ethyl 250 mg group, versus 0% in the placebo group (0/26) (p=0.001). The long-term safety and tolerability of telotristat was evaluated in a nonpivotal (nonrandomized), phase 3, multicentre, open-label, long-term extension study. Patients having participated in any Xermelo phase 2 or phase 3 carcinoid syndrome study were eligible to enter the study at the same dose level and regimen as identified in their original study, for at least 84 weeks of treatment. No new significant safety signals were identified. The secondary objective of this study was to evaluate changes in patients’ quality of life (QOL) through Week 84. QOL was generally stable over the course of the study. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with telotristat in all subsets of the paediatric population in the treatment of carcinoid syndrome (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics of telotristat ethyl and its active metabolite have been characterised in healthy volunteers and patients with carcinoid syndrome. Absorption After oral administration to healthy volunteers, telotristat ethyl was rapidly absorbed, and almost completely converted to its active metabolite. Peak plasma levels of telotristat ethyl were achieved in 0.53 to 2.00 hours and those of the active metabolite in 1.50 to 3.00 hours after oral administration. Following administration of a single 500 mg dose of telotristat ethyl (twice the recommended dose) under fasted conditions in healthy subjects, the mean Cmax and AUC0-inf were 4.4 ng/mL and 6.23 ng•hr/mL, respectively for telotristat ethyl. The mean Cmax and AUC0-inf were 610 ng/mL and 2320 ng•hr/mL, respectively for telotristat. 10 In patients with carcinoid syndrome on long-acting SSA therapy, there was also a rapid conversion of telotristat ethyl to its active metabolite. A high variability (% CV range of 18% to 99%) in telotristat ethyl and its active metabolite parameters was observed within the overall PK. The mean PK parameters for telotristat ethyl and the active metabolite appeared unchanged between week 24 and week 48, suggesting the achievement of steady-state conditions at or prior to week 24. Food effect In a food effect study administration of telotristat ethyl 500 mg with a high-fat meal resulted in higher exposure to the parent compound (Cmax, AUC0-tlast, and AUC0-∞ being 112%, 272%, and 264% higher, respectively compared with the fasted state) and its active metabolite (Cmax, AUC0-tlast, and AUC0-∞, 47%, 32%, and 33% higher, respectively compared with the fasted state). Distribution Both telotristat ethyl and its active metabolite are > 99% bound to human plasma proteins. Biotransformation After oral administration, telotristat ethyl undergoes hydrolysis via carboxylesterases to its active and major metabolite. The only metabolite of telotristat (active metabolite) representing consistently > 10% of total plasma drug-related material was its oxidative decarboxylated deaminated metabolite, LP-951757. Systemic exposure to LP-951757 was about 35% of the systemic exposure to telotristat (active metabolite) in the mass balance study. LP-951757 was pharmacologically inactive at TPH1 in vitro. Interactions Cytochromes CYP2B6 In vitro telotristat (active metabolite) caused a concentration dependent increase in CYP2B6 mRNA levels (>2-fold increase and > 20% of the positive control, with a maximum observed effect similar to the positive control), suggesting possible CYP2B6 induction (see section 4.5). CYP3A4 Telotristat ethyl and its active metabolite were not shown to be inducers of CYP3A4 at systemically relevant concentrations, based on in vitro findings. The potential of telotristat ethyl as an inducer of CYP3A4 was not assessed at concentrations expectable at the intestinal level, due to its low solubility in vitro. In vitro telotristat ethyl engages in an allosteric interaction with CYP3A4 resulting at the same time in a reduced conversion of midazolam to 1’-OH-MDZ, and increased conversion to 4-OH-MDZ. In an in vivo clinical drug-drug interaction (DDI) study with midazolam (a sensitive CYP3A4 substrate), following administration of multiple doses of telotristat ethyl, the systemic exposure to concomitant midazolam was significantly decreased (see section 4.5). When 3 mg midazolam was coadministered orally after 5-day treatment with telotristat ethyl 500 mg tid (twice the recommended dose), the mean Cmax, and AUC0-inf for midazolam were decreased by 25%, and 48%, respectively, compared with administration of midazolam alone. The mean Cmax, and AUC0-inf for the active metabolite, 1’-hydroxymidazolam, were also decreased by 34%, and 48%, respectively. Other CYPs Based on in vitro findings, no clinically-relevant interaction is expected with other cytochromes P450. Carboxylesterases The IC50 of the inhibition of loperamide on the metabolism of telotristat ethyl by CES2 was 5.2 µM (see section 4.5). In vitro, telotristat ethyl inhibited CES2 with an IC50 approximately of 0.56 μM. Transporters P-glycoprotein (P-gp) and Multi-drug Resistance associated Protein 2 (MRP-2) 11 In vitro telotristat ethyl inhibited P-gp, but its active metabolite did not at the clinically relevant concentrations. Telotristat ethyl inhibited MRP2-mediated transport (98% inhibition). In a specific clinical DDI study, the Cmax and AUC of fexofenadine (a P-gp and MRP-2 substrate) increased by 16% when a single 180 mg dose of fexofenadine was co-administered orally with a dose of telotristat ethyl 500 mg administered tid (twice the recommended dose) for 5 days. Based on the small increase observed, clinically meaningful interactions with P-gp and MRP-2 substrates are unlikely. Breast Cancer Resistance Protein (BCRP) In vitro telotristat ethyl inhibited BCRP (IC50 = 20 µM), but its active metabolite telotristat did not show any significant inhibition of BCRP activity (IC50 > 30 µM). The potential for in vivo drug interaction via inhibition of BCRP is considered low. Other transporters Based on in vitro findings, no clinically-relevant interaction is expected with other transporters. Short-acting octreotide A study examining the effect of short-acting octreotide (3 doses of 200◦micrograms given 8◦hours apart) on the single dose pharmacokinetics of Xermelo in normal healthy volunteers showed an 83% and 81% decrease in Cmax and AUC of telotristat ethyl and telotristat, respectively (see section 4.5). Reduced exposures were not observed in a 12◦week double-blind, placebo-controlled, randomised, multicentre clinical trial in adult patients with carcinoid syndrome on long-acting SSA therapy. Pharmacokinetic/pharmacodynamic relationship(s) Acid Reducers Concomitant use of telotristat etiprate (Xermelo, the hippurate salt of telotristat ethyl) with acid- reducers (omeprazole and famotidine) showed that the AUC of telotristat ethyl was increased 2-3 fold, while the AUC of the active metabolite (telotristat) was not changed. Since telotristat ethyl is rapidly converted to its active metabolite, which is > 25× more active than telotristat ethyl, no dose adjustments are required when using Xermelo with acid reducers. Elimination Following a single 500 mg oral dose of 14C-telotristat ethyl, approximately 93% of the dose was recovered. The majority was eliminated in the faeces. Telotristat ethyl and telotristat have a low renal elimination following oral administration (less than 1% of the dose recovered from the urine). Following a single oral 250 mg dose of telotristat ethyl to heathy volunteers, urine concentrations of telotristat ethyl were close to or below the limit of quantification (<0.1 ng/mL). The renal clearance of telotristat was 0.126 L/h. The apparent half-life of telotristat ethyl in normal healthy volunteers following a single 500 mg oral dose 14C-telotristat ethyl was approximately 0.6 hour and that of its active metabolite was 5 hours. Following administration of 500 mg tid, the apparent terminal half-life was approximately 11 hours. Linearity/non-linearity In patients treated at 250 mg tid, a slight accumulation of telotristat levels was observed with a median accumulation ratio based on AUC0-4h of 1.55 [minimum, 0.25; maximum, 5.00; n=11; week 12], with a high inter-subject variability (%CV = 72%). In patients treated at 500 mg tid (twice the recommended dose), a median accumulation ratio based on AUC0-4h of 1.095 (minimum, 0.274; maximum, 11.46; n=16; week 24) was observed, with a high inter-subject variability (%CV = 141.8%). Based on the high inter-subject variability observed, accumulation in a subset of patients with CS cannot be excluded. Special populations 12 Elderly The influence of age on the pharmacokinetics of telotristat ethyl and its active metabolite has not been conclusively evaluated. No specific study has been performed in the elderly population. Renal impairment A study was conducted to investigate the impact of renal impairment on the pharmacokinetics of a single dose of telotristat ethyl 250 mg. Eight subjects with severe to moderate renal impairment not requiring dialysis [eGFR ≤ 33 mL/min at screening and ≤40 mL/min at the day prior to dosing] and eight healthy to mildly impaired subjects [eGFR ≥88 mL/min at screening and ≥83 mL/min at the day prior to dosing] were included in this study. In the subjects with severe to moderate renal impairment, an increase (1.3- fold) in peak exposure Cmax of telotristat ethyl and an increase (<1.52- fold) in plasma exposure (AUC) and Cmax of its active metabolite telotristat was observed compared to healthy to mildly impaired subjects. Variability of the main plasma telotristat PK parameters was higher in subjects with severe to moderate renal impairment, with CV% ranging from 53.3% for Cmax to 77.3% for AUC as compared to 45.4% for Cmax and 39.7% for AUC in healthy to mildly impaired subjects, respectively. Administration of a single dose of 250 mg was well tolerated in subjects with severe to moderate renal impairment. Overall, severe to moderate renal impairment did not result in a clinically meaningful change in the PK profile or safety of telotristat ethyl and its metabolite telotristat. Therefore, dose adjustment does not appear necessary in patients with mild, moderate or severe renal impairment; who are not requiring dialysis. Given the high variability observed, it is recommended as a precautionary measure that patients with severe renal impairment will be monitored for signs of reduced tolerability. The efficacy and safety in patients with end-stage renal disease who require dialysis (eGFR < 15 mL/min/1.73 m² requiring dialysis) has not been established. Hepatic impairment A hepatic impairment study was conducted in subjects with mild and moderate hepatic impairment and in healthy subjects. At a single dose of 500 mg, exposures to the parent compound and its active metabolite (based on AUC0-last) were higher in patients with mild hepatic impairment (2.3- and 2.4- fold, respectively) and in patients with moderate hepatic impairment (3.2- and 3.5-fold, respectively) compared with healthy subjects. Administration of a single dose of 500 mg was well tolerated. A reduction in dose may be necessary in patients with mild or moderate hepatic impairment (respectively Child Pugh score A and B) based on tolerability (see section 4.2). A further hepatic impairment study was conducted in subjects with severe hepatic impairment and in healthy subjects. At a single dose of 250 mg, exposure to the parent compound (AUCt and Cmax) was increased 317.0% and 529.5%, respectively, and to the active metabolite (AUCt, AUCinf, and Cmax) 497%, 500%, and 217%, respectively, for subjects with severe hepatic impairment compared to subjects with normal hepatic function. In addition, the half-life of the active metabolite was increased, i.e. the mean half life was 16.0 hours in subjects with severe hepatic impairment compared to 5.47 hours in healthy subjects. Based on these findings, the use of telotristat etiprate is not recommended in patients with severe hepatic impairment (Child Pugh score C) (see section 4.2). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. In rats decrease in brain serotonin (5-HT) was observed at doses≥1,000 mg/kg/day of telotristat etiprate per os. Brain 5-HIAA levels were unchanged at all doses of telotristat ethyl examined. This is 13 approximately 14 times the human exposure (AUC total) at the maximum recommended human dose (MRHD) of 750 mg/day for the active metabolite LP-778902. In a 26-week repeat-dose toxicity study in rats a No-Observed Adverse Effect Level (NOAEL) of 50 mg/kg/day was determined. This is approximately 0.4 times the human exposure (AUC total) at MRHD of 750 mg/day for the active metabolite LP-778902. At doses of 200 and 500 mg/kg/day degeneration/necrosis in the nonglandular and/or glandular portions of the stomach and/or increased protein droplets in the glandular portions were observed. The microscopic changes in the gastrointestinal tract reversed with a 4-week recovery period. Relevance of these gastrointestinal findings to humans is unknown. In dogs decreases in brain 5-HT and 5-HIAA levels were observed at dose of 200 mg/kg/day and 30 mg/kg/day of telotristat etiprate per os, respectively. This is approximately 21 times the human exposure (AUC total) at MRHD of 750 mg/day for the active metabolite LP-778902. No decrease in brain 5-HT and 5-HIAA levels were observed after intravenous application of active metabolite. The clinical significance of the decrease in brain 5-HIAA with or without a concomitant decrease in brain 5-HT is unknown. In a 39-week repeat-dose toxicity study in dogs NOAEL of 300 mg/kg/day was determined. Clinical signs were limited to increase in frequency of liquid faeces at all doses. This is approximately 20 times the human exposure (AUC total) at MRHD of 750 mg/day for the active metabolite LP-778902. The carcinogenic potential of telotristat etiprate was studied in transgenic mice (26 weeks) and rats (104 weeks). These studies confirmed that telotristat did not increase the incidence of tumours in both species and sexes, at doses corresponding to an exposure of approximately 10- to 15-fold and 2- to 4.5-fold the human exposure to the active metabolite at the MRHD in mice and rats, respectively. In rats, there were no adverse effects on male and female fertility. Prenatal development in rats and rabbits was affected by increased prenatal lethality (increased early and late resorptions), while no adverse effects were noted on postnatal development in rats. The NOAEL for parental / maternal / prenatal and postnatal toxicity is 500 mg/kg/day in rats corresponding to 3 to 4 times the estimated human exposure (AUC0-24) of the active metabolite LP-778902 at the MRHD. In rabbits the NOAEL for maternal and prenatal toxicity is 125 mg/kg/d corresponding to 1.5 to 4 times the estimated human exposure (AUC0-24) of the active metabolite LP-778902 at the MRHD. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Lactose anhydrous Hydroxypropylcellulose Croscarmellose sodium Magnesium stearate Silica, colloidal anhydrous Film-coating Poly(vinyl alcohol) (partially hydrolysed) (E1203) Titanium dioxide (E171) Macrogol 3350 (E1521) Talc (E553b) 6.2 Incompatibilities Not applicable. 14 6.3 Shelf life 4 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container PVC/PCTFE/PVC/Al blister The blisters are packaged in a carton. Pack sizes of 90 and 180 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Ipsen Pharma 65 quai Georges Gorse 92100 Boulogne-Billancourt France 8. MARKETING AUTHORISATION NUMBER(S) EU/1/17/1224/001 EU/1/17/1224/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 18 September 2017 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 15 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 16 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release BEAUFOUR IPSEN INDUSTRIE RUE ETHE VIRTON DREUX 28100 France B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this medicinal product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 17 ANNEX III LABELLING AND PACKAGE LEAFLET 18 A. LABELLING 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Xermelo 250 mg film-coated tablets telotristat ethyl 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains telotristat etiprate equivalent to 250 mg telotristat ethyl. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 90 film-coated tablets 180 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 20 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Ipsen Pharma 65 quai Georges Gorse 92100 Boulogne-Billancourt France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/17/1224/001 EU/1/17/1224/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE xermelo 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC {number} SN {number} NN {number} 21 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Xermelo 250 mg film-coated tablets telotristat ethyl 2. NAME OF THE MARKETING AUTHORISATION HOLDER Ipsen Pharma 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 22 B. PACKAGE LEAFLET 23 Package leaflet: Information for the patient Xermelo 250 mg film-coated tablets telotristat ethyl This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Xermelo is and what it is used for 2. What you need to know before you take Xermelo 3. How to take Xermelo 4. Possible side effects 5. How to store Xermelo 6. Contents of the pack and other information 1. What Xermelo is and what it is used for What Xermelo is This medicine contains the active substance telotristat ethyl. What Xermelo is used for This medicine is used in adults with a condition called ‘carcinoid syndrome’. This is when a tumour, called a ‘neuroendocrine tumour’, releases a substance called serotonin into your bloodstream. Your doctor will prescribe this medicine if your diarrhoea is not well controlled with injections of other medicines called ‘somatostatin analogues’ (lanreotide or octreotide). You should keep having injections of these other medicines when taking Xermelo. How Xermelo works When the tumour releases too much serotonin into your bloodstream you can get diarrhoea. This medicine works by reducing the amount of serotonin made by the tumour. It will reduce your diarrhoea. 2. What you need to know before you take Xermelo Do not take Xermelo - if you are allergic to telotristat or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor or pharmacist before taking Xermelo: • if you have liver problems. This is because this medicine is not recommended for use in patients with severe liver problems. Your doctor may decide to decrease your daily dose of Xermelo in 24 cases where your liver problems are considered mild or moderate. Your doctor will also monitor your liver. • if you have end-stage kidney disease or are on dialysis. This is because this medicine has not been tested in patients with end-stage kidney disease, requiring dialysis. Look out for side effects Tell your doctor straight away if you notice any of the following signs and symptoms that suggest that your liver may not be working properly: • feeling or being sick (unexplained nausea or vomiting), abnormally dark urine, yellow skin or eyes, pain in the upper right belly. Your doctor will do blood tests to check your liver and will decide whether you should keep taking this medicine. Talk to your doctor or pharmacist: • if you feel down, depressed, or if you feel you have no interest or take any pleasure in doing your normal activities, whilst taking this medicine • if you have signs of constipation, as telotristat reduces the number of your bowel movements. Tests • Your doctor may carry out blood tests before you start taking this medicine and while you are taking it. This is to check that your liver is working normally. Children and adolescents This medicine is not recommended in patients below 18 years old. This is because the medicine has not been tested in this age group. Other medicines and Xermelo Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because Xermelo can affect the way some other medicines work, or other medicines can affect the way Xermelo works. This could mean that your doctor needs to change the dose(s) that you take. You should tell your doctor about every medicine. This includes: • medicines for diarrhoea. Xermelo and these medicines reduce the number of your bowel movements and taken together, they can cause severe constipation. Your doctor may need to change the dose of your medicines. • medicines used to treat epilepsy, such as valproic acid. • medicines used to treat your neuroendocrine tumour, such as sunitinib or everolimus. • medicines to treat depression, such as bupropion or sertraline. • medicines used to avoid transplant rejection, such as cyclosporine. • medicines used to lower cholesterol levels, such as simvastatin. • oral contraceptives, such as ethinyloestradiol. • medicines used to treat high blood pressure, such as amlodipine. • medicines used to treat some types of cancers, such as irinotecan, capecitabine and flutamide. • medicines used to reduce the chance of a blood clot forming, such as prasugrel. • octreotide. If you need treatment with octreotide subcutaneous injections, you should have your injection at least 30 minutes after taking Xermelo. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. You should not take this medicine if you are pregnant or might become pregnant. It is not known how telotristat may affect the baby. Women should use effective methods of contraception while taking this medicine. You should not breast-feed if you are taking Xermelo, as this medicine may be passed on to your baby. 25 Driving and using machines Telotristat may have a small effect on your ability to drive or use any tools or machines. If you feel tired, you should wait until you feel better before driving or using any tools or machines. Xermelo contains lactose Xermelo contains lactose (a type of sugar). If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicine. 3. How to take Xermelo Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. How much to take The recommended dose is one tablet (250 mg) three times a day. The maximum dose of Xermelo is 750 mg in 24 hours. Your doctor will decide for how long you should take Xermelo. If you have liver problems, your doctor may decide to reduce your daily dose of Xermelo. Taking this medicine • Always take this medicine with a meal or some food. • You should keep having injections of somatostatin analogues (lanreotide or octreotide) when taking Xermelo. If you take more Xermelo than you should You may feel sick or be sick, have diarrhoea or stomach ache. Talk to a doctor. Take the medicine pack with you. If you forget to take Xermelo If you forget to take a dose, take your next dose when it is due, skipping the missed dose. Do not take a double dose to make up for a forgotten dose. If you stop taking Xermelo Do not stop taking Xermelo without talking with your doctor. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor immediately if you notice any of the following side effects: • feeling or being sick, abnormally dark urine, yellow skin or eyes, pain in the upper right belly. These may be signs that your liver is not working properly. This might also be shown by changes in your blood test results, such as an increase of liver enzymes: gamma-glutamyl transferase (very common, may affect more than 1 in 10 people), transaminases and blood alkaline phosphatase (common, may affect up to 1 in 10 people). Other side effects Tell your doctor, pharmacist or nurse if you notice any of the following side effects: Very common side effects (may affect more than 1 in 10 people): • Belly (abdominal) pain • Feeling tired or weak (fatigue) • Feeling sick (nausea) 26 Common side effects (may affect up to 1 in 10 people): • Wind • Fever • Headache • Constipation • Swollen stomach • Decreased appetite • Swelling (build-up of fluid in the body) • Depression, you may experience decreased self-esteem, lack of motivation, sadness or low mood Uncommon side effects (may affect up to 1 in 100 people): • Impacted stools (bowel obstruction, faecaloma), you may experience, constipation, watery diarrhoea, pale skin (anaemia), nausea, vomiting, weight loss, back pain or stomach pains particularly after eating or a reduction in passing water (urination). Tell your doctor immediately if you experience any of the following side effects: • Breathing problems, rapid heartbeat, fever, incontinence (uncontrollable urination), confusion, dizziness or agitation. Tell your doctor, pharmacist or nurse if you notice any of the side effects listed above. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Xermelo Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and the blister after EXP. The expiry date refers to the last day of that month. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Xermelo contains • The active substance is telotristat ethyl. Each tablet contains telotristat etiprate equivalent to 250 mg telotristat ethyl. • The other ingredients are: lactose anhydrous (see section 2 under ‘Xermelo contains lactose’), hydroxypropylcellulose, croscarmellose sodium, magnesium stearate, colloidal anhydrous silica, poly(vinyl alcohol) (partially hydrolysed) (E1203), titanium dioxide (E171), macrogol 3350 (E1521) and talc (E553b). What Xermelo looks like and contents of the pack The tablets are white to off-white, film-coated and oval shaped. Each tablet is approximately 17 mm long by 7.5 mm wide with ‘T-E’ debossed on one side and ‘250’ debossed on the other. The tablets are packaged in a PVC/PCTFE/PVC/Al blister. The blisters are packaged in a carton. Cartons of 90 and 180 tablets. Not all pack sizes may be marketed. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 27 Marketing Authorisation Holder Ipsen Pharma 65 quai Georges Gorse 92100 Boulogne-Billancourt France Manufacturer Beaufour Ipsen Industrie Rue Ethé Virton 28100 Dreux France For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien, Luxembourg/Luxemburg Ipsen NV Guldensporenpark 87 B-9820 Merelbeke België/Belgique/Belgien Tél/Tel: + 32 - 9 - 243 96 00 Latvija Ipsen Pharma pārstāvniecība Latvijā Kalnciema iela 33-5 Rīga LV 1046 Tel: +371 67622233 България Pharmaswiss EOOD 16, Troyanski Prohod Street Floor 3, Office 8, Lagera 1612 Sofia Teл.: +359 28952 110 Lietuva Ipsen Pharma SAS Lietuvos filialas T. Narbuto g. 5, 08105 Vilnius Tel: + 370 700 33305 Česká republika Ipsen Pharma, s.r.o. Olbrachtova 2006/9, 140 00 Praha 4 Tel: + 420 242 481 821 Magyarország IPSEN Pharma Hungary Kft. Váci út 33 IX. em. 1134 Budapest Tel.: +36-1-555-5930 Danmark, Norge, Suomi/Finland, Sverige, Ísland Institut Produits Synthèse (IPSEN) AB Kista Science Tower Färögatan 33 SE- 164 51 Kista Sverige/Ruotsi/Svíþjóð Tlf/Puh/Tel/Sími: +46 8 451 60 00 Nederland Ipsen Farmaceutica B.V. Taurusavenue 33b 2132 LS Hoofddorp Tel: + 31 (0) 23 554 1600 Deutschland, Österreich Ipsen Pharma GmbH Einsteinstraße 174 D-81677 München Tel.: +49 89 262043289 Polska Ipsen Poland Sp. z o.o. Al. Jana Pawła II 29 00-867 Warszawa Tel.: + 48 22 653 68 00 Eesti CentralPharma Communications OÜ Selise 26 - 11 13522 Tallinn Portugal Ipsen Portugal - Produtos Farmacêuticos S.A. Alameda Fernão Lopes, n° 16A–1°B 1495 - 190 Algés 28 Estonia Tel: +372 6015540 Portugal Tel: + 351 - 21 - 412 3550 Ελλάδα, Κύπρος, Malta Ipsen Μονοπρόσωπη EΠΕ Αγ. Δημητρίου 63 Άλιμος GR-17456 Αθήνα Ελλάδα Τηλ: + 30 - 210 - 984 3324 România Ipsen Pharma România SRL Sectorul 1, Strada Grigore Alexandrescu nr. 59, Etaj 1 Bucureşti, 010623 Tel: + 40 21 231 27 20 España Ipsen Pharma, S.A. Torre Realia, Plaza de Europa, 41-43 08908 L’Hospitalet de Llobregat Barcelona Tel: + 34 936 858 100 Slovenija Pharmaswiss d.o.o. Brodišče 32 SI-1236 Trzin Tel: +386 1 236 47 00 France, Hrvatska Ipsen Pharma 65 quai Georges Gorse 92100 Boulogne-Billancourt France Tél: + 33 1 58 33 50 00 Slovenská republika Ipsen Pharma, organizačná zložka Zámocká 3 SK-811 01 Bratislava Slovenská republika Tel: + 420 242 481 821 Ireland Ipsen Pharmaceuticals Ltd. Blanchardstown Industrial Park Blanchardstown IRL-Dublin 15 Tel: +353-1-809-8256 United Kingdom Ipsen Ltd. 190 Bath Road Slough, Berkshire SL1 3XE United Kingdom Tel: + 44 (0)1753 - 62 77 00 Italia Ipsen SpA Via del Bosco Rinnovato n. 6 Milanofiori Nord Palazzo U7 20090 Assago (MI) Tel: + 39 - 02 - 39 22 41 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. http://www.ema.europa.eu/ ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT ANNEX III A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take xermelo', 'Section_Content': 'do not take xermelo - if you are allergic to telotristat or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor or pharmacist before taking xermelo: if you have liver problems. this is because this medicine is not recommended for use in patients with severe liver problems. your doctor may decide to decrease your daily dose of xermelo in 24 cases where your liver problems are considered mild or moderate. your doctor will also monitor your liver. if you have end-stage kidney disease or are on dialysis. this is because this medicine has not been tested in patients with end-stage kidney disease, requiring dialysis. look out for side effects tell your doctor straight away if you notice any of the following signs and symptoms that suggest that your liver may not be working properly: feeling or being sick (unexplained nausea or vomiting), abnormally dark urine, yellow skin or eyes, pain in the upper right belly. your doctor will do blood tests to check your liver and will decide whether you should keep taking this medicine. talk to your doctor or pharmacist: if you feel down, depressed, or if you feel you have no interest or take any pleasure in doing your normal activities, whilst taking this medicine if you have signs of constipation, as telotristat reduces the number of your bowel movements. tests your doctor may carry out blood tests before you start taking this medicine and while you are taking it. this is to check that your liver is working normally. children and adolescents this medicine is not recommended in patients below 18 years old. this is because the medicine has not been tested in this age group. other medicines and xermelo tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. this is because xermelo can affect the way some other medicines work, or other medicines can affect the way xermelo works. this could mean that your doctor needs to change the dose(s) that you take. you should tell your doctor about every medicine. this includes: medicines for diarrhoea. xermelo and these medicines reduce the number of your bowel movements and taken together, they can cause severe constipation. your doctor may need to change the dose of your medicines. medicines used to treat epilepsy, such as valproic acid. medicines used to treat your neuroendocrine tumour, such as sunitinib or everolimus. medicines to treat depression, such as bupropion or sertraline. medicines used to avoid transplant rejection, such as cyclosporine. medicines used to lower cholesterol levels, such as simvastatin. oral contraceptives, such as ethinyloestradiol. medicines used to treat high blood pressure, such as amlodipine. medicines used to treat some types of cancers, such as irinotecan, capecitabine and flutamide. medicines used to reduce the chance of a blood clot forming, such as prasugrel. octreotide. if you need treatment with octreotide subcutaneous injections, you should have your injection at least 30 minutes after taking xermelo. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. you should not take this medicine if you are pregnant or might become pregnant. it is not known how telotristat may affect the baby. women should use effective methods of contraception while taking this medicine. you should not breast-feed if you are taking xermelo, as this medicine may be passed on to your baby. driving and using machines telotristat may have a small effect on your ability to drive or use any tools or machines. if you feel tired, you should wait until you feel better before driving or using any tools or machines. xermelo contains lactose xermelo contains lactose (a type of sugar). if you have been told by your doctor 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor immediately if you notice any of the following side effects: feeling or being sick, abnormally dark urine, yellow skin or eyes, pain in the upper right belly. these may be signs that your liver is not working properly. this might also be shown by changes in your blood test results, such as an increase of liver enzymes: gamma-glutamyl transferase (very common, may affect more than 1 in 10 people), transaminases and blood alkaline phosphatase (common, may affect up to 1 in 10 people). other side effects tell your doctor, pharmacist or nurse if you notice any of the following side effects: very common side effects (may affect more than 1 in 10 people): belly (abdominal) pain feeling tired or weak (fatigue) feeling sick (nausea) 26 common side effects (may affect up to 1 in 10 people): wind fever headache constipation swollen stomach decreased appetite swelling (build-up of fluid in the body) depression, you may experience decreased self-esteem, lack of motivation, sadness or low mood uncommon side effects (may affect up to 1 in 100 people): impacted stools (bowel obstruction, faecaloma), you may experience, constipation, watery diarrhoea, pale skin (anaemia), nausea, vomiting, weight loss, back pain or stomach pains particularly after eating or a reduction in passing water (urination). tell your doctor immediately if you experience any of the following side effects: breathing problems, rapid heartbeat, fever, incontinence (uncontrollable urination), confusion, dizziness or agitation. tell your doctor, pharmacist or nurse if you notice any of the side effects listed above. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'xermelo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 14, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9649657011032104, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7921227216720581}]}, {'Id': 15, 'BeginOffset': 156, 'EndOffset': 168, 'Score': 0.9046098589897156, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8620209097862244}]}, {'Id': 16, 'BeginOffset': 170, 'EndOffset': 191, 'Score': 0.6642621159553528, 'Text': 'feeling or being sick', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': 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382}, {'Id': 75, 'BeginOffset': 415, 'EndOffset': 428, 'Score': 0.8891412019729614, 'Text': 'liver enzymes', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.19468900561332703, 'RelationshipScore': 0.9998670816421509, 'RelationshipType': 'TEST_VALUE', 'Id': 74, 'BeginOffset': 403, 'EndOffset': 411, 'Text': 'increase', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 76, 'BeginOffset': 430, 'EndOffset': 456, 'Score': 0.37144333124160767, 'Text': 'gamma-glutamyl transferase', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 492, 'EndOffset': 493}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 497, 'EndOffset': 499}, {'Id': 77, 'BeginOffset': 509, 'EndOffset': 522, 'Score': 0.7289000749588013, 'Text': 'transaminases', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 78, 'BeginOffset': 527, 'EndOffset': 553, 'Score': 0.7813498377799988, 'Text': 'blood alkaline phosphatase', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 580, 'EndOffset': 581}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 585, 'EndOffset': 587}, {'Id': 20, 'BeginOffset': 603, 'EndOffset': 615, 'Score': 0.665469229221344, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4764288067817688}]}, {'Id': 21, 'BeginOffset': 689, 'EndOffset': 701, 'Score': 0.8822066783905029, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8276538848876953}]}, {'Text': 'very common side effects', 'Type': 'PROBLEM', 'BeginOffset': 703, 'EndOffset': 727}, {'Id': 23, 'BeginOffset': 733, 'EndOffset': 739, 'Score': 0.3040958046913147, 'Text': 'affect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, 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'BeginOffset': 922, 'EndOffset': 934, 'Score': 0.9961643218994141, 'Text': 'constipation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9723738431930542}]}, {'Text': 'swollen stomach', 'Type': 'PROBLEM', 'BeginOffset': 935, 'EndOffset': 950}, {'Text': 'decreased appetite swelling', 'Type': 'PROBLEM', 'BeginOffset': 951, 'EndOffset': 978}, {'Id': 38, 'BeginOffset': 992, 'EndOffset': 1009, 'Score': 0.5462520122528076, 'Text': 'fluid in the body', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6738650798797607}]}, {'Id': 39, 'BeginOffset': 1011, 'EndOffset': 1021, 'Score': 0.9920138716697693, 'Text': 'depression', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.889482319355011}]}, {'Id': 40, 'BeginOffset': 1042, 'EndOffset': 1063, 'Score': 0.9295510649681091, 'Text': 'decreased self-esteem', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.955096960067749}]}, {'Id': 41, 'BeginOffset': 1065, 'EndOffset': 1083, 'Score': 0.9811991453170776, 'Text': 'lack of motivation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9491069912910461}]}, {'Id': 42, 'BeginOffset': 1085, 'EndOffset': 1092, 'Score': 0.9239980578422546, 'Text': 'sadness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9385508298873901}]}, {'Text': 'low mood uncommon side effects', 'Type': 'PROBLEM', 'BeginOffset': 1096, 'EndOffset': 1126}, {'Id': 45, 'BeginOffset': 1132, 'EndOffset': 1160, 'Score': 0.21934859454631805, 'Text': 'affect up to 1 in 100 people', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1145, 'EndOffset': 1146}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 1150, 'EndOffset': 1153}, {'Text': 'impacted stools (bowel obstruction', 'Type': 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0.9727529287338257}]}, {'Id': 54, 'BeginOffset': 1292, 'EndOffset': 1300, 'Score': 0.9991148114204407, 'Text': 'vomiting', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9803552627563477}]}, {'Id': 55, 'BeginOffset': 1302, 'EndOffset': 1313, 'Score': 0.9957379102706909, 'Text': 'weight loss', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9567047357559204}]}, {'Id': 56, 'BeginOffset': 1315, 'EndOffset': 1324, 'Score': 0.986751914024353, 'Text': 'back pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9728907942771912}]}, {'Id': 57, 'BeginOffset': 1328, 'EndOffset': 1341, 'Score': 0.9792813062667847, 'Text': 'stomach pains', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9713233709335327}]}, {'Id': 58, 'BeginOffset': 1386, 'EndOffset': 1410, 'Score': 0.4803595244884491, 'Text': 'passing water (urination', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.951076090335846}]}, {'Id': 59, 'BeginOffset': 1481, 'EndOffset': 1493, 'Score': 0.9519266486167908, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8606849908828735}]}, {'Id': 60, 'BeginOffset': 1495, 'EndOffset': 1513, 'Score': 0.973178505897522, 'Text': 'breathing problems', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9347089529037476}]}, {'Id': 61, 'BeginOffset': 1515, 'EndOffset': 1530, 'Score': 0.7847920656204224, 'Text': 'rapid heartbeat', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9737072587013245}]}, {'Id': 62, 'BeginOffset': 1532, 'EndOffset': 1537, 'Score': 0.9984696507453918, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9810317158699036}]}, {'Text': 'incontinence (uncontrollable urination', 'Type': 'PROBLEM', 'BeginOffset': 1539, 'EndOffset': 1577}, {'Id': 65, 'BeginOffset': 1580, 'EndOffset': 1589, 'Score': 0.9974798560142517, 'Text': 'confusion', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9692043662071228}]}, {'Id': 66, 'BeginOffset': 1591, 'EndOffset': 1600, 'Score': 0.9995768666267395, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9766140580177307}]}, {'Id': 67, 'BeginOffset': 1604, 'EndOffset': 1613, 'Score': 0.9992651343345642, 'Text': 'agitation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8937117457389832}]}, {'Id': 68, 'BeginOffset': 1678, 'EndOffset': 1690, 'Score': 0.8193387389183044, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6957488656044006}]}, 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{'Title': '5. how to store xermelo', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and the blister after exp. the expiry date refers to the last day of that month. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what xermelo contains the active substance is telotristat ethyl. each tablet contains telotristat etiprate equivalent to 250 mg telotristat ethyl. the other ingredients are: lactose anhydrous (see section 2 under 'xermelo contains lactose'), hydroxypropylcellulose, croscarmellose sodium, magnesium stearate, colloidal anhydrous silica, poly(vinyl alcohol) (partially hydrolysed) (e1203), titanium dioxide (e171), macrogol 3350 (e1521) and talc (e553b). what xermelo looks like and contents of the pack the tablets are white to off-white, film-coated and oval shaped. each tablet is approximately 17 mm long by 7.5 mm wide with 't-e' debossed on one side and '250' debossed on the other. the tablets are packaged in a pvc/pctfe/pvc/al blister. the blisters are packaged in a carton. cartons of 90 and 180 tablets. not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'xermelo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 12, 'Score': 0.27490055561065674, 'Text': 'xermelo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 46, 'EndOffset': 63, 'Score': 0.7622259259223938, 'Text': 'telotristat ethyl', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.9110138416290283, 'RelationshipScore': 0.999832272529602, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 70, 'EndOffset': 76, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 3, 'BeginOffset': 86, 'EndOffset': 106, 'Score': 0.7317599058151245, 'Text': 'telotristat etiprate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.9110138416290283, 'RelationshipScore': 0.9259844422340393, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 70, 'EndOffset': 76, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 121, 'EndOffset': 124}, {'Id': 5, 'BeginOffset': 128, 'EndOffset': 145, 'Score': 0.9738465547561646, 'Text': 'telotristat ethyl', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.96865314245224, 'RelationshipScore': 0.9996196031570435, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 121, 'EndOffset': 127, 'Text': '250 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'lactose anhydrous', 'Type': 'PROBLEM', 'BeginOffset': 174, 'EndOffset': 191}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 205, 'EndOffset': 206}, {'Text': "lactose'", 'Type': 'TREATMENT', 'BeginOffset': 231, 'EndOffset': 239}, {'Id': 6, 'BeginOffset': 242, 'EndOffset': 264, 'Score': 0.9451807737350464, 'Text': 'hydroxypropylcellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 266, 'EndOffset': 287, 'Score': 0.990557074546814, 'Text': 'croscarmellose sodium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 289, 'EndOffset': 307, 'Score': 0.9912881255149841, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 309, 'EndOffset': 335, 'Score': 0.89292973279953, 'Text': 'colloidal anhydrous silica', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 342, 'EndOffset': 355, 'Score': 0.21326252818107605, 'Text': 'vinyl alcohol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 389, 'EndOffset': 405, 'Score': 0.9711769819259644, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 414, 'EndOffset': 427, 'Score': 0.9572644829750061, 'Text': 'macrogol 3350', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 459, 'EndOffset': 466, 'Score': 0.19982083141803741, 'Text': 'xermelo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'the pack the tablets', 'Type': 'TREATMENT', 'BeginOffset': 494, 'EndOffset': 514}, {'Text': '17', 'Type': 'NUMBER', 'BeginOffset': 597, 'EndOffset': 599}, {'Text': '7.5', 'Type': 'NUMBER', 'BeginOffset': 611, 'EndOffset': 614}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 660, 'EndOffset': 663}, {'Text': 'a pvc/pctfe', 'Type': 'TREATMENT', 'BeginOffset': 716, 'EndOffset': 727}, {'Text': 'pvc', 'Type': 'TREATMENT', 'BeginOffset': 728, 'EndOffset': 731}, {'Text': 'al blister', 'Type': 'PROBLEM', 'BeginOffset': 732, 'EndOffset': 742}, {'Text': 'the blisters', 'Type': 'PROBLEM', 'BeginOffset': 744, 'EndOffset': 756}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 794, 'EndOffset': 796}, {'Text': '180', 'Type': 'NUMBER', 'BeginOffset': 801, 'EndOffset': 804}]}

6B783065FFDD65D778AFD71E2DBD5029

https://www.ema.europa.eu/documents/product-information/imatinib-medac-epar-product-information_en.pdf

Imatinib medac

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Me dic ina l p rod uc t n o l on ge r a uth ori se d 2 1. NAME OF THE MEDICINAL PRODUCT Imatinib medac 100 mg hard capsules Imatinib medac 400 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Imatinib medac 100 mg hard capsules Each hard capsule contains 100 mg of imatinib (as mesilate). Imatinib medac 400 mg hard capsules Each hard capsule contains 400 mg of imatinib (as mesilate). Excipient(s) with known effect: Imatinib medac 100 mg hard capsules Each hard capsule contains 12.518 mg lactose monohydrate. Imatinib medac 400 mg hard capsules Each hard capsule contains 50.072 mg lactose monohydrate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule Imatinib medac 100 mg hard capsules Size “3” hard capsules with orange body and cap. Imatinib medac 400 mg hard capsules Size “00” hard capsules with caramel body and cap. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Imatinib medac is indicated for the treatment of • paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment. • paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase. • adult and paediatric patients with Ph+ CML in blast crisis. • adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy. • adult patients with relapsed or refractory Ph+ ALL as monotherapy. • adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. • adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement. • adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. The effect of imatinib on the outcome of bone marrow transplantation has not been determined. Me dic ina l p rod uc t n o l on ge r a uth ori se d 3 In adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic DFSP. The experience with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited (see section 5.1). Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases. 4.2 Posology and method of administration Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate. For doses of 400 mg and above (see dosage recommendation below) a 400 mg capsule (not divisible) is available. The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening. For patients unable to swallow the capsules (e.g. paediatric patients), their content may be dispersed in a glass of still mineral water or apple juice. Posology for CML in adult patients The recommended dose of imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts ≥ 30 % in blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated. Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages. Posology for CML in paediatric patients Dosing for paediatric patients should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for paediatric patients with chronic phase CML and accelerated phase CML (not to exceed the total dose of 800 mg). Accelerated phase is an intermediate phase among the chronic phase and the onset of the blast crisis; it is considered as the first manifestation of resistance to therapy. Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening. The dose recommendation is currently based on a small number of paediatric patients (see sections 5.1 and 5.2). There is no experience with the treatment of children below 2 years of age. Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved Me dic ina l p rod uc t n o l on ge r a uth ori se d 4 haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages. Posology for Ph+ ALL in adult patients The recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological experts in the management of this disease should supervise the therapy throughout all phases of care. Treatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe when administered at 600 mg/day in combination with chemotherapy in the induction phase, the consolidation and maintenance phases of chemotherapy (see section 5.1) for patients with newly diagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment program selected, but generally longer exposures to imatinib have yielded better results. For adult patients with relapsed or refractory Ph+ALL imatinib monotherapy at 600 mg/day can be given until disease progression occurs. Posology for Ph+ ALL in children Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg). Posology for MDS/MPD in adult patients The recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD. Treatment duration: In the only clinical trial performed up to now, treatment with imatinib was continued until disease progression (see section 5.1). At the time of analysis, the median treatment duration was 47 months (24 days - 60 months). Posology for HES/CEL in adult patients The recommended dose of imatinib is 100 mg/day for patients with HES/CEL. Dose increases from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. Treatment should be continued as long as the patient continues to benefit. Posology for DFSP in adult patients The recommended dose of imatinib is 800 mg/day for patients with DFSP. Dose adjustment for adverse reactions in all indications in adults and paediatric patients Non-haematological adverse reactions If a severe non-haematological adverse reaction develops with imatinib use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 mg to 300 mg or from 600 mg to 400 mg, or from 800 mg to 600 mg, and in paediatric patients from 340 mg to 260 mg/m2/day. Haematological adverse reactions Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below. Dose adjustments for neutropenia and thrombocytopenia: Me dic ina l p rod uc t n o l on ge r a uth ori se d 5 Therapeutic indication Neutropenia and thrombocytopenia toxicity Posology modification HES/CEL (starting dose 100 mg) ANC < 1.0 x 109/l and/or platelets < 50 x 109/l 1. Stop imatinib until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). Chronic phase CML, MDS/MPD (starting dose 400 mg) HES/CEL (at dose 400 mg) ANC < 1.0 x 109/l and/or platelets < 50 x 109/l 1. Stop imatinib until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x 109/l and/or platelets < 50 x 109/l, repeat step 1 and resume imatinib at reduced dose of 300 mg. Paediatric chronic phase CML (at dose 340 mg/m2) ANC < 1.0 x 109/l and/or platelets < 50 x 109/l 1. Stop imatinib until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x109/l and/or platelets < 50 x109/l, repeat step 1 and resume imatinib at reduced dose of 260 mg/m2. Accelerated phase CML and blast crisis and Ph+ ALL (starting dose 600 mg) aANC < 0.5 x 109/l and/or platelets < 10 x 109/l 1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 400 mg. 3. If cytopenia persists for 2 weeks, reduce further to 300 mg. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then resume treatment at 300 mg. Paediatric accelerated phase CML and blast crisis (starting dose 340 mg/m2) aANC < 0.5 x 109/l and/or platelets < 10 x 109/l 1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 260 mg/m2. 3. If cytopenia persists for 2 weeks, reduce further to Me dic ina l p rod uc t n o l on ge r a uth ori se d 6 Therapeutic indication Neutropenia and thrombocytopenia toxicity Posology modification 200 mg/m2. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then resume treatment at 200 mg/m2. DFSP (at dose 800 mg) ANC < 1.0 x 109/l and/or platelets < 50 x 109/l 1. Stop imatinib until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. 2. Resume treatment with imatinib at 600 mg. 3. In the event of recurrence of ANC < 1.0 x 109/l and/or platelets < 50 x 109/l, repeat step 1 and resume imatinib at reduced dose of 400 mg. ANC = absolute neutrophil count a occurring after at least 1 month of treatment Special populations Paediatric use: There is no experience in children with CML below 2 years of age and with Ph+ ALL below 1 year of age (see section 5.1). There is very limited experience in children with MDS/MPD and DFSP. There is no experience in children or adolescents with HES/CEL. The safety and efficacy of imatinib in children with MDS/MPD, DFSP and HES/CEL aged less than 18 years of age have not been established in clinical trials. Currently available published data are summarised in section 5.1 but no recommendation on a posology can be made. Hepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). Liver dysfunction classification: Liver dysfunction Liver function tests Mild Total bilirubin: = 1.5 ULN AST: >ULN (can be normal or < ULN if total bilirubin is >ULN) Moderate Total bilirubin: >1.5–3.0 ULN AST: any Severe Total bilirubin: >3–10 ULN AST: any ULN = upper limit of normal for the institution AST = aspartate aminotransferase Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum recommended dose of 400 mg daily as starting dose. However, in these patients caution is recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack of efficacy (see sections 4.4 and 5.2). Older people: Imatinib pharmacokinetics have not been studied in older people. No significant age-related pharmacokinetic differences have been observed in patients in clinical trials which Me dic ina l p rod uc t n o l on ge r a uth ori se d 7 included over 20 % of patients aged 65 and older. No specific dose recommendation is necessary in older people. Method of administration The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still water or apple juice. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use When imatinib is co-administered with other medicinal products, there is a potential for drug interactions. Caution should be used when taking imatinib with protease inhibitors, azole antifungals, certain macrolides (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (see section 4.5). Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided (see section 4.5). Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib (see section 4.5). Thyroid-stimulating hormone (TSH) levels should be closely monitored in such patients. Hepatotoxicity Metabolism of imatinib is mainly hepatic, and only 13 % of excretion is through the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see sections 4.2, 4.8 and 5.2). It should be noted that GIST patients may have hepatic metastases which could lead to hepatic impairment. Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic reactions has been detected. Hepatic function should be carefully monitored in circumstances where imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see section 4.5 and 4.8). Hepatitis B reactivation Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with imatinib. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with imatinib Me dic ina l p rod uc t n o l on ge r a uth ori se d 8 should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8). Fluid retention Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 2.5 % of newly diagnosed CML patients taking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in older people and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction. Patients with cardiac disease Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated. In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL population before treatment initiation. Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids (1–2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of therapy. Gastrointestinal haemorrhage In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra- tumoural haemorrhages were reported (see section 4.8). Based on the available data, no predisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified that place patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard practices and procedures for the monitoring and management of haemorrhage in all patients should be applied. In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has been reported in post-marketing experience in patients with CML, ALL and other diseases (see section 4.8). When needed, discontinuation of imatinib treatment may be considered. Tumour lysis syndrome Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (see section 4.8). Laboratory tests Complete blood counts must be performed regularly during therapy with imatinib. Treatment of CML patients with imatinib has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely to be related to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, as recommended in section 4.2. Me dic ina l p rod uc t n o l on ge r a uth ori se d 9 Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving imatinib. In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment should be given the minimum starting dose. Patients with severe renal impairment should be treated with caution. The dose can be reduced if not tolerated (see section 4.2 and 5.2). Long-term treatment with imatinib may be associated with a clinically significant decline in renal function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and closely monitored during therapy, with particular attention to those patients exhibiting risk factors for renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be prescribed in accordance with standard treatment guidelines. Paediatric population There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib. In an observational study in the CML paediatric population, a statistically significant decrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and 24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. Close monitoring of growth in paediatric patients under treatment with imatinib is recommended (see section 4.8). Lactose Imatinib medac contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Active substances that may increase imatinib plasma concentrations Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib with inhibitors of the CYP3A4 family. Active substances that may decrease imatinib plasma concentrations Substances that are inducers of CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-∞) by at least 54 % and 74 %, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic medicinal products (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for imatinib decreased by 73 % compared to patients not on EIAEDs. Concomitant use of rifampicin or other strong CYP3A4 inducers and imatinib should be avoided. Active substances that may have their plasma concentration altered by imatinib Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporin, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, Me dic ina l p rod uc t n o l on ge r a uth ori se d 10 terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.). Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. haemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard heparin, instead of coumarin derivatives such as warfarin. In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23 % (90 %CI [1.16 - 1.30]). Dose adjustments do not seem to be necessary when imatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol. Clinical monitoring should be considered when administering imatinib to patients treated with metoprolol. In vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/l. This inhibition has not been observed in vivo after the administration of imatinib 400 mg and paracetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied. Caution should therefore be exercised when using high doses of imatinib and paracetamol concomitantly. In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when imatinib is co-administered (see section 4.4). However, the mechanism of the observed interaction is presently unknown. Caution is recommended in thyroidectomy patients receiving levothyroxine and imatinib. In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see section 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not well characterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase and it has been reported that concomitant use with L-asparaginase could be associated with increased hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination with other chemotherapeutic agents requires special precaution. Paediatric population Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential must be advised to use effective contraception during treatment. Pregnancy There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib. Studies in animals have however shown reproductive toxicity (see section 5.3) and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus. Breast-feeding There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk/plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (~10 % of a therapeutic dose). However, since the effects of Me dic ina l p rod uc t n o l on ge r a uth ori se d 11 low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not breast-feed. Fertility In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies on patients receiving imatinib and its effect on fertility and gametogenesis have not been performed. Patients on imatinib treatment who are concerned about their fertility should consult with their physician. 4.7 Effects on ability to drive and use machines Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery. 4.8 Undesirable effects Summary of the safety profile Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and the co-administration of numerous medicinal products. In clinical trials in CML, discontinuation of the investigational medicinal product for treatment-related adverse reactions was observed in 2.4 % of newly diagnosed patients, 4 % of patients in late chronic phase after failure of interferon therapy, 4 % of patients in accelerated phase after failure of interferon therapy and 5 % of blast crisis patients after failure of interferon therapy. In GIST the investigational medicinal product was discontinued for imatinib-related adverse reactions in 4 % of patients. The adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression seen in CML patients than in GIST, which is probably due to the underlying disease. In the study in patients with unresectable and/or metastatic GIST, 7 (5 %) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour sites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be serious and sometimes fatal. The most commonly reported (≥ 10 %) treatment-related adverse reactions were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial oedemas were a common finding in all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of imatinib. When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering the limited safety database, the adverse events thus far reported in children are consistent with the known safety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ ALL is very limited though no new safety concerns have been identified. Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight gain with or without superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding imatinib temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may be serious or life- threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials. Tabulated list of adverse reactions Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: very common Me dic ina l p rod uc t n o l on ge r a uth ori se d 12 (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first. Adverse reactions and their frequencies are reported in Table 1. Table 1 Tabulated summary of adverse reactions Infections and infestations Uncommon: Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis Rare: Fungal infection Not known: Hepatitis B reactivation* Neoplasm benign, malignant and unspecified (including cysts and polyps) Rare: Tumour lysis syndrome Not known: Tumour haemorrhage/tumour necrosis* Immune system disorders Not known: Anaphylactic shock* Blood and lymphatic system disorders Very common: Neutropenia, thrombocytopenia, anaemia Common: Pancytopenia, febrile neutropenia Uncommon: Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Rare: Haemolytic anaemia Metabolism and nutrition disorders Common: Anorexia Uncommon: Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia Rare: Hyperkalaemia, hypomagnesaemia Psychiatric disorders Common: Insomnia Uncommon: Depression, libido decreased, anxiety Rare: Confusional state Nervous system disorders Very common: Headache2 Common: Dizziness, paraesthesia, taste disturbance, hypoaesthesia Uncommon: Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage Rare: Increased intracranial pressure, convulsions, optic neuritis Not known: Cerebral oedema* Eye disorders Common: Eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision Uncommon: Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema Rare: Cataract, glaucoma, papilloedema Not known: Vitreous haemorrhage* Ear and labyrinth disorders Uncommon: Vertigo, tinnitus, hearing loss Cardiac disorders Uncommon: Palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema Rare: Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Me dic ina l p rod uc t n o l on ge r a uth ori se d 13 Not known: Pericarditis*, cardiac tamponade* Vascular disorders4 Common: Flushing, haemorrhage Uncommon: Hypertension, haematoma, subdural haematoma, peripheral coldness, hypotension, Raynaud’s phenomenon Not known: Thrombosis/embolism* Respiratory, thoracic and mediastinal disorders Common: Dyspnoea, epistaxis, cough Uncommon: Pleural effusion5, pharyngolaryngeal pain, pharyngitis Rare: Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage Not known: Acute respiratory failure11*, interstitial lung disease* Gastrointestinal disorders Very common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain6 Common: Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis Uncommon: Stomatitis, mouth ulceration, gastrointestinal haemorrhage7, eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis Rare: Colitis, ileus, inflammatory bowel disease Not known: Ileus/intestinal obstruction*, gastrointestinal perforation*, diverticulitis*, gastric antral vascular ectasia (GAVE)* Hepatobiliary disorders Common: Increased hepatic enzymes Uncommon: Hyperbilirubinaemia, hepatitis, jaundice Rare: Hepatic failure8, hepatic necrosis Skin and subcutaneous tissue disorders Very common: Periorbital oedema, dermatitis/eczema/rash Common: Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction Uncommon: Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptions Rare: Acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discolouration, angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis (AGEP) Not known: Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)* Musculoskeletal and connective tissue disorders Very common: Muscle spasm and cramps, musculoskeletal pain including myalgia9, arthralgia, bone pain10 Common: Joint swelling Uncommon: Joint and muscle stiffness Rare: Muscular weakness, arthritis, rhabdomyolysis/myopathy Not known: Avascular necrosis/hip necrosis*, growth retardation in children* Renal and urinary disorders Uncommon: Renal pain, haematuria, renal failure acute, urinary frequency increased Not known: Renal failure chronic Reproductive system and breast disorders Uncommon: Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema Rare: Haemorrhagic corpus luteum/haemorrhagic ovarian cyst General disorders and administration site conditions Very common: Fluid retention and oedema, fatigue Me dic ina l p rod uc t n o l on ge r a uth ori se d 14 Common: Weakness, pyrexia, anasarca, chills, rigors Uncommon: Chest pain, malaise Investigations Very common: Weight increased Common: Weight decreased Uncommon: Blood creatinine increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased Rare: Blood amylase increased * These types of reactions have been reported mainly from post-marketing experience with imatinib. This includes spontaneous case reports as well as serious adverse events from ongoing studies, the expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved indications. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure. 1) Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST. Transformed CML is the stage of the disease after its progression from chronic phase to accelerated phase (AP) or blast crisis (BC). 2) Headache was the most common in GIST patients. 3) On a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML. 4) Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC). 5) Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML. 6+7) Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients. 8) Some fatal cases of hepatic failure and of hepatic necrosis have been reported. 9) Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed in post-marketing 10) Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients. 11) Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions. Description of selected adverse reactions: Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4). Laboratory test abnormalities Haematology In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/l) and thrombocytopenias (platelet count < 50 x 109/l) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64 % and 44–63 % for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7 % neutropenia and 8.9 % thrombocytopenia). In newly diagnosed chronic phase CML grade 4 neutropenia (ANC < 0.5 x 109/l) and thrombocytopenia (platelet count < 10 x 109/l) were observed in 3.6 % and < 1 % of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the first several months of therapy. Me dic ina l p rod uc t n o l on ge r a uth ori se d 15 In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported in 5.4 % and 0.7 % of patients, respectively, and may have been related to gastrointestinal or intratumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5 % and 2.7 % of patients, respectively, and grade 3 thrombocytopenia in 0.7 % of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter. Biochemistry Severe elevation of transaminases (< 5 %) or bilirubin (< 1 %) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1 % of CML patients. In GIST patients (study B2222), 6.8 % of grade 3 or 4 ALT (alanine aminotransferase) elevations and 4.8 % of grade 3 or 4 AST (aspartate aminotransferase) elevations were observed. Bilirubin elevation was below 3 %. There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal, including one patient on high dose paracetamol. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of imatinib overdose have been reported spontaneously and in the literature. In the event of overdose the patient should be observed and appropriate symptomatic treatment given. Generally the reported outcome in these cases was “improved” or “recovered”. Events that have been reported at different dose ranges are as follows: Adult population 1200 mg to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1800 mg to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain. 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases. 8 g to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. Paediatric population One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given. Me dic ina l p rod uc t n o l on ge r a uth ori se d 16 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: protein kinase inhibitor, ATC code: L01XE01 Mechanism of action Imatinib is a small molecule protein kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases. Pharmacodynamic effects Imatinib is a protein kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML and ALL patients. In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl positive tumour cells. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), PDGF-R, and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. Constitutive activation of the PDGF receptor or the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. Imatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase activity. Clinical studies in chronic myeloid leukaemia The effectiveness of imatinib is based on overall haematological and cytogenetic response rates and progression-free survival. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. A large, international, open-label, non-controlled phase II study was conducted in patients with Philadelphia chromosome positive (Ph+) CML in the blast crisis phase of the disease. In the clinical study 38 % of patients were ≥ 60 years of age and 12 % of patients were ≥ 70 years of age. In addition, paediatric patients have been treated in two phase I studies and one phase II study. Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37 %) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63 %) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 223 patients were started at 600 mg. The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. In this study, 31 % of patients achieved a haematological response (36 % in previously untreated patients and 22 % in previously treated patients). The rate of response was also higher in the patients treated at 600 mg (33 %) as compared to the patients treated at 400 mg (16 %, p = 0.0220). The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively. Me dic ina l p rod uc t n o l on ge r a uth ori se d 17 Table 2 Response in adult CML study Study 0102 38-month data Myeloid blast crisis (n = 260) % of patients (CI95 %) Haematological response1 31 % (25.2–36.8) Complete haematological response (CHR) 8 % No evidence of leukaemia (NEL) 5 % Return to chronic phase (RTC) 18 % Major cytogenetic response2 15 % (11.2–20.4) Complete (Confirmed3) [95 % CI] 7 % (2 %) [0.6–4.4] Partial 8 % 1 Haematological response criteria (all responses to be confirmed after ≥ 4 weeks): CHR: In study 0102 [ANC ≥ 1.5 x 109/l, platelets ≥ 100 x 109/l, no blood blasts, BM blasts < 5 % and no extramedullary disease] NEL: Same criteria as for CHR but ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l RTC: < 15 % blasts BM and PB, < 30 % blasts+promyelocytes in BM and PB, < 20 % basophils in PB, no extramedullary disease other than spleen and liver. BM = bone marrow, PB = peripheral blood 2 Cytogenetic response criteria: A major response combines both complete and partial responses: complete (0 % Ph+ metaphases), partial (1–35 %) 3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least one month after the initial bone marrow study. Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n = 10). The rate of haematological response was 70 % with a duration of 2–3 months. Paediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML (n = 11) or CML in blast crisis or Ph+ acute leukaemias (n = 15) were enrolled in a dose-escalation phase I trial. This was a population of heavily pretreated patients, as 46 % had received prior BMT and 73 % a prior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n = 5), 340 mg/m2/day (n = 9), 440 mg/m2/day (n = 7) and 570 mg/m2/day (n = 5). Out of 9 patients with chronic phase CML and cytogenetic data available, 4 (44 %) and 3 (33 %) achieved a complete and partial cytogenetic response, respectively, for a rate of MCyR of 77 %. A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been enrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib 340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. imatinib treatment induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78 % after 8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete cytogenetic response (CCyR) of 65 % which is comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16 % for a MCyR of 81 %. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months. The European Medicines Agency has waived the obligation to submit the results of studies with imatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)- positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use). Clinical studies in Ph+ ALL Me dic ina l p rod uc t n o l on ge r a uth ori se d 18 Newly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction in 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a significantly higher rate of complete haematological response than chemotherapy (96.3 % vs. 50 %; p = 0.0001). When salvage therapy with imatinib was administered in patients who did not respond or who responded poorly to chemotherapy, it resulted in 9 patients (81.8 %) out of 11 achieving a complete haematological response. This clinical effect was associated with a higher reduction in bcr-abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy (p = 0.02). All patients received imatinib and consolidation chemotherapy (see Table 3) after induction and the levels of bcr-abl transcripts were identical in the two arms at 8 weeks. As expected on the basis of the study design, no difference was observed in remission duration, disease-free survival or overall survival, although patients with complete molecular response and remaining in minimal residual disease had a better outcome in terms of both remission duration (p = 0.01) and disease-free survival (p = 0.02). The results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled clinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. Imatinib in combination with chemotherapy induction (see Table 3) resulted in a complete haematological response rate of 93 % (147 out of 158 evaluable patients) and in a major cytogenetic response rate of 90 % (19 out of 21 evaluable patients). The complete molecular response rate was 48 % (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and were superior to historical control (DFS p < 0.001; OS p < 0.0001) in two studies (AJP01 and AUS01). Table 3 Chemotherapy regimen used in combination with imatinib Study ADE10 Prephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3, 4, 5; MTX 12 mg intrathecal, day 1 Remission induction DEX 10 mg/m2 oral, days 6-7, 13-16; VCR 1 mg i.v., days 7, 14; IDA 8 mg/m2 i.v. (0.5 h), days 7, 8, 14, 15; CP 500 mg/m2 i.v.(1 h) day 1; Ara-C 60 mg/m2 i.v., days 22-25, 29-32 Consolidation therapy I, III, V MTX 500 mg/m2 i.v. (24 h), days 1, 15; 6-MP 25 mg/m2 oral, days 1-20 Consolidation therapy II, IV Ara-C 75 mg/m2 i.v. (1 h), days 1-5; VM26 60 mg/m2 i.v. (1 h), days 1-5 Study AAU02 Induction therapy (de novo Ph+ ALL) Daunorubicin 30 mg/m2 i.v., days 1-3, 15-16; VCR 2 mg total dose i.v., days 1, 8, 15, 22; CP 750 mg/m2 i.v., days 1, 8; Prednisone 60 mg/m2 oral, days 1-7, 15-21; IDA 9 mg/m2 oral, days 1-28; MTX 15 mg intrathecal, days 1, 8, 15, 22; Ara-C 40 mg intrathecal, days 1, 8, 15, 22; Methylprednisolone 40 mg intrathecal, days 1, 8, 15, 22 Consolidation (de novo Ph+ ALL) Ara-C 1,000 mg/m2/12 h i.v.(3 h), days 1-4; Mitoxantrone 10 mg/m2 i.v. days 3-5; MTX 15 mg intrathecal, day 1; Methylprednisolone 40 mg intrathecal, day 1 Study ADE04 Prephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3-5; MTX 15 mg intrathecal, day 1 Me dic ina l p rod uc t n o l on ge r a uth ori se d 19 Study ADE10 Induction therapy I DEX 10 mg/m2 oral, days 1-5; VCR 2 mg i.v., days 6, 13, 20; Daunorubicin 45 mg/m2 i.v., days 6-7, 13-14 Induction therapy II CP 1 g/m2 i.v. (1 h), days 26, 46; Ara-C 75 mg/m2 i.v. (1 h), days 28-31, 35-38, 42-45; 6-MP 60 mg/m2 oral, days 26-46 Consolidation therapy DEX 10 mg/m2 oral, days 1-5; Vindesine 3 mg/m2 i.v., day 1; MTX 1.5 g/m2 i.v. (24 h), day 1; Etoposide 250 mg/m2 i.v. (1 h) days 4-5; Ara-C 2x 2 g/m2 i.v. (3 h, q 12 h), day 5 Study AJP01 Induction therapy CP 1.2 g/m2 i.v. (3 h), day 1; Daunorubicin 60 mg/m2 i.v. (1 h), days 1-3; Vincristine 1.3 mg/m2 i.v., days 1, 8, 15, 21; Prednisolone 60 mg/m2/day oral Consolidation therapy Alternating chemotherapy course: high dose chemotherapy with MTX 1 g/m2 i.v. (24 h), day 1, and Ara-C 2 g/m2 i.v. (q 12 h), days 2-3, for 4 cycles Maintenance VCR 1.3 g/m2 i.v., day 1; Prednisolone 60 mg/m2 oral, days 1-5 Study AUS01 Induction-consolidation therapy Hyper-CVAD regimen: CP 300 mg/m2 i.v. (3 h, q 12 h), days 1-3; Vincristine 2 mg i.v., days 4, 11; Doxorubicine 50 mg/m2 i.v. (24 h), day 4; DEX 40 mg/day on days 1-4 and 11-14, alternated with MTX 1 g/m2 i.v. (24 h), day 1, Ara-C 1 g/m2 i.v. (2 h, q 12 h), days 2-3 (total of 8 courses) Maintenance VCR 2 mg i.v. monthly for 13 months; Prednisolone 200 mg oral, 5 days per month for 13 months All treatment regimens include administration of steroids for CNS prophylaxis. Ara-C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; 6-MP: 6-mercaptopurine VM26: Teniposide; VCR: vincristine; IDA: idarubicine; i.v.: intravenous Paediatric patients: In study I2301, a total of 93 paediatric, adolescent and young adult patients (from 1 to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort, non- randomised phase III trial, and were treated with imatinib (340 mg/m2/day) in combination with intensive chemotherapy after induction therapy. imatinib was administered intermittently in cohorts 1-5, with increasing duration and earlier start of imatinib from cohort to cohort; cohort 1 receiving the lowest intensitiy and cohort 5 receiving the highest intensity of imatinib (longest duration in days with continuous daily imatinib dosing during the first chemotherapy treatment courses). Continuous daily exposure to imatinib early in the course of treatment in combination with chemotherapy in cohort 5- patients (n=50) improved the 4-year event-free survival (EFS) compared to historical controls (n=120), who received standard chemotherapy without imatinib (69.6 % vs. 31.6 %, respectively). The estimated 4-year OS in cohort 5-patients was 83.6 % compared to 44.8 % in the historical controls. 20 out of the 50 (40 %) patients in cohort 5 received haematopoietic stem cell transplant. Table 4 Chemotherapy regimen used in combination with imatinib in study I2301 Consolidation block 1 (3 weeks) VP-16 (100 mg/m2/day, IV): days 1-5 Ifosfamide (1.8 g/m2/day, IV): days 1-5 MESNA (360 mg/m2/dose q3h, x 8 doses/day, IV): days 1-5 G-CSF (5 μg/kg, SC): days 6-15 or until ANC > 1500 post nadir IT Methotrexate (age-adjusted): day 1 ONLY Triple IT therapy (age-adjusted): day 8, 15 Me dic ina l p rod uc t n o l on ge r a uth ori se d 20 Consolidation block 2 (3 weeks) Methotrexate (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: Days 2 and 3 Triple IT therapy (age-adjusted): day 1 ARA-C (3 g/m2/dose q 12 h x 4, IV): days 2 and 3 G-CSF (5 μg/kg, SC): days 4-13 or until ANC > 1500 post nadir Reinduction block 1 (3 weeks) VCR (1.5 mg/m2/day, IV): days 1, 8, and 15 DAUN (45 mg/m2/day bolus, IV): days 1 and 2 CPM (250 mg/m2/dose q12h x 4 doses, IV): days 3 and 4 PEG-ASP (2500 IUnits/m2, IM): day 4 G-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir Triple IT therapy (age-adjusted): days 1 and 15 DEX (6 mg/m2/day, PO): days 1-7 and 15-21 Intensification block 1 (9 weeks) Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: Days 2, 3, 16, and 17 Triple IT therapy (age-adjusted): days 1 and 22 VP-16 (100 mg/m2/day, IV): days 22-26 CPM (300 mg/m2/day, IV): days 22-26 MESNA (150 mg/m2/day, IV): days 22-26 G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir ARA-C (3 g/m2, q12h, IV): days 43, 44 L-ASP (6000 IUnits/m2, IM): day 44 Reinduction block 2 (3 weeks) VCR (1.5 mg/m2/day, IV): days 1, 8 and 15 DAUN (45 mg/m2/day bolus, IV): days 1 and 2 CPM (250 mg/m2/dose q12h x 4 doses, iv): Days 3 and 4 PEG-ASP (2500 IUnits/m2, IM): day 4 G-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir Triple IT therapy (age-adjusted): days 1 and 15 DEX (6 mg/m2/day, PO): days 1-7 and 15-21 Intensification block 2 (9 weeks) Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2, 3, 16, and 17 Triple IT therapy (age-adjusted): days 1 and 22 VP-16 (100 mg/m2/day, IV): days 22-26 CPM (300 mg/m2/day, IV): days 22-26 MESNA (150 mg/m2/day, IV): days 22-26 G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir ARA-C (3 g/m2, q12h, IV): days 43, 44 L-ASP (6000 IUnits/m2, IM): day 44 Maintenance (8-week cycles) Cycles 1–4 MTX (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2 and 3 Triple IT therapy (age-adjusted): days 1, 29 VCR (1.5 mg/m2, IV): days 1, 29 DEX (6 mg/m2/day PO): days 1-5; 29-33 6-MP (75 mg/m2/day, PO): days 8-28 Methotrexate (20 mg/m2/week, PO): days 8, 15, 22 VP-16 (100 mg/m2, IV): days 29-33 CPM (300 mg/m2, IV): days 29-33 MESNA IV days 29-33 G-CSF (5 μg/kg, SC): days 34-43 Maintenance (8-week cycles) Cycle 5 Cranial irradiation (Block 5 only) 12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis 18 Gy in 10 fractions for patients that are CNS3 at diagnosis VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1-5; 29-33 Me dic ina l p rod uc t n o l on ge r a uth ori se d 21 6-MP (75 mg/m2/day, PO): days 11-56 (Withhold 6-MP during the 6-10 days of cranial irradiation beginning on day 1 of Cycle 5. Start 6-MP the 1st day after cranial irradiation completion.) Methotrexate (20 mg/m2/week, PO): days 8, 15, 22, 29, 36, 43, 50 Maintenance (8-week cycles) Cycles 6-12 VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1-5; 29-33 6-MP (75 mg/m2/day, PO): days 1-56 Methotrexate (20 mg/m2/week, PO): days 1, 8, 15, 22, 29, 36, 43, 50 G-CSF = granulocyte colony stimulating factor, VP-16 = etoposide, MTX = methotrexate, IV = intravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = cytarabine, CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = daunorubicin, 6-MP = 6-mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = PEG asparaginase, MESNA= 2-mercaptoethane sulfonate sodium, iii= or until MTX level is < 0.1 µM, q6h = every 6 hours, Gy= Gray Study AIT07 was a multicentre, open-label, randomised, phase II/III study that included 128 patients (1 to < 18 years) treated with imatinib in combination with chemotherapy. Safety data from this study seem to be in line with the safety profile of imatinib in Ph+ ALL patients. Relapsed/refractory Ph+ ALL: When imatinib was used as single agent in patients with relapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a haematological response rate of 30 % (9 % complete) and a major cytogenetic response rate of 23 %. (Of note, out of the 411 patients, 353 were treated in an expanded access program without primary response data collected.) The median time to progression in the overall population of 411 patients with relapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the 401 evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to include only those patients age 55 or older. Clinical studies in MDS/MPD Experience with imatinib in this indication is very limited and is based on haematological and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit or increased survival. One open label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD who were treated with imatinib 400 mg daily. Three patients presented a complete haematological response (CHR) and one patient experienced a partial haematological response (PHR). At the time of the original analysis, three of the four patients with detected PDGFR gene rearrangements developed haematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years. An observational registry (study L2401) was conducted to collect long-term safety and efficacy data in patients suffering from myeloproliferative neoplasms with PDGFR- β rearrangement and who were treated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily dose of 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due to the observational nature of this registry, haematologic, cytogenetic and molecular assessment data were available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assuming conservatively that patients with missing data were non-responders, CHR was observed in 20/23 (87%) patients, CCyR in 9/23 (39.1%) patients, and MR in 11/23 (47.8%) patients, respectively. When the response rate is calculated from patients with at least one valid assessment, the response rate for CHR, CCyR and MR was 20/22 (90.9%), 9/9 (100%) and 11/17 (64.7%), respectively. In addition a further 24 patients with MDS/MPD were reported in 13 publications. 21 patients were treated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients PDGFR gene rearrangements were detected, 9 of them achieved a CHR and 1 PHR. The age of these patients ranged from 2 to 79 years. In a recent publication updated information from 6 of these 11 patients revealed that all these patients remained in cytogenetic remission (range 32 - 38 months). The same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR gene rearrangements (5 patients from study B2225). These patients received imatinib for a median of 47 Me dic ina l p rod uc t n o l on ge r a uth ori se d 22 months (range 24 days - 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease or disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic responses have been sustained for a median of 49 months (range 19 - 60) and 47 months (range 16-59), respectively. The overall survival is 65 months since diagnosis (range 25-234). Imatinib administration to patients without the genetic translocation generally results in no improvement. There are no controlled trials in paediatric patients with MDS/MPD. Five (5) patients with MDS/MPD associated with PDGFR gene re-arrangements were reported in 4 publications. The age of these patients ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses ranging from 92.5 to 340 mg/m2 daily. All patients achieved complete haematological response, cytogenetic response and/or clinical response. Clinical studies in HES/CEL One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL were treated with 100 mg to 1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published case reports and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogenetic abnormalities were evaluated in 117 of the total population of 176 patients. In 61 of these 117 patients FIP1L1-PDGFRα fusion kinase was identified. An additional four HES patients were found to be FIP1L1-PDGFRα-positive in other 3 published reports. All 65 FIP1L1-PDGFRα fusion kinase positive patients achieved a CHR sustained for months (range from 1+ to 44+ months censored at the time of the reporting). As reported in a recent publication 21 of these 65 patients also achieved complete molecular remission with a median follow-up of 28 months (range 13-67 months). The age of these patients ranged from 25 to 72 years. Additionally, improvements in symptomatology and other organ dysfunction abnormalities were reported by the investigators in the case reports. Improvements were reported in cardiac, nervous, skin/subcutaneous tissue, respiratory/thoracic/mediastinal, musculoskeletal/connective tissue/vascular, and gastrointestinal organ systems. There are no controlled trials in paediatric patients with HES/CEL. Three (3) patients with HES and CEL associated with PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from 2 to 16 years and imatinib was given at dose 300 mg/m2 daily or doses ranging from 200 to 400 mg daily. All patients achieved complete haematological response, complete cytogenetic response and/or complete molecular response. Clinical studies in DFSP One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients with DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to 75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered amenable to further resective surgery at the time of study entry. The primary evidence of efficacy was based on objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and 8 partially. Three of the partial responders were subsequently rendered disease free by surgery. The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. A further 6 DFSP patients treated with imatinib were reported in 5 published case reports, their ages ranging from 18 months to 49 years. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. The paediatric patient received 400 mg/m2/daily, subsequently increased to 520 mg/m2/daily. Five (5) patients responded, 3 completely and 2 partially. The median duration of therapy in the published literature ranged between 4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, was present in nearly all responders to imatinib treatment. Me dic ina l p rod uc t n o l on ge r a uth ori se d 23 There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from newborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to 520 mg/m2 daily. All patients achieved partial and/or complete response. 5.2 Pharmacokinetic properties Pharmacokinetics of imatinib The pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg. Plasma pharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma concentrations had reached steady state. Absorption Mean absolute bioavailability for imatinib is 98 %. There was high between-patient variability in plasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of absorption of imatinib was minimally reduced (11 % decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4 %) compared to fasting conditions. The effect of prior gastrointestinal surgery on imatinib absorption has not been investigated. Distribution At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95 % on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein. Biotransformation The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16 % of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound. Imatinib and the N-demethyl metabolite together accounted for about 65 % of the circulating radioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor metabolites. The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V) only erythromycin (IC50 50 μM) and fluconazole (IC50 118 μM) showed inhibition of imatinib metabolism which could have clinical relevance (see section 4.5). Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/l, respectively. Maximal plasma concentrations of imatinib in patients are 2–4 μmol/l, consequently an inhibition of CYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered medicinal products is possible. Imatinib did not interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a result of competitive inhibition of CYP2C8 (Ki = 34.7 μM). This Ki value is far higher than the expected plasma levels of imatinib in patients, consequently no interaction is expected upon co-administration of either 5-fluorouracil or paclitaxel and imatinib. Elimination Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81 % of the dose was recovered within 7 days in faeces (68 % of dose) and urine (13 % of dose). Unchanged imatinib accounted for 25 % of the dose (5 % urine, 20 % faeces), the remainder being metabolites. Me dic ina l p rod uc t n o l on ge r a uth ori se d 24 Plasma pharmacokinetics Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when dosed once daily. Population pharmacokinetics Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on the volume of distribution (12 % increase in patients > 65 years old). This change is not thought to be clinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient weighing 50 kg the mean clearance is expected to be 8.5 l/h, while for a patient weighing 100 kg the clearance will rise to 11.8 l/h. These changes are not considered sufficient to warrant dose adjustment based on kg bodyweight. There is no effect of gender on the kinetics of imatinib. Pharmacokinetics in paediatric patients As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in both phase I and phase II studies. Dosing in paediatric patients at 260 and 340 mg/m2/day achieved the same exposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold accumulation after repeated once-daily dosing. Based on pooled population pharmacokinetic analysis in paediatric patients with haematological disorders (CML, Ph+ ALL, or other haematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily. Organ function impairment Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4). Although the results of pharmacokinetic analysis showed that there is considerable inter-subject variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8). 5.3 Preclinical safety data The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits. Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and monkeys, accompanied by bone marrow changes in rats and dogs. The liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. No histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were Me dic ina l p rod uc t n o l on ge r a uth ori se d 25 observed in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal papilla and in the urinary bladder was observed at doses > 6 mg/kg in the 13-week study, without changes in serum or urinary parameters. An increased rate of opportunistic infections was observed with chronic imatinib treatment. In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the lowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on body surface. Treatment resulted in worsening of normally suppressed malarial infections in these animals. Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation at a concentration of 125 μg/ml.Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post- implantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg. In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn pups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not affected, while an increased number of resorptions and a decreased number of viable foetuses was noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. These effects were not seen at doses ≤ 30 mg/kg. No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 postpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, effects upon growth, delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at approximately 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥ 30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. Me dic ina l p rod uc t n o l on ge r a uth ori se d 26 Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 times the daily exposure in paediatric patients (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 1.2 times the daily exposure in paediatric patients (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 30 mg/kg/day. The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet clarified. Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. The active substance imatinib demonstrates an environmental risk for sediment organisms. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Imatinib medac 100 mg hard capsules Capsule content Crospovidone (type A) Lactose monohydrate Magnesium stearate Capsule shell Gelatin Yellow iron oxide (E172) Titanium dioxide (E171) Red iron oxide (E172) Imatinib medac 400 mg hard capsules Capsule content Crospovidone (type A) Lactose monohydrate Magnesium stearate Capsule shell Gelatin Yellow iron oxide (E172) Titanium dioxide (E171) Red iron oxide (E172) Black iron oxide (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years Me dic ina l p rod uc t n o l on ge r a uth ori se d 27 6.4 Special precautions for storage Do not store above 30 ºC. 6.5 Nature and contents of container Imatinib medac 100 mg hard capsules PA-Aluminium/PVC//Aluminium blisters. Packs containing 60 hard capsules. Imatinib medac 400 mg hard capsules PA-Aluminium/PVC//Aluminium blisters. Packs containing 30 hard capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER medac Gesellschaft für klinische Spezialpräparate mbH Theaterstr. 6 22880 Wedel Germany 8. MARKETING AUTHORISATION NUMBER(S) Imatinib medac 100 mg hard capsules EU/1/13/876/001 Imatinib medac 400 mg hard capsules EU/1/13/876/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 25 September 2013 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu Me dic ina l p rod uc t n o l on ge r a uth ori se d 28 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Me dic ina l p rod uc t n o l on ge r a uth ori se d 29 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release medac Gesellschaft für klinische Spezialpräparate mbH Theaterstr. 6 22880 Wedel GERMANY Pabianickie Zaklady Farmaceutyczne Polfa S.A. ul. Marszalka J. Pilsudskiego 5 95-200 Pabianice Poland The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in theagreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. Me dic ina l p rod uc t n o l on ge r a uth ori se d 30 ANNEX III LABELLING AND PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 31 A. LABELLING Me dic ina l p rod uc t n o l on ge r a uth ori se d 32 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imatinib medac 100 mg hard capsules Imatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 100 mg of imatinib (as mesilate). 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 60 hard capsules. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Do not store above 30 ºC. Me dic ina l p rod uc t n o l on ge r a uth ori se d 33 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER medac GmbH Theaterstr. 6 22880 Wedel Germany 12. MARKETING AUTHORISATION NUMBER (S) EU/1/13/876/001 13. BATCH NUMBER Lot: 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imatinib medac 100 mg 17. UNIQUE IDENTIFIER – 2D BARCODE {2D barcode carrying the unique identifier included.} 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: Me dic ina l p rod uc t n o l on ge r a uth ori se d 34 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Imatinib medac 100 mg hard capsules Imatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER medac GmbH 3. EXPIRY DATE EXP: 4. BATCH NUMBER Lot: 5. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 35 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imatinib medac 400 mg hard capsules Imatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 400 mg of imatinib (as mesilate). 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 30 hard capsules. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Do not store above 30 ºC. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Me dic ina l p rod uc t n o l on ge r a uth ori se d 36 Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER medac GmbH Theaterstr. 6 22880 Wedel Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/876/002 13. BATCH NUMBER Lot: 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imatinib medac 400 mg 17. UNIQUE IDENTIFIER – 2D BARCODE {2D barcode carrying the unique identifier included.} 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: Me dic ina l p rod uc t n o l on ge r a uth ori se d 37 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Imatinib medac 400 mg hard capsules Imatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER medac GmbH 3. EXPIRY DATE EXP: 4. BATCH NUMBER Lot: 5. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 38 B. PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 39 Package leaflet: Information for the user Imatinib medac 100 mg hard capsules Imatinib medac 400 mg hard capsules Imatinib Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, pharmacist or nurse. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Imatinib medac is and what it is used for 2. What you need to know before you take Imatinib medac 3. How to take Imatinib medac 4. Possible side effects 5. How to store Imatinib medac 6. Contents of the pack and other information 1. What Imatinib medac is and what it is used for Imatinib medac is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer. Imatinib medac is a treatment for adults and children and adolescents for: • Chronic myeloid leukaemia (CML) in blast crisis. Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia in which certain abnormal white cells (named myeloid cells) start growing out of control. Imatinib medac inhibits the growth of these cells. Blast crisis is the most advanced stage of this disease. • Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib medac inhibits the growth of these cells. Imatinib medac is also a treatment for children and adolescents for: • Newly diagnosed CML for whom bone marrow transplantation is not considered as the first line of treatment; • CML in the chronic phase after failure of interferon-alpha therapy, or in the accelerated phase. Accelerated phase is an intermediate phase among the chronic phase and the onset of blast crisis; it is considered as the first manifestation of resistance to therapy. Me dic ina l p rod uc t n o l on ge r a uth ori se d 40 Imatinib medac is also a treatment for adults for: • Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib medac inhibits the growth of these cells in a certain subtype of these diseases. • Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib medac inhibits the growth of these cells in a certain subtype of these diseases. • Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib medac inhibits the growth of these cells. In the rest of this leaflet, we will use the abbreviations when talking about these diseases. If you have any questions about how Imatinib medac works or why this medicine has been prescribed for you, ask your doctor. 2. What you need to know before you take Imatinib medac Imatinib medac will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. Follow all your doctor’s instructions carefully, even if they differ from the general information contained in this leaflet. Do not take Imatinib medac: • if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor without taking Imatinib medac. If you think you may be allergic but are not sure, ask your doctor for advice. Warnings and precautions Talk to your doctor before taking Imatinib medac: • if you have or have ever had a liver, kidney or heart problem. • if you are taking the medicine levothyroxine because your thyroid has been removed. • if you have ever had or might now have a hepatitis B infection. This is because Imatinib medac could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started. If any of these apply to you, tell your doctor before taking Imatinib medac. During treatment with Imatinib medac, tell your doctor straight away if you put on weight very quickly. Imatinib medac may cause your body to retain water (severe fluid retention). While you are taking Imatinib medac, your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly. Children and adolescents Imatinib medac is also a treatment for children and adolescents with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children and adolescents with Ph-positive ALL. Some children and adolescents taking Imatinib medac may have slower than normal growth. The doctor will monitor the growth at regular visits. Me dic ina l p rod uc t n o l on ge r a uth ori se d 41 Other medicines and Imatinib medac Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib medac when taken together. They may increase or decrease the effect of Imatinib medac, either leading to increased side effects or making Imatinib medac less effective. Imatinib medac may do the same to some other medicines. Tell your doctor if you are using medicines that prevent the formation of blood clots. Pregnancy, breast-feeding and fertility • If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. • Imatinib medac is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib medac during pregnancy. • Women who might become pregnant are advised to use effective contraception during treatment. • Do not breast-feed during the treatment with Imatinib medac as there is limited information on the distribution of imatinib into the breast milk. • Patients who are concerned about their fertility while taking Imatinib medac are advised to consult with their doctor. Driving and using machines You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not drive or use any tools or machines until you are feeling well again. Imatinib medac contains lactose monohydrate If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. 3. How to take Imatinib medac Your doctor has prescribed Imatinib medac because you suffer from a serious condition. Imatinib medac can help you to fight this condition. However, always take this medicine exactly as your doctor, pharmacist or nurse has told you. It is important that you do this as long as your doctor, pharmacist or nurse tells you to. Check with your doctor, pharmacist or nurse if you are not sure. Do not stop taking Imatinib medac unless your doctor tells you to. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away. How much Imatinib medac to take Use in adults Your doctor will tell you exactly how many capsules of Imatinib medac to take. The usual starting dose in treatment in CML in blast crisis is 600 mg, to be taken as 6 capsules of 100 mg (or 1 capsule of 400 mg plus 2 capsules of 100 mg) once a day. Your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg, you should take 1 capsule of 400 mg in the morning and 1 capsule of 400 mg in the evening. Me dic ina l p rod uc t n o l on ge r a uth ori se d 42 • If you are being treated for Ph-positive ALL: The starting dose is 600 mg to be taken as 6 capsules of 100 mg (or 1 capsule of 400 mg plus 2 capsules of 100 mg) once a day. • If you are being treated for MDS/MPD: The starting dose is 400 mg, to be taken as 1 capsule of 400 mg once a day. • If you are being treated for HES/CEL: The starting dose is 100 mg, to be taken as 1 capsule of 100 mg once a day. Your doctor may decide to increase the dose to 400 mg, to be taken as 1 capsule of 400 mg once a day, depending on how you respond to treatment. • If you are being treated for DFSP: The dose is 800 mg per day, to be taken as 1 capsule of 400 mg in the morning and 1 capsule of 400 mg in the evening. Use in children and adolescents The doctor will tell you how many capsules of Imatinib medac to give to your child. The amount of Imatinib medac given will depend on your child’s condition, body weight and height. The total daily dose in children and adolescents must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). When and how to take Imatinib medac • Take Imatinib medac with a meal. This will help protect you from stomach problems when taking Imatinib medac. • Swallow the capsules whole with a large glass of water. Do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children). • If you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still mineral water or apple juice. • If you are a woman who is pregnant or might get pregnant and are trying to open the capsules for your children or another patient unable to swallow, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. You should wash your hands immediately after opening the capsules. How long to take Imatinib medac Keep taking Imatinib medac every day for as long as your doctor tells you. If you take more Imatinib medac than you should If you have accidentally taken too many capsules, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you. If you forget to take Imatinib medac • If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose. • Then continue with your normal schedule. • Do not take a double dose to make up a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate. Me dic ina l p rod uc t n o l on ge r a uth ori se d 43 Some side effects may be serious. Tell your doctor straight away if you get any of the following: Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): • Rapid weight gain. Imatinib medac may cause your body to retain water (severe fluid retention). • Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib medac can reduce the number of white blood cells, so you might get infections more easily. • Unexpected bleeding or bruising (when you have not hurt yourself). Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): • Chest pain, irregular heart rhythm (signs of heart problems). • Cough, having difficulty breathing or painful breathing (signs of lung problems). • Feeling light-headed, dizzy or fainting (signs of low blood pressure). • Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). • Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). • Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). • Severely decreased urine output, feeling thirsty (signs of kidney problems). • Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). • Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). • Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). • Eye pain or deterioration in vision, bleeding in the eyes. • Pain in your hips or difficulty walking. • Numb or cold toes and fingers (signs of Raynaud’s syndrome). • Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). • Difficulty hearing. • Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). • Bruising. • Stomach pain with feeling sick (nausea). • Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). • Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). • Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorus levels in the blood). Not known (frequency cannot be estimated from the available data): • Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). • Chronic renal failure. If you get any of the above, tell your doctor straight away. Me dic ina l p rod uc t n o l on ge r a uth ori se d 44 Other side effects may include: Very common (may affect more than 1 in 10 people): • Headache or feeling tired. • Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. • Rash. • Muscle cramps or joint, muscle or bone pain, during Imatinib medac treatment or after you have stopped taking Imatinib medac • Swelling such as round your ankles or puffy eyes. • Weight gain. If any of these affects you severely, tell your doctor. Common (may affect up to 1 in 10 people): • Anorexia, weight loss or a disturbed sense of taste. • Feeling dizzy or weak. • Difficulty in sleeping (insomnia). • Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. • Nose bleeds. • Pain or swelling in your abdomen, flatulence, heartburn or constipation. • Itching. • Unusual hair loss or thinning. • Numbness of the hands or feet. • Mouth ulcers. • Joint pain with swelling. • Dry mouth, dry skin or dry eye. • Decreased or increased skin sensitivity. • Hot flushes, chills or night sweats. If any of these affects you severely, tell your doctor. Not known (frequency cannot be estimated from the available data): • Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. • Slowing of growth in children and adolescents. • Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a liver infection). If any of these affects you severely, tell your doctor. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Imatinib medac Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. Do not store above 30 °C. Do not use any pack that is damaged or shows signs of tampering. Me dic ina l p rod uc t n o l on ge r a uth ori se d 45 Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Imatinib medac contains • The active substance is imatinib (as mesilate). Each 100 mg hard capsule of Imatinib medac contains 100 mg imatinib (as mesilate). Each 400 mg hard capsule of Imatinib medac contains 400 mg imatinib (as mesilate). • The other ingredients are crospovidone (type A), lactose monohydrate, magnesium stearate. The capsule shell for 100 mg capsule is composed of gelatine, yellow iron oxide (E172), titanium dioxide (E171) and red iron oxide (E172). The capsule shell for 400 mg capsule is composed of gelatine, yellow iron oxide (E172), titanium dioxide (E171), red iron oxide (E172) and black iron oxide (E172). What Imatinib medac looks like and contents of the pack Imatinib medac 100 mg hard capsules are gelatin capsules of size “3” with orange body and cap. Imatinib medac 400 mg hard capsules are gelatin capsules of size “00” with caramel body and cap. Imatinib medac 100 mg capsules are supplied in packs containing 60 capsules in blisters. Imatinib medac 400 mg capsules are supplied in packs containing 30 capsules in blisters. Marketing Authorisation Holder medac Gesellschaft für klinische Spezialpräparate mbH Theaterstr. 6 22880 Wedel Germany Manufacturer Pabianickie Zakłady Farmaceutyczne Polfa S.A. Marszałka Józefa Piłsudskiego 5 95-200 Pabianice Poland medac Gesellschaft für klinische Spezialpräparate mbH Theaterstr. 6 22880 Wedel Germany This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu Me dic ina l p rod uc t n o l on ge r a uth ori se d SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take imatinib medac', 'Section_Content': "imatinib medac will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. follow all your doctor's instructions carefully, even if they differ from the general information contained in this leaflet. do not take imatinib medac: if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6). if this applies to you, tell your doctor without taking imatinib medac. if you think you may be allergic but are not sure, ask your doctor for advice. warnings and precautions talk to your doctor before taking imatinib medac: if you have or have ever had a liver, kidney or heart problem. if you are taking the medicine levothyroxine because your thyroid has been removed. if you have ever had or might now have a hepatitis b infection. this is because imatinib medac could cause hepatitis b to become active again, which can be fatal in some cases. patients will be carefully checked by their doctor for signs of this infection before treatment is started. if any of these apply to you, tell your doctor before taking imatinib medac. during treatment with imatinib medac, tell your doctor straight away if you put on weight very quickly. imatinib medac may cause your body to retain water (severe fluid retention). while you are taking imatinib medac, your doctor will regularly check whether the medicine is working. you will also have blood tests and be weighed regularly. children and adolescents imatinib medac is also a treatment for children and adolescents with cml. there is no experience in children with cml below 2 years of age. there is limited experience in children and adolescents with ph-positive all. some children and adolescents taking imatinib medac may have slower than normal growth. the doctor will monitor the growth at regular visits. other medicines and imatinib medac tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as st. john's wort). some medicines can interfere with the effect of imatinib medac when taken together. they may increase or decrease the effect of imatinib medac, either leading to increased side effects or making imatinib medac less effective. imatinib medac may do the same to some other medicines. tell your doctor if you are using medicines that prevent the formation of blood clots. pregnancy, breast-feeding and fertility if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. imatinib medac is not recommended during pregnancy unless clearly necessary as it may harm your baby. your doctor will discuss with you the possible risks of taking imatinib medac during pregnancy. women who might become pregnant are advised to use effective contraception during treatment. do not breast-feed during the treatment with imatinib medac as there is limited information on the distribution of imatinib into the breast milk. patients who are concerned about their fertility while taking imatinib medac are advised to consult with their doctor. driving and using machines you may feel dizzy or drowsy or get blurred vision while taking this medicine. if this happens, do not drive or use any tools or machines until you are feeling well again. imatinib medac contains lactose monohydrate if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.", 'Entity_Recognition': [{'Text': 'imatinib medac', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 0, 'EndOffset': 14, 'Score': 0.5555475354194641, 'Text': 'imatinib medac', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 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{'Title': '3. how to take imatinib medac', 'Section_Content': "your doctor has prescribed imatinib medac because you suffer from a serious condition. imatinib medac can help you to fight this condition. however, always take this medicine exactly as your doctor, pharmacist or nurse has told you. it is important that you do this as long as your doctor, pharmacist or nurse tells you to. check with your doctor, pharmacist or nurse if you are not sure. do not stop taking imatinib medac unless your doctor tells you to. if you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away. how much imatinib medac to take use in adults your doctor will tell you exactly how many capsules of imatinib medac to take. the usual starting dose in treatment in cml in blast crisis is 600 mg, to be taken as 6 capsules of 100 mg (or 1 capsule of 400 mg plus 2 capsules of 100 mg) once a day. your doctor may prescribe a higher or lower dose depending on how you respond to treatment. if your daily dose is 800 mg, you should take 1 capsule of 400 mg in the morning and 1 capsule of 400 mg in the evening. if you are being treated for ph-positive all: the starting dose is 600 mg to be taken as 6 capsules of 100 mg (or 1 capsule of 400 mg plus 2 capsules of 100 mg) once a day. if you are being treated for mds/mpd: the starting dose is 400 mg, to be taken as 1 capsule of 400 mg once a day. if you are being treated for hes/cel: the starting dose is 100 mg, to be taken as 1 capsule of 100 mg once a day. your doctor may decide to increase the dose to 400 mg, to be taken as 1 capsule of 400 mg once a day, depending on how you respond to treatment. if you are being treated for dfsp: the dose is 800 mg per day, to be taken as 1 capsule of 400 mg in the morning and 1 capsule of 400 mg in the evening. use in children and adolescents the doctor will tell you how many capsules of imatinib medac to give to your child. the amount of imatinib medac given will depend on your child's condition, body weight and height. the total daily dose in children and adolescents must not exceed 800 mg with cml and 600 mg with ph+all. the treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). when and how to take imatinib medac take imatinib medac with a meal. this will help protect you from stomach problems when taking imatinib medac. swallow the capsules whole with a large glass of water. do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children). if you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still mineral water or apple juice. if you are a woman who is pregnant or might get pregnant and are trying to open the capsules for your children or another patient unable to swallow, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. you should wash your hands immediately after opening the capsules. how long to take imatinib medac keep taking imatinib medac every day for as long as your doctor tells you. if you take more imatinib medac than you should if you have accidentally taken too many capsules, talk to your doctor straight away. you may require medical attention. take the medicine pack with you. if you forget to take imatinib medac if you forget a dose, take it as soon as you remember. however if it is nearly time for the next dose, skip the missed dose. then continue with your normal schedule. do not take a double dose to make up a forgotten dose. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.", 'Entity_Recognition': [{'Text': 'imatinib medac', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 27, 'EndOffset': 41, 'Score': 0.6416614651679993, 'Text': 'imatinib medac', 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. they are usually mild to moderate. some side effects may be serious. tell your doctor straight away if you get any of the following: very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): rapid weight gain. imatinib medac may cause your body to retain water (severe fluid retention). signs of infection such as fever, severe chills, sore throat or mouth ulcers. imatinib medac can reduce the number of white blood cells, so you might get infections more easily. unexpected bleeding or bruising (when you have not hurt yourself). uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): chest pain, irregular heart rhythm (signs of heart problems). cough, having difficulty breathing or painful breathing (signs of lung problems). feeling light-headed, dizzy or fainting (signs of low blood pressure). feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). severely decreased urine output, feeling thirsty (signs of kidney problems). feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). eye pain or deterioration in vision, bleeding in the eyes. pain in your hips or difficulty walking. numb or cold toes and fingers (signs of raynaud's syndrome). sudden swelling and redness of the skin (signs of a skin infection called cellulitis). difficulty hearing. muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). bruising. stomach pain with feeling sick (nausea). muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorus levels in the blood). not known (frequency cannot be estimated from the available data): combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). chronic renal failure. if you get any of the above, tell your doctor straight away. other side effects may include: very common (may affect more than 1 in 10 people): headache or feeling tired. feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. rash. muscle cramps or joint, muscle or bone pain, during imatinib medac treatment or after you have stopped taking imatinib medac swelling such as round your ankles or puffy eyes. weight gain. if any of these affects you severely, tell your doctor. common (may affect up to 1 in 10 people): anorexia, weight loss or a disturbed sense of taste. feeling dizzy or weak. difficulty in sleeping (insomnia). discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. nose bleeds. pain or swelling in your abdomen, flatulence, heartburn or constipation. itching. unusual hair loss or thinning. numbness of the hands or feet. mouth ulcers. joint pain with swelling. dry mouth, dry skin or dry eye. decreased or increased skin sensitivity. hot flushes, chills or night sweats. if any of these affects you severely, tell your doctor. not known (frequency cannot be estimated from the available data): reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. slowing of growth in children and adolescents. recurrence (reactivation) of hepatitis b infection when you have had hepatitis b in the past (a liver infection). if any of these affects you severely, tell your doctor. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can 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{'Title': '5. how to store imatinib medac', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. do not store above 30 . do not use any pack that is damaged or shows signs of tampering. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'imatinib medac', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 178, 'EndOffset': 180}, {'Text': 'any pack', 'Type': 'TREATMENT', 'BeginOffset': 194, 'EndOffset': 202}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what imatinib medac contains the active substance is imatinib (as mesilate). each 100 mg hard capsule of imatinib medac contains 100 mg imatinib (as mesilate). each 400 mg hard capsule of imatinib medac contains 400 mg imatinib (as mesilate). the other ingredients are crospovidone (type a), lactose monohydrate, magnesium stearate. the capsule shell for 100 mg capsule is composed of gelatine, yellow iron oxide (e172), titanium dioxide (e171) and red iron oxide (e172). the capsule shell for 400 mg capsule is composed of gelatine, yellow iron oxide (e172), titanium dioxide (e171), red iron oxide (e172) and black iron oxide (e172). what imatinib medac looks like and contents of the pack imatinib medac 100 mg hard capsules are gelatin capsules of size "3" with orange body and cap. imatinib medac 400 mg hard capsules are gelatin capsules of size "00" with caramel body and cap. imatinib medac 100 mg capsules are supplied in packs containing 60 capsules in blisters. imatinib medac 400 mg capsules are supplied in packs containing 30 capsules in blisters.', 'Entity_Recognition': [{'Text': 'imatinib medac', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'what imatinib medac', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 19}, {'Id': 1, 'BeginOffset': 53, 'EndOffset': 61, 'Score': 0.989434540271759, 'Text': 'imatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9798335433006287, 'RelationshipScore': 0.9835878610610962, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 82, 'EndOffset': 88, 'Text': '100 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.18651242554187775, 'RelationshipScore': 0.9985789060592651, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 89, 'EndOffset': 101, 'Text': 'hard capsule', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '100', 'Type': 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6CEDC70614C3A802A5692D9CE10694A3

https://www.ema.europa.eu/documents/product-information/grasustek-epar-product-information_en.pdf

Grasustek

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Grasustek 6 mg solution for injection in pre-filled syringe 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre-filled syringe contains 6 mg of pegfilgrastim* in 0.6 ml solution for injection. The concentration is 10 mg/ml based on protein only**. *Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with polyethylene glycol (PEG). ** The concentration is 20 mg/ml if the PEG moiety is included. The potency of this product should not be compared to the potency of another pegylated or non- pegylated protein of the same therapeutic class. For more information, see section 5.1. Excipient(s) with known effect Each pre-filled syringe contains 30 mg sorbitol (E 420) (see section 4.4). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection. Clear, colourless solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes). 4.2 Posology and method of administration Pegfilgrastim therapy should be initiated and supervised by physicians experienced in oncology and/or haematology. Posology One 6 mg dose (a single pre-filled syringe) of pegfilgrastim is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy. Special populations Renal impairment 3 No dose adjustment is recommended in patients with renal impairment, including those with end-stage renal disease. Paediatric population The safety and efficacy of pegfilgrastim in children has not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no dosing recommendations can be made. Method of administration Grasustek is injected subcutaneously. The injections should be given in the thigh, abdomen or upper arm. 4.3 Contraindications Hypersensitivity to the active ingredient or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded. Limited clinical data suggest a comparable effect on time to recovery from severe neutropenia for pegfilgrastim to filgrastim in patients with de novo acute myeloid leukaemia (AML) (see section 5.1). However, the long-term effects of pegfilgrastim have not been established in AML; therefore, it should be used with caution in this patient population. Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro. The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from AML. The safety and efficacy of pegfilgrastim administration in de novo AML patients aged < 55 years with cytogenetics t (15;17) have not been established. General The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high-dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dose regimens. Pulmonary adverse events Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk (see section 4.8). The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of Acute Respiratory Distress Syndrome (ARDS). In such circumstances, pegfilgrastim should be discontinued at the discretion of the doctor and the appropriate treatment given (see section 4.8). 4 Glomerulonephritis Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended. Capillary leak syndrome Capillary leak syndrome has been reported after granulocyte-colony stimulating factor administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include the need for intensive care (see section 4.8). Splenomegaly and splenic rupture Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see section 4.8). Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain. Thrombocytopenia and anaemia Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic medicinal products which are known to cause severe thrombocytopenia. Sickle cell anaemia Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease (see section 4.8). Therefore, doctors should use caution when prescribing pegfilgrastim in patients with sickle cell trait or sickle cell disease, should monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of this medicinal product with splenic enlargement and vaso-occlusive crisis. Leucocytosis White blood cell (WBC) counts of 100 x 109/L or greater have been observed in less than 1 % of patients receiving pegfilgrastim. No adverse events directly attributable to this degree of leucocytosis have been reported. Such elevation in white blood cells is transient, typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of this medicinal product. Consistent with the clinical effects and the potential for leucocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 x 109/L after the expected nadir, this medicinal product should be discontinued immediately. Hypersensitivity Hypersensitivity, including anaphylactic reactions, occurring during initial or subsequent treatment have been reported in patients treated with pegfilgrastim. Pegfilgrastim should be permanently discontinued in patients with clinically significant hypersensitivity. Pegfilgrastim should not be administered to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. 5 Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against pegfilgrastim are generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present. Aortitis Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. c-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and generally resolved after discontinuation of GCSF. See also section 4.8. Other warnings The safety and efficacy of pegfilgrastim for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated. Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging findings. This should be considered when interpreting bone-imaging results. Excipients This medicinal product contains 30 mg sorbitol in each 6 mg dose which is equivalent to 50 mg/ml. This medicinal product contains less than 1 mmol sodium (23 mg) per 6 mg dose, i.e. it is essentially ‘sodium-free’. 4.5 Interaction with other medicinal products and other forms of interaction Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ pegfilgrastim should be administered at least 24 hours after administration of cytotoxic chemotherapy. In clinical trials, pegfilgrastim has been safely administered 14 days before chemotherapy. Concomitant use of pegfilgrastim with any chemotherapy medicinal product has not been evaluated in patients. In animal models, concomitant administration of pegfilgrastim and 5-fluorouracil (5-FU) or other antimetabolites has been shown to potentiate myelosuppression. Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated in clinical trials. The potential for interaction with lithium, which also promotes the release of neutrophils, has not been specifically investigated. There is no evidence that such an interaction would be harmful. The safety and efficacy of Grasustek have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression e.g., nitrosoureas. Specific interaction or metabolism studies have not been performed; however, clinical trials have not indicated an interaction of pegfilgrastim with any other medicinal products. 6 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited data on the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Grasustek is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding There is insufficient information on the excretion of pegfilgrastim / metabolites in breast milk. Therefore a risk for new-borns/infants cannot be ruled out. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Grasustek therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother. Fertility Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 6 to 9 times higher than the recommended human dose (based on body surface area) (see section 5.3). 4.7 Effects on ability to drive and use machines Pegfilgrastim has no or a negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and musculoskeletal pain (common). Bone pain was generally of mild to moderate severity, transient and could be controlled in most patients with standard analgesics. Hypersensitivity-type reactions, including skin rash, urticaria, angiooedema, dyspnoea, erythema, flushing, and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon [≥ 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patients receiving pegfilgrastim (uncommon) (see section 4.4). Capillary Leak Syndrome, which can be life-threatening if treatment is delayed, has been reported as uncommon (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following administration of granulocyte colony-stimulating factors; see section 4.4 and section “Description of selected adverse reactions” below. Splenomegaly, generally asymptomatic, is uncommon. Splenic rupture including some fatal cases is uncommonly reported following administration of pegfilgrastim (see section 4.4). Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly, cases have resulted in respiratory failure or ARDS, which may be fatal (see section 4.4). Isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell disease (uncommon in sickle cell patients) (see section 4.4). Tabulated list of adverse reactions 7 The data in the table below describe adverse reactions reported from clinical trials and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing severity. MedDRA system organ class Adverse reactions Very common (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) Rare (≥1/10,000 to < 1/1,000) Very rare (<1/10,000) Blood and lymphatic system disorders Thrombocytopenia1; Leukocytosis1 Sickle cell crisis2; Splenomegaly2; Splenic rupture2 Immune system Disorders Hypersensitivity reactions; Anaphylaxis Metabolism and nutrition disorders Elevations in uric acid Nervous system Disorders Headache1 Vascular Disorders Capillary leak syndrome1 Aortitis Respiratory, thoracic and mediastinal disorders Acute Respiratory Distress Syndrome2; Pulmonary adverse reactions (interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis) Haemoptysis Pulmonary haemorrhage Gastrointestinal disorders Nausea1 Skin and subcutaneous tissue disorders Sweet’s syndrome (acute febrile dermatosis)1,2; Cutaneous Vasculitis1,2 Stevens- Johnson syndrome Musculoskeletal and connective tissue disorders Bone pain Musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain) Renal and urinary disorders Glomerulonephritis2 General disorders and administration site conditions Injection site pain1 Non-cardiac chest pain Injection site Reactions2 Investigations Elevations in lactate dehydrogenase and alkaline phosphatase1; Transient elevations in LFTs for ALT or AST1 1 See section “Description of selected adverse reactions” below. 8 2 This adverse reaction was identified through post-marketing surveillance of pegfilgrastim but not observed in randomised, controlled clinical trials in adults. The frequency category was estimated from a statistical calculation based upon 1,576 patients receiving pegfilgrastim in nine randomised clinical trials. Description of selected adverse reactions Uncommon cases of Sweet's syndrome have been reported, although in some cases underlying haematological malignancies may play a role. Uncommon events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim. The mechanism of vasculitis in patients receiving pegfilgrastim is unknown. Injection site reactions, including injection-site erythema (uncommon) as well as injection-site pain (common events) have occurred during initial or subsequent treatment with pegfilgrastim. Common cases of leucocytosis (White Blood Count [WBC] > 100 x 109/l) have been reported (see section 4.4). Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical effects, were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase, with no associated clinical effects, were uncommon in patients receiving pegfilgrastim following cytotoxic chemotherapy. Nausea and headaches were very commonly observed in patients receiving chemotherapy. Uncommon elevations in liver function tests (LFTs) for ALT (alanine aminotransferase) or AST (aspartate aminotransferase), have been observed in patients after receiving pegfilgrastim following cytotoxic chemotherapy. These elevations are transient and return to baseline. Common cases of thrombocytopenia have been reported. Cases of capillary leak syndrome have been reported in the post marketing setting with granulocyte colony-stimulating factor use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy medicinal products or undergoing apheresis (see section 4.4). Paediatric population Experience in children is limited. A higher frequency of serious adverse reactions in younger children aged 0-5 years (92 %) has been observed compared to older children aged 6-11 and 12-21 years respectively (80 % and 67 %) and adults. The most common adverse reaction reported was bone pain (see section 5.1 and 5.2). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Single doses of 300 μg/kg have been administered subcutaneously to a limited number of healthy volunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverse events were similar to those in subjects receiving lower doses of pegfilgrastim. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties Pharmacotherapeutic group: immunostimulants, colony stimulating factors; ATC Code: L03AA13. Grasustek is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule. Pegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Pegfilgrastim and filgrastim have been shown to have identical modes of action, causing a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes. Similar to filgrastim, neutrophils produced in response to pegfilgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similar effects may be seen on some non-myeloid cells in vitro. In two randomised, double-blind, pivotal studies in patients with high risk stage II-IV breast cancer undergoing myelosuppressive chemotherapy consisting of doxorubicin and docetaxel, use of pegfilgrastim, as a single once per cycle dose, reduced the duration of neutropenia and the incidence of febrile neutropenia similarly to that observed with daily administrations of filgrastim (a median of 11 daily administrations). In the absence of growth factor support, this regimen has been reported to result in a mean duration of grade 4 neutropenia of 5 to7 days, and a 30-40 % incidence of febrile neutropenia. In one study (n = 157), which used a 6 mg fixed dose of pegfilgrastim the mean duration of grade 4 neutropenia for the pegfilgrastim group was 1.8 days compared with 1.6 days in the filgrastim group (difference 0.23 days, 95 % CI -0.15, 0.63). Over the entire study, the rate of febrile neutropenia was 13 % of pegfilgrastim-treated patients compared with 20 % of filgrastim-treated patients (difference 7 %, 95 % CI of-19 %, 5 %). In a second study (n = 310), which used a weight-adjusted dose (100 μg /kg), the mean duration of grade 4 neutropenia for the pegfilgrastim group was 1.7 days, compared with 1.8 days in the filgrastim group (difference 0.03 days, 95 % CI -0.36, 0.30). The overall rate of febrile neutropenia was 9 % of patients treated with pegfilgrastim and 18 % of patients treated with filgrastim (difference 9 %, 95 % CI of-16.8 %,-1.1 %). In a placebo-controlled, double blind study in patients with breast cancer the effect of pegfilgrastim on the incidence of febrile neutropenia was evaluated following administration of a chemotherapy regimen associated with a febrile neutropenia rate of 10-20 % (docetaxel 100 mg/m2 every 3 weeks for 4 cycles). Nine hundred and twenty-eight patients were randomised to receive either a single dose of pegfilgrastim or placebo approximately 24 hours (day 2) after chemotherapy in each cycle. The incidence of febrile neutropenia was lower for patients randomised to receive pegfilgrastim compared with placebo (1% versus 17 %, p < 0.001). The incidence of hospitalisations and intravenous anti-infective use associated with a clinical diagnosis of febrile neutropenia was lower in the pegfilgrastim group compared with placebo (1 % versus 14 %, p < 0.001; and 2 % versus 10 %, p < 0.001). A small (n = 83), Phase II, randomised, double-blind study in patients receiving chemotherapy for de novo acute myeloid leukaemia compared pegfilgrastim (single dose of 6 mg) with filgrastim, administered during induction chemotherapy. Median time to recovery from severe neutropenia was estimated as 22 days in both treatment groups. Long-term outcome was not studied (see section 4.4). In a phase II (n = 37) multicentre, randomised, open-label study of paediatric sarcoma patients receiving 100 μg/kg pegfilgrastim following cycle 1 of vincristine, doxorubicin and cyclophosphamide http://www.ema.europa.eu/ 10 (VAdriaC/IE) chemotherapy, a longer duration of severe neutropenia (neutrophils < 0.5 x 109) was observed in younger children aged 0-5 years (8.9 days) compared to older children aged 6-11 years and 12-21 years (6 days and 3.7 days, respectively) and adults. Additionally, a higher incidence of febrile neutropenia was observed in younger children aged 0-5 years (75 %) compared to older children aged 6-11 years and 12-21 years (70 % and 33 %, respectively) and adults (see sections 4.8 and 5.2). 5.2. Pharmacokinetic properties After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim occurs at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintained during the period of neutropenia after myelosuppressive chemotherapy. The elimination of pegfilgrastim is non-linear with respect to dose; serum clearance of pegfilgrastim decreases with increasing dose. Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the serum concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery (see figure 1). Figure 1. Profile of median pegfilgrastim serum concentration and absolute neutrophil count (ANC) in chemotherapy treated patients after a single 6 mg injection Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not expected to be affected by renal or hepatic impairment. In an open label, single dose study (n = 31) various stages of renal impairment, including end-stage renal disease, had no impact on the pharmacokinetics of pegfilgrastim. Elderly Limited data suggest that the pharmacokinetics of pegfilgrastim in elderly subjects (> 65 years) is similar to that in adults. Paediatric population The pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma, who received 100 μg/kg pegfilgrastim after the completion of VAdriaC/IE chemotherapy. The youngest age group (0-5 years) had a higher mean exposure to pegfilgrastim (AUC) (± Standard Deviation) 11 (47.9 ± 22.5 μg·hr/ml) than older children aged 6-11 years and 12-21 years (22.0 ± 13.1 μg·hr/ml and 29.3 ± 23.2 μg·hr/ml, respectively) (see section 5.1). With the exception of the youngest age group (0 5 years), the mean AUC in paediatric subjects appeared similar to that for adult patients with high-risk stage II-IV breast cancer and receiving 100 μg/kg pegfilgrastim after the completion of doxorubicin/docetaxel (see sections 4.8 and 5.1). 5.3. Preclinical safety data Preclinical data from conventional studies of repeated dose toxicity revealed the expected pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow, extramedullary haematopoiesis and splenic enlargement. There were no adverse effects observed in offspring of pregnant rats given pegfilgrastim subcutaneously, but in rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity (embryo loss) at cumulative doses approximately 4 times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose. In rat studies, it was shown that pegfilgrastim may cross the placenta. Studies in rats indicated that reproductive performance, fertility, oestrous cycling, days between pairing and coitus, and intrauterine survival were unaffected by pegfilgrastim given subcutaneously. The relevance of these findings for humans is not known. 6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients Sodium acetate * Sorbitol (E420) Polysorbate 20 Water for injections *Sodium acetate is formed by titrating glacial acetic acid with sodium hydroxide. 6.2. Incompatibilities This medicinal product must not be mixed with other medicinal products, particularly with sodium chloride solutions. 6.3. Shelf life 3 years. 6.4. Special precautions for storage Store in a refrigerator (2 °C-8 °C). Grasustek may be exposed to room temperature (not above 30 °C) for a maximum single period of up to 72 hours. Grasustek left at room temperature for more than 72 hours should be discarded. Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hours does not adversely affect the stability of Grasustek. Keep the container in the outer carton to protect from light. 6.5. Nature and contents of container Pre-filled syringe (Type I glass), with a (butyl) rubber stopper and a stainless-steel needle with automatic needle guard. The needle has flexible, rigid needle shield. 12 Each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 ml of solution for injection. Pack size of one pre-filled syringe with automatic needle guard (0.6 ml) and supplied in a dispensing pack containing one syringe. 6.6. Special precautions for disposal and other handling Before administration, Grasustek solution should be visually inspected for particulate matter. Only a solution that is clear and colourless should be injected. Excessive shaking may aggregate pegfilgrastim, rendering it biologically inactive. Allow the pre-filled syringe to reach room temperature before injecting. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Juta Pharma GmbH, Gutenbergstr. 13, 24941 Flensburg, Germany 8. MARKETING AUTHORISATION NUMBER(S) EU/1/19/1375/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 20 June 2019 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 13 ANNEX II A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 14 A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) of the biological active substance(s) USV Private Limited D-115, TTC Industrial Area, Shirvane Navi Mumbai - 400706, Maharashtra, India Name and address of the manufacturer(s) responsible for batch release Juta Pharma GmbH Gutenbergstr. 13 24941 Flensburg Germany B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 15 ANNEX III LABELLING AND PACKAGE LEAFLET 16 A. LABELLING 17 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON FOR BLISTERED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Grasustek 6 mg solution for injection in pre-filled syringe pegfilgrastim 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 ml (10 mg/ml) solution for injection. 3. LIST OF EXCIPIENTS Excipients: Sorbitol (E420), polysorbate 20, sodium acetate, water for injection. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in pre-filled syringe 1 pre-filled syringe with automatic needle guard (0.6 ml). 5. METHOD AND ROUTE(S) OF ADMINISTRATION For single use only. Read the package leaflet before use. Important: Read the package leaflet before handling the pre-filled syringe. For subcutaneous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Avoid vigorous shaking. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 18 Store in a refrigerator. Do not freeze. Keep the container in the outer carton to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Juta Pharma GmbH, Gutenbergstr. 13, 24941 Flensburg, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/19/1375/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Grasustek 6 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 19 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER WITH SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Grasustek 6 mg solution for injection in pre-filled syringe pegfilgrastim 2. NAME OF THE MARKETING AUTHORISATION HOLDER Juta Pharma GmbH 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Important: read the package leaflet before handling the pre-filled syringe. 20 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS BLISTERED SYRINGE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Grasustek 6 mg pegfilgrastim SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.6 ml 6. OTHER Juta Pharma GmbH 21 B. PACKAGE LEAFLET 22 Package leaflet: Information for the user Grasustek 6 mg solution for injection in a pre-filled syringe pegfilgrastim This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects Read all of this leaflet carefully before you start using this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, pharmacist or nurse. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Grasustek is and what it is used for 2. What you need to know before you use Grasustek 3. How to use Grasustek 4. Possible side effects 5. How to store Grasustek 6. Contents of the pack and other information 1. What Grasustek is and what it is used for Grasustek is for use in adults aged 18 and over. Grasustek contains the active substance pegfilgrastim. Pegfilgrastim is a protein produced by biotechnology in bacteria called E. coli. It belongs to a group of proteins called cytokines and is very similar to a natural protein (granulocyte-colony stimulating factor) produced by your own body. Grasustek is used to reduce the duration of neutropenia (low white blood cell count) and the occurrence of febrile neutropenia (low white blood cell count with a fever) which can be caused by the use of cytotoxic chemotherapy (medicines that destroy rapidly growing cells). White blood cells are important as they help your body fight infection. These cells are very sensitive to the effects of chemotherapy which can cause the number of these cells in your body to decrease. If white blood cells fall to a low level, there may not be enough left in the body to fight bacteria and you may have an increased risk of infection. Your doctor has given you Grasustek to encourage your bone marrow (part of the bone which makes blood cells) to produce more white blood cells that help your body fight infection. 2. What you need to know before you use Grasustek Do not use Grasustek • if you are allergic to pegfilgrastim, filgrastim, E. coli derived proteins, or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor, pharmacist or nurse before using Grasustek: 23 • if you experience an allergic reaction including weakness, drop in blood pressure, difficulty breathing, swelling of the face (anaphylaxis), redness and flushing, skin rash and areas of the skin that itch • if you experience a cough, fever and difficulty breathing. This can be a sign of Acute Respiratory Distress Syndrome (ARDS) • if you have any of the following or combination of the following side effects: ­ swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. These could be symptoms of condition called “Capillary Leak Syndrome” which causes blood to leak from the small blood vessels into your body (see section 4). • If you get left upper abdominal pain or pain at the tip of your shoulder. This may be a sign of a problem with your spleen (splenomegaly) • If you have recently had a serious lung infection (pneumonia), fluid in the lungs (pulmonary oedema), inflammation of the lungs (interstitial lung disease) or an abnormal chest x-ray (lung infiltration) • If you are aware of any altered blood cell counts (e.g. increase in white blood cells or anaemia) or decreased blood platelet counts, which reduces the ability of your blood to clot (thrombocytopenia). Your doctor may want to monitor you more closely • If you have sickle cell anaemia. Your doctor may monitor your condition more closely. • if you have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing. These could be signs of a severe allergic reaction. • Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported rarely in cancer patients and healthy donors. The symptoms can include fever, abdominal pain, malaise, back pain and increased inflammatory markers. Tell your doctor if you experience those symptoms. Your doctor will check your blood and urine regularly as Grasustek can harm the tiny filters inside your kidneys (glomerulonephritis). Severe skin reactions (Stevens-Johnson syndrome) have been reported with the use of Grasustek. Stop using Grasustek and seek medical attention immediately if you notice any of the symptoms described in section 4. You should talk to your doctor about your risks of developing cancers of the blood. If you develop or are likely to develop cancers of the blood, you should not use Grasustek, unless instructed by your doctor. Loss of response to pegfilgrastim If you experience a loss of response or failure to maintain a response with pegfilgrastim treatment, your doctor will investigate the reasons why, including whether you have developed antibodies which neutralise pegfilgrastim’s activity. Other medicines and Grasustek Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Pregnancy, breast-feeding and fertility Ask your doctor or pharmacist for advice before taking any medicine. Grasustek has not been tested in pregnant women. It is important to tell your doctor if you: • are pregnant or breast-feeding • think you may be pregnant or • are planning to have a baby If you become pregnant during Grasustek treatment, please inform your doctor. 24 Unless your doctor directs you otherwise, you must stop breast-feeding if you use Grasustek. Driving and using machines Grasustek has no or a negligible effect on the ability to drive or use machines. Grasustek contains sorbitol (E420) and sodium This medicine contains 30 mg sorbitol in each 6 mg dose, which is equivalent to 50 mg/ml This medicine contains less than 1 mmol sodium (23 mg) per 6 mg dose, that is to say essentially ‘sodium-free’. 3. How to use Grasustek Always use Grasustek exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. The usual dose is one 6 mg subcutaneous injection (injection under your skin) using a pre-filled syringe and it should be given at least 24 hours after your last dose of chemotherapy at the end of each chemotherapy cycle. Injecting Grasustek yourself Your doctor may decide that it would be more convenient for you to inject Grasustek yourself. Your doctor or nurse will show you how to inject yourself. Do not try to inject yourself if you have not been trained. For further instructions on how to inject yourself with Grasustek, please read the section at the end of this leaflet. Do not shake Grasustek vigorously as this may affect its activity. If you use more Grasustek than you should If you use more Grasustek than you should contact your doctor, pharmacist or nurse. If you forget to inject Grasustek If you have forgotten a dose of Grasustek, contact your doctor to discuss when you should inject the next dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine may have side effects, although not everybody gets them. Please tell your doctor immediately if you have any of the following or combination of the following side effects: • swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. These symptoms generally develop in a rapid fashion. These could be symptoms of an uncommon (may affect up to 1 in 100 people) condition called “Capillary Leak Syndrome”, which causes blood to leak from the small blood vessels into your body and needs urgent medical attention. Very common side effects (may affect more than 1 in 10 people) • bone pain. Your doctor will tell you what you can take to ease the bone pain. • nausea and headaches. 25 Common side effects (may affect up to 1 in 10 people) • pain at the site of injection. • general aches and pains in the joints and muscles. • some changes may occur in your blood, but these will be detected by routine blood tests. Your white blood cell count may become high for a short period of time. Your platelet count may become low which might result in bruising. Uncommon side effects (may affect up to 1 in 100 people) • allergic-type reactions, including redness and flushing, skin rash, and raised areas of the skin that itch. • serious allergic reactions, including anaphylaxis (weakness, drop in blood pressure, difficulty breathing, swelling of the face). • increased spleen size. • spleen rupture. Some cases of splenic rupture were fatal. It is important that you contact your doctor immediately if you experience pain in the upper left side of the abdomen or left shoulder pain since this may relate to a problem with your spleen. • breathing problems. If you have a cough, fever and difficulty breathing please tell your doctor. • Sweet’s syndrome (plum-coloured, raised, painful lesions on the limbs and sometimes the face and neck with fever) has occurred but other factors may play a role. • cutaneous vasculitis (inflammation of the blood vessels in the skin). • damage to the tiny filters inside your kidneys (glomerulonephritis). • redness at the site of injection. • coughing up blood (haemoptysis) Rare side effects (may affect up to 1 in 1,000) • Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body), see section 2. • bleeding from the lung (pulmonary haemorrhage) • Stevens-Johnson syndrome, which can appear as reddish target-like or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. Stop using Grasustek if you develop these symptoms and contact your doctor or seek medical attention immediately. See also section 2. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Grasustek Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the syringe label after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C-8°C). You may take Grasustek out of the refrigerator and keep it at room temperature (not above 30 °C) for no longer than 3 days. Once a syringe has been removed from the refrigerator and has reached room temperature (not above 30 °C) it must either be used within 3 days or disposed of. Do not freeze. Grasustek may be used if it is accidentally frozen for a single period of less than 24 hours. 26 Keep the container in the outer carton in order to protect from light. Do not use this medicine if you notice it is cloudy or there are particles in it. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Grasustek contains − The active substance is pegfilgrastim. Each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 ml of solution. − The other ingredients are sodium acetate, sorbitol (E420), polysorbate 20 and water for injections (see section 2). What Grasustek looks like and contents of the pack Grasustek is a clear, colourless solution for injection in pre-filled syringe (6 mg/0.6 ml). Each pack contains 1 glass pre-filled syringe with an attached stainless-steel needle and needle cap. The syringes are provided with an automatic needle safety guard. Marketing Authorisation Holder Juta Pharma GmbH, Gutenbergstr. 13, 24941Flensburg, Germany Manufacturer Juta Pharma GmbH, Gutenbergstr. 13, 24941 Flensburg, Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: Ελλάδα RAFARM A.E.B.E Κορίνθου 12, Ν. Ψυχικό, Ελλάδα τηλ 210 6776550-1 България Алвоген Фарма България ЕООД бул. България 86А, ет. 1, София 1680, България +359 2 441 7136 Hrvatska Alvogen d.o.o. Av. V. Holjevca 40 , 10000 Zagreb, Hrvatska Tel:+385 1 6641 830 Ísland Alvogen ehf. Sæmundargötu 15-19, 101 Reykjavík, Ísland Tel: +354 522 2900 Magyarország Aramis Pharma Kft 1095 Mester u. 28 Budapest Hungary Tel:+36-1-299-1051 Polska Alvogen Pharma Sp. Z o.o. Ul Kniaźnina 4a lok 7 01-607 Warsaw, Poland Tel: + 48 22 460 92 00 27 România Alvogen Romania SRL 44B, Theodor Pallady Blvd. 3rd district, 032266 Bucharest, Romania Tel: +40 21 318 0377 Česká republika EGIS Praha, spol. s r.o., Praha1-Staré Město,Ovocný trh 1096/8, PSČ 11000 Tel: +420 227 129 111 Eesti Apteegikaubanduse Hulgimüük OÜ (Auxilia Pharma) Karamelli 6, 11317 Tallinn Tel: +372 605 0005 Italia medac Pharma S.r.l. Via Viggiano 90, 00178 Rome Italien Tel: +39 06 51 59 121 Suomi/Finland medac GmbH Hirsalantie 11 02420 Jorvas Finland Tel: +358 10 420 4000 Österreich Vertrieb G.L.Pharma GmbH Schlossplatz 1, 8502 Lannach, Osterreich Tel: +43 3136 82577 Slovenská republika EGIS Slovakia spol. s r.o., Prievozská 4D, 821 09 Bratislava Tel: +421 2 32409422 Deutschland medac GmbH Theaterstr. 6 22880 Wedel, Deutschland Tel: +49 4103 / 8006-777 France medac SAS 23 rue Pierre Gilles de Gennes 69007 Lyon Frankreich Tel: +33 4 37 66 14 70 Sverige, Danmark, Norge medac GmbH Malmöhusvägen 1 211 18 Malmö Schweden Tel: +46 0340 64 54 70 This leaflet was last revised in {MM/YYYY} Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu http://www.ema.europa.eu/ 28 --------------------------------------------------------------------------------------------------------------------- Instructions for use: Guide to parts Syringe before administration Caution: Avoid contact with the plunger and needle during the preparation of the syringe, The safety device is normally activated by pressure from the plunger on the syringe. Syringe after administration (Guard is released and covers the needle) 29 Important Before you use a Grasustek pre-filled syringe with automatic needle guard, read this important information: • It is important that you do not try to give yourself the injection unless you have received training from your doctor or healthcare provider. • Grasustek is given as an injection into the tissue just under the skin (subcutaneous use). Do not remove the grey needle cap from the pre-filled syringe until you are ready to inject. Do not use the pre-filled syringe if it has been dropped on a hard surface. Use a new pre- filled syringe and call your doctor or healthcare provider. Do not attempt to activate the pre-filled syringe prior to injection. Do not attempt to remove the clear pre-filled syringe safety guard from the pre-filled syringe. Do not attempt to remove the peelable label on the pre-filled syringe barrel before administering your injection. Call your doctor or healthcare provider if you have any questions. Step 1: Prepare A. Remove the pre-filled syringe tray from the package and gather the supplies needed for your injection: alcohol wipes, a cotton ball or gauze pad, a plaster and a sharps disposal container (not included). For a more comfortable injection, leave the pre-filled syringe at room temperature for about 30 minutes before injecting. Wash your hands thoroughly with soap and water. On a clean, well-lit work surface, place the new pre-filled syringe and the other supplies. Do not try to warm the syringe by using a heat source such as hot water or microwave. Do not leave the pre-filled syringe exposed to direct sunlight. Do not shake the pre-filled syringe. Keep pre-filled syringes out of the sight and reach of children. B. Warning/Precaution: Check to ensure there is no loose fragment or fluid inside the pack. In case of doubt DO NOT open this pack and take another pack instead. Open the blister by peeling back the top layer all the way off the blister as shown. C. Warning/Precaution: DO NOT lift the product by the plunger or needle cover. Remove the pre-filled syringe from blister as shown. 30 D. Inspect the medicine content through the viewing window of the pre-filled syringe. Do not use the pre-filled syringe if: • The medicine is cloudy or there are particles in it. It must be a clear and colourless liquid. • Any part appears cracked or broken. • The grey needle cap is missing or not securely attached. • The expiry date printed on the label has passed the last day of the month shown. In all cases, call your doctor or healthcare provider. Step 2: Get ready A. Wash your hands thoroughly. Prepare and clean your injection site. You can use: • Upper part of your thigh • Belly, except for a 5 cm (2-inch) area right around your belly button. • Outer area of upper arm (only if someone else is giving you the injection). Clean the injection site with an alcohol wipe. Let your skin dry. Do not touch the injection site before injecting. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. 31 B. Warning/Precaution: DO NOT twist the needle cover or touch the needle or plunger. Pull the needle cover straight off as shown and handle the guard to avoid injuries or bending the needle. C. Pinch your injection site to create a firm surface. It is important to keep the skin pinched when injecting. Step 3: Inject A. INSERT the needle into skin. Push the plunger while grasping the finger flanges. Push the plunger all the way down as far as it will go to inject all of the solution. Do not touch the injection site before injecting. B. The entire dose has to be administered to trigger the guard. 32 C. After the injection is complete, one of the below alternatives can be followed: -Remove the needle from the injection site and release the plunger until the entire needle is covered by the guard. -Release the plunger until the needle is covered and then remove the syringe from the injection site Warning/Precaution: If the guard is not activated or only partially activated, discard the syringe without replacing the needle cover. 33 Healthcare professionals only The trade name of the medicine should be clearly recorded in the patient file. Turn the plunger to move the label into a position where you can remove the syringe label. Step 4: Finish A. Dispose of the used medicine immediately in a Sharps container or as instructed by your healthcare provider. Medicines should be disposed of in accordance with local requirements. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.Keep the syringe and sharps disposal container out of sight and reach of children. Do not reuse the pre-filled syringe. Do not recycle pre-filled syringes or throw them away via household waste. B. Examine the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply a plaster if needed. 34 ANNEX IV SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S) 35 Scientific conclusions Taking into account the PRAC Assessment Report on the PSUR(s) for pegfilgrastim, the scientific conclusions of the CHMP are as follows: Three reported cases show a causal relationship between the adverse drug reaction (ADR) Stevens- Johnson syndrome and pegfilgrastim. The number of cases is small, but because of the seriousness of the ADR, the PRAC recommends that the Product Information should be updated accordingly. The CHMP agrees with the scientific conclusions made by the PRAC. Grounds for the variation to the terms of the marketing authorisation(s) On the basis of the scientific conclusions for pegfilgrastim the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing pegfilgrastim is unchanged subject to the proposed changes to the product information. The CHMP recommends that the terms of the marketing authorisation(s) should be varied. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what grasustek is and what it is used for', 'Section_Content': 'grasustek is for use in adults aged 18 and over. grasustek contains the active substance pegfilgrastim. pegfilgrastim is a protein produced by biotechnology in bacteria called e. coli. it belongs to a group of proteins called cytokines and is very similar to a natural protein (granulocyte-colony stimulating factor) produced by your own body. grasustek is used to reduce the duration of neutropenia (low white blood cell count) and the occurrence of febrile neutropenia (low white blood cell count with a fever) which can be caused by the use of cytotoxic chemotherapy (medicines that destroy rapidly growing cells). white blood cells are important as they help your body fight infection. these cells are very sensitive to the effects of chemotherapy which can cause the number of these cells in your body to decrease. if white blood cells fall to a low level, there may not be enough left in the body to fight bacteria and you may have an increased risk of infection. your doctor has given you grasustek to encourage your bone marrow (part of the bone which makes blood cells) to produce more white blood cells that help your body fight infection.', 'Entity_Recognition': [{'Text': 'grasustek', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 11, 'BeginOffset': 36, 'EndOffset': 38, 'Score': 0.3784639239311218, 'Text': '18', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'AGE', 'Traits': []}, {'Id': 2, 'BeginOffset': 89, 'EndOffset': 102, 'Score': 0.9750239849090576, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 104, 'EndOffset': 117, 'Score': 0.9577056765556335, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a protein', 'Type': 'PROBLEM', 'BeginOffset': 121, 'EndOffset': 130}, {'Text': 'bacteria', 'Type': 'PROBLEM', 'BeginOffset': 160, 'EndOffset': 168}, {'Text': 'e. coli', 'Type': 'PROBLEM', 'BeginOffset': 176, 'EndOffset': 183}, {'Text': 'a natural protein', 'Type': 'TEST', 'BeginOffset': 259, 'EndOffset': 276}, {'Id': 4, 'BeginOffset': 388, 'EndOffset': 399, 'Score': 0.9629733562469482, 'Text': 'neutropenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9089072942733765}]}, {'Text': 'low white blood cell count', 'Type': 'PROBLEM', 'BeginOffset': 401, 'EndOffset': 427}, {'Id': 5, 'BeginOffset': 451, 'EndOffset': 470, 'Score': 0.7156661748886108, 'Text': 'febrile neutropenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9225345849990845}]}, {'Id': 6, 'BeginOffset': 472, 'EndOffset': 498, 'Score': 0.4015416204929352, 'Text': 'low white blood cell count', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6246850490570068}]}, {'Text': 'a fever', 'Type': 'PROBLEM', 'BeginOffset': 504, 'EndOffset': 511}, {'Id': 15, 'BeginOffset': 547, 'EndOffset': 569, 'Score': 0.9144141674041748, 'Text': 'cytotoxic chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 571, 'EndOffset': 580}, {'Id': 16, 'BeginOffset': 618, 'EndOffset': 635, 'Score': 0.41660788655281067, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'your body fight infection', 'Type': 'PROBLEM', 'BeginOffset': 663, 'EndOffset': 688}, {'Text': 'these cells', 'Type': 'PROBLEM', 'BeginOffset': 690, 'EndOffset': 701}, {'Id': 17, 'BeginOffset': 739, 'EndOffset': 751, 'Score': 0.9235928654670715, 'Text': 'chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'white blood cells fall', 'Type': 'PROBLEM', 'BeginOffset': 823, 'EndOffset': 845}, {'Text': 'fight bacteria', 'Type': 'PROBLEM', 'BeginOffset': 906, 'EndOffset': 920}, {'Id': 9, 'BeginOffset': 959, 'EndOffset': 968, 'Score': 0.9825108647346497, 'Text': 'infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7970544099807739}]}, {'Text': 'your bone marrow', 'Type': 'PROBLEM', 'BeginOffset': 1019, 'EndOffset': 1035}, {'Id': 1, 'BeginOffset': 1049, 'EndOffset': 1053, 'Score': 0.776227593421936, 'Text': 'bone', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 21, 'BeginOffset': 1066, 'EndOffset': 1077, 'Score': 0.31665459275245667, 'Text': 'blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'white blood cells', 'Type': 'TREATMENT', 'BeginOffset': 1095, 'EndOffset': 1112}, {'Text': 'your body fight infection', 'Type': 'PROBLEM', 'BeginOffset': 1123, 'EndOffset': 1148}]}

{'Title': '2. what you need to know before you use grasustek', 'Section_Content': 'do not use grasustek if you are allergic to pegfilgrastim, filgrastim, e. coli derived proteins, or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor, pharmacist or nurse before using grasustek: 23 if you experience an allergic reaction including weakness, drop in blood pressure, difficulty breathing, swelling of the face (anaphylaxis), redness and flushing, skin rash and areas of the skin that itch if you experience a cough, fever and difficulty breathing. this can be a sign of acute respiratory distress syndrome (ards) if you have any of the following or combination of the following side effects: \xad swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. these could be symptoms of condition called "capillary leak syndrome" which causes blood to leak from the small blood vessels into your body (see section 4). if you get left upper abdominal pain or pain at the tip of your shoulder. this may be a sign of a problem with your spleen (splenomegaly) if you have recently had a serious lung infection (pneumonia), fluid in the lungs (pulmonary oedema), inflammation of the lungs (interstitial lung disease) or an abnormal chest x-ray (lung infiltration) if you are aware of any altered blood cell counts (e.g. increase in white blood cells or anaemia) or decreased blood platelet counts, which reduces the ability of your blood to clot (thrombocytopenia). your doctor may want to monitor you more closely if you have sickle cell anaemia. your doctor may monitor your condition more closely. if you have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing. these could be signs of a severe allergic reaction. inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported rarely in cancer patients and healthy donors. the symptoms can include fever, abdominal pain, malaise, back pain and increased inflammatory markers. tell your doctor if you experience those symptoms. your doctor will check your blood and urine regularly as grasustek can harm the tiny filters inside your kidneys (glomerulonephritis). severe skin reactions (stevens-johnson syndrome) have been reported with the use of grasustek. stop using grasustek and seek medical attention immediately if you notice any of the symptoms described in section 4. you should talk to your doctor about your risks of developing cancers of the blood. if you develop or are likely to develop cancers of the blood, you should not use grasustek, unless instructed by your doctor. loss of response to pegfilgrastim if you experience a loss of response or failure to maintain a response with pegfilgrastim treatment, your doctor will investigate the reasons why, including whether you have developed antibodies which neutralise pegfilgrastim\'s activity. other medicines and grasustek tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. pregnancy, breast-feeding and fertility ask your doctor or pharmacist for advice before taking any medicine. grasustek has not been tested in pregnant women. it is important to tell your doctor if you: are pregnant or breast-feeding think you may be pregnant or are planning to have a baby if you become pregnant during grasustek treatment, please inform your doctor. unless your doctor directs you otherwise, you must stop breast-feeding if you use grasustek. driving and using machines grasustek has no or a negligible effect on the ability to drive or use machines. grasustek contains sorbitol (e420) and sodium this medicine contains 30 mg sorbitol in each 6 mg dose, which is equivalent to 50 mg/ml this medicine contains less than 1 mmol sodium (23 mg) per 6 mg dose, that is to say essentially \'sodium-free\'.', 'Entity_Recognition': [{'Text': 'grasustek', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'grasustek', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 20}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 32, 'EndOffset': 40}, {'Id': 21, 'BeginOffset': 44, 'EndOffset': 57, 'Score': 0.9796242713928223, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 22, 'BeginOffset': 59, 'EndOffset': 69, 'Score': 0.9966999888420105, 'Text': 'filgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'e. coli derived proteins', 'Type': 'TREATMENT', 'BeginOffset': 71, 'EndOffset': 95}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 132, 'EndOffset': 145}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 165, 'EndOffset': 166}, {'Text': '23', 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'Score': 0.9669172763824463}]}, {'Text': 'the skin that itch', 'Type': 'PROBLEM', 'BeginOffset': 448, 'EndOffset': 466}, {'Text': 'a cough', 'Type': 'PROBLEM', 'BeginOffset': 485, 'EndOffset': 492}, {'Id': 34, 'BeginOffset': 494, 'EndOffset': 499, 'Score': 0.9911493062973022, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9493857026100159}]}, {'Id': 35, 'BeginOffset': 504, 'EndOffset': 524, 'Score': 0.9879854321479797, 'Text': 'difficulty breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9527600407600403}]}, {'Text': 'acute respiratory distress syndrome', 'Type': 'PROBLEM', 'BeginOffset': 548, 'EndOffset': 583}, {'Id': 38, 'BeginOffset': 585, 'EndOffset': 589, 'Score': 0.6185668706893921, 'Text': 'ards', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.9684438109397888, 'RelationshipScore': 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'capillary leak syndrome', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4738799035549164}]}, {'Text': 'blood to leak from the small blood vessels into your body', 'Type': 'PROBLEM', 'BeginOffset': 940, 'EndOffset': 997}, {'Text': '4.', 'Type': 'NUMBER', 'BeginOffset': 1011, 'EndOffset': 1013}, {'Text': 'left upper abdominal pain', 'Type': 'PROBLEM', 'BeginOffset': 1026, 'EndOffset': 1051}, {'Id': 50, 'BeginOffset': 1055, 'EndOffset': 1059, 'Score': 0.9951306581497192, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.825097918510437}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.963090181350708, 'RelationshipScore': 0.796696126461029, 'RelationshipType': 'DIRECTION', 'Id': 6, 'BeginOffset': 1026, 'EndOffset': 1030, 'Text': 'left', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'DIRECTION', 'Score': 0.9684386849403381, 'RelationshipScore': 0.9095020890235901, 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{'Title': '3. how to use grasustek', 'Section_Content': 'always use grasustek exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. the usual dose is one 6 mg subcutaneous injection (injection under your skin) using a pre-filled syringe and it should be given at least 24 hours after your last dose of chemotherapy at the end of each chemotherapy cycle. injecting grasustek yourself your doctor may decide that it would be more convenient for you to inject grasustek yourself. your doctor or nurse will show you how to inject yourself. do not try to inject yourself if you have not been trained. for further instructions on how to inject yourself with grasustek, please read the section at the end of this leaflet. do not shake grasustek vigorously as this may affect its activity. if you use more grasustek than you should if you use more grasustek than you should contact your doctor, pharmacist or nurse. if you forget to inject grasustek if you have forgotten a dose of grasustek, contact your doctor to discuss when you should inject the next dose. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'grasustek', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 138, 'EndOffset': 139}, {'Id': 0, 'BeginOffset': 188, 'EndOffset': 192, 'Score': 0.9351133108139038, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 200, 'EndOffset': 220}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 253, 'EndOffset': 255}, {'Id': 3, 'BeginOffset': 286, 'EndOffset': 298, 'Score': 0.8677874803543091, 'Text': 'chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'each chemotherapy cycle', 'Type': 'TREATMENT', 'BeginOffset': 313, 'EndOffset': 336}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1086, 'EndOffset': 1099}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine may have side effects, although not everybody gets them. please tell your doctor immediately if you have any of the following or combination of the following side effects: swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. these symptoms generally develop in a rapid fashion. these could be symptoms of an uncommon (may affect up to 1 in 100 people) condition called "capillary leak syndrome", which causes blood to leak from the small blood vessels into your body and needs urgent medical attention. very common side effects (may affect more than 1 in 10 people) bone pain. your doctor will tell you what you can take to ease the bone pain. nausea and headaches. common side effects (may affect up to 1 in 10 people) pain at the site of injection. general aches and pains in the joints and muscles. some changes may occur in your blood, but these will be detected by routine blood tests. your white blood cell count may become high for a short period of time. your platelet count may become low which might result in bruising. uncommon side effects (may affect up to 1 in 100 people) allergic-type reactions, including redness and flushing, skin rash, and raised areas of the skin that itch. serious allergic reactions, including anaphylaxis (weakness, drop in blood pressure, difficulty breathing, swelling of the face). increased spleen size. spleen rupture. some cases of splenic rupture were fatal. it is important that you contact your doctor immediately if you experience pain in the upper left side of the abdomen or left shoulder pain since this may relate to a problem with your spleen. breathing problems. if you have a cough, fever and difficulty breathing please tell your doctor. sweet\'s syndrome (plum-coloured, raised, painful lesions on the limbs and sometimes the face and neck with fever) has occurred but other factors may play a role. cutaneous vasculitis (inflammation of the blood vessels in the skin). damage to the tiny filters inside your kidneys (glomerulonephritis). redness at the site of injection. coughing up blood (haemoptysis) rare side effects (may affect up to 1 in 1,000) inflammation of the aorta (the large blood vessel which transports blood from the heart to the body), see section 2. bleeding from the lung (pulmonary haemorrhage) stevens-johnson syndrome, which can appear as reddish target-like or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. stop using grasustek if you develop these symptoms and contact your doctor or seek medical attention immediately. see also section 2. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any 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'Score': 0.852807343006134, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6836211681365967}]}, {'Id': 110, 'BeginOffset': 3069, 'EndOffset': 3080, 'Score': 0.36598360538482666, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5909224152565002}]}, {'Id': 111, 'BeginOffset': 3094, 'EndOffset': 3106, 'Score': 0.8528962135314941, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7248383164405823}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 3162, 'EndOffset': 3175}]}

{'Title': '5. how to store grasustek', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and on the syringe label after exp. the expiry date refers to the last day of that month. store in a refrigerator (2-8). you may take grasustek out of the refrigerator and keep it at room temperature (not above 30 ) for no longer than 3 days. once a syringe has been removed from the refrigerator and has reached room temperature (not above 30 ) it must either be used within 3 days or disposed of. do not freeze. grasustek may be used if it is accidentally frozen for a single period of less than 24 hours. keep the container in the outer carton in order to protect from light. do not use this medicine if you notice it is cloudy or there are particles in it. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'grasustek', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 347, 'EndOffset': 349}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 371, 'EndOffset': 372}, {'Text': 'a syringe', 'Type': 'TREATMENT', 'BeginOffset': 384, 'EndOffset': 393}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 477, 'EndOffset': 479}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 512, 'EndOffset': 513}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 634, 'EndOffset': 636}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 666, 'EndOffset': 682}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 726, 'EndOffset': 739}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 760, 'EndOffset': 766}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 931, 'EndOffset': 945}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what grasustek contains − the active substance is pegfilgrastim. each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 ml of solution. − the other ingredients are sodium acetate, sorbitol (e420), polysorbate 20 and water for injections (see section 2). what grasustek looks like and contents of the pack grasustek is a clear, colourless solution for injection in pre-filled syringe (6 mg/0.6 ml). each pack contains 1 glass pre-filled syringe with an attached stainless-steel needle and needle cap. the syringes are provided with an automatic needle safety guard.', 'Entity_Recognition': [{'Text': 'grasustek', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 50, 'EndOffset': 63, 'Score': 0.9881283640861511, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.37280043959617615, 'RelationshipScore': 0.9883109927177429, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 70, 'EndOffset': 97, 'Text': 'pre-filled syringe contains', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 65, 'EndOffset': 88}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 98, 'EndOffset': 99}, {'Id': 3, 'BeginOffset': 106, 'EndOffset': 119, 'Score': 0.9908376336097717, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.37280043959617615, 'RelationshipScore': 0.9711418747901917, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 70, 'EndOffset': 97, 'Text': 'pre-filled syringe contains', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9550043344497681, 'RelationshipScore': 0.9999833106994629, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 98, 'EndOffset': 102, 'Text': '6 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9367120862007141, 'RelationshipScore': 0.9701940417289734, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 123, 'EndOffset': 129, 'Text': '0.6 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9065635204315186, 'RelationshipScore': 0.8828418850898743, 'RelationshipType': 'FORM', 'Id': 5, 'BeginOffset': 133, 'EndOffset': 141, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '0.6', 'Type': 'NUMBER', 'BeginOffset': 123, 'EndOffset': 126}, {'Id': 6, 'BeginOffset': 171, 'EndOffset': 185, 'Score': 0.9800916314125061, 'Text': 'sodium acetate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9550043344497681, 'RelationshipScore': 0.8393469452857971, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 98, 'EndOffset': 102, 'Text': '6 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9367120862007141, 'RelationshipScore': 0.9842743277549744, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 123, 'EndOffset': 129, 'Text': '0.6 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'sorbitol (e', 'Type': 'TREATMENT', 'BeginOffset': 187, 'EndOffset': 198}, {'Id': 8, 'BeginOffset': 204, 'EndOffset': 215, 'Score': 0.3858562409877777, 'Text': 'polysorbate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.3167004883289337, 'RelationshipScore': 0.998099148273468, 'RelationshipType': 'STRENGTH', 'Id': 9, 'BeginOffset': 216, 'EndOffset': 218, 'Text': '20', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 216, 'EndOffset': 218}, {'Text': 'injection in pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 358, 'EndOffset': 389}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 391, 'EndOffset': 392}, {'Text': '0.6', 'Type': 'NUMBER', 'BeginOffset': 396, 'EndOffset': 399}, {'Text': '1 glass pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 424, 'EndOffset': 450}, {'Text': 'an attached stainless-steel needle and needle cap', 'Type': 'TREATMENT', 'BeginOffset': 456, 'EndOffset': 505}, {'Text': 'the syringes', 'Type': 'TREATMENT', 'BeginOffset': 507, 'EndOffset': 519}, {'Text': 'an automatic needle safety guard', 'Type': 'TREATMENT', 'BeginOffset': 538, 'EndOffset': 570}]}

3C92CFC7FF68FF6393EA2F4405A40B29

https://www.ema.europa.eu/documents/product-information/epclusa-epar-product-information_en.pdf

Epclusa

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Epclusa 400 mg/100 mg film-coated tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Pink, diamond-shaped, film-coated tablet of dimensions 20 mm x 10 mm, debossed on one side with “GSI” and “7916” on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Epclusa is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults (see sections 4.2, 4.4 and 5.1). 4.2 Posology and method of administration Epclusa treatment should be initiated and monitored by a physician experienced in the management of patients with HCV infection. Posology The recommended dose of Epclusa is one tablet, taken orally, once daily with or without food (see section 5.2). Table 1: Recommended treatment and duration for all HCV genotypes Patient populationa Treatment and duration Patients without cirrhosis and patients with compensated cirrhosis Epclusa for 12 weeks Addition of ribavirin may be considered for genotype 3 infected patients with compensated cirrhosis (see section 5.1.) Patients with decompensated cirrhosis Epclusa + ribavirin for 12 weeks a Includes patients co-infected with human immunodeficiency virus (HIV) and patients with recurrent HCV post-liver transplant (see section 4.4.). When used in combination with ribavirin, refer also to the Summary of Product Characteristics of the medicinal product containing ribavirin. 3 The following dosing is recommended where ribavirin is divided in two daily doses and given with food: Table 2: Guidance for ribavirin dosing when administered with Epclusa to patients with decompensated cirrhosis Patient Ribavirin Dose Child-Pugh-Turcotte (CPT) Class B cirrhosis pre-transplant 1,000 mg per day for patients < 75 kg and 1,200 mg for those weighing ≥ 75 kg CPT Class C cirrhosis pre-transplant CPT Class B or C post-transplant Starting dose of 600 mg, which can be titrated up to a maximum of 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 1,200 mg for patients weighing ≥ 75 kg) if well tolerated. If the starting dose is not well tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels If ribavirin is used in genotype 3 infected patients with compensated cirrhosis (pre- or post-transplant) the recommended dose of ribavirin is 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 1,200 mg for patients weighing ≥ 75 kg). For ribavirin dose modifications, refer to the Summary of Product Characteristics of the medicinal product containing ribavirin. Patients should be instructed that if vomiting occurs within 3 hours of dosing an additional tablet of Epclusa should be taken. If vomiting occurs more than 3 hours after dosing, no further dose of Epclusa is needed (see section 5.1). If a dose of Epclusa is missed and it is within 18 hours of the normal time, patients should be instructed to take the tablet as soon as possible and then patients should take the next dose at the usual time. If it is after 18 hours then patients should be instructed to wait and take the next dose of Epclusa at the usual time. Patients should be instructed not to take a double dose of Epclusa. Patients who have previously failed therapy with an NS5A-containing regimen Epclusa + ribavirin for 24 weeks may be considered (see section 4.4). Elderly No dose adjustment is warranted for elderly patients (see section 5.2). Renal impairment No dose adjustment of Epclusa is required for patients with mild or moderate renal impairment. Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2)and end stage renal disease (ESRD) requiring haemodialysis. Epclusa can be used in these patients with no dose adjustment when no other relevant treatment options are available (see section 4.4, 4.8, 5.1 and 5.2). Hepatic impairment No dose adjustment of Epclusa is required for patients with mild, moderate, or severe hepatic impairment (CPT Class A, B, or C) (see section 5.2). Safety and efficacy of Epclusa have been assessed in patients with CPT Class B cirrhosis, but not in patients with CPT Class C cirrhosis (see sections 4.4, 4.8 and 5.1). Paediatric population The safety and efficacy of Epclusa in children and adolescents aged less than 18 years have not yet been established. No data are available. Method of administration For oral use. 4 Patients should be instructed to swallow the tablet whole with or without food (see section 5.2). Due to the bitter taste, it is recommended that the film-coated tablet is not chewed or crushed. 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Use with strong P-gp and strong CYP inducers Medicinal products that are strong P-glycoprotein (P-gp) and/or strong cytochrome P450 (CYP) inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort). Co-administration will significantly decrease sofosbuvir or velpatasvir plasma concentrations and could result in loss of efficacy of Epclusa (see section 4.5). 4.4 Special warnings and precautions for use Epclusa should not be administered concurrently with other medicinal products containing sofosbuvir. Severe bradycardia and heart block Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir- containing regimens are used in combination with amiodarone. Bradycardia has generally occurred within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks after initiating HCV treatment. Amiodarone should only be used in patients on Epclusa when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated. Should concomitant use of amiodarone be considered necessary, it is recommended that patients undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Epclusa. All patients with concurrent or recent use of amiodarone should be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them. HCV/HBV (hepatitis B virus) co-infection Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines. Patients who have previously failed therapy with an NS5A-containing regimen There are no clinical data to support the efficacy of sofosbuvir/velpatasvir for the treatment of patients who have failed treatment with a regimen containing another NS5A inhibitor. However, on the basis of NS5A resistance associated variants (RAVs) typically seen in patients who have failed therapy with other NS5A inhibitor containing regimens, the in vitro pharmacology of velpatasvir, and the outcomes of sofosbuvir/velpatasvir treatment in NS5A-naïve patients with baseline NS5A RAVs enrolled into the ASTRAL-studies, treatment with Epclusa + RBV for 24 weeks can be considered for patients who have failed therapy on an NS5A-containing regimen and who are deemed at high risk for clinical disease progression and who do not have alternative treatment options. 5 Renal impairment Safety data are limited in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Epclusa can be used in these patients with no dose adjustment when no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Epclusa is used in combination with ribavirin refer also to the Summary of Product Characteristics for ribavirin for patients with creatinine clearance < 50 mL/min (see section 5.2). Use with moderate P-gp inducers and/or moderate CYP inducers Medicinal products that are moderate P-gp and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir or velpatasvir plasma concentrations leading to reduced therapeutic effect of Epclusa. Co-administration of such medicinal products with Epclusa is not recommended (see section 4.5). Use with certain HIV antiretroviral regimens Epclusa has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of Epclusa and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of Epclusa with the fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Epclusa concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of Product Characteristics for recommendations on renal monitoring. Use in diabetic patients Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated. CPT Class C cirrhosis Safety and efficacy of Epclusa has not been assessed in patients with CPT Class C cirrhosis (see sections 4.8 and 5.1). Liver transplant patients The safety and efficacy of Epclusa in the treatment of HCV infection in patients who are post-liver transplant have not been assessed. Treatment with Epclusa in accordance with the recommended posology (see section 4.2) should be guided by an assessment of the potential benefits and risks for the individual patient. 4.5 Interaction with other medicinal products and other forms of interaction As Epclusa contains sofosbuvir and velpatasvir, any interactions that have been identified with these active substances individually may occur with Epclusa. Potential for Epclusa to affect other medicinal products Velpatasvir is an inhibitor of drug transporter P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of Epclusa with medicinal products that are substrates of these transporters may increase the exposure of such medicinal products. See Table 3 for examples of interactions with sensitive substrates of P-gp (digoxin), BCRP (rosuvastatin), and OATP (pravastatin). 6 Potential for other medicinal products to affect Epclusa Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP. Velpatasvir is also a substrate of drug transporter OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8 and CYP3A4 was observed. Medicinal products that are strong inducers of P-gp and/or strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. carbamazepine, phenobarbital and phenytoin, rifampicin, rifabutin and St. John’s wort) may decrease plasma concentrations of sofosbuvir or velpatasvir leading to reduced therapeutic effect of sofosbuvir/velpatasvir. The use of such medicinal products with Epclusa is contraindicated (see section 4.3). Medicinal products that are moderate P-gp inducers and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir or velpatasvir plasma concentration leading to reduced therapeutic effect of Epclusa. Co-administration with such medicinal products is not recommended with Epclusa (see section 4.4). Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir or velpatasvir plasma concentrations. Medicinal products that inhibit OATP, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. Clinically significant medicinal product interactions with Epclusa mediated by P-gp, BCRP, OATP, or CYP450 inhibitors are not expected; Epclusa may be co-administered with P-gp, BCRP, OATP and CYP inhibitors. Patients treated with vitamin K antagonists As liver function may change during treatment with Epclusa, a close monitoring of International Normalised Ratio (INR) values is recommended. Impact of DAA therapy on drugs metabolized by the liver The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV. Interactions between Epclusa and other medicinal products Table 3 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined interaction boundaries). The medicinal product interactions described are based on studies conducted with either sofosbuvir/velpatasvir or velpatasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with sofosbuvir/velpatasvir. The table is not all-inclusive. Table 3: Interactions between Epclusa and other medicinal products Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels. Mean ratio (90% confidence interval)a,b Recommendation concerning co-administration with Epclusa Active Cmax AUC Cmin ACID REDUCING AGENTS Velpatasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease the concentration of velpatasvir. Antacids e.g. Aluminium or magnesium hydroxide; calcium carbonate (Increase in gastric pH) Interaction not studied. Expected. ↔ Sofosbuvir ↓ Velpatasvir It is recommended to separate antacid and Epclusa administration by 4 hours. 7 Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels. Mean ratio (90% confidence interval)a,b Recommendation concerning co-administration with Epclusa Active Cmax AUC Cmin H2-receptor antagonists Famotidine (40 mg single dose)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose)c Famotidine dosed simultaneously with Epclusad Cimetidinee Nizatidinee Ranitidinee (Increase in gastric pH) Sofosbuvir ↔ ↔ H2-receptor antagonists may be administered simultaneously with or staggered from Epclusa at a dose that does not exceed doses comparable to famotidine 40 mg twice daily. Velpatasvir ↓ 0.80 (0.70, 0.91) ↓ 0.81 (0.71, 0.91) Famotidine (40 mg single dose)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose)c Famotidine dosed 12 hours prior to Epclusad (Increase in gastric pH) Sofosbuvir ↓ 0.77 (0.68, 0.87) ↓ 0.80 (0.73, 0.88) Velpatasvir ↔ ↔ Proton pump inhibitors Omeprazole (20 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose fasted)c Omeprazole dosed simultaneously with Epclusad Lansoprazolee Rabeprazolee Pantoprazolee Esomeprazolee (Increase in gastric pH) Sofosbuvir ↓ 0.66 (0.55, 0.78) ↓ 0.71 (0.60, 0.83) Co-administration with proton pump inhibitors is not recommended. If it is considered necessary to co-administer, then Epclusa should be administered with food and taken 4 hours before proton pump inhibitor at max doses comparable to omeprazole 20 mg. Velpatasvir ↓ 0.63 (0.50, 0.78) ↓ 0.64 (0.52, 0.79) Omeprazole (20 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose fed)c Omeprazole dosed 4 hours after Epclusad (Increase in gastric pH) Sofosbuvir ↓ 0.79 (0.68, 0.92) ↔ Velpatasvir ↓ 0.67 (0.58, 0.78) ↓ 0.74 (0.63, 0.86) 8 Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels. Mean ratio (90% confidence interval)a,b Recommendation concerning co-administration with Epclusa Active Cmax AUC Cmin ANTIARRHYTHMICS Amiodarone Effect on amiodarone, velpatasvir, and sofosbuvir concentrations unknown. Coadministration of amiodarone with a sofosbuvir containing regimen may result in serious symptomatic bradycardia. Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with Epclusa (see sections 4.4 and 4.8). Digoxin Interaction only studied with velpatasvir. Expected: ↔ Sofosbuvir Co-administration of Epclusa with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when co-administered with Epclusa. Digoxin (0.25 mg single dose)f/ velpatasvir (100 mg single dose) (Inhibition of P-gp) Effect on velpatasvir exposure not studied Expected: ↔ Velpatasvir Observed: Digoxin ↑ 1.9 (1.7, 2.1) ↑ 1.3 (1.1, 1.6) ANTICOAGULANTS Dabigatran etexilate (Inhibition of P-gp) Interaction not studied. Expected: ↑ Dabigatran ↔ Sofosbuvir ↔ Velpatasvir Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with Epclusa. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure. Vitamin K antagonists Interaction not studied Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Epclusa. ANTICONVULSANTS Phenytoin Phenobarbital (Induction of P-gp and CYPs) Interaction not studied. Expected: ↓ Sofosbuvir ↓ Velpatasvir Epclusa is contraindicated with phenobarbital and phenytoin (see section 4.3). Carbamazepine (Induction of P-gp and CYPs) Interaction not studied. Expected: ↓ Velpatasvir Epclusa is contraindicated with carbamazepine (see section 4.3). Observed: Sofosbuvir ↓0.52 (0.43, 0.62) ↓ 0.52 (0.46, 0.59) Oxcarbazepine (Induction of P-gp and CYPs) Interaction not studied. Expected: ↓ Sofosbuvir ↓ Velpatasvir Co-administration of Epclusa with oxcarbazepine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of Epclusa. Co-administration is not recommended (see section 4.4). 9 Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels. Mean ratio (90% confidence interval)a,b Recommendation concerning co-administration with Epclusa Active Cmax AUC Cmin ANTIFUNGALS Ketoconazole Interaction only studied with velpatasvir Expected: ↔ Sofosbuvir No dose adjustment of Epclusa or ketoconazole is required. Ketoconazole (200 mg twice daily)/ velpatasvir (100 mg single dose)d (Inhibition of P-gp and CYPs) Itraconazolee Voriconazolee Posaconazolee Isavuconazolee Effect on ketoconazole exposure not studied. Expected: ↔ Ketoconazole Observed: Velpatasvir ↑ 1.3 (1.0, 1.6) ↑ 1.7 (1.4, 2.2) ANTIMYCOBACTERIALS Rifampicin (600 mg once daily)/ sofosbuvir (400 mg single dose)d (Induction of P-gp and CYPs) Effect on rifampicin exposure not studied. Expected: ↔ Rifampicin Epclusa is contraindicated with rifampicin (see section 4.3). Observed: Sofosbuvir ↓ 0.23 (0.19, 0.29) ↓ 0.28 (0.24, 0.32) Rifampicin (600 mg once daily)/ velpatasvir (100 mg single dose) (Induction of P-gp and CYPs) Effect on rifampicin exposure not studied. Expected: ↔ Rifampicin Observed: Velpatasvir ↓ 0.29 (0.23, 0.37) ↓ 0.18 (0.15, 0.22) Rifabutin (Induction of P-gp and CYPs) Interaction not studied. Expected: ↓ Velpatasvir Epclusa is contraindicated with rifabutin (see section 4.3). Observed: Sofosbuvir ↓ 0.64 (0.53, 0.77) ↓ 0.76 (0.63, 0.91) 10 Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels. Mean ratio (90% confidence interval)a,b Recommendation concerning co-administration with Epclusa Active Cmax AUC Cmin Rifapentine (Induction of P-gp and CYPs) Interaction not studied. Expected: ↓ Sofosbuvir ↓ Velpatasvir Co-administration of Epclusa with rifapentine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of Epclusa. Co-administration is not recommended (see section 4.4). HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS Tenofovir disoproxil fumarate Epclusa has been shown to increase tenofovir exposure (P-gp-inhibition). The increase in tenofovir exposure (AUC and Cmax) was around 40-80% during co- treatment with Epclusa and tenofovir disoproxil fumarate/emtricitabine as part of various HIV regimens. Patients receiving tenofovir disoproxil fumarate and Epclusa concomitantly should be monitored for adverse reactions associated with tenofovir disoproxil fumarate. Refer to the tenofovir disoproxil fumarate-containing product’s Summary of Product Characteristics for recommendations on renal monitoring (see section 4.4). Efavirenz/ emtricitabine/ tenofovir disoproxil fumarate (600/ 200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Efavirenz ↔ ↔ ↔ Co-administration of Epclusa with efavirenz/ emtricitabine/ tenofovir disoproxil fumarate is expected to decrease the concentration of velpatasvir. Co-administration of Epclusa with efavirenz-containing regimens is not recommended (see section 4.4). Sofosbuvir ↑ 1.4 (1.1, 1.7) ↔ Velpatasvir ↓ 0.53 (0.43, 0.64) ↓ 0.47 (0.39, 0.57) ↓ 0.43 (0.36, 0.52) Emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate (200/ 25/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Rilpivirine ↔ ↔ ↔ No dose adjustment of Epclusa or emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate is required. Sofosbuvir ↔ ↔ Velpatasvir ↔ ↔ ↔ HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS Atazanavir boosted with ritonavir (300/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Atazanavir ↔ ↔ ↑ 1.4 (1.2, 1.6) No dose adjustment of Epclusa, atazanavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required. Ritonavir ↔ ↑ 1.3 (1.5, 1.4) Sofosbuvir ↔ ↔ Velpatasvir ↑ 1.6 (1.4, 1.7) ↑ 2.4 (2.2, 2.6) ↑ 4.0 (3.6, 4.5) Darunavir boosted with ritonavir (800/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Darunavir ↔ ↔ ↔ No dose adjustment of Epclusa, darunavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required. Ritonavir ↔ ↔ ↔ Sofosbuvir ↓ 0.62 (0.54, 0.71) ↓ 0.72 (0.66, 0.80) Velpatasvir ↓ 0.76 (0.65, 0.89) ↔ ↔ 11 Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels. Mean ratio (90% confidence interval)a,b Recommendation concerning co-administration with Epclusa Active Cmax AUC Cmin Lopinavir boosted with ritonavir (4x200 mg/ 50 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Lopinavir ↔ ↔ ↔ No dose adjustment of Epclusa, lopinavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required. Ritonavir ↔ ↔ ↔ Sofosbuvir ↓ 0.59 (0.49 0.71) ↓ 0.7 (0.6, 0.8) Velpatasvir ↓ 0.70 (0.59, 0.83) ↔ ↑ 1.6 (1.4, 1.9) HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS Raltegravir (400 mg twice daily)g + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Raltegravir ↔ ↔ ↓ 0.79 (0.42, 1.5) No dose adjustment of Epclusa, raltegravir or emtricitabine/ tenofovir disoproxil fumarate is required. Sofosbuvir ↔ ↔ Velpatasvir ↔ ↔ ↔ Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide fumarate (150/ 150/ 200/ 10 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Elvitegravir ↔ ↔ ↔ No dose adjustment of Epclusa or elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide fumarate is required. Cobicistat ↔ ↔ ↑ 2.0 (1.7, 2.5) Tenofovir alafenamide ↔ ↔ Sofosbuvir ↔ ↑ 1.4 (1.2, 1.5) Velpatasvir ↑ 1.3 (1.2, 1.5) ↑ 1.5 (1.4, 1.7) ↑ 1.6 (1.4, 1.8) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate (150/ 150/ 200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Elvitegravir ↔ ↔ ↔ No dose adjustment of Epclusa or elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate is required. Cobicistat ↔ ↔ ↑ 1.7 (1.5, 1.9) Sofosbuvir ↔ ↔ Velpatasvir ↔ ↔ ↑ 1.4 (1.2, 1.5) Dolutegravir (50 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily) Dolutegravir ↔ ↔ ↔ No dose adjustment of Epclusa or dolutegravir is required. Sofosbuvir ↔ ↔ Velpatasvir ↔ ↔ ↔ HERBAL SUPPLEMENTS St. John’s wort (Induction of P-gp and CYPs) Interaction not studied. Expected: ↓ Sofosbuvir ↓ Velpatasvir Epclusa is contraindicated with St. John’s wort (see section 4.3). 12 Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels. Mean ratio (90% confidence interval)a,b Recommendation concerning co-administration with Epclusa Active Cmax AUC Cmin HMG-CoA REDUCTASE INHIBITORS Atorvastatin (40 mg single dose) + sofosbuvir / velpatasvir (400/ 100 mg once daily)d Observed: Atorvastatin ↑ 1.7 (1.5, 1.9) ↑ 1.5 (1.5, 1.6) No dose adjustment of Epclusa or atorvastatin is required. Rosuvastatin Interaction only studied with velpatasvir Expected: ↔ Sofosbuvir Co-administration of Epclusa with rosuvastatin increases the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Rosuvastatin, at a dose that does not exceed 10 mg, may be administered with Epclusa. Rosuvastatin (10 mg single dose)/ velpatasvir (100 mg once daily)d (Inhibition of OATP1B and BCRP) Observed: Rosuvastatin ↑ 2.6 (2.3, 2.9) ↑ 2.7 (2.5, 2.9) Effect on velpatasvir exposure not studied Expected: ↔ Velpatasvir Pravastatin Interaction only studied with velpatasvir Expected: ↔ Sofosbuvir No dose adjustment of Epclusa or pravastatin is required. Pravastatin (40 mg single dose)/ velpatasvir (100 mg once daily)d (Inhibition of OATP1B) Observed: Pravastatin ↑ 1.3 (1.1, 1.5) ↑ 1.4 (1.2, 1.5) Effect on velpatasvir exposure not studied Expected: ↔ Velpatasvir Other statins Expected: ↑ Statins Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When co-administered with Epclusa, careful monitoring for statin adverse reactions should be undertaken and a reduced dose of statins should be considered if required. NARCOTIC ANALGESICS Methadone (Methadone maintenance therapy [30 to 130 mg daily])/ sofosbuvir (400 mg once daily)d R-methadone ↔ ↔ ↔ No dose adjustment of Epclusa or methadone is required. S-methadone ↔ ↔ ↔ Sofosbuvir ↔ ↑ 1.3 (1.0, 1.7) Methadone Interaction only studied with sofosbuvir Expected: ↔ Velpatasvir 13 Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels. Mean ratio (90% confidence interval)a,b Recommendation concerning co-administration with Epclusa Active Cmax AUC Cmin IMMUNOSUPPRESSANTS Ciclosporin (600 mg single dose)/ sofosbuvir (400 mg single dose)f Ciclosporin ↔ ↔ No dose adjustment of Epclusa or ciclosporin is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required. Sofosbuvir ↑ 2.5 (1.9, 3.5) ↑ 4.5 (3.3, 6.3) Ciclosporin (600 mg single dose)f/ velpatasvir (100 mg single dose)d Ciclosporin ↔ ↓ 0.88 (0.78, 1.0) Velpatasvir ↑ 1.6 (1.2, 2.0) ↑ 2.0 (1.5, 2.7) Tacrolimus (5 mg single dose)f/ sofosbuvir (400 mg single dose)d Tacrolimus ↓ 0.73 (0.59, 0.90) ↑ 1.1 (0.84, 1.4) No dose adjustment of Epclusa or tacrolimus is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required. Sofosbuvir ↓ 0.97 (0.65, 1.4) ↑ 1.1 (0.81, 1.6) Tacrolimus Effect on velpatasvir exposure not studied. Expected: ↔ Velpatasvir ORAL CONTRACEPTIVES Norgestimate/ ethinyl estradiol (norgestimate 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ sofosbuvir (400 mg once daily)d Norel- gestromin ↔ ↔ ↔ No dose adjustment of oral contraceptives is required. Norgestrel ↔ ↑ 1.2 (0.98, 1.5) ↑ 1.2 (1.0, 1.5) Ethinyl estradiol ↔ ↔ ↔ Norgestimate/ ethinyl estradiol (norgestimate 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ velpatasvir (100 mg once daily)d Norel- gestromin ↔ ↔ ↔ Norgestrel ↔ ↔ ↔ Ethinyl estradiol ↑ 1.4 (1.2, 1.7) ↔ ↓ 0.83 (0.65, 1.1) a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. No effect = 1.00. b All interaction studies conducted in healthy volunteers. c Administered as Epclusa. d Lack of pharmacokinetics interaction bounds 70-143%. e These are medicinal products within class where similar interactions could be predicted. f Bioequivalence/Equivalence boundary 80-125%. g Lack of pharmacokinetics interaction bounds 50-200%. 14 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir, velpatasvir or Epclusa in pregnant women. Sofosbuvir Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). It has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3). Velpatasvir Animal studies have shown a possible link to reproductive toxicity (see section 5.3). As a precautionary measure, Epclusa use is not recommended during pregnancy. Breast-feeding It is unknown whether sofosbuvir, metabolites of sofosbuvir or velpatasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites of sofosbuvir in milk. A risk to the newborns/infants cannot be excluded. Therefore, Epclusa should not be used during breast-feeding. Fertility No human data on the effect of Epclusa on fertility are available. Animal studies do not indicate harmful effects of sofosbuvir or velpatasvir on fertility. If ribavirin is co-administered with Epclusa, refer to the Summary of Product Characterisitics for ribavirin for detailed recommendations regarding pregnancy, contraception, and breast-feeding. 4.7 Effects on ability to drive and use machines Epclusa has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile In pooled Phase 3 clinical studies of patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection the proportion of patients who permanently discontinued treatment due to adverse events was 0.2% and the proportion of patients who experienced any severe adverse events was 3.2% for patients receiving Epclusa for 12 weeks. In clinical studies, headache, fatigue and nausea were the most common (incidence ≥ 10%) treatment emergent adverse events reported in patients treated with 12 weeks of Epclusa. These and other adverse events were reported at a similar frequency in placebo treated patients compared with Epclusa treated patients in the Phase 3 pivotal clinical studies. 15 Tabulated summary of adverse reactions Assessment of adverse reactions for Epclusa is based on safety data from clinical studies and postmarketing experience. All adverse reactions are presented in Table 4. The adverse reactions are listed below by system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000) or very rare (< 1/10,000). Table 4: Adverse drug reactions identified with Epclusa Frequency Adverse drug reaction Skin and subcutaneous tissue disorders: Common rasha Uncommon angioedemaa a. Adverse reaction identified through post-marketing surveillance for sofosbuvir/velpatasvir-containing products Patients with decompensated cirrhosis The safety profile of Epclusa has been evaluated in one open-label study in which patients with CPT Class B cirrhosis received Epclusa for 12 weeks (n = 90), Epclusa + RBV for 12 weeks (n = 87) or Epclusa for 24 weeks (n = 90). The adverse events observed were consistent with expected clinical sequelae of decompensated liver disease, or the known toxicity profile of ribavirin for patients receiving Epclusa in combination with ribavirin. Among the 87 patients who were treated with Epclusa + RBV for 12 weeks, decreases in haemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were experienced by 23% and 7% patients, respectively. Ribavirin was discontinued in 15% of patients treated with Epclusa + RBV for 12 weeks due to adverse events. Patients with renal impairment The safety of Epclusa has been evaluated in a 12-week non-controlled study including 59 subjects with ESRD requiring dialysis (Study 4062). In this setting, exposure of sofosbuvir metabolite GS- 331007 was 20-fold increased, exceeding levels where adverse reactions have been observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not clearly elevated from what is expected in ESRD patients. Description of selected adverse reactions Cardiac arrhythmias Cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens are used in combination with amiodarone and/or other medicinal products that lower heart rate (see sections 4.4 and 4.5). Skin disorders Frequency not known: Stevens-Johnson syndrome Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The highest documented doses of sofosbuvir and velpatasvir were a single dose of 1,200 mg and a single dose of 500 mg, respectively. In these healthy volunteer studies, there were no untoward effects observed at these dose levels, and adverse events were similar in frequency and severity to those reported in the placebo groups. The effects of higher doses/exposures are not known. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 16 No specific antidote is available for overdose with Epclusa. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Epclusa consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient. Haemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Haemodialysis is unlikely to result in significant removal of velpatasvir, since velpatasvir is highly bound to plasma protein. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Direct acting antiviral, ATC code: J05AP55 Mechanism of action Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. Velpatasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. In vitro resistance selection and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action. Antiviral activity The 50% effective concentration (EC50) values of sofosbuvir and velpatasvir against full-length or chimeric replicons encoding NS5B and NS5A sequences from the laboratory strains are presented in Table 5. The EC50 values of sofosbuvir and velpatasvir against clinical isolates are presented in Table 6. Table 5: Activity of sofosbuvir and velpatasvir against full-length or chimeric laboratory replicons Replicon genotype Sofosbuvir EC50, nMa Velpatasvir EC50, nMa 1a 40 0.014 1b 110 0.016 2a 50 0.005-0.016c 2b 15b 0.002-0.006c 3a 50 0.004 4a 40 0.009 4d NA 0.004 5a 15b 0.021-0.054d 6a 14b 0.006-0.009 6e NA 0.130d NA = Not available a Mean value from multiple experiments of same laboratory replicon. b Stable chimeric 1b replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing. c Data from various strains of full length NS5A replicons or chimeric NS5A replicons carrying full-length NS5A genes that contain L31 or M31 polymorphisms. d Data from a chimeric NS5A replicon carrying NS5A amino acids 9-184. 17 Table 6: Activity of sofosbuvir and velpatasvir against transient replicons containing NS5A or NS5B from clinical isolates Replicon genotype Replicons containing NS5B from clinical isolates Replicons containing NS5A from clinical isolates Number of clinical isolates Median sofosbuvir EC50, nM (range) Number of clinical isolates Median velpatasvir EC50, nM (range) 1a 67 62 (29-128) 23 0.019 (0.011-0.078) 1b 29 102 (45-170) 34 0.012 (0.005-0.500) 2a 15 29 (14-81) 8 0.011 (0.006-0.364) 2b NA NA 16 0.002 (0.0003-0.007) 3a 106 81 (24-181) 38 0.005 (0.002-1.871) 4a NA NA 5 0.002 (0.001-0.004) 4d NA NA 10 0.007 (0.004-0.011) 4r NA NA 7 0.003 (0.002-0.006) 5a NA NA 42 0.005 (0.001-0.019) 6a NA NA 26 0.007 (0.0005-0.113) 6e NA NA 15 0.024 (0.005-0.433)) NA = Not available The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir but reduced the anti-HCV activity of velpatasvir by 13-fold against genotype 1a HCV replicons. Evaluation of sofosbuvir in combination with velpatasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Resistance In cell culture HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, the ability of the active triphosphate of sofosbuvir (GS-461203) to inhibit recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution was reduced compared to its ability to inhibit wild-type recombinant NS5B polymerase, as indicated by a 8.5- to 24-fold increase in the 50% inhibitory concentration (IC50). In vitro selection of HCV replicons with reduced susceptibility to velpatasvir was performed in cell culture for multiple genotypes including 1a, 1b, 2a, 3a, 4a, 5a and 6a. Variants were selected at NS5A resistance associated positions 24, 28, 30, 31, 32, 58, 92 and 93. The resistance associated variants (RAVs) selected in 2 or more genotypes were F28S, L31I/V and Y93H. Site-directed mutagenesis of known NS5A RAVs showed that substitutions conferring a > 100-fold reduction in velpatasvir susceptibility are M28G, A92K and Y93H/N/R/W in genotype 1a, A92K in genotype 1b, C92T and Y93H/N in genotype 2b, Y93H in genotype 3, and L31V and P32A/L/Q/R in genotype 6. No individual substitutions tested in genotypes 2a, 4a, or 5a conferred a > 100-fold reduction in velpatasvir susceptibility. Combinations of these variants often showed greater reductions in susceptibility to velpatasvir than single RAVs alone. In clinical studies Studies in patients without cirrhosis and patients with compensated cirrhosis In a pooled analysis of patients without cirrhosis or with compensated cirrhosis who received Epclusa for 12 weeks in three Phase 3 studies, 12 patients (2 with genotype 1 and 10 with genotype 3) qualified for resistance analysis due to virologic failure. One additional patient with genotype 3 HCV infection at baseline was reinfected with genotype 1a HCV at virologic failure and was excluded from the virological analysis. No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologic failure. 18 Of the 2 genotype 1 virologic failure patients, one patient had virus with emergent NS5A RAV Y93N and the other patient had virus with emergent NS5A RAVs L31I/V and Y93H at virologic failure. Both patients had virus at baseline harboring NS5A RAVs. No NS5B nucleoside inhibitor (NI) RAVs were observed at failure in the 2 patients. Of the 10 genotype 3 virologic failure patients, Y93H was observed in all 10 patients at failure (6 had Y93H emerge post-treatment and 4 patients had Y93H at baseline and post-treatment). No NS5B NI RAVs were observed at failure in the 10 patients. Studies in patients with decompensated cirrhosis In one Phase 3 study in patients with decompensated cirrhosis who received Epclusa + RBV for 12 weeks, 3 patients (1 with genotype 1 and 2 with genotype 3) qualified for resistance analysis due to virologic failure. No patients with genotype 2 or 4 HCV infection in the Epclusa + RBV 12 weeks group experienced virologic failure. The 1 virologic failure patient with genotype 1 HCV had no NS5A or NS5B RAVs at failure. Of the 2 genotype 3 virologic failure patients, one had NS5A RAV Y93H emerge at failure. Another patient had virus with Y93H at baseline and virologic failure and also developed low levels (< 5%) of NS5B NI RAVs N142T and E237G at failure. Pharmacokinetic data from this patient was consistent with non-adherence to treatment. In this study, 2 patients treated with Epclusa for 12 or 24 weeks without ribavirin had emergent NS5B S282T at low levels (< 5%) along with L159F. Effect of baseline HCV resistance-associated variants on treatment outcome Studies in patients without cirrhosis and patients with compensated cirrhosis Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients without cirrhosis or with compensated cirrhosis in three Phase 3 clinical studies (ASTRAL-1, ASTRAL-2 and ASTRAL-3). Of the 1,035 patients treated with sofosbuvir/velpatasvir in the three Phase 3 clinical studies, 1,023 patients were included in the analysis of NS5A RAVs; 7 patients were excluded as they neither achieved sustained virologic response (SVR12) nor had virologic failure and 5 additional patients were excluded as NS5A gene sequencing failed. In the pooled analysis of the Phase 3 studies, 380/1,023 (37%) patients’ virus had baseline NS5A RAVs. Genotype 2, 4, and 6 HCV-infected patients had a higher prevalence of NS5A RAVs (70%, 63% and 52%, respectively) compared to genotype 1 (23%), genotype 3 (16%), and genotype 5 (18%) HCV-infected patients. Baseline RAVs had no relevant impact on SVR12 rates in patients infected with genotype 1, 2, 4, 5 and 6 HCV, as summarised in Table 7. Genotype 3 infected patients with the NS5A RAV Y93H at baseline had a lower SVR12 rate than patients without Y93H after treatment with Epclusa for 12 weeks, as summarised in Table 8. In the ASTRAL-3 study, the Y93H RAV was detected at baseline in 9% of patients treated with Epclusa. Table 7: SVR12 in patients with or without baseline NS5A RAVs by HCV genotype (studies ASTRAL-1, ASTRAL-2 and ASTRAL-3) Epclusa 12 weeks Genotype 1 Genotype 3 Genotypes 2, 4, 5 or 6 Total With any baseline NS5A RAVs 97% (73/75) 88% (38/43) 100% (262/262) 98% (373/380) Without baseline NS5A RAVs 100% (251/251) 97% (225/231) 100% (161/161) 99% (637/643) 19 Table 8: SVR12 in patients with and without baseline Y93H, 1% Cut-off (Resistance Analysis Population Set) ASTRAL 3 Epclusa 12 Weeks All Subjects (n = 274) Cirrhotic (n = 80) Non-Cirrhotic (n = 197) Overall 95.3% (263/274) 91.3% (73/80) 97.9% (190/194) 95% CI 92.9% to 98.0% 82.8% to 96.4% 92.8% to 98.6% SVR with Y93H 84.0% (21/25) 50.0% (2/4) 90.5% (19/21) 95% CI 63.9% to 95.5% 6.8% to 93.2% 69.6% to 98.8% SVR without Y93H 96.4% (242/249) 93.4% (71/76) 98.8% (171/173) 95% CI 94.3% to 98.9% 85.3% to 97.8% 95.9% to 99.9% The NS5B NI RAV S282T was not detected in the baseline NS5B sequence of any patient in Phase 3 studies. SVR12 was achieved in all 77 patients who had baseline NS5B NI RAVs including N142T, L159F, E/N237G, C/M289L/I, L320F/I/V, V321A/I, and S282G+V321I. Studies in patients with decompensated cirrhosis (CPT Class B) Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients with decompensated cirrhosis in one Phase 3 study (ASTRAL-4). Of the 87 patients treated with Epclusa + RBV, 85 patients were included in the analysis of NS5A RAVs; 2 patients were excluded as they neither achieved SVR12 nor had virologic failure. Among the patients who received treatment with Epclusa + RBV for 12 weeks, 29% (25/85) of patients had baseline virus with NS5A RAVs: 29% (19/66), 75% (3/4), 15% (2/13), and 50% (1/2) for patients with genotype 1, 2, 3 and 4 HCV, respectively. SVR12 in patients with or without baseline NS5A RAVs in the Epclusa + RBV 12 week group for this study is shown in Table 9. Table 9: SVR12 in patients with or without baseline NS5A RAVs by HCV genotype (study ASTRAL-4) Epclusa + RBV 12 weeks Genotype 1 Genotype 3 Genotypes 2 or 4 Total With any baseline NS5A RAVs 100% (19/19) 50% (1/2) 100% (4/4) 96% (24/25) Without baseline NS5A RAVs 98% (46/47) 91% (10/11) 100% (2/2) 98% (58/60) The single genotype 3 patient who had baseline NS5A RAVs and failed to achieve SVR12 had NS5A substitution Y93H at baseline; pharmacokinetic data from this patient was consistent with non-adherence to treatment. Three patients in the Epclusa + RBV 12 week group had baseline NS5B NI RAVs (N142T and L159F) and all three patients achieved SVR12. Cross-resistance In vitro data suggests that the majority of NS5A RAVs that confer resistance to ledipasvir and daclatasvir remained susceptible to velpatasvir. Velpatasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B while all velpatasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and velpatasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The efficacy of Epclusa has not been assessed in patients who have previously failed treatment with other regimens that include an NS5A inhibitor. 20 Clinical efficacy and safety The efficacy of Epclusa was evaluated in three Phase 3 studies in patients with genotype 1 to 6 HCV infection with or without compensated cirrhosis, one Phase 3 study in patients with genotype 1 to 6 HCV infection with decompensated cirrhosis, one Phase 3 study in HCV/HIV-1 co-infected patients with genotype 1 to 6 HCV infection and one Phase 2 trial in patients with HCV infection and ESRD requiring dialysis, as summarised in Table 10. Table 10: Studies conducted with Epclusa in patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection Study Population Study arms (Number of patients treated) ASTRAL-1 Genotype 1, 2, 4, 5 and 6 TN and TE, without cirrhosis or with compensated cirrhosis Epclusa 12 weeks (624) Placebo 12 weeks (116) ASTRAL-2 Genotype 2 TN and TE, without cirrhosis or with compensated cirrhosis Epclusa 12 weeks (134) SOF+RBV 12 weeks (132) ASTRAL-3 Genotype 3 TN and TE, without cirrhosis or with compensated cirrhosis Epclusa 12 weeks (277) SOF+RBV 24 weeks (275) ASTRAL-4 Genotype 1, 2, 3, 4, 5 and 6 TN and TE, with CPT Class B decompensated cirrhosis Epclusa 12 weeks (90) Epclusa + RBV 12 weeks (87) Epclusa 24 weeks (90) ASTRAL-5 Genotype 1, 2, 3, 4, 5 and 6 TN and TE, without cirrhosis or with compensated cirrhosis, with HCV/HIV-1 co-infection Epclusa 12 weeks (106) GS-US-342-4062 TN and TE with or without cirrhosis, with ESRD requiring dialysis Epclusa 12 weeks (59) TN = treatment-naïve patients; TE = treatment-experienced patients (including those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor) The ribavirin dose was weight-based (1,000 mg daily administered in two divided doses for patients < 75 kg and 1,200 mg for those ≥ 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 studies or in combination with Epclusa in the ASTRAL-4 study. Ribavirin dose adjustments were performed according to the ribavirin prescribing information. Serum HCV RNA values were measured during the clinical studies using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint to determine the HCV cure rate. Clinical studies in patients without cirrhosis and patients with compensated cirrhosis Genotype 1, 2, 4, 5 and 6 HCV-infected adults – ASTRAL-1 (study 1138) ASTRAL-1 was a randomised, double-blind, placebo-controlled study that evaluated 12 weeks of treatment with Epclusa compared with 12 weeks of placebo in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Patients with genotype 1, 2, 4 or 6 HCV infection were randomised in a 5:1 ratio to treatment with Epclusa for 12 weeks or placebo for 12 weeks. Patients with genotype 5 HCV infection were enrolled to the Epclusa group. Randomisation was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of cirrhosis. Demographics and baseline characteristics were balanced between the Epclusa and placebo group. Of the 740 treated patients, the median age was 56 years (range: 18 to 82); 60% of the patients were male; 79% were White, 9% were Black; 21% had a baseline body mass index of at least 30 kg/m2; the proportions of patients with genotype 1, 2, 4, 5, or 6 HCV infection were 53%, 17%, 19%, 5% and 7%, respectively; 69% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment-experienced. 21 Table 11 presents the SVR12 for the ASTRAL-1 study by HCV genotypes. No patients in the placebo group achieved SVR12. Table 11: SVR12 in study ASTRAL-1 by HCV genotype Epclusa 12 weeks (n = 624) Total (all GTs) (n = 624) GT-1 GT-2 (n = 104) GT-4 (n = 116) GT-5 (n = 35) GT-6 (n = 41) GT-1a (n = 210) GT-1b (n = 118) Total (n = 328) SVR12 99% (618/624) 98% (206/210) 99% (117/118) 98% (323/328) 100% (104/104) 100% (116/116) 97% (34/35) 100% (41/41) Outcome for patients without SVR12 On- treatment virologic failure 0/624 0/210 0/118 0/328 0/104 0/116 0/35 0/41 Relapsea < 1% (2/623) < 1% (1/209) 1% (1/118) 1% (2/327) 0/104 0/116 0/35 0/41 Otherb 1% (4/624) 1% (3/210) 0/118 1% (3/328) 0/104 0/116 3% (1/35) 0/41 GT = genotype a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria. Genotype 2 HCV-infected adults – ASTRAL-2 (study 1139) ASTRAL-2 was a randomised, open-label study that evaluated 12 weeks of treatment with Epclusa compared with 12 weeks of treatment with SOF+RBV in patients with genotype 2 HCV infection. Patients were randomised in a 1:1 ratio to treatment with Epclusa for 12 weeks or SOF+RBV for 12 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve versus treatment-experienced). Demographics and baseline characteristics were balanced across the two treatment groups. Of the 266 treated patients, the median age was 58 years (range: 23 to 81); 59% of the patients were male; 88% were White, 7% were Black; 33% had a baseline body mass index of at least 30 kg/m2; 62% had non-CC IL28B alleles (CT or TT); 80% had baseline HCV RNA levels of at least 800,000 IU/mL; 14% had compensated cirrhosis and 15% were treatment-experienced. Table 12 presents the SVR12 for the ASTRAL-2 study. Table 12: SVR12 in study ASTRAL-2 (HCV genotype 2) Epclusa 12 weeks (n = 134) SOF+RBV 12 weeks (n = 132) SVR12 99% (133/134) 94% (124/132) Outcome for patients without SVR12 On-treatment virologic failure 0/134 0/132 Relapsea 0/133 5% (6/132) Otherb 1% (1/134) 2% (2/132) a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria. Treatment with Epclusa for 12 weeks demonstrated the statistical superiority (p = 0.018) over treatment with SOF+RBV for 12 weeks (treatment difference +5.2%; 95% confidence interval: +0.2% to +10.3%). Genotype 3 HCV-infected adults – ASTRAL-3 (study 1140) ASTRAL-3 was a randomised, open-label study that evaluated 12 weeks of treatment with Epclusa compared with 24 weeks of treatment with SOF+RBV in patients with genotype 3 HCV infection. 22 Patients were randomised in a 1:1 ratio to treatment with Epclusa for 12 weeks or SOF+RBV for 24 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve versus treatment-experienced). Demographics and baseline characteristics were balanced across the two treatment groups. Of the 552 treated patients, the median age was 52 years (range: 19 to 76); 62% of the patients were male; 89% were White, 9% were Asian; 1% were Black; 20% had a baseline body mass index of at least 30 kg/m2; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels of at least 800,000 IU/mL, 30% had compensated cirrhosis and 26% were treatment-experienced. Table 13 presents the SVR12 for the ASTRAL-3 study. Table 13: SVR12 in study ASTRAL-3 (HCV genotype 3) Epclusa 12 weeks (n = 277) SOF+RBV 24 weeks (n = 275) SVR12 95% (264/277) 80% (221/275) Outcome for patients without SVR12 On-treatment virologic failure 0/277 < 1% (1/275) Relapsea 4% (11/276) 14% (38/272) Otherb 1% (2/277) 5% (15/275) a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria. Treatment with Epclusa for 12 weeks demonstrated the statistical superiority (p < 0.001) compared to treatment with SOF+RBV for 24 weeks (treatment difference +14.8%; 95% confidence interval: +9.6% to +20.0%). SVR12 for selected subgroups are presented in Table 14. Table 14: SVR12 for selected subgroups in study ASTRAL-3 (HCV genotype 3) Epclusa 12 weeks SOF+RBV 24 weeksa SVR12 Treatment-naïve (n = 206) Treatment- experienced (n = 71) Treatment-naïve (n = 201) Treatment- experienced (n = 69) Without cirrhosis 98% (160/163) 91% (31/34) 90% (141/156) 71% (22/31) With cirrhosis 93% (40/43) 89% (33/37) 73% (33/45) 58% (22/38) a Five patients with missing cirrhosis status in the SOF+RBV 24 week group were excluded from this subgroup analysis. Clinical studies in patients with decompensated cirrhosis – ASTRAL-4 (study 1137) ASTRAL-4 was a randomised, open-label study in patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection and CPT Class B cirrhosis. Patients were randomised in a 1:1:1 ratio to treatment with Epclusa for 12 weeks, Epclusa + RBV for 12 weeks or Epclusa for 24 weeks. Randomisation was stratified by HCV genotype (1, 2, 3, 4, 5, 6 and indeterminate). Demographics and baseline characteristics were balanced across the treatment groups. Of the 267 treated patients, the median age was 59 years (range: 40 to 73); 70% of the patients were male; 90% were White, 6% were Black; 42% had a baseline body mass index of at least 30 kg/m2. The proportions of patients with genotype 1, 2, 3, 4 or 6 HCV were 78%, 4%, 15%, 3%, and < 1% (1 patient), respectively. No patients with genotype 5 HCV infection were enrolled. 76% of the patients had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels of at least 800,000 IU/mL, 55% were treatment-experienced; 90% and 95% of patients had CPT Class B cirrhosis and Model for End Stage Liver Disease (MELD) score ≤ 15 at baseline, respectively. Table 15 presents the SVR12 for the ASTRAL-4 study by HCV genotype. 23 Table 15: SVR12 in study ASTRAL-4 by HCV genotype Epclusa 12 weeks (n = 90) Epclusa + RBV 12 weeks (n = 87) Epclusa 24 weeks (n = 90) Overall SVR12 83% (75/90) 94% (82/87) 86% (77/90) Genotype 1 88% (60/68) 96% (65/68) 92% (65/71) Genotype 1a 88% (44/50) 94% (51/54) 93% (51/55) Genotype 1b 89% (16/18) 100% (14/14) 88% (14/16) Genotype 3 50% (7/14) 85% (11/13) 50% (6/12) Genotype 2, 4 and 6 100% (8/8)a 100% (6/6)b 86% (6/7)c a n = 4 for genotype 2 and n = 4 for genotype 4. b n = 4 for genotype 2 and n = 2 for genotype 4. c n = 4 for genotype 2, n = 2 for genotype 4 and n = 1 for genotype 6. Table 16 presents the virologic outcome for patients with genotype 1 or 3 HCV infection in the ASTRAL-4 study. No patients with genotype 2, 4 or 6 HCV infection experienced virologic failure. Table 16: Virologic outcome for patients with genotype 1 and 3 HCV infection in study ASTRAL-4 Epclusa 12 weeks Epclusa + RBV 12 weeks Epclusa 24 weeks Virologic failure (relapse and on-treatment failure) Genotype 1a 7% (5/68) 1% (1/68) 4% (3/71) Genotype 1a 6% (3/50) 2% (1/54) 4% (2/55) Genotype 1b 11% (2/18) 0% (0/14) 6% (1/16) Genotype 3 43% (6/14) 15% (2b/13) 42% (5c/12) Otherd 5% (4/82) 2% (2/81) 5% (4/83) a No patients with genotype 1 HCV had on-treatment virologic failure. b One patient had on-treatment virologic failure; pharmacokinetic data from this patient was consistent with non-adherence to treatment. c One patient had on-treatment virologic failure. d Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria. Changes in the parameters found in the CPT score system in patients achieving SVR12 in ASTRAL-4 (all 3 regimens) are shown in Table 17. Table 17: Changes in CPT score parameters from baseline to week 12 and 24 post-treatment in patients achieving SVR12, ASTRAL-4 Albumin Bilirubin INR Ascites Encephalopathy Post-treatment Week 12 (N = 236), % (n/N) Decreased score (Improvement) 34.5% (79/229) 17.9% (41/229) 2.2% (5/229) 7.9% (18/229) 5.2% (12/229) No change 60.3% (138/229) 76.4% (175/229) 96.5% (221/229) 89.1% (204/229) 91.3% (209/229) Increased score (Worsening) 5.2% (12/229) 5.7% (13/229) 1.3% (3/229) 3.1% (7/229) 3.5% (8/229) No assessment 7 7 7 7 7 Post-treatment Week 24 (N = 236), % (n/N) Decreased score (Improvement) 39.4% (84/213) 16.4% (35/213) 2.3% (5/213) 15.0% (32/213) 9.4% (20/213) No change 54.0% (115/213) 80.8% (172/213) 94.8% (202/213) 81.2% (173/213) 88.3% (188/213) Increased score (Worsening) 6.6% (14/213) 2.8% (6/213) 2.8% (6/213) 3.8% (8/213) 2.3% (5/213) No assessment 23 23 23 23 23 Note: Baseline frequency of ascites was: 20% none, 77% mild/moderate, 3% severe Baseline frequency of encephalopathy was: 38% none, 62% grade 1-2. 24 Clinical studies in patients with HCV/HIV-1 Co-infection – ASTRAL-5 (study 1202) ASTRAL-5 evaluated 12 weeks of treatment with Epclusa in patients with genotype 1, 2, 3, or 4 HCV infection who were co-infected with HIV-1 (HCV genotype 5 and 6 allowed, but no such patients were included). Patients were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with a ritonavir boosted protease inhibitor (atazanavir, darunavir, or lopinavir), rilpivirine, raltegravir or emtricitabine/tenofovir disoproxil fumarate /elvitegravir/cobicistat. Of the 106 treated patients, the median age was 57 years (range: 25 to 72); 86% of the patients were male; 51% were white; 45% were black; 22% had a baseline body mass index ≥ 30 kg/m2; 19 patients (18%) had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+ count was 598 cells/µL (range: 183−1513 cells/µL). Table 18 presents the SVR12 for the ASTRAL-5 study by HCV genotype. Table 18: SVR12 in study ASTRAL-5 by HCV genotype Epclusa 12 weeks (n = 106) Total (all GTs) (n = 106) GT-1 GT-2 (n = 11) GT-3 (n = 12) GT-4 (n = 5) GT-1a (n = 66) GT-1b (n = 12) Total (n = 78) SVR12 95% (101/106) 95% (63/66) 92% (11/12) 95% (74/78) 100% (11/11) 92% (11/12) 100% (5/5) Outcome for patients without SVR On- treatment virologic failure 0/106 0/66 0/12 0/78 0/11 0/12 0/5 Relapsea 2% (2/103) 3% (2/65) 0/11 3% (2/76) 0/11 0/11 0/5 Otherb 3% (3/106) 2% (1/66) 8% (1/12) 3% (2/78) 0/11 8% (1/12) 0/5 GT = genotype a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria. SVR12 was achieved by 19/19 patients with cirrhosis. No patient had HIV-1 rebound during the study, and CD4+ counts were stable during treatment. Clinical studies in patients with Renal Impairment – study 4062 Study 4062 was an open-label clinical trial that evaluated 12 weeks of treatment with Epclusa in 59 HCV-infected patients with ESRD requiring dialysis. The proportions of patients with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%, 12%, 27%, 7% , 3%, and 9%, respectively. At baseline, 29% of patients had cirrhosis, 22% were treatment experienced, 32% had received a kidney transplant, 92% were on haemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7.3 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59); of the three patients that did not achieve SVR12, one had completed Epclusa treatment and relapsed and two did not meet virologic failure criteria. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Epclusa in one or more subsets of the paediatric population in the treatment of chronic hepatitis C (see section 4.2 for information on paediatric use). Elderly Clinical studies of Epclusa included 156 patients aged 65 and over (12% of total number of patients in the Phase 3 clinical studies). The response rates observed for patients ≥ 65 years of age were similar to that of patients < 65 years of age, across treatment groups. 25 5.2 Pharmacokinetic properties Absorption The pharmacokinetic properties of sofosbuvir, GS-331007 and velpatasvir have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oral administration of Epclusa, sofosbuvir was absorbed quickly and the peak median plasma concentration was observed 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed 3 hours post-dose. Velpatasvir median peak concentrations were observed at 3 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected patients, mean steady-state AUC0-24 for sofosbuvir (n = 982), GS-331007 (n = 1,428) and velpatasvir (n = 1,425) were 1,260, 13,970 and 2,970 ng•h/mL, respectively. Steady-state Cmax for sofosbuvir, GS-331007 and velpatasvir were 566, 868 and 259 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects (n = 331), velpatasvir AUC0-24 and Cmax were 37% lower and 41% lower, respectively in HCV-infected patients. Effects of food Relative to fasting conditions, the administration of a single dose of Epclusa with a moderate fat (~600 kcal, 30% fat) or high fat (~800 kcal, 50% fat) meal resulted in a 34% and 21% increase in velpatasvir AUC0-inf, respectively, and a 31% and 5% increase in velpatasvir Cmax, respectively. The moderate or high fat meal increased sofosbuvir AUC0-inf by 60% and 78%, respectively, but did not substantially affect the sofosbuvir Cmax. The moderate or high fat meal did not alter GS-331007 AUC0-inf, but resulted in a 25% and 37% decrease in its Cmax, respectively. The response rates in Phase 3 studies were similar in HCV-infected patients who received Epclusa with food or without food. Epclusa can be administered without regard to food. Distribution Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity was approximately 0.7. Velpatasvir is > 99.5% bound to human plasma proteins and binding is independent of drug concentration over the range of 0.09 µg/mL to 1.8 µg/mL. After a single 100 mg dose of [14C]-velpatasvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.52 and 0.67. Biotransformation Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately > 90% of total systemic exposure. Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover. Following a single dose of 100 mg [14C]-velpatasvir, the majority (> 98%) of radioactivity in plasma was parent drug. The monohydroxylated and desmethylated velpatasvir were the metabolites identified in human plasma. Unchanged velpatasvir is the major species present in faeces. 26 Elimination Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the [14C]-radioactivity was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of Epclusa were 0.5 and 25 hours, respectively. Following a single 100 mg oral dose of [14C]-velpatasvir, mean total recovery of the [14C]-radioactivity was 95%, consisting of approximately 94% and 0.4% recovered from the faeces and urine, respectively. Unchanged velpatasvir was the major species in faeces accounting for a mean of 77% of the administered dose, followed by monohydroxylated velpatasvir (5.9%) and desmethylated velpatasvir (3.0%). These data indicate that biliary excretion of parent drug was a major route of elimination for velpatasvir. The median terminal half-life of velpatasvir following administration of Epclusa was approximately 15 hours. Linearity/non-linearity Velpatasvir AUC increases in a nearly dose proportional manner over the dose range of 25 mg to 150 mg. Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1,200 mg. In vitro potential for sofosbuvir/velpatasvir drug-drug interactions Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Velpatasvir is also a substrate of OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1 and OATP1B3 and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant plasma concentration, velpatasvir is not an inhibitor of hepatic transporters bile salt export pump (BSEP), sodium taurocholate cotransporter protein (NTCP), OATP2B1, OATP1A2 or organic cation transporter (OCT) 1, renal transporters OCT2, OAT1, OAT3, multidrug resistance-associated protein 2 (MRP2) or multidrug and toxin extrusion protein (MATE) 1, or CYP or uridine glucuronosyltransferase (UGT) 1A1 enzymes. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1. Pharmacokinetics in special populations Race and gender No clinically relevant pharmacokinetic differences due to race or gender have been identified for sofosbuvir, GS-331007 or velpatasvir. Elderly Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 82 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, or velpatasvir. Renal impairment A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the components of Epclusa compared to subjects with normal renal function, as described in the text below, are provided in Table 19. 27 Table 19: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir, GS-331007, and Velpatasvir Compared to Subjects with Normal Renal Function HCV-Negative Subjects HCV-Infected Subjects Mild RI (eGFR ≥50 and <80 mL/min/1.7 3m2) Moderate RI (eGFR ≥30 and <50 mL/min/1.73 m2) Severe RI (eGFR <30 mL/min/1.7 3m2) ESRD Requiring Dialysis Severe RI (eGFR <30 mL/min/1. 73m2) ESRD Requiring Dialysis Dosed 1 hr Before Dialysis Dosed 1 hr After Dialysis Sofosbuvir 1.6-fold↑ 2.1-fold↑ 2.7-fold↑ 1.3-fold↑ 1.6-fold↑ ~2-fold↑ 1.8-fold↑ GS-331007 1.6-fold↑ 1.9-fold↑ 5.5-fold↑ ≥10-fold↑ ≥20-fold↑ ~7-fold↑ 18-fold↑ Velpatasvir - - 1.5-fold↑ - - - 1.4-fold↑ The pharmacokinetics of sofosbuvir was studied in HCV negative patients with mild (eGFR ≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir, relative to patients with normal renal function (eGFR > 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered dose. In HCV-infected patients with severe renal impairment treated with sofosbuvir 200 mg with ribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir 90/400 mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with that observed in HCV negative patients with severe renal impairment. The pharmacokinetics of velpatasvir was studied with a single dose of 100 mg velpatasvir in HCV negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault). The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected patients with ESRD requiring dialysis treated with Epclusa (n=59) for 12 weeks, and compared to patients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3 trials. Hepatic impairment The pharmacokinetics of sofosbuvir was studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected patients with moderate and severe hepatic impairment (CPT Class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. The pharmacokinetics of velpatasvir was studied with a single dose of 100 mg velpatasvir in HCV negative patients with moderate and severe hepatic impairment (CPT Class B and C). Compared to subjects with normal hepatic function velpatasvir total plasma exposure (AUCinf) was similar in patients with moderate or severe hepatic impairment. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to velpatasvir (see section 4.2). Body weight Body weight did not have a clinically significant effect on sofosbuvir or velpatasvir exposure according to a population pharmacokinetic analysis. Paediatric population The pharmacokinetics of sofosbuvir, GS-331007 and velpatasvir in paediatric patients have not been established (see section 4.2). 28 5.3 Preclinical safety data Sofosbuvir Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity and exposure to the major metabolite GS-331007 was instead used to estimate exposure margins. Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. No teratogenic effects were observed in the rat and rabbit developmental toxicity studies with sofosbuvir. Sofosbuvir had no adverse effects on behaviour, reproduction, or development of the offspring in the rat pre- and post-natal development study. Sofosbuvir was not a carcinogen in the 2-year mouse and rat carcinogenicity studies at GS-331007 exposures up to 15 and 9 times, respectively, higher than human exposure. Velpatasvir Velpatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays. Velpatasvir was not carcinogenic in the 6-month rasH2 transgenic mouse and 2-year rat carcinogenicity studies at exposures at least 50-times and 5-times higher than human exposure, respectively. Velpatasvir had no adverse effects on mating and fertility. No teratogenic effects were observed in the mouse and rat developmental toxicity studies with velpatasvir at AUC exposures approximately 31- and 6-fold higher, respectively, than the human exposure at the recommended clinical dose. However, a possible teratogenic effect was indicated in rabbits where an increase in total visceral malformations was seen in exposed animals at AUC exposures up to 0.7 fold the human exposure at recommended clinical dose. The human relevance of this finding is not known. Velpatasvir had no adverse effects on behaviour, reproduction, or development of the offspring in the rat pre- and post-natal development study at AUC exposures approximately 5-fold higher than the human exposure at the recommended clinical dose. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Copovidone Microcrystalline cellulose Croscarmellose sodium Magnesium stearate Film-coating Polyvinyl alcohol Titanium dioxide Polyethylene glycol Talc Iron oxide red 6.2 Incompatibilities Not applicable. 29 6.3 Shelf life 4 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Epclusa tablets are supplied in high density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 28 film-coated tablets with polyester coil. The following pack sizes are available: outer cartons containing 1 bottle of 28 film-coated tablets. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Gilead Sciences Ireland UC Carrigtohill County Cork, T45 DP77 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1116/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 06 July 2016 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 30 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 31 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Gilead Sciences Ireland UC IDA Business & Technology Park Carrigtohill County Cork IRELAND B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The marketing authorisation holder shall submit the first PSUR for this product within 6 months following authorisation. Subsequently, the marketing authorisation holder (MAH) shall submit PSUR for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date In order to evaluate the recurrence of hepatocellular carcinoma associated with Epclusa, the MAH shall conduct and submit the results of a prospective safety study using data deriving from a cohort of a well-defined group of patients, based on an agreed protocol. The final study report shall be submitted by: Q2 2023 32 ANNEX III LABELLING AND PACKAGE LEAFLET 33 A. LABELLING 34 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING BOTTLE AND CARTON LABELLING 1. NAME OF THE MEDICINAL PRODUCT Epclusa 400 mg/100 mg film-coated tablets sofosbuvir/velpatasvir 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 35 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Gilead Sciences Ireland UC Carrigtohill County Cork, T45 DP77 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1116/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epclusa [Outer packaging only] 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 36 B. PACKAGE LEAFLET 37 Package leaflet: Information for the user Epclusa 400 mg/100 mg film-coated tablets sofosbuvir/velpatasvir This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Epclusa is and what it is used for 2. What you need to know before you take Epclusa 3. How to take Epclusa 4. Possible side effects 5. How to store Epclusa 6. Contents of the pack and other information 1. What Epclusa is and what it is used for Epclusa is a medicine that contains the active substances sofosbuvir and velpatasvir in a single tablet. It is given to treat a chronic (long-term) viral infection of the liver called hepatitis C in adults of 18 years and older. The active substances in this medicine work together by blocking two different proteins that the virus needs to grow and reproduce itself, allowing the infection to be permanently eliminated from the body. Epclusa is sometimes taken with another medicine, ribavirin. It is very important that you also read the leaflets for the other medicines that you will be taking with Epclusa. If you have any questions about your medicines, please ask your doctor or pharmacist. 2. What you need to know before you take Epclusa Do not take Epclusa • If you are allergic to sofosbuvir, velpatasvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet).  If this applies to you, do not take Epclusa and tell your doctor immediately. • If you are currently taking any of the following medicines: • rifampicin and rifabutin (antibiotics used to treat infections, including tuberculosis); • St. John’s wort (herbal medicine used to treat depression); • carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and prevent seizures). 38 Warnings and precautions Talk to your doctor if you: • have liver problems other than from hepatitis C, for instance • if you have a current or previous infection with the hepatitis B virus, since your doctor may want to monitor you more closely; • if you have had a liver transplant • have kidney problems or if you are on kidney dialysis, since Epclusa has not been fully tested in patients with some severe kidney problems; • are taking treatment for human immunodeficiency virus (HIV) infection, since your doctor may want to monitor you more closely. Talk to your doctor or pharmacist before taking Epclusa if: • you currently take, or have taken in the last few months, the medicine amiodarone to treat irregular heartbeats, as it may result in a life-threatening slowing of your heart beat. Your doctor may consider alternative treatments if you have taken this medicine. If treatment with Epclusa is needed, you may require additional heart monitoring. • you have diabetes. You may need closer monitoring of your blood glucose levels and/or adjustment of your diabetes medication after starting Epclusa. Some diabetic patients have experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like Epclusa. Tell your doctor immediately if you currently take, or have taken in the last months any medicines for heart problems and during treatment you experience: • slow or irregular heartbeat, or heart rhythm problems; • shortness of breath or worsening of existing shortness of breath; • chest pain; • light-headedness; • palpitations; • near fainting or fainting. Blood tests Your doctor will test your blood before, during and after your treatment with Epclusa. This is so that: • Your doctor can decide if you should take Epclusa and for how long; • Your doctor can confirm that your treatment has worked and you are free of the hepatitis C virus. Children and adolescents Do not give this medicine to children and adolescents under 18 years of age. The use of Epclusa in children and adolescents has not yet been studied. Other medicines and Epclusa Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Warfarin and other similar medicines called vitamin K antagonists used to thin the blood. Your doctor may need to increase the frequency of your blood tests to check how well your blood can clot. Your liver function may change with treatment of hepatitis C and therefore may affect other medications (e.g. medicines used to suppress your immune system, etc.). Your doctor may need to closely monitor these other medicines you are taking and make adjustments after starting Epclusa. If you are not sure talk to your doctor or pharmacist. 39 Some medicines should not be taken with Epclusa. • Do not take any other medicine that contains sofosbuvir, one of the active substances in Epclusa. Tell your doctor or pharmacist if you are taking any of the medicines below: • amiodarone used to treat irregular heartbeats; • rifapentine (antibiotic used to treat infections, including tuberculosis); • oxcarbazepine (medicine used to treat epilepsy and prevent seizures); • tenofovir disoproxil fumarate or any medicine containing tenofovir disoproxil fumarate, used to treat HIV infection; • efavirenz used to treat HIV infection; • digoxin used to treat heart conditions; • dabigatran used to thin the blood; • modafinil used to treat sleep disorders; • rosuvastatin or other statins used to treat high cholesterol. Taking Epclusa with any of these may stop your medicines from working properly, or make any side effects worse. Your doctor may need to give you a different medicine or adjust the dose of medicine you are taking. This change could be to Epclusa or another medicine you are taking. • Get advice from a doctor or pharmacist if you take medicines used to treat stomach ulcers, heartburn or acid reflux as they can decrease the amount of velpatasvir in your blood. These medicines include: • antacids (such as aluminium/magnesium hydroxide or calcium carbonate). These should be taken at least 4 hours before or 4 hours after Epclusa; • proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole). Epclusa should be taken with food 4 hours before using a proton pump inhibitor. • H2-receptor antagonists (such as famotidine, cimetidine, nizatidine or ranitidine). If you need high doses of these medicines your doctor may give you a different medicine instead or adjust the dose of the medicine you are taking. These medicines can decrease the amount of velpatasvir in your blood. If you are taking one of these medicines your doctor will either give you a different medicine for stomach ulcers, heartburn or acid reflux, or recommend how and when you take that medicine. Pregnancy and contraception The effects of Epclusa during pregnancy are not known. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Epclusa is sometimes used together with ribavirin. Ribavirin can harm your unborn baby. It is therefore very important that you (or your partner) do not become pregnant during this treatment or for a period of time after completing treatment. You must read the “Pregnancy” section in the ribavirin package leaflet very carefully. Ask your doctor for effective contraception method suitable for you and your partner. Breast-feeding Do not breast-feed during treatment with Epclusa. It is not known whether sofosbuvir or velpatasvir, the two active substances of Epclusa, pass into human breast milk. Driving and using machines Epclusa should not affect your ability to drive or use any tools or machinery. 40 3. How to take Epclusa Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Recommended dose The recommended dose is one tablet once a day for 12 weeks. Swallow the tablet whole with or without food. Do not chew, crush or split the tablet as it has a very bitter taste. If you are taking an antacid, take it at least 4 hours before or at least 4 hours after Epclusa. If you are taking a proton pump inhibitor, take Epclusa with food 4 hours before using a proton pump inhibitor. If you are sick (vomit) after taking Epclusa it may affect the amount of Epclusa in your blood. This may make Epclusa work less well. • If you are sick (vomit) less than 3 hours after taking Epclusa, take another tablet. • If you are sick (vomit) more than 3 hours after taking Epclusa, you do not need to take another tablet until your next scheduled tablet. If you take more Epclusa than you should If you accidentally take more than the recommended dose you should contact your doctor or nearest emergency department immediately for advice. Keep the tablet bottle with you so that you can easily describe what you have taken. If you forget to take Epclusa It is important not to miss a dose of this medicine. If you do miss a dose, work out how long it is since you last took your Epclusa: • If you notice within 18 hours of the time you usually take Epclusa, you must take the tablet as soon as possible. Then take the next dose at your usual time. • If it’s 18 hours or more after the time you usually take Epclusa, wait and take the next dose at your usual time. Do not take a double dose (two doses close together). Do not stop taking Epclusa Do not stop taking this medicine unless your doctor tells you to. It is very important that you complete the full course of treatment to give the medicine the best chance to treat your hepatitis C virus infection. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 41 4. Possible side effects Like all medicines, this medicine may cause side effects, although not everybody gets them. Common side effects (may affect up to 1 in 10 people) • rash Uncommon side effects (may affect up to 1 in 100 people) • swelling of the face, lips, tongue or throat (angioedema). Other effects that may be seen during treatment with sofosbuvir: The frequency of the following side effects is not known (frequency cannot be estimated from the available data). • a wide spread severe rash with peeling skin which may be accompanied by fever, flu like symptoms, blisters in the mouth, eyes, and/or genitals (Stevens Johnson syndrome).  If you get any side effects tell your doctor. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Epclusa Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the bottle and carton after “EXP”. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Epclusa contains • The active substances are sofosbuvir and velpatasvir. Each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. • The other ingredients are Tablet core: Copovidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate Film-coating: Polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red What Epclusa looks like and contents of the pack The film-coated tablets are pink, diamond-shaped tablets debossed with “GSI” on one side and “7916” on the other side. The tablet is 20 mm long and 10 mm wide. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 42 The following pack sizes are available: • outer cartons containing 1 bottle of 28 film-coated tablets Marketing Authorisation Holder Gilead Sciences Ireland UC Carrigtohill County Cork, T45 DP77 Ireland Manufacturer Gilead Sciences Ireland UC IDA Business & Technology Park Carrigtohill County Cork Ireland For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Gilead Sciences Belgium SPRL-BVBA Tél/Tel: + 32 (0) 24 01 35 50 Lietuva Gilead Sciences Poland Sp. z o.o. Tel: + 48 22 262 8702 България Gilead Sciences Ireland UC Тел.: + 353 (0) 1 686 1888 Luxembourg/Luxemburg Gilead Sciences Belgium SPRL-BVBA Tél/Tel: + 32 (0) 24 01 35 50 Česká republika Gilead Sciences s.r.o. Tel: + 420 910 871 986 Magyarország Gilead Sciences Ireland UC Tel: + 353 (0) 1 686 1888 Danmark Gilead Sciences Sweden AB Tlf: + 46 (0) 8 5057 1849 Malta Gilead Sciences Ireland UC Tel: + 353 (0) 1 686 1888 Deutschland Gilead Sciences GmbH Tel: + 49 (0) 89 899890-0 Nederland Gilead Sciences Netherlands B.V. Tel: + 31 (0) 20 718 36 98 Eesti Gilead Sciences Poland Sp. z o.o. Tel: + 48 22 262 8702 Norge Gilead Sciences Sweden AB Tlf: + 46 (0) 8 5057 1849 Ελλάδα Gilead Sciences Ελλάς Μ.ΕΠΕ. Τηλ: + 30 210 8930 100 Österreich Gilead Sciences GesmbH Tel: + 43 1 260 830 España Gilead Sciences, S.L. Tel: + 34 91 378 98 30 Polska Gilead Sciences Poland Sp. z o.o. Tel: + 48 22 262 8702 France Gilead Sciences Tél: + 33 (0) 1 46 09 41 00 Portugal Gilead Sciences, Lda. Tel: + 351 21 7928790 43 Hrvatska Gilead Sciences Ireland UC Tel: + 353 (0) 1 686 1888 România Gilead Sciences Ireland UC Tel: + 353 (0) 1 686 1888 Ireland Gilead Sciences Ireland UC Tel: + 353 (0) 214 825 999 Slovenija Gilead Sciences Ireland UC Tel: + 353 (0) 1 686 1888 Ísland Gilead Sciences Sweden AB Sími: + 46 (0) 8 5057 1849 Slovenská republika Gilead Sciences Slovakia s.r.o. Tel: + 421 232 121 210 Italia Gilead Sciences S.r.l. Tel: + 39 02 439201 Suomi/Finland Gilead Sciences Sweden AB Puh/Tel: + 46 (0) 8 5057 1849 Κύπρος Gilead Sciences Ελλάς Μ.ΕΠΕ. Τηλ: + 30 210 8930 100 Sverige Gilead Sciences Sweden AB Tel: + 46 (0) 8 5057 1849 Latvija Gilead Sciences Poland Sp. z o.o. Tel: + 48 22 262 8702 United Kingdom Gilead Sciences Ltd. Tel: + 44 (0) 8000 113 700 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ 44 ANNEX IV SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S) 45 Scientific conclusions Taking into account the PRAC Assessment Report on the PSUR(s) for sofosbuvir / velpatasvir, the scientific conclusions of CHMP are as follows: The MAH performed an updated cumulative review of bradyarrhythmia occurring when sofosbuvir- containing products are co-administered with amiodarone, cumulative to 27 June 2019. The review identified 40 valid cases, of which 31 occurred after 5 March 2015, when warnings regarding bradyarrhythmia were implemented. Of these, 5 cases involved discontinuation of amiodarone prior to initiation of the sofosbuvir-containing regimen. While this suggests that some physicians are aware of the risk of bradyarrhythmia and discontinue amiodarone prior to initiation of the sofosbuvir-containing products, not all physicians appear to take into account the long half-life of amiodarone, despite the existing labelling. Of note, two cases reported discontinuation of amiodarone on the day of starting the sofosbuvir- containing regimen, which would result in significant levels of amiodarone still being present in the patient’s plasma while on sofosbuvir. In the instances where amiodarone is coadministered, the reasons for coadministration were not reported in the majority of cases. However, when reported, prescribing error, patient error, medical need or the hepatologist not being aware of concomitant amiodarone treatment were cited as reasons for the concomitant use. In this context, it was considered that warnings regarding bradyarrhythmia and the recommendation of cardiac monitoring should be strengthened. The CHMP agrees with the scientific conclusions made by the PRAC. Grounds for the variation to the terms of the marketing authorisation(s) On the basis of the scientific conclusions for sofosbuvir / velpatasvir the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing sofosbuvir / velpatasvir is unchanged subject to the proposed changes to the product information The CHMP recommends that the terms of the marketing authorisation(s) should be varied. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)

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{'Title': '2. what you need to know before you take epclusa', 'Section_Content': 'do not take epclusa if you are allergic to sofosbuvir, velpatasvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet). if this applies to you, do not take epclusa and tell your doctor immediately. if you are currently taking any of the following medicines: rifampicin and rifabutin (antibiotics used to treat infections, including tuberculosis); st. john\'s wort (herbal medicine used to treat depression); carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and prevent seizures). warnings and precautions talk to your doctor if you: have liver problems other than from hepatitis c, for instance if you have a current or previous infection with the hepatitis b virus, since your doctor may want to monitor you more closely; if you have had a liver transplant have kidney problems or if you are on kidney dialysis, since epclusa has not been fully tested in patients with some severe kidney problems; are taking treatment for human immunodeficiency virus (hiv) infection, since your doctor may want to monitor you more closely. talk to your doctor or pharmacist before taking epclusa if: you currently take, or have taken in the last few months, the medicine amiodarone to treat irregular heartbeats, as it may result in a life-threatening slowing of your heart beat. your doctor may consider alternative treatments if you have taken this medicine. if treatment with epclusa is needed, you may require additional heart monitoring. you have diabetes. you may need closer monitoring of your blood glucose levels and/or adjustment of your diabetes medication after starting epclusa. some diabetic patients have experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like epclusa. tell your doctor immediately if you currently take, or have taken in the last months any medicines for heart problems and during treatment you experience: slow or irregular heartbeat, or heart rhythm problems; shortness of breath or worsening of existing shortness of breath; chest pain; light-headedness; palpitations; near fainting or fainting. blood tests your doctor will test your blood before, during and after your treatment with epclusa. this is so that: your doctor can decide if you should take epclusa and for how long; your doctor can confirm that your treatment has worked and you are free of the hepatitis c virus. children and adolescents do not give this medicine to children and adolescents under 18 years of age. the use of epclusa in children and adolescents has not yet been studied. other medicines and epclusa tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. warfarin and other similar medicines called vitamin k antagonists used to thin the blood. your doctor may need to increase the frequency of your blood tests to check how well your blood can clot. your liver function may change with treatment of hepatitis c and therefore may affect other medications (e.g. medicines used to suppress your immune system, etc.). your doctor may need to closely monitor these other medicines you are taking and make adjustments after starting epclusa. if you are not sure talk to your doctor or pharmacist. some medicines should not be taken with epclusa. do not take any other medicine that contains sofosbuvir, one of the active substances in epclusa. tell your doctor or pharmacist if you are taking any of the medicines below: amiodarone used to treat irregular heartbeats; rifapentine (antibiotic used to treat infections, including tuberculosis); oxcarbazepine (medicine used to treat epilepsy and prevent seizures); tenofovir disoproxil fumarate or any medicine containing tenofovir disoproxil fumarate, used to treat hiv infection; efavirenz used to treat hiv infection; digoxin used to treat heart conditions; dabigatran used to thin the blood; modafinil used to treat sleep disorders; rosuvastatin or other statins used to treat high cholesterol. taking epclusa with any of these may stop your medicines from working properly, or make any side effects worse. your doctor may need to give you a different medicine or adjust the dose of medicine you are taking. this change could be to epclusa or another medicine you are taking. get advice from a doctor or pharmacist if you take medicines used to treat stomach ulcers, heartburn or acid reflux as they can decrease the amount of velpatasvir in your blood. these medicines include: antacids (such as aluminium/magnesium hydroxide or calcium carbonate). these should be taken at least 4 hours before or 4 hours after epclusa; proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole). epclusa should be taken with food 4 hours before using a proton pump inhibitor. h2-receptor antagonists (such as famotidine, cimetidine, nizatidine or ranitidine). if you need high doses of these medicines your doctor may give you a different medicine instead or adjust the dose of the medicine you are taking. these medicines can decrease the amount of velpatasvir in your blood. if you are taking one of these medicines your doctor will either give you a different medicine for stomach ulcers, heartburn or acid reflux, or recommend how and when you take that medicine. pregnancy and contraception the effects of epclusa during pregnancy are not known. if you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. epclusa is sometimes used together with ribavirin. ribavirin can harm your unborn baby. it is therefore very important that you (or your partner) do not become pregnant during this treatment or for a period of time after completing treatment. you must read the "pregnancy" section in the ribavirin package leaflet very carefully. ask your doctor for effective contraception method suitable 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{'Title': '3. how to take epclusa', 'Section_Content': "always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. recommended dose the recommended dose is one tablet once a day for 12 weeks. swallow the tablet whole with or without food. do not chew, crush or split the tablet as it has a very bitter taste. if you are taking an antacid, take it at least 4 hours before or at least 4 hours after epclusa. if you are taking a proton pump inhibitor, take epclusa with food 4 hours before using a proton pump inhibitor. if you are sick (vomit) after taking epclusa it may affect the amount of epclusa in your blood. this may make epclusa work less well. if you are sick (vomit) less than 3 hours after taking epclusa, take another tablet. if you are sick (vomit) more than 3 hours after taking epclusa, you do not need to take another tablet until your next scheduled tablet. if you take more epclusa than you should if you accidentally take more than the recommended dose you should contact your doctor or nearest emergency department immediately for advice. keep the tablet bottle with you so that you can easily describe what you have taken. if you forget to take epclusa it is important not to miss a dose of this medicine. if you do miss a dose, work out how long it is since you last took your epclusa: if you notice within 18 hours of the time you usually take epclusa, you must take the tablet as soon as possible. then take the next dose at your usual time. if it's 18 hours or more after the time you usually take epclusa, wait and take the next dose at your usual time. do not take a double dose (two doses close together). do not stop taking epclusa do not stop taking this medicine unless your doctor tells you to. it is very important that you complete the full course of treatment to give the medicine the best chance to treat your hepatitis c virus infection. if you have any further questions on the use of this 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine may cause side effects, although not everybody gets them. common side effects (may affect up to 1 in 10 people) rash uncommon side effects (may affect up to 1 in 100 people) swelling of the face, lips, tongue or throat (angioedema). other effects that may be seen during treatment with sofosbuvir: the frequency of the following side effects is not known (frequency cannot be estimated from the available data). a wide spread severe rash with peeling skin which may be accompanied by fever, flu like symptoms, blisters in the mouth, eyes, and/or genitals (stevens johnson syndrome). if you get any side effects tell your doctor. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'epclusa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 10, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9658252000808716, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6677505373954773}]}, {'Text': 'common side effects', 'Type': 'PROBLEM', 'BeginOffset': 92, 'EndOffset': 111}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 130, 'EndOffset': 131}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 135, 'EndOffset': 137}, {'Text': 'rash uncommon side effects', 'Type': 'PROBLEM', 'BeginOffset': 146, 'EndOffset': 172}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 191, 'EndOffset': 192}, {'Text': '100', 'Type': 'NUMBER', 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0.5452802777290344, 'Text': 'flu like symptoms', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9336265325546265}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9749422669410706, 'RelationshipScore': 0.5078482627868652, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 6, 'BeginOffset': 567, 'EndOffset': 571, 'Text': 'eyes', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'blisters in the mouth, eyes, and/or genitals (stevens johnson syndrome', 'Type': 'PROBLEM', 'BeginOffset': 544, 'EndOffset': 614}, {'Id': 22, 'BeginOffset': 632, 'EndOffset': 644, 'Score': 0.9372559189796448, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8238974213600159}]}, {'Id': 23, 'BeginOffset': 676, 'EndOffset': 688, 'Score': 0.9480778574943542, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7829972505569458}]}, 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'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7419390678405762}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1000, 'EndOffset': 1013}]}

{'Title': '5. how to store epclusa', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle and carton after "exp". the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what epclusa contains the active substances are sofosbuvir and velpatasvir. each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. the other ingredients are tablet core: copovidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate film-coating: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red what epclusa looks like and contents of the pack the film-coated tablets are pink, diamond-shaped tablets debossed with "gsi" on one side and "7916" on the other side. the tablet is 20 mm long and 10 mm wide. the following pack sizes are available: outer cartons containing 1 bottle of 28 film-coated tablets', 'Entity_Recognition': [{'Text': 'epclusa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 48, 'EndOffset': 58, 'Score': 0.8724136352539062, 'Text': 'sofosbuvir', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 63, 'EndOffset': 74, 'Score': 0.987575352191925, 'Text': 'velpatasvir', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.831534206867218, 'RelationshipScore': 0.9879042506217957, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 93, 'EndOffset': 99, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each film', 'Type': 'TEST', 'BeginOffset': 76, 'EndOffset': 85}, {'Text': '400', 'Type': 'NUMBER', 'BeginOffset': 109, 'EndOffset': 112}, {'Id': 4, 'BeginOffset': 116, 'EndOffset': 126, 'Score': 0.9952406883239746, 'Text': 'sofosbuvir', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9799649715423584, 'RelationshipScore': 0.999779999256134, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 109, 'EndOffset': 115, 'Text': '400 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.972553014755249, 'RelationshipScore': 0.7440653443336487, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 131, 'EndOffset': 137, 'Text': '100 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 131, 'EndOffset': 134}, {'Id': 6, 'BeginOffset': 138, 'EndOffset': 149, 'Score': 0.9959027171134949, 'Text': 'velpatasvir', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.972553014755249, 'RelationshipScore': 0.999870777130127, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 131, 'EndOffset': 137, 'Text': '100 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 7, 'BeginOffset': 190, 'EndOffset': 200, 'Score': 0.9840126037597656, 'Text': 'copovidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 202, 'EndOffset': 228, 'Score': 0.9950329065322876, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 230, 'EndOffset': 251, 'Score': 0.9955283999443054, 'Text': 'croscarmellose sodium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'magnesium stearate film', 'Type': 'TREATMENT', 'BeginOffset': 253, 'EndOffset': 276}, {'Text': 'polyvinyl alcohol, titanium dioxide', 'Type': 'TREATMENT', 'BeginOffset': 286, 'EndOffset': 321}, {'Id': 14, 'BeginOffset': 323, 'EndOffset': 348, 'Score': 0.9992967844009399, 'Text': 'polyethylene glycol, talc', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the pack the film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 405, 'EndOffset': 437}, {'Text': 'diamond-shaped tablets', 'Type': 'TREATMENT', 'BeginOffset': 448, 'EndOffset': 470}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 547, 'EndOffset': 549}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 562, 'EndOffset': 564}, {'Text': 'the following pack sizes', 'Type': 'TREATMENT', 'BeginOffset': 574, 'EndOffset': 598}, {'Text': 'outer cartons', 'Type': 'TREATMENT', 'BeginOffset': 614, 'EndOffset': 627}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 639, 'EndOffset': 640}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 651, 'EndOffset': 653}, {'Text': 'film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 654, 'EndOffset': 673}]}

0AA9B4EF46C83A76DDB04D916CDF4EAC

https://www.ema.europa.eu/documents/product-information/imnovid-epar-product-information_en.pdf

Imnovid

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Imnovid 1 mg hard capsules Imnovid 2 mg hard capsules Imnovid 3 mg hard capsules Imnovid 4 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Imnovid 1 mg hard capsules Each hard capsule contains 1 mg of pomalidomide. Imnovid 2 mg hard capsules Each hard capsule contains 2 mg of pomalidomide. Imnovid 3 mg hard capsules Each hard capsule contains 3 mg of pomalidomide. Imnovid 4 mg hard capsules Each hard capsule contains 4 mg of pomalidomide. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule Imnovid 1 mg hard capsules Dark blue opaque cap and yellow opaque body, imprinted “POML” in white ink and “1 mg” in black ink, size 4 gelatin hard capsule. Imnovid 2 mg hard capsules Dark blue opaque cap and orange opaque body, imprinted “POML 2 mg” in white ink, size 2 gelatin hard capsule. 3 Imnovid 3 mg hard capsules Dark blue opaque cap and green opaque body, imprinted “POML 3 mg” in white ink, size 2 gelatin hard capsule. Imnovid 4 mg hard capsules Dark blue opaque cap and blue opaque body, imprinted “POML 4 mg” in white ink, size 2 gelatin hard capsule. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Imnovid in combination with bortezomib and dexamethasone is indicated in the treatment of adult patients with multiple myeloma who have received at least one prior treatment regimen including lenalidomide. Imnovid in combination with dexamethasone is indicated in the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. 4.2 Posology and method of administration Treatment must be initiated and monitored under the supervision of physicians experienced in the management of multiple myeloma. Dosing is continued or modified based upon clinical and laboratory findings (see section 4.4). Posology • Pomalidomide in combination with bortezomib and dexamethasone The recommended starting dose of Imnovid is 4 mg orally once daily on Days 1 to 14 of repeated 21-day cycles. Pomalidomide is administered in combination with bortezomib and dexamethasone, as shown in Table 1. The recommended starting dose of bortezomib is 1.3 mg/m2 intravenous or subcutaneous once daily, on the days shown in Table 1. The recommended dose of dexamethasone is 20 mg orally once daily, on the days shown in Table 1. Treatment with pomalidomide combined with bortezomib and dexamethasone should be given until disease progression or until unacceptable toxicity occurs. 4 Table 1. Recommended dosing scheme for Imnovid in combination with bortezomib and dexamethasone Cycle 1-8 Day (of 21-day cycle) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Pomalidomide (4 mg) • • • • • • • • • • • • • • Bortezomib (1.3 mg/m2) • • • • Dexamethasone (20 mg) * • • • • • • • • Cycle 9 onwards Day (of 21-day cycle) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Pomalidomide (4 mg) • • • • • • • • • • • • • • Bortezomib (1.3 mg/m2) • • Dexamethasone (20 mg) * • • • • * For patients > 75 years of age, see Special populations. Pomalidomide dose modification or interruption To initiate a new cycle of pomalidomide, the neutrophil count must be  1 x 109/l and the platelet count must be  50 x 109/l. Instructions on dose interruptions or reductions for pomalidomide related adverse reactions are outlined in the Table 2 and dose levels are defined in Table 3 below: Table 2. Pomalidomide dose modification instructions∞ Toxicity Dose modification Neutropenia* ANC** < 0.5 x 109/l or febrile neutropenia (fever ≥38.5°C and ANC <1 x 109/l) Interrupt pomalidomide treatment for remainder of cycle. Follow CBC*** weekly. ANC return to ≥ 1 x 109/l Resume pomalidomide treatment at one dose level lower than previous dose. For each subsequent drop < 0.5 x 109/l Interrupt pomalidomide treatment. ANC return to ≥ 1 x 109/l Resume pomalidomide treatment at one dose level lower than the previous dose. Thrombocytopenia Platelet count < 25 x 109/l Interrupt pomalidomide treatment for remainder of cycle. Follow CBC*** weekly. Platelet count return to ≥ 50 x 109/l Resume pomalidomide treatment at one dose level lower than previous dose. For each subsequent drop < 25 x 109/l Interrupt pomalidomide treatment. Platelet count return to ≥ 50 x 109/l Resume pomalidomide treatment at one dose level lower than the previous dose. 5 Rash Rash = Grade 2-3 Consider dose interruption or discontinuation of pomalidomide treatment. Rash = Grade 4 or blistering (including angioedema, exfoliative or bullous rash or if Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected) Permanently discontinue treatment (see section 4.4). Other Other ≥ Grade 3 pomalidomide-related adverse events Interrupt pomalidomide treatment for remainder of cycle. Resume at one dose level lower than previous dose at next cycle (adverse event must be resolved or improved to ≤ Grade 2 before restarting dosing). ∞ Dose modification instructions in this table are applicable to pomalidomide in combination with bortezomib and dexamethasone and to pomalidomide in combination with dexamethasone. *In case of neutropenia, the physician should consider the use of growth factors. **ANC – Absolute Neutrophil Count; ***CBC – Complete Blood Count. Table 3. Pomalidomide dose reduction∞ Dose level Oral pomalidomide dose Starting dose 4 mg Dose level -1 3 mg Dose level -2 2 mg Dose level -3 1 mg ∞Dose reduction in this table is applicable to pomalidomide in combination with bortezomib and dexamethasone and to pomalidomide in combination with dexamethasone. If adverse reactions occur after dose reductions to 1 mg, then the medicinal product should be discontinued. Strong CYP1A2 inhibitors If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administered with pomalidomide, reduce the dose of pomalidomide by 50% (see sections 4.5 and 5.2). Bortezomib dose modification or interruption For instructions on dose interruptions or reductions for bortezomib related adverse reactions, physicians should refer to bortezomib Summary of Product Characteristics (SmPC). Dexamethasone dose modification or interruption Instructions on dose interruptions or reductions for low-dose dexamethasone related adverse reactions are outlined in Tables 4 and 5 below. However, dose interruption or resumption decisions are at the physician’s discretion per Summary of Product Characteristics (SmPC). 6 Table 4. Dexamethasone dose modification instructions Toxicity Dose Modification Dyspepsia = Grade 1-2 Maintain dose and treat with histamine (H2) blockers or equivalent. Decrease by one dose level if symptoms persist. Dyspepsia ≥ Grade 3 Interrupt dose until symptoms are controlled. Add H2 blocker or equivalent and resume at one dose level lower than previous dose. Oedema ≥ Grade 3 Use diuretics as needed and decrease dose by one dose level. Confusion or mood alteration ≥ Grade 2 Interrupt dose until symptoms resolve. Resume at one dose level lower than previous dose. Muscle weakness ≥ Grade 2 Interrupt dose until muscle weakness ≤ Grade 1. Resume at one dose level lower than previous dose. Hyperglycaemia ≥ Grade 3 Decrease dose by one dose level. Treat with insulin or oral hypoglycaemic agents as needed. Acute pancreatitis Discontinue dexamethasone from treatment regimen. Other ≥ Grade 3 dexamethasone-related adverse events Stop dexamethasone dosing until the adverse event resolves to ≤ Grade 2. Resume at one dose level lower than previous dose. If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will be resumed at one dose level lower than the previous dose. Table 5. Dexamethasone dose reduction Dose Level ≤ 75 years old Dose (Cycle 1-8: Days 1, 2, 4, 5, 8, 9, 11, 12 of a 21-day cycle Cycle ≥ 9: Days 1, 2, 8, 9 of a 21-day cycle) > 75 years old Dose (Cycle 1-8: Days 1, 2, 4, 5, 8, 9, 11, 12 of a 21-day cycle Cycle ≥ 9: Days 1, 2, 8, 9 of a 21-day cycle) Starting Dose 20 mg 10 mg Dose Level -1 12 mg 6 mg Dose Level -2 8 mg 4 mg 7 Dexamethasone should be discontinued if the patient is unable to tolerate 8 mg if ≤ 75 years old or 4 mg if > 75 years old. In case of permanent discontinuation of any component of the treatment regimen, continuation of the remaining medicinal products is at the physician’s discretion. • Pomalidomide in combination with dexamethasone The recommended starting dose of Imnovid is 4 mg orally once daily on Days 1 to 21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on Days 1, 8, 15 and 22 of each 28- day treatment cycle. Treatment with pomalidomide combined with dexamethasone should be given until disease progression or until unacceptable toxicity occurs. Pomalidomide dose modification or interruption Instructions for dose interruptions or reductions for pomalidomide related adverse reactions are outlined in Table 2 and 3. Dexamethasone dose modification or interruption Instructions for dose modification for dexamethasone related adverse reactions are outlined in Table 4. Instructions for dose reduction for dexamethasone related adverse reactions are outlined in Table 6 below. However, dose interruption / resumption decisions are at physician’s discretion per the current Summary of Product Characteristics (SmPC). Table 6. Dexamethasone dose reduction Dose Level ≤ 75 years old Days 1, 8, 15 and 22 of each 28-day treatment cycle > 75 years old Days 1, 8, 15 and 22 of each 28-day treatment cycle Starting Dose 40 mg 20 mg Dose Level -1 20 mg 12 mg Dose Level -2 10mg 8 mg Dexamethasone should be discontinued if the patient is unable to tolerate 10 mg if ≤ 75 years old or 8 mg if > 75 years old. Special populations Elderly • Pomalidomide in combination with bortezomib and dexamethasone No dose adjustment is required for pomalidomide. For information on bortezomib given in combination with Imnovid, refer to the respective current SmPC. 8 For patients >75 years of age, the starting dose of dexamethasone is: • For Cycles 1 to 8: 10 mg once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each 21-day cycle • For Cycles 9 and onwards: 10 mg once daily on Days 1, 2, 8 and 9 of each 21-day cycle. • Pomalidomide in combination with dexamethasone No dose adjustment is required for pomalidomide. For patients > 75 years of age, the starting dose of dexamethasone is: • 20 mg once daily on days 1, 8, 15 and 22 of each 28-day treatment cycle. Hepatic impairment Patients with serum total bilirubin > 1.5 x ULN (upper limit of normal range) were excluded from clinical studies. Hepatic impairment has a modest effect on the pharmacokinetics of pomalidomide (see section 5.2). No adjustment of the starting dose of pomalidomide is required for patients with hepatic impairment as defined by the Child-Pugh criteria. However, patients with hepatic impairment should be carefully monitored for adverse reactions and dose reduction or interruption of pomalidomide should be used as needed. Renal impairment No dose adjustment of pomalidomide is required for patients with renal impairment. On haemodialysis days, patients should take their pomalidomide dose following haemodialysis. Paediatric population There is no relevant use of pomalidomide in children aged 0-17 years for the indication of multiple myeloma. Method of administration Oral use. Imnovid hard capsules should be taken orally at the same time each day. The capsules should not be opened, broken or chewed (see section 6.6). The capsules should be swallowed whole, preferably with water, with or without food. If the patient forgets to take a dose of pomalidomide on one day, then the patient should take the normal prescribed dose as scheduled on the next day. Patients should not adjust the dose to make up for a missing dose on previous days. It is recommended to press only on one end of the capsule to remove it from the blister thereby reducing the risk of capsule deformation or breakage. For information on other medicinal products given in combination with Imnovid, refer to the respective current SmPC. 4.3 Contraindications • Pregnancy. • Women of childbearing potential, unless all the conditions of the pregnancy prevention programme are met (see sections 4.4 and 4.6). • Male patients unable to follow or comply with the required contraceptive measures (see section 4.4). • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 9 For information on other medicinal products given in combination with Imnovid, refer to the respective current SmPC. 4.4 Special warnings and precautions for use Teratogenicity Pomalidomide must not be taken during pregnancy, since a teratogenic effect is expected. Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogen that causes severe life-threatening birth defects. Pomalidomide was found to be teratogenic in both rats and rabbits when administered during the period of major organogenesis (see section 5.3). The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential. Criteria for women of non-childbearing potential A female patient or a female partner of a male patient is considered of non-childbearing potential if she meets at least one of the following criteria: • Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer therapy or during breast-feeding does not rule out childbearing potential) • Premature ovarian failure confirmed by a specialist gynaecologist • Previous bilateral salpingo-oophorectomy, or hysterectomy • XY genotype, Turner syndrome, uterine agenesis. Counselling For women of childbearing potential, pomalidomide is contraindicated unless all of the following are met: • She understands the expected teratogenic risk to the unborn child • She understands the need for effective contraception, without interruption, at least 4 weeks before starting treatment, throughout the entire duration of treatment, and at least 4 weeks after the end of treatment • Even if a woman of childbearing potential has amenorrhoea she must follow all the advice on effective contraception • She should be capable of complying with effective contraceptive measures • She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy • She understands the need to commence the treatment as soon as pomalidomide is dispensed following a negative pregnancy test • She understands the need and accepts to undergo pregnancy testing at least every 4 weeks except in case of confirmed tubal sterilisation • She acknowledges that she understands the hazards and necessary precautions associated with the use of pomalidomide. The prescriber must ensure that for women of childbearing potential: • The patient complies with the conditions of the Pregnancy Prevention Programme, including confirmation that she has an adequate level of understanding • The patient has acknowledged the aforementioned conditions. 10 For male patients taking pomalidomide, pharmacokinetic data has demonstrated that pomalidomide is present in human semen during treatment. As a precaution, and taking into account special populations with potentially prolonged elimination time such as hepatic impairment, all male patients taking pomalidomide must meet the following conditions: • He understands the expected teratogenic risk if engaged in sexual activity with a pregnant woman or a woman of childbearing potential • He understands the need for the use of a condom if engaged in sexual activity with a pregnant woman or a woman of childbearing potential not using effective contraception, throughout treatment duration, during dose interruption and for 7 days after dose interruptions and/or cessation of treatment. This includes vasectomised males who should wear a condom if engaged in sexual activity with a pregnant woman or a woman of childbearing potential as seminal fluid may still contain pomalidomide in the absence of spermatozoa. • He understands that if his female partner becomes pregnant whilst he is taking pomalidomide or 7 days after he has stopped taking pomalidomide, he should inform his treating physician immediately and that it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice. Contraception Women of childbearing potential must use at least one effective method of contraception for at least 4 weeks before therapy, during therapy, and until at least 4 weeks after pomalidomide therapy and even in case of dose interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated. The following can be considered to be examples of suitable methods of contraception: • Implant • Levonorgestrel-releasing intrauterine system • Medroxyprogesterone acetate depot • Tubal sterilisation • Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses • Ovulation inhibitory progesterone-only pills (i.e. desogestrel) Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking pomalidomide and dexamethasone, combined oral contraceptive pills are not recommended (see also section 4.5). If a patient is currently using combined oral contraception the patient should switch to one of the effective methods listed above. The risk of venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during cotreatment with dexamethasone (see section 4.5). Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia. Insertion of copper-releasing intrauterine devices is not recommended due to the potential risks of infection at the time of insertion and menstrual blood loss which may compromise patients with severe neutropenia or severe thrombocytopenia. 11 Pregnancy testing According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for women of childbearing potential as outlined below. This requirement includes women of childbearing potential who practice absolute and continuous abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of pomalidomide to women of childbearing potential should occur within 7 days of the prescription. Prior to starting treatment A medically supervised pregnancy test should be performed during the consultation, when pomalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with pomalidomide. Follow-up and end of treatment A medically supervised pregnancy test should be repeated at least every 4 weeks, including at least 4 weeks after the end of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber. Additional precautions Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment. Patients should not donate blood, semen or sperm during treatment (including during dose interruptions) and for 7 days following discontinuation of pomalidomide. Educational materials, prescribing and dispensing restrictions In order to assist patients in avoiding foetal exposure to pomalidomide, the Marketing Authorisation Holder will provide educational material to health care professionals to reinforce the warnings about the expected teratogenicity of pomalidomide, to provide advice on contraception before therapy is started, and to provide guidance on the need for pregnancy testing. The prescriber must inform the patient about the expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme and provide patients with appropriate patient educational brochure, patient card and/or equivalent tool in accordance with the national implemented patient card system. A national controlled distribution system has been implemented in collaboration with each National Competent Authority. The controlled distribution system includes the use of a patient card and/or equivalent tool for prescribing and /or dispensing controls, and the collection of detailed data relating to the indication in order to monitor the off-label use within the national territory. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of pomalidomide to women of childbearing potential should occur within 7 days of the prescription and following a medically supervised negative pregnancy test result. Prescriptions for women of childbearing potential can be for a maximum duration of 4 weeks, and prescriptions for all other patients can be for a maximum duration of 12 weeks. Haematological events Neutropenia was the most frequently reported Grade 3 or 4 haematological adverse reaction in patients 12 with relapsed/refractory multiple myeloma, followed by anaemia and thrombocytopenia. Patients should be monitored for haematological adverse reactions, especially neutropenia. Patients should be advised to report febrile episodes promptly. Physicians should observe patients for signs of bleeding including epistaxes, especially with use of concomitant medicinal products known to increase the risk of bleeding (see section 4.8). Complete blood counts should be monitored at baseline, weekly for the first 8 weeks and monthly thereafter. A dose modification may be required (see section 4.2). Patients may require use of blood product support and /or growth factors. Thromboembolic events Patients receiving pomalidomide either in combination with bortezomib and dexamethasone or in combination with dexamethasone have developed venous thromboembolic events (predominantly deep vein thrombosis and pulmonary embolism) and arterial thrombotic events (myocardial infarction and cerebrovascular accident). Patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Anti- coagulation therapy (unless contraindicated) is recommended, (such as acetylsalicylic acid, warfarin, heparin or clopidogrel), especially in patients with additional thrombotic risk factors. A decision to take prophylactic measures should be made after a careful assessment of the individual patient’s underlying risk factors. In clinical studies, patients received prophylactic acetylsalicylic acid or alternative anti- thrombotic therapy. The use of erythropoietic agents carries a risk of thrombotic events including thromboembolism. Therefore, erythropoietic agents, as well as other agents that may increase the risk of thromboembolic events, should be used with caution. Peripheral neuropathy Patients with ongoing ≥ Grade 2 peripheral neuropathy were excluded from clinical studies with pomalidomide. Appropriate caution should be exercised when considering the treatment of such patients with pomalidomide. Significant cardiac dysfunction Patients with significant cardiac dysfunction (congestive heart failure [NY Heart Association Class III or IV]; myocardial infarction within 12 months of starting study; unstable or poorly controlled angina pectoris) were excluded from clinical studies with pomalidomide. Cardiac events, including congestive cardiac failure, pulmonary oedema and atrial fibrillation (see section 4.8), have been reported, mainly in patients with pre-existing cardiac disease or cardiac risk factors. Appropriate caution should be exercised when considering the treatment of such patients with pomalidomide, including periodic monitoring for signs or symptoms of cardiac events. Tumour lysis syndrome Patients at greatest risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Second primary malignancies Second primary malignancies, such as non-melanoma skin cancer, have been reported in patients receiving pomalidomide (see section 4.8). Physicians should carefully evaluate patients before and during 13 treatment using standard cancer screening for occurrence of second primary malignancies and institute treatment as indicated. Allergic reactions and severe skin reactions Angioedema and severe dermatologic reactions including SJS, TEN and DRESS have been reported with the use of pomalidomide (see section 4.8). Patients should be advised of the signs and symptoms of these reactions by their prescribers and should be told to seek medical attention immediately if they develop these symptoms. Pomalidomide must be discontinued for exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation for these reactions. Patients with a prior history of serious allergic reactions associated with thalidomide or lenalidomide were excluded from clinical studies. Such patients may be at higher risk of hypersensitivity reactions and should not receive pomalidomide. Pomalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash. Pomalidomide must be discontinued permanently for angioedema. Dizziness and confusion Dizziness and confusional state have been reported with pomalidomide. Patients must avoid situations where dizziness or confusion may be a problem and not to take other medicinal products that may cause dizziness or confusion without first seeking medical advice. Interstitial lung disease (ILD) ILD and related events, including cases of pneumonitis, have been observed with pomalidomide. Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. Pomalidomide should be interrupted pending investigation of these symptoms and if ILD is confirmed, appropriate treatment should be initiated. Pomalidomide should only be resumed after a thorough evaluation of the benefits and the risks. Hepatic disorders Markedly elevated levels of alanine aminotransferase and bilirubin have been observed in patients treated with pomalidomide (see section 4.8). There have also been cases of hepatitis that resulted in discontinuation of pomalidomide. Regular monitoring of liver function is recommended for the first 6 months of treatment with pomalidomide and as clinically indicated thereafter. Infections Reactivation of hepatitis B has been reported rarely in patients receiving pomalidomide in combination with dexamethasone who have previously been infected with the hepatitis B virus (HBV). Some of these cases have progressed to acute hepatic failure, resulting in discontinuation of pomalidomide. Hepatitis B virus status should be established before initiating treatment with pomalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when pomalidomide in combination with dexamethasone is used in patients previously infected with HBV, including patients who are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy. 14 Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, i.e. essentially ‘sodium-free’. For information on other medicinal products given in combination with Imnovid, refer to the respective current SmPC. 4.5 Interaction with other medicinal products and other forms of interaction Effect of pomalidomide on other medicinal products Pomalidomide is not anticipated to cause clinically relevant pharmacokinetic drug-drug interactions due to P450 isoenzyme inhibition or induction or transporter inhibition when co-administered with substrates of these enzymes or transporters. The potential for such drug-drug interactions, including the potential impact of pomalidomide on the pharmacokinetics of combined oral contraceptives, has not been evaluated clinically (see section 4.4 Teratogenicity). Effect of other medicinal products on pomalidomide Pomalidomide is partly metabolised by CYP1A2 and CYP3A4/5. It is also a substrate for P-glycoprotein. Co-administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole, or the strong CYP3A4/5 inducer carbamazepine, had no clinically relevant effect on exposure to pomalidomide. Co-administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole, increased mean exposure to pomalidomide by 107% with a 90% confidence interval [91% to 124%] compared to pomalidomide plus ketoconazole. In a second study to evaluate the contribution of a CYP1A2 inhibitor alone to metabolism changes, co-administration of fluvoxamine alone with pomalidomide increased mean exposure to pomalidomide by 125% with a 90% confidence interval [98% to 157%] compared to pomalidomide alone. If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administered with pomalidomide, reduce the dose of pomalidomide by 50%. Dexamethasone Co-administration of multiple doses of up to 4 mg pomalidomide with 20 mg to 40 mg dexamethasone (a weak to moderate inducer of several CYP enzymes including CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. The effect of dexamethasone on warfarin is unknown. Close monitoring of warfarin concentration is advised during treatment. For information on other medicinal products given in combination with Imnovid, refer to the respective current SmPC. 4.6 Fertility, pregnancy and lactation Women of childbearing potential / Contraception in males and females Women of childbearing potential should use effective method of contraception. If pregnancy occurs in a woman treated with pomalidomide, treatment must be stopped and the patient should be referred to a 15 physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking pomalidomide, it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice. Pomalidomide is present in human semen. As a precaution, all male patients taking pomalidomide should use condoms throughout treatment duration, during dose interruption and for 7 days after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception (see sections 4.3 and 4.4). Pregnancy A teratogenic effect of pomalidomide in humans is expected. Pomalidomide is contraindicated during pregnancy and in women of childbearing potential, except when all the conditions for pregnancy prevention have been met, see section 4.3 and section 4.4. Breast-feeding It is unknown whether pomalidomide is excreted in human milk. Pomalidomide was detected in milk of lactating rats following administration to the mother. Because of the potential for adverse reactions in breastfed infants from pomalidomide, a decision must be made whether to discontinue breast-feeding or to discontinue the medicinal product, taking into account the benefit of breast-feeding for the child and the benefit of the therapy for the woman. Fertility Pomalidomide was found to impact negatively on fertility and be teratogenic in animals. Pomalidomide crossed the placenta and was detected in foetal blood following administration to pregnant rabbits , see section 5.3. 4.7 Effects on ability to drive and use machines Pomalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue, depressed level of consciousness, confusion, and dizziness have been reported with the use of pomalidomide. If affected, patients should be instructed not to drive cars, use machines or perform hazardous tasks while being treated with pomalidomide. 4.8 Undesirable effects Summary of the safety profile • Pomalidomide in combination with bortezomib and dexamethasone The most commonly reported blood and lymphatic system disorders were neutropenia (46.8%), thrombocytopenia (36.7%) and anaemia (28.4%). The most frequently reported adverse reaction was peripheral sensory neuropathy (47.8%). The most commonly reported Grade 3 or 4 adverse reactions were blood and lymphatic system disorders including neutropenia (41.7%), thrombocytopenia (27.3%) and anaemia (14.0%). The most commonly reported serious adverse reaction was pneumonia (11.5%). Other serious adverse reactions reported included pyrexia (4.0%), lower respiratory tract infection (2.9%), pulmonary embolism (2.9%), influenza (2.9%), and acute kidney injury (2.9%). • Pomalidomide in combination with dexamethasone The most commonly reported adverse reactions in clinical studies have been blood and lymphatic system disorders including anaemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); in general disorders and administration site conditions including fatigue (28.3%), pyrexia (21%) and oedema 16 peripheral (13%); and in infections and infestations including pneumonia (10.7%). Peripheral neuropathy adverse reactions were reported in 12.3% of patients and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3% of patients. The most commonly reported Grade 3 or 4 adverse reactions were in the blood and lymphatic system disorders including neutropenia (41.7%), anaemia (27%) and thrombocytopenia (20.7%); in infections and infestations including pneumonia (9%); and in general disorders and administration site conditions including fatigue (4.7%), pyrexia (3%) and oedema peripheral (1.3%). The most commonly reported serious adverse reaction was pneumonia (9.3%). Other serious adverse reactions reported included febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%) and VTE adverse reactions (1.7 %). Adverse reactions tended to occur more frequently within the first 2 cycles of treatment with pomalidomide. Tabulated list of adverse reactions • Pomalidomide in combination with bortezomib and dexamethasone In randomised study CC-4047-MM-007, 278 patients received pomalidomide, bortezomib and dexamethasone (Pom+Btz+Dex arm). See section 4.2 for dosing information. The adverse reactions observed in patients treated with pomalidomide in combination with bortezomib and dexamethasone are listed in Table 7 by system organ class (SOC) and frequency for all adverse reactions and for Grade 3 or 4 adverse reactions. Frequencies for Pom+Btz+Dex (any grade) are defined in accordance with current guidance, as: very common (≥1/10), common (≥1/100 to <1/10); and uncommon (≥1/1,000 to <1/100). 17 Table 7. All Adverse Reactions (ADRs) reported in clinical trial MM-007 in patients treated with pomalidomide in combination with bortezomib and dexamethasone. System Organ Class/ Preferred Term All Adverse Reactions /Frequency Grade 3−4 Adverse Reactions /Frequency Infections and infestations Very Common Pneumonia Bronchitis Upper respiratory tract infection Viral upper respiratory tract infection Common Sepsis Septic shock Clostridium difficile colitis Respiratory tract infection Lower respiratory tract infection Lung infection Influenza Bronchiolitis Urinary tract infection Very Common Pneumonia Common Sepsis Septic shock Clostridium difficile colitis Bronchitis Upper respiratory tract infection Respiratory tract infection Lower respiratory tract infection Lung infection Influenza Bronchiolitis Urinary tract infection Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Basal cell carcinoma Blood and lymphatic system disorders Very Common Neutropenia Thrombocytopenia Leucopenia Anaemia Common Febrile neutropenia Lymphopenia Very Common Neutropenia Thrombocytopenia Anaemia Common Febrile neutropenia Leucopenia Lymphopenia 18 System Organ Class/ Preferred Term All Adverse Reactions /Frequency Grade 3−4 Adverse Reactions /Frequency Metabolism and nutrition disorders Very Common Hypokalaemia Hyperglycaemia Common Hypomagnesaemia Hypocalcaemia Hypophosphataemia Hyperkalaemia Hypercalcaemia Common Hypokalaemia Hyperglycaemia Hypomagnaesaemia Hypocalcaemia Hypophosphataemia Hyperkalaemia Hypercalcaemia Psychiatric disorders Very Common Insomnia Common Depression Common Depression Insomnia Nervous system disorders Very Common Peripheral sensory neuropathy Dizziness Tremor Common Syncope Peripheral sensorimotor neuropathy Paraesthesia Dysgeusia Common Syncope Peripheral sensory neuropathy Peripheral sensorimotor neuropathy Uncommon Dizziness Tremor Eye disorders Common Cataract Common Cataract Cardiac disorders Common Atrial fibrillation Common Atrial fibrillation Vascular disorders Common Deep vein thrombosis Hypotension Hypertension Common Hypotension Hypertension Uncommon Deep vein thrombosis 19 System Organ Class/ Preferred Term All Adverse Reactions /Frequency Grade 3−4 Adverse Reactions /Frequency Respiratory, thoracic and mediastinal disorders Very Common Dyspnoea Cough Common Pulmonary embolism Common Pulmonary embolism Dyspnoea Gastrointestinal disorders Very Common Diarrhoea Vomiting Nausea Constipation Common Abdominal pain Abdominal pain upper Stomatitis Dry mouth Abdominal distension Common Diarrhoea Vomiting Abdominal pain Constipation Uncommon Abdominal pain upper Stomatitis Nausea Abdominal distension Skin and subcutaneous tissue disorders Common Rash Common Rash Musculoskeletal and connective tissue disorders Very Common Muscular weakness Back pain Common Bone pain Muscle spasms Common Muscular weakness Back pain Uncommon Bone pain Renal and urinary disorders Common Acute kidney injury Chronic kidney injury Urinary retention Common Acute kidney injury Chronic kidney injury Urinary retention General disorders and administration site conditions Very Common Fatigue Pyrexia Oedema peripheral Common Non-cardiac chest pain Oedema Common Fatigue Pyrexia Non-cardiac chest pain Oedema peripheral Oedema 20 System Organ Class/ Preferred Term All Adverse Reactions /Frequency Grade 3−4 Adverse Reactions /Frequency Investigations Common Alanine aminotransferase increased Weight decreased Common Weight decreased Uncommon Alanine aminotransferase increased Injury, poisoning and procedural complications Common Fall Uncommon Fall Tabulated list of adverse reactions • Pomalidomide in combination with dexamethasone In randomised study CC-4047-MM-003, 302 patients with relapsed and refractory multiple myeloma were exposed to 4 mg pomalidomide administered once daily for 21 days of each 28–day cycle in combination with a weekly low dose of dexamethasone. The adverse reactions observed in patients treated with pomalidomide plus dexamethasone are listed below in Table 8 by system organ class (SOC) and frequency for all adverse reactions (ADRs) and for Grade 3 or 4 adverse reactions. The frequencies of adverse reactions are those reported in the pomalidomide plus dexamethasone arm of study CC-4047-MM-003 (n = 302). Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined in accordance with current guidance, as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); and uncommon (≥ 1/1,000 to < 1/100). Table 8. ADRs reported in clinical study MM-003 in patients treated with pomalidomide in combination with dexamethasone. System Organ Class/ Preferred Term All ADRs/Frequency Grade 3−4 ADRs/Frequency Infections and infestations Very Common Pneumonia (bacterial, viral and fungal infections, including opportunistic infections) Common Neutropenic sepsis Bronchopneumonia Bronchitis Respiratory tract infection Upper respiratory tract infection Nasopharyngitis Herpes zoster Common Neutropenic sepsis Pneumonia (bacterial, viral and fungal infections, including opportunistic infections) Bronchopneumonia Respiratory tract infection Upper respiratory tract infection Uncommon Bronchitis Herpes zoster 21 System Organ Class/ Preferred Term All ADRs/Frequency Grade 3−4 ADRs/Frequency Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Basal cell carcinoma of the skin, Squamous cell carcinoma of the skin Uncommon Basal cell carcinoma of the skin, Squamous cell carcinoma of the skin Blood and lymphatic system disorders Very Common Neutropenia Thrombocytopenia Leucopenia Anaemia Common Febrile neutropenia Very Common Neutropenia Thrombocytopenia Anaemia Common Febrile neutropenia Leucopenia Metabolism and nutrition disorders Very Common Decreased appetite Common Hyperkalaemia Hyponatraemia Common Hyperkalaemia Hyponatraemia Uncommon Decreased appetite Psychiatric disorders Common Confusional state Common Confusional state Nervous system disorders Common Depressed level of consciousness Peripheral sensory neuropathy Dizziness Tremor Common Depressed level of consciousness Uncommon Peripheral sensory neuropathy Dizziness Tremor Ear and labyrinth disorders Common Vertigo Common Vertigo Vascular disorders Common Deep vein thrombosis Uncommon Deep vein thrombosis Respiratory, thoracic and mediastinal disorders Very Common Dyspnoea Cough Common Pulmonary embolism Common Dyspnoea Uncommon Pulmonary embolism Cough 22 System Organ Class/ Preferred Term All ADRs/Frequency Grade 3−4 ADRs/Frequency Gastrointestinal disorders Very Common Diarrhoea Nausea Constipation Common Vomiting Gastrointestinal haemorrhage Common Diarrhoea Vomiting Constipation Uncommon Nausea Gastrointestinal haemorrhage Hepatobiliary disorders Uncommon Hyperbilirubinaemia Uncommon Hyperbilirubinaemia Skin and subcutaneous tissue disorders Common Rash Pruritus Common Rash Musculoskeletal and connective tissue disorders Very Common Bone pain Muscle spasms Common Bone pain Uncommon Muscle spasms Renal and urinary disorders Common Renal failure Urinary retention Common Renal failure Uncommon Urinary retention Reproductive system and breast disorders Common Pelvic pain Common Pelvic pain General disorders and administration site conditions Very Common Fatigue Pyrexia Oedema peripheral Common Fatigue Pyrexia Oedema peripheral Investigations Common Neutrophil count decreased White blood cell count decreased Platelet count decreased Alanine aminotransferase increased Common Neutrophil count decreased White blood cell count decreased Platelet count decreased Alanine aminotransferase increased Tabulated list of post-marketing adverse reactions In addition to the above adverse reactions identified from the pivotal clinical trials, the following Table 9 is derived from data gathered from post-marketing surveillance. 23 Table 9. ADRs reported in post-marketing use in patients treated with pomalidomide. System Organ Class/ Preferred Term All Adverse Reactions /Frequency Grade 3−4 Adverse Reactions /Frequency Infections and infestations Not Known Hepatitis B reactivation Not Known Hepatitis B reactivation Blood and lymphatic system disorders Common Pancytopenia Common Pancytopenia Metabolism and nutrition disorders Common Hyperuricaemia Uncommon Tumour lysis syndrome Common Hyperuricaemia Uncommon Tumour lysis syndrome Nervous system disorders Common Intracranial haemorrhage Uncommon Cerebrovascular accident Uncommon Cerebrovascular accident Intracranial haemorrhage Cardiac disorders Common Cardiac failure Atrial fibrillation Myocardial infarction Common Cardiac failure Atrial fibrillation Uncommon Myocardial infarction Immune system disorders Common Angioedema Urticaria Uncommon Angioedema Urticaria Respiratory, thoracic and mediastinal disorders Common Epistaxis Interstitial lung disease Uncommon Epistaxis Interstitial lung disease Hepatobiliary disorders Uncommon Hepatitis Skin and subcutaneous tissue disorders Not Known Drug Reaction with Eosinophilia and Systemic Symptoms Toxic Epidermal Necrolysis Stevens-Johnson Syndrome Not Known Drug Reaction with Eosinophilia and Systemic Symptoms Toxic Epidermal Necrolysis Stevens-Johnson Syndrome Investigations Common Blood uric acid increased Uncommon Blood uric acid increased Description of selected adverse reactions 24 Teratogenicity Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Pomalidomide was found to be teratogenic in both rats and rabbits when administered during the period of major organogenesis (see sections 4.6 and 5.3). If pomalidomide is taken during pregnancy, a teratogenic effect of pomalidomide in humans is expected (see section 4.4). Neutropenia and thrombocytopenia In patients receiving combination therapy with pomalidomide in clinical studies, neutropenia occurred in up to 46.8% of patients (41.7% Grade 3 or 4). Neutropenia did not lead to pomalidomide discontinuation in any patient and was infrequently serious. Febrile neutropenia (FN) was reported in 3.2-6.7% of patients and was serious in 1.8-4.0% of patients (see section 4.2 and 4.4). In patients receiving combination therapy with pomalidomide in clinical studies, thrombocytopenia occurred in 27.0-36.7% of patients. Thrombocytopenia was Grade 3 or 4 in 20.7-27.3% of patients, led to pomalidomide discontinuation in 0.7% of patients and was serious in 0.4-1.7% of patients (see sections 4.2 and 4.4). Neutropenia and thrombocytopenia tended to occur more frequently within the first 2 cycles of treatment with pomalidomide. Infection Infection was the most common non haematological toxicity. In patients receiving combination therapy with pomalidomide in clinical studies, infection occurred in 55.0-80.2% of patients (24.0-30.9% Grade 3 or 4). Upper respiratory tract infection and pneumonia were the most frequently occurring infections. Fatal infections (Grade 5) occurred in 2.7-4.0% of patients. Infections led to pomalidomide discontinuation in 2.0-2.9% of patients. Thromboembolic events Prophylaxis with acetylsalicylic acid (and other anticoagulants in high risk patients) was mandatory for all patients in clinical studies. Anticoagulation therapy (unless contraindicated) is recommended (see section 4.4). In patients receiving combination therapy with pomalidomide in clinical studies, venous thromboembolic events (VTE) occurred in 3.3-11.5% of patients (1.3-5.4% Grade 3 or 4). VTE was reported as serious in 1.7-4.3% of patients, no fatal reactions were reported, and VTE was associated with pomalidomide discontinuation in up to 1.8% of patients. Peripheral neuropathy • Pomalidomide in combination with bortezomib and dexamethasone Patients with ongoing peripheral neuropathy ≥ Grade 2 with pain within 14 days prior to randomisation were excluded from clinical trials. Peripheral neuropathy occurred in 55.4 % of patients (10.8% Grade 3; 0.7% Grade 4). Exposure-adjusted rates were comparable across treatment arms. Approximately 30% of the patients experiencing peripheral neuropathy had a history of neuropathy at baseline. Peripheral neuropathy led to discontinuation of bortezomib in approximately 12.9% of patients, pomalidomide in 1.8% and dexamethasone in 2.2 - 8.9% of patients, respectively. Refer also to the bortezomib SmPC. 25 • Pomalidomide in combination with dexamethasone Patients with ongoing peripheral neuropathy ≥ Grade 2 were excluded from clinical studies. Peripheral neuropathy occurred in 12.3% of patients (1.0% Grade 3 or 4). No peripheral neuropathy reactions were reported as serious, and peripheral neuropathy led to dose discontinuation in 0.3% of patients (see section 4.4). Haemorrhage Haemorrhagic disorders have been reported with pomalidomide, especially in patients with risk factors such as concomitant medicinal products that increase susceptibility to bleeding. Haemorrhagic events have included epistaxis, intracranial haemorrhage and gastrointestinal haemorrhage. Allergic reactions and severe skin reactions Angioedema and severe cutaneous reactions including SJS, TEN and DRESS has been reported with the use of pomalidomide. Patients with a history of severe rash associated with lenalidomide or thalidomide should not receive pomalidomide (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Pomalidomide doses as high as 50 mg as a single dose in healthy volunteers, and 10 mg as once-daily multiple doses in multiple myeloma patients have been studied without reported serious adverse reactions related to overdose. In studies, pomalidomide was found to be removed by haemodialysis. In the event of overdose, supportive care is advised. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, Other immunosuppressants, ATC code: L04AX06 Mechanism of action Pomalidomide has direct anti-myeloma tumoricidal activity, immunomodulatory activities and inhibits stromal cell support for multiple myeloma tumour cell growth. Specifically, pomalidomide inhibits proliferation and induces apoptosis of haematopoietic tumour cells. Additionally, pomalidomide inhibits the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergises with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumour cell apoptosis. Pomalidomide enhances T cell- and natural killer (NK) cell-mediated immunity and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide also inhibits angiogenesis by blocking the migration and adhesion of endothelial cells. Pomalidomide binds directly to the protein cereblon (CRBN), which is part of an E3 ligase complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins-1 (Roc1), and can inhibit the auto-ubiquitination of CRBN within the complex. E3 ubiquitin http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 26 ligases are responsible for the poly-ubiquitination of a variety of substrate proteins, and may partially explain the pleiotropic cellular effects observed with pomalidomide treatment. In the presence of pomalidomide in vitro, substrate proteins Aiolos and Ikaros are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. In vivo, pomalidomide therapy led to reduction in the levels of Ikaros in patients with relapsed lenalidomide- refractory multiple myeloma. Clinical efficacy and safety • Pomalidomide in combination with bortezomib and dexamethasone The efficacy and safety of pomalidomide in combination with bortezomib and low-dose dexamethasone (Pom+Btz+LD-Dex) was compared with bortezomib and low-dose dexamethasone (Btz+LD-Dex) in a Phase III multi-centre, randomised, open-label study (CC-4047-MM-007), in previously treated adult patients with multiple myeloma, who had received at least one prior regimen, including lenalidomide and have demonstrated disease progression on or after the last therapy. A total of 559 patients were enrolled and randomised in the study: 281 in the Pom+Btz+LD-Dex arm and 278 in the Btz+LD-Dex arm. 54% of patients were male with median age for the overall population of 68 years (min, max: 27, 89 years). Approximately 70% of patients were refractory to lenalidomide (71.2% in Pom+Btz+LD-Dex, 68.7 % in Btz+LD-Dex). Approximately 40% of patients were in 1st relapse and approximately 73% of patients received bortezomib as prior treatment. Patients in the Pom+Btz+LD-Dex arm were administered 4 mg pomalidomide orally on Days 1 to 14 of each 21-day cycle. Bortezomib (1.3 mg/m2/dose) was administered to patients in both study arms on Days 1, 4, 8 and 11 of a 21-day cycle for Cycles 1 to 8; and on Days 1 and 8 of a 21-day cycle for Cycles 9 and onwards. Low-dose dexamethasone (20 mg/day [≤ 75 years old] or 10 mg/day [> 75 years old]) was administered to patients in both study arms on Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle for Cycles 1 to 8; and on Days 1, 2, 8 and 9 of each subsequent 21-day cycle from Cycles 9 onwards. Doses were reduced and treatment was temporarily interrupted or stopped as needed to manage toxicity (see section 4.2). The primary efficacy endpoint was Progression Free Survival (PFS) assessed by an Independent Response Adjudication Committee (IRAC) according to the IMWG criteria using the intent to treat population (ITT). After a median follow-up of 15.9 months, median PFS time was 11.20 months (95% CI: 9.66, 13.73) in the Pom+Btz+LD-Dex arm. In the Btz+LD-Dex arm, median PFS time was 7.1 months (95% CI: 5.88, 8.48). Summary of overall efficacy data are presented in Table 10 using a cut-off date of 26 Oct 2017. Kaplan- Meier curve for PFS for the ITT population is provided in Figure 1. Table 10. Summary of overall efficacy data Pom+Btz+LD-Dex (N = 281) Btz+LD-Dex (N = 278) PFS (months) Mediana time (95% CI) b 11.20 (9.66, 13.73) 7.10 (5.88, 8.48) HR c (95% CI), p-valued 0.61 (0.49, 0.77), <0.0001 ORR, n (%) 82.2 % 50.0% sCR 9 (3.2) 2 (0.7) 27 CR 35 (12.5) 9 (3.2) VGPR 104 (37.0) 40 (14.4) PR 83 (29.5) 88 (31.7) OR (95% CI) e, p-valuef 5.02 (3.35, 7.52), <0.001 DoR (months) Mediana time (95% CI) b 13.7 (10.94, 18.10) 10.94 (8.11, 14.78) HRc (95% CI) 0.76 (0.56, 1.02) Btz = bortezomib; CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard Ratio; LD-Dex = low-dose dexamethasone; OR = Odds ratio; ORR = Overall response rate; PFS = Progression free survival; POM = pomalidomide; PR = Partial Response; sCR = Stringent complete response VGPR = Very good partial response. a The median is based on the Kaplan-Meier estimate. b 95% CI about the median. c Based on Cox proportional hazards model. d The p-value is based on a stratified log-rank test. e Odds ratio is for Pom+Btz+LD-Dex:Btz+LD-Dex. f The p-value is based on a CMH test, stratified by age (<=75 vs >75), Prior number of antimyeloma regimens (1 vs >1), and Beta-2 microglobulin at screening (< 3.5 mg/L versus ≥ 3.5 mg/L — ≤ 5.5 mg/L versus > 5.5 mg/L). The median duration of treatment was 8.8 months (12 treatment cycles) in the Pom+Btz+LD-Dex arm and 4.9 months (7 treament cycles) in the Btz+LD-Dex arm. The PFS advantage was more pronounced in patients who received only one prior line of therapy. In patients who received 1 prior antimyeloma line, median PFS time was 20.73 months (95% CI: 15.11, 27.99) in the Pom + Btz + LD-Dex arm and 11.63 months (95% CI: 7.52, 15.74) in the Btz + LD-Dex arm. A 46% risk reduction was observed with Pom + Btz + LD-Dex treatment (HR = 0.54, 95% CI: 0.36, 0.82). Figure 1. Progression Free Survival Based on IRAC Review of Response by IMWG Criteria (Stratified Log Rank Test) (ITT Population). 28 Data cutoff: 26 Oct 2017 As per an interim analysis for Overall Survival (OS), using a cut-off of 15 September 2018 (median follow-up period of 26.2 months), median OS time from Kaplan-Meier estimates was 40.5 months for the Pom + Btz + LD-Dex arm and 30.5 months for the Btz + LD-Dex arm; HR = 0.91, 95% CI: 0.70, 1.18, with an overall event rate of 43.3%. • Pomalidomide in combination with dexamethasone The efficacy and safety of pomalidomide in combination with dexamethasone were evaluated in a Phase III multi-centre, randomised, open-label study (CC-4047-MM-003), where pomalidomide plus low-dose dexamethasone therapy (Pom+LD-Dex) was compared to high-dose dexamethasone alone (HD-Dex) in previously treated adult patients with relapsed and refractory multiple myeloma, who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. A total of 455 patients were enrolled in the study: 302 in the Pom+LD-Dex arm and 153 in the HD-Dex arm. The majority of patients were male (59%) and white (79%); the median age for the overall population was 64 years (min, max: 35, 87 years). Patients in the Pom+LD-Dex arm were administered 4 mg pomalidomide orally on days 1 to 21 of each 28-day cycle. LD-Dex (40 mg) was administered once per day on days 1, 8, 15 and 22 of a 28-day cycle. For the HD-Dex arm, dexamethasone (40 mg) was administered once per day on days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle. Patients > 75 years of age started treatment with 20 mg dexamethasone. Treatment continued until patients had disease progression. The primary efficacy endpoint was progression free survival by International Myeloma Working Group (IMWG criteria). For the intention to treat (ITT) population, median PFS time by Independent Review Adjudication Committee (IRAC) review based on IMWG criteria was 15.7 weeks (95% CI: 13.0, 20.1) in the Pom + LD-Dex arm; the estimated 26-week event-free survival rate was 35.99% (±3.46%). In the HD-Dex arm, median PFS time was 8.0 weeks (95% CI: 7.0, 9.0); the estimated 26-week event-free survival rate was 12.15% (±3.63%). PFS was evaluated in several relevant subgroups: gender, race, ECOG performance status, stratification factors (age, disease population, prior anti-myeloma therapies [2, > 2]), selected parameters of prognostic significance (baseline beta-2 microglobulin level, baseline albumin levels, baseline renal impairment, and cytogenetic risk), and exposure and refractoriness to prior anti-myeloma therapies. Regardless of the subgroup evaluated, PFS was generally consistent with that observed in the ITT population for both treatment groups. PFS is summarised in Table 11 for the ITT population. Kaplan-Meier curve for PFS for the ITT population is provided in Figure 2. Table 11. Progression Free Survival Time by IRAC Review Based on IMWG Criteria (Stratified Log Rank Test) (ITT Population) Pom+LD-Dex (N=302) HD-Dex (N=153) Progression free survival (PFS), N 302 (100.0) 153 (100.0) Censored, n (%) 138 (45.7) 50 (32.7) Progressed/Died, n (%) 164 (54.3) 103 (67.3) 29 Progression Free Survival Time (weeks) Mediana 15.7 8.0 Two sided 95% CIb [13.0, 20.1] [7.0, 9.0] Hazard Ratio (Pom+LD-Dex:HD-Dex) 2-Sided 95% CI c 0.45 [0.35,0.59] Log-Rank Test Two sided P-Value d <0.001 Note: CI=Confidence interval; IRAC=Independent Review Adjudication Committee; NE = Not Estimable. a The median is based on Kaplan-Meier estimate. b 95% confidence interval about the median progression free survival time. c Based on Cox proportional hazards model comparing the hazard functions associated with treatment groups, stratified by age (≤75 vs >75),diseases population (refractory to both lenalidomide and bortezomib vs not refractory to both active substances), and prior number of anti myeloma therapy (=2 vs >2). d The p-value is based on a stratified log-rank test with the same stratification factors as the above Cox model. Data cutoff: 07 Sep 2012 Figure 2. Progression Free Survival Based on IRAC Review of Response by IMWG Criteria (Stratified Log Rank Test) (ITT Population) Data cutoff: 07 Sep 2012 Overall Survival was the key secondary study endpoint. A total of 226 (74.8%) of the Pom + LD-Dex patients and 95 (62.1%) of the HD-Dex patients were alive as of the cutoff date (07 Sep 2012). Median OS time from Kaplan-Meier estimates has not been reached for the Pom + LD-Dex, but would be expected to be at least 48 weeks, which is the lower boundary of the 95% CI. Median OS time for the HD-Dex arm was 34 weeks (95% CI: 23.4, 39.9). The 1-year event free rate was 52.6% (± 5.72%) for the Pom + LD-Dex arm and 28.4% (± 7.51%) for the HD-Dex arm. The difference in OS between the two treatment arms was statistically significant (p < 0.001). 0 13 26 39 52 65 HD - DEX POM+LD - DEX 1.0 0.8 0.6 0.4 0.2 0.0 Progression Free Survival (weeks) POM+LD-DEX vs HD-DEX Logrank p-value = < 0.001 (2-sided) HR (95% CI) 0.45 (0.35, 0.59) Events: POM+LD-DEX=164/302 HD-DEX=103/153 P ro p o ti o n o f P at ie n ts 30 Overall survival is summarised in Table 12 for the ITT population. Kaplan-Meier curve for OS for the ITT population is provided in Figure 3. Based on the results of both PFS and OS endpoints, the Data Monitoring Committee established for this study recommended that the study be completed and patients in the HD-Dex arm be crossed over to the Pom + LD-Dex arm. Table 12. Overall Survival: ITT Population Statistics Pom+LD-Dex (N=302) HD-Dex (N=153) N 302 (100.0) 153 (100.0) Censored n (%) 226 (74.8) 95 (62.1) Died n (%) 76 (25.2) 58 (37.9) Survival Time (weeks) Mediana NE 34.0 Two sided 95% CIb [48.1, NE] [23.4, 39.9] Hazard Ratio (Pom+LD-Dex:HD-Dex) [Two sided 95% CIc] 0.53[0.37, 0.74] Log-Rank Test Two sided P-Valued <0.001 Note: CI=Confidence interval. NE = Not Estimable. a The median is based on Kaplan-Meier estimate. b 95% confidence interval about the median overall survival time. c Based on Cox proportional hazards model comparing the hazard functions associated with treatment groups. d The p-value is based on an unstratified log-rank test. Data cutoff: 07 Sep 2012 31 Figure 3. Kaplan-Meier Curve of Overall Survival (ITT Population) cutoff: 07 Sep 2012 5.2 Pharmacokinetic properties Absorption Pomalidomide is absorbed with a maximum plasma concentration (Cmax) occurring between 2 and 3 hours and is at least 73% absorbed following administration of single oral dose. The systemic exposure (AUC) of pomalidomide increases in an approximately linear and dose proportional manner. Following multiple doses, pomalidomide has an accumulation ratio of 27 to 31% on AUC. Coadministration with a high-fat and high-calorie meal slows the rate of absorption, decreasing mean plasma Cmax by approximately 27%, but has minimal effect on the overall extent of absorption with an 8% decrease in mean AUC. Therefore, pomalidomide can be administered without regard to food intake. Distribution Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours post-dose (approximately Tmax) after 4 days of once daily dosing at 2 mg. In vitro binding of pomalidomide enantiomers to proteins in human plasma ranges from 12% to 44% and is not concentration dependent. HD - DEX POM+LD - DEX Overall Survival (week) POM+LD-DEX vs HD-DEX Logrank p-value = < 0.001 (2-sided) HR (95% CI) 0.53 (0.37, 0.74) KM median: POM+LD-DEX=NE [48.1, NE] KM median: HD-DEX = 34.0[23.4, 39.9] Events: POM+LD-DEX=75/284 HD-DEX=56/139 1.0 0.8 0.6 0.4 0.2 0.0 0 13 26 39 52 65 P ro p o ti o n o f P at ie n ts 32 Biotransformation Pomalidomide is the major circulating component (approximately 70% of plasma radioactivity) in vivo in healthy subjects who received a single oral dose of [14C]-pomalidomide (2 mg). No metabolites were present at >10% relative to parent or total radioactivity in plasma. The predominant metabolic pathways of excreted radioactivity are hydroxylation with subsequent glucuronidation, or hydrolysis. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6. Pomalidomide is also a substrate of P-glycoprotein in vitro. Co-administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole, or the strong CYP3A4/5 inducer carbamazepine, had no clinically relevant effect on exposure to pomalidomide. Co-administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole, increased mean exposure to pomalidomide by 107% with a 90% confidence interval [91% to 124%] compared to pomalidomide plus ketoconazole. In a second study to evaluate the contribution of a CYP1A2 inhibitor alone to metabolism changes, co-administration of fluvoxamine alone with pomalidomide increased mean exposure to pomalidomide by 125% with a 90% confidence interval [98% to 157%] compared to pomalidomide alone. If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administered with pomalidomide, reduce the dose of pomalidomide to 50%. Administration of pomalidomide in smokers, with smoking tobacco known to induce the CYP1A2 isoform, had no clinically relevant effect on exposure to pomalidomide compared to that exposure to pomalidomide observed in non-smokers. Based on in vitro data, pomalidomide is not an inhibitor or inducer of cytochrome P-450 isoenzymes, and does not inhibit any drug transporters that were studied. Clinically relevant drug-drug interactions are not anticipated when pomalidomide is coadministered with substrates of these pathways. Elimination Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide has a mean total body clearance (CL/F) of approximately 7-10 L/hr. Following a single oral administration of [14C] -pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and faeces, respectively, with approximately 2% and 8% of the dosed radiocarbon eliminated as pomalidomide in urine and faeces. Pomalidomide is extensively metabolised prior to excretion, with the resulting metabolites eliminated primarily in the urine. The 3 predominant metabolites in urine (formed via hydrolysis or hydroxylation with subsequent glucuronidation) account for approximately 23%, 17%, and 12%, respectively, of the dose in the urine. CYP dependent metabolites account for approximately 43% of the total excreted radioactivity, while non- CYP dependent hydrolytic metabolites account for 25%, and excretion of unchanged pomalidomide accounted for 10% (2% in urine and 8% in faeces). Population Pharmacokinetics (PK) Based on population PK analysis using a two-compartment model, healthy subjects and MM patients had comparable apparent clearance (CL/F) and apparent central volume of distribution (V2/F). In peripheral tissues, pomalidomide was preferentially taken up by tumors with apparent peripheral distribution 33 clearance (Q/F) and apparent peripheral volume of distribution (V3/F) 3.7-fold and 8-fold higher, respectively, than that of healthy subjects. Paediatric population No data are available on administration of pomalidomide to paediatric patients (< 18 years of age). Elderly Based on population pharmacokinetic analyses in healthy subjects and multiple myeloma patients, no significant influence of age (19-83 years) on oral clearance of pomalidomide was observed. In clinical studies, no dose adjustment was required in elderly (> 65 years) patients exposed to pomalidomide (see section 4.2). Renal impairment Population pharmacokinetic analyses showed that the pomalidomide pharmacokinetic parameters were not remarkably affected in renally impaired patients (defined by creatinine clearance or estimated glomerular filtration rate [eGFR]) compared to patients with normal renal function (CrCl ≥60 mL/minute). Mean normalised AUC exposure to pomalidomide was 98.2% with a 90% confidence interval [77.4% to 120.6%] in moderate renal impairment patients (eGFR ≥30 to ≤45 mL/minute/1.73 m2) compared to patients with normal renal function. Mean normalised AUC exposure to pomalidomide was 100.2% with a 90% confidence interval [79.7% to 127.0%] in severe renal impairment patients not requiring dialysis (CrCl <30 or eGFR <30 mL/minute/1.73 m2) compared to patients with normal renal function. Mean normalised AUC exposure to pomalidomide increased by 35.8% with a 90% CI [7.5% to 70.0%] in severe renal impairment patients requiring dialysis (CrCl <30mL/minute requiring dialysis) compared to patients with normal renal function. The mean changes in exposure to pomalidomide in each of these renal impairment groups are not of a magnitude that requires dosage adjustments. Hepatic impairment The pharmacokinetic parameters were modestly changed in hepatically impaired patients (defined by Child-Pugh criteria) compared to healthy subjects. Mean exposure to pomalidomide increased by 51% with a 90% confidence interval [9% to 110%] in mildly hepatically impaired patients compared to healthy subjects. Mean exposure to pomalidomide increased by 58% with a 90% confidence interval [13% to 119%] in moderately hepatically impaired patients compared to healthy subjects. Mean exposure to pomalidomide increased by 72% with a 90% confidence interval [24% to 138%] in severely hepatically impaired patients compared to healthy subjects. The mean increases in exposure to pomalidomide in each of these impairment groups are not of a magnitude for which adjustments in schedule or dose are required (see section 4.2). 5.3 Preclinical safety data Repeat-dose toxicology studies In rats, chronic administration of pomalidomide at doses of 50, 250, and 1000 mg/kg/day for 6 months was well tolerated. No adverse findings were noted up to 1000 mg/kg/day (175-fold exposure ratio relative to a 4 mg clinical dose). 34 In monkeys, pomalidomide was evaluated in repeat-dose studies of up to 9 months in duration. In these studies, monkeys exhibited greater sensitivity to pomalidomide effects than rats. The primary toxicities observed in monkeys were associated with the haematopoietic/lymphoreticular systems. In the 9-month study in monkeys with doses of 0.05, 0.1, and 1 mg/kg/day, morbidity and early euthanasia of 6 animals were observed at the dose of 1 mg/kg/day and were attributed to immunosuppressive effects (staphylococcal infection, decreased peripheral blood lymphocytes, chronic inflammation of the large intestine, histologic lymphoid depletion, and hypocellularity of bone marrow) at high exposures of pomalidomide (15-fold exposure ratio relative to a 4 mg clinical dose). These immunosuppressive effects resulted in early euthanasia of 4 monkeys due to poor health condition (watery stool, inappetence, reduced food intake, and weight loss); histopathologic evaluation of these animals showed chronic inflammation of the large intestine and villous atrophy of the small intestine. Staphylococcal infection was observed in 4 monkeys; 3 of these animals responded to antibiotic treatment and 1 died without treatment. In addition, findings consistent with acute myelogenous leukemia led to euthanasia of 1 monkey; clinical observations and clinical pathology and/or bone marrow alterations observed in this animal were consistent with immunosuppression. Minimal or mild bile duct proliferation with associated increases in ALP and GGT were also observed at 1 mg/kg/day. Evaluation of recovery animals indicated that all treatment-related findings were reversible after 8 weeks of dosing cessation, except for proliferation of intrahepatic bile ducts observed in 1 animal in the 1 mg/kg/day group. The No Observed Adverse Effect Level (NOAEL) was 0.1 mg/kg/day (0.5-fold exposure ratio relative to a 4 mg clinical dose). Genotoxicity/carcinogenicity Pomalidomide was not mutagenic in bacterial and mammalian mutation assays, and did not induce chromosomal aberrations in human peripheral blood lymphocytes or micronuclei formation in polychromatic erythrocytes in bone marrow of rats administered doses up to 2000 mg/kg/day. Carcinogenicity studies have not been conducted. Fertility and early embryonic development In a fertility and early embryonic development study in rats, pomalidomide was administered to males and females at dosages of 25, 250, and 1000 mg/kg/day. Uterine examination on Gestation Day 13 showed a decrease in mean number of viable embryos and an increase in postimplantation loss at all dosage levels. Therefore, the NOAEL for these observed effects was < 25 mg/kg/day (AUC 24h was 39960 ng•h/mL (nanogram•hour/millilitres) at this lowest dose tested, and the exposure ratio was 99-fold relative to a 4 mg clinical dose). When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. Embryo-foetal development Pomalidomide was found to be teratogenic in both rats and rabbits when administered during the period of major organogenesis. In the rat embryofoetal developmental toxicity study, malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (central and/or neural arches) were observed at all dosage levels (25, 250, and 1000 mg/kg/day). There was no maternal toxicity observed in this study. Therefore, the maternal NOAEL was 1000 mg/kg/day, and the NOAEL for developmental toxicity was < 25 mg/kg/day (AUC24h was 34340 ng•h/mL on Gestation Day 17 at this lowest dose tested, and the exposure ratio was 85-fold relative to a 4 mg clinical dose). In rabbits, pomalidomide at dosages ranging from 10 to 250 mg/kg 35 produced embryo-foetal developmental malforma tions. Increased cardiac anomalies were seen at all doses with significant increases at 250 mg/kg/day. At 100 and 250 mg/kg/day, there were slight increases in post-implantation loss and slight decreases in fetal body weights. At 250 mg/kg/day, fetal malformations included limb anomalies (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia); moderate dilation of the lateral ventricle in the brain; abnormal placement of the right subclavian artery; absent intermediate lobe in the lungs; low-set kidney; altered liver morphology; incompletely or not ossified pelvis; an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. Slight reduction in maternal body weight gain, significant reduction in triglycerides, and significant dec rease in absolute and relative spleen weights were observed at 100 and 250 mg/kg/day. The maternal NOAEL was 10 mg/kg/day, and the developmental NOAEL was <10 mg/kg/day (AUC24h was 418 ng•h/mL on Gestation Day 19 at this lowest dose tested, which was similar to that obtained from a 4 mg clinical dose). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule contents Mannitol (E421) Starch, pregelatinised Sodium stearyl fumarate Capsule shell Imnovid 1 mg hard capsules Gelatin Titanium dioxide (E171) Indigotine (E132) Yellow iron oxide (E172) White and black ink Imnovid 2 mg hard capsules Gelatin Titanium dioxide (E171) Indigotine (E132) Yellow iron oxide (E172) Erythrosin (E127) White ink Imnovid 3 mg hard capsules Gelatin Titanium dioxide (E171) Indigotine (E132) Yellow iron oxide (E172) White ink 36 Imnovid 4 mg hard capsules Gelatin Titanium dioxide (E171) Indigotine (E132) Brilliant blue FCF (E133) White ink Printing ink Imnovid 1 mg hard capsules White ink Shellac Titanium dioxide (E171) Simeticone Propylene glycol (E1520) Ammonium hydroxide (E527) Black ink Shellac Iron oxide black (E172) Propylene glycol (E1520) Ammonium hydroxide (E527) Imnovid 2 mg hard capsules, Imnovid 3 mg hard capsules, Imnovid 4 mg hard capsules White ink Shellac Titanium dioxide (E171) Simeticone Propylene glycol (E1520) Ammonium hydroxide (E527) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container The capsules are packaged in Polyvinyl chloride (PVC)/ polychlorotrifluoroethylene (PCTFE) blisters with push through aluminium foil. Pack size of 14 or 21 capsules. Not all pack size may be marketed. 37 6.6 Special precautions for disposal and other handling Capsules should not be opened or crushed. If powder from pomalidomide makes contact with the skin, the skin should be washed immediately and thoroughly with soap and water. If pomalidomide makes contact with the mucous membranes, they should be thoroughly flushed with water. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Unused medicinal product should be returned to the pharmacist at the end of treatment. 7. MARKETING AUTHORISATION HOLDER Celgene Europe B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands 8. MARKETING AUTHORISATION NUMBER(S) Imnovid 1 mg hard capsules EU/1/13/850/001 EU/1/13/850/005 Imnovid 2 mg hard capsules EU/1/13/850/002 EU/1/13/850/006 Imnovid 3 mg hard capsules EU/1/13/850/003 EU/1/13/850/007 Imnovid 4 mg hard capsules EU/1/13/850/004 EU/1/13/850/008 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 05 August 2013 Date of latest renewal: 11 July 2018 10. DATE OF REVISION OF THE TEXT 38 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 39 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 40 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Celgene Distribution B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures 1. The MAH shall agree the details of a controlled distribution system with the National Competent Authorities and must implement such programme nationally to ensure that: • Prior to launch, all doctors who intend to prescribe pomalidomide and all pharmacists who may dispense pomalidomide receive a Direct Healthcare Professional Communication as described below. • Prior to prescribing (where appropriate, and in agreement with the National Competent Authority, dispensing) all healthcare professionals who intend to prescribe (and dispense) pomalidomide are provided with a physician information pack containing the following: 41 o Educational Health Care Professional’s kit o Educational brochures for patients o Patient cards o Summary of Product Characteristics (SmPC) and Package Leaflet and Labelling. 2. The MAH shall implement a pregnancy prevention programme (PPP) in each Member State. Details of the PPP should be agreed with the National Competent Authorities in each Member State and put in place prior to the marketing of the product. 3. The MAH should agree the final text of the Direct Healthcare Professional Communication and the physician information pack contents with the National Competent Authority in each Member State and ensure that the materials contain the key elements as described below. 4. The MAH should agree on the implementation of the patient card system in each Member State. Key elements to be included Direct Healthcare Professional Communications (Prior to Launch) The Direct Healthcare Professional Communication shall consist of two parts: • A core text as agreed by the CHMP. • National specific requirements agreed with the National Competent Authority regarding: o Distribution of the product o To ensure that all appropriate measures have been performed prior to pomalidomide being dispensed The Educational Healthcare Professional’s Kit The Educational Health Care Professional’s Kit shall contain the following elements: • Brief background on pomalidomide and its licensed indication • Maximum duration of prescription o 4 weeks for women with childbearing potential o 12 weeks for men and women without childbearing potential • The need to avoid foetal exposure due to teratogenicity of pomalidomide in animals and the expected teratogenic effect of pomalidomide in humans • Obligations of the health care professional in relation to the prescribing of pomalidomide o Need to provide comprehensive advice and counselling to patients o That patients should be capable of complying with the requirements for the safe use of pomalidomide o Need to provide patients with appropriate patient educational brochure and patient card • Safety advice relevant to all patients o Description and management of thrombocytopenia including incidence rates from clinical studies o Description and management of cardiac failure o Disposal of unwanted medicine o Local country specific arrangements for a prescription for pomalidomide to be dispensed • Description of the PPP and categorisation of patients based on sex and childbearing potential o Algorithm for implementation of PPP o Definition of women of childbearing potential (WCBP) and actions the physician should take if unsure • Safety advice for women of childbearing potential o The need to avoid foetal exposure o Description of the PPP o Need for effective contraception (even if woman has amenorrhoea) and definition of effective contraception 42 ▪ Pregnancy test regime ▪ Advice on suitable tests ▪ Before commencing treatment ▪ During treatment based on method of contraception ▪ After finishing treatment o Need to stop pomalidomide immediately upon suspicion of pregnancy o Need to tell treating doctor immediately upon suspicion of pregnancy • Safety advice for men o The need to avoid foetal exposure o The need to use condoms if sexual partner is pregnant or a WCBP and has no contraception (even if man has had a vasectomy) ▪ During pomalidomide treatment ▪ For one week following final dose o That he should not donate semen or sperm during therapy (including during dose interruptions) and for 7 days after discontinuation of pomalidomide treatment o That if his partner becomes pregnant whilst he is taking pomalidomide or shortly after he has stopped taking pomalidomide he should inform his treating doctor immediately • Requirements in the event of pregnancy o Instructions to stop pomalidomide immediately upon suspicion of pregnancy if female patients o Need to refer to physician specialised or experienced in dealing with teratology and its diagnosis for evaluation and advice o Local contact details for reporting of any suspected pregnancy o Pregnancy reporting form • Patient confirmation form ensuring that patients receive the appropriate counselling concerning the treatment, contraceptive methods and pregnancy prevention appropriate for their sex and childbearing status • Adverse event reporting forms Educational Brochures for patients The Educational brochures for patients should be of 3 types: • Brochure for women patients of childbearing potential and their partners • Brochure for women patients who are not of childbearing potential • Brochure for male patients All patient brochures should contain the following elements: • That pomalidomide is teratogenic in animals and is expected to be teratogenic in humans • That pomalidomide may cause thrombocytopenia and the need for regular blood tests • Description of the patient card and its necessity • Disposal of unwanted medicine • Guidance on handling pomalidomide for patients, caregivers and family members • National or other applicable specific arrangements for a prescription for pomalidomide to be dispensed • That the patient should not give pomalidomide to any other person • That the patient should not donate blood during therapy (including during dose interruptions) and for 7 days after discontinuation of pomalidomide treatment • That the patient should tell their doctor about any adverse events The following information should also be provided in the appropriate brochure: 43 Brochure for women patients with childbearing potential • The need to avoid foetal exposure • Description of the PPP • Need for effective contraception and definition of effective contraception • Pregnancy test regime o Before commencing treatment o During treatment (including dose interruptions), at least every 4 weeks except in case of confirmed tubal sterilisation o After finishing treatment • The need to stop pomalidomide immediately upon suspicion of pregnancy • The need to contact their doctor immediately upon suspicion of pregnancy Brochure for male patients • The need to avoid fetal exposure • The need to use condoms if sexual partner is pregnant or a WCBP and has no contraception (even if man has had vasectomy) o During pomalidomide treatment (including dose interruptions) o For 7 days following final dose • That if his partner becomes pregnant he should inform his treating doctor immediately • That he should not donate semen or sperm during therapy (including during dose interruptions) and for 7 days after discontinuation of pomalidomide treatment Patient Card The patient card shall contain the following elements: • Verification that appropriate counselling has taken place • Documentation of childbearing potential status • Pregnancy test dates and results • Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date • To conduct a non-interventional post-authorisation registry of patients treated with pomalidomide for relapsed and refractory multiple myeloma to monitor the incidence of adverse drug reactions in the “real world situation” and to monitor the implementation and compliance of the Celgene PPP and controlled distribution system on a country basis in agreement with the relevant National Competent Authority (ie., monitoring of Patient Card completion). Final clinical study report: 31 August 2023 • Post-authorisation efficacy study (PAES) MM-007: In order to further investigate the efficacy of pomalidomide in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior treatment regimen including lenalidomide, the MAH should submit the final analysis of OS from the phase 3, randomized, open label study MM-007. 30 September 2021 44 ANNEX III LABELLING AND PACKAGE LEAFLET 45 A. LABELLING 46 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imnovid 1 mg hard capsules pomalidomide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 1 mg of pomalidomide. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 hard capsules. 21 hard capsules. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY WARNING: Risk of severe birth defects. Do not use while pregnant or breast-feeding. You must follow the Imnovid Pregnancy Prevention Programme. 8. EXPIRY DATE EXP 47 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Unused medicinal product should be returned to the pharmacist. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Celgene Europe B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/850/005 (Pack size of 14 hard capsules) EU/1/13/850/001 (Pack size of 21 hard capsules) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imnovid 1 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2 D bar code carrying the unique identifier 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 48 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Imnovid 1 mg hard capsules pomalidomide 2. NAME OF THE MARKETING AUTHORISATION HOLDER Celgene Europe B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 49 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imnovid 2 mg hard capsules pomalidomide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 2 mg of pomalidomide. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 hard capsules. 21 hard capsules. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY WARNING: Risk of severe birth defects. Do not use while pregnant or breast-feeding. You must follow the Imnovid Pregnancy Prevention Programme. 8. EXPIRY DATE EXP 50 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Unused medicinal product should be returned to the pharmacist. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Celgene Europe B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/850/006 (Pack size of 14 hard capsules) EU/1/13/850/002 (Pack size of 21 hard capsules) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imnovid 2 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2 D bar code carrying the unique identifier 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 51 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Imnovid 2 mg hard capsules pomalidomide 2. NAME OF THE MARKETING AUTHORISATION HOLDER Celgene Europe B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 52 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imnovid 3 mg hard capsules pomalidomide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 3 mg of pomalidomide. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 hard capsules. 21 hard capsules. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY WARNING: Risk of severe birth defects. Do not use while pregnant or breast-feeding. You must follow the Imnovid Pregnancy Prevention Programme. 8. EXPIRY DATE EXP 53 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Unused medicinal product should be returned to the pharmacist. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Celgene Europe B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/850/007 (Pack size of 14 hard capsules) EU/1/13/850/003 (Pack size of 21 hard capsules) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imnovid 3 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2 D bar code carrying the unique identifier 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 54 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Imnovid 3 mg hard capsules pomalidomide 2. NAME OF THE MARKETING AUTHORISATION HOLDER Celgene Europe B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 55 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imnovid 4 mg hard capsules pomalidomide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 4 mg of pomalidomide. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 hard capsules. 21 hard capsules. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY WARNING: Risk of severe birth defects. Do not use while pregnant or breast-feeding. You must follow the Imnovid Pregnancy Prevention Programme. 8. EXPIRY DATE EXP 56 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Unused medicinal product should be returned to the pharmacist. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Celgene Europe B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/850/008 (Pack size of 14 hard capsules) EU/1/13/850/004 (Pack size of 21 hard capsules) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imnovid 4 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2 D bar code carrying the unique identifier 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 57 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Imnovid 4 mg hard capsules pomalidomide 2. NAME OF THE MARKETING AUTHORISATION HOLDER Celgene Europe B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 58 B. PACKAGE LEAFLET 59 Package leaflet: Information for the patient Imnovid 1 mg hard capsules Imnovid 2 mg hard capsules Imnovid 3 mg hard capsules Imnovid 4 mg hard capsules pomalidomide This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Imnovid is expected to cause severe birth defects and may lead to the death of an unborn baby. • Do not take this medicine if you are pregnant or could become pregnant. • You must follow the contraception advice described in this leaflet. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, pharmacist or nurse. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor, pharmacist or nurse. • This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Imnovid is and what it is used for 2. What you need to know before you take Imnovid 3. How to take Imnovid 4. Possible side effects 5. How to store Imnovid 6. Contents of the pack and other information 1. What Imnovid is and what it is used for What Imnovid is Imnovid contains the active substance ‘pomalidomide’. This medicine is related to thalidomide and belongs to a group of medicines which affect the immune system (the body’s natural defences). What Imnovid is used for Imnovid is used to treat adults with a type of cancer called ‘multiple myeloma’. Imnovid is either used with: • two other medicines - called ‘bortezomib’ (a type of chemotherapy medicine) and ‘dexamethasone’ (an anti-inflammatory medicine) in people who have had at least one other treatment - including lenalidomide. Or 60 • one other medicine - called ‘dexamethasone’ in people whose myeloma has become worse, despite having at least two other treatments - including lenalidomide and bortezomib. What is multiple myeloma Multiple myeloma is a type of cancer which affects a certain type of white blood cell (called the ‘plasma cell’). These cells grow out of control and accumulate in the bone marrow. This results in damage to the bones and kidneys. Multiple myeloma generally cannot be cured. However, treatment can reduce the signs and symptoms of the disease, or make them disappear for a period of time. When this happens, it is called ‘response’. How Imnovid works Imnovid works in a number of different ways: • by stopping the myeloma cells developing • by stimulating the immune system to attack the cancer cells • by stopping the formation of blood vessels supplying the cancer cells. The benefit of using Imnovid with bortezomib and dexamethasone When Imnovid is used with bortezomib and dexamethasone, in people who have had at least one other treatment, it can stop multiple myeloma getting worse: • On average, Imnovid when used with bortezomib and dexamethasone stopped multiple myeloma from coming back for up to 11 months - compared with 7 months for those patients who only used bortezomib and dexamethasone. The benefit of using Imnovid with dexamethasone When Imnovid is used with dexamethasone, in people who have had at least two other treatments, it can stop multiple myeloma getting worse: • On average, Imnovid when used with dexamethasone stopped multiple myeloma from coming back for up to 4 months - compared with 2 months for those patients who used only dexamethasone. 2. What you need to know before you take Imnovid Do not take Imnovid: • if you are pregnant or think you may be pregnant or are planning to become pregnant – this is because Imnovid is expected to be harmful to an unborn child. (Men and women taking this medicine must read the section “Pregnancy, contraception and breast-feeding – information for women and men” below). • if you are able to become pregnant, unless you follow all the necessary measures to prevent you from becoming pregnant (see “Pregnancy, contraception and breast-feeding – information for women and men”). If you are able to become pregnant, your doctor will record with each prescription that the necessary measures have been taken and will provide you with this confirmation. • if you are allergic to pomalidomide or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice. If you are uncertain whether any of the conditions above apply to you, talk to your doctor, pharmacist or nurse before taking Imnovid. 61 Warnings and precautions Talk to your doctor, pharmacist or nurse before taking Imnovid if: • you have ever had blood clots in the past. During the treatment with Imnovid you have an increased risk of getting blood clots in your veins and arteries. Your doctor may recommend you take additional treatments (e.g. warfarin) or lower the dose of Imnovid to reduce the chance that you get blood clots. • you have ever had an allergic reaction such as rash, itching, swelling, feeling dizzy or trouble breathing while taking related medicines called ‘thalidomide’ or ‘lenalidomide’. • you have had a heart attack, have heart failure, have difficulty breathing, or if you smoke, have high blood pressure or high cholesterol levels. • you have a high total amount of tumour throughout the body, including your bone marrow. This could lead to a condition where the tumours break down and cause unusual levels of chemicals in the blood which can lead to kidney failure. You may also experience an uneven heartbeat. This condition is called tumour lysis syndrome. • you have or have had neuropathy (nerve damage causing tingling or pain in your hands or feet). • you have or have ever had hepatitis B infection. Treatment with Imnovid may cause the hepatitis B virus to become active again in patients who carry the virus, resulting in a recurrence of the infection. Your doctor should check whether you have ever had hepatitis B infection. • you experience or have experienced in the past a combination of any of the following symptoms: rash on face or extended rash, red skin, high fever, flu-like symptoms, enlarged lymph nodes (signs of severe skin reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) or drug hypersensitivity syndrome, Toxic Epidermal Necrolysis (TEN) or Stevens-Johnson Syndrome (SJS). See also section 4 “Possible side effects”). It is important to note that patients with multiple myeloma treated with pomalidomide may develop additional types of cancer, therefore your doctor should carefully evaluate the benefit and risk when you are prescribed this medicine. At the end of the treatment you should return all unused capsules to the pharmacist. Pregnancy, contraception and breast-feeding – information for women and men The following must be followed as stated in the Imnovid Pregnancy Prevention Programme. Women and men taking Imnovid must not become pregnant or father a child. This is because pomalidomide is expected to harm the unborn baby. You and your partner should use effective methods of contraception while taking this medicine. Women Do not take Imnovid if you are pregnant, think you may be pregnant or are planning to become pregnant. This is because this medicine is expected to harm the unborn baby. Before starting the treatment, you should tell your doctor if you are able to become pregnant, even if you think this is unlikely. If you are able to become pregnant: • you must use effective methods of contraception for at least 4 weeks before starting treatment, for the whole time you are taking treatment, and until at least 4 weeks after stopping treatment. Talk to your doctor about the best method of contraception for you. • each time your doctor writes a prescription for you, he will ensure you understand the necessary measures that have to be taken to prevent pregnancy. • your doctor will arrange pregnancy tests before treatment, at least every 4 weeks during treatment, and at least 4 weeks after the treatment has finished. 62 If you become pregnant despite the prevention measures: • you must stop the treatment immediately and talk to your doctor straight away. Breast-feeding It is not known if Imnovid passes into human breast milk. Tell your doctor if you are breast-feeding or intend to breast-feed. Your doctor will advise if you should stop or continue breast-feeding. Men Imnovid passes into human semen. • If your partner is pregnant or able to become pregnant, you must use condoms for the whole time you are taking treatment and for 7 days after the end of treatment. • If your partner becomes pregnant while you are taking Imnovid, tell your doctor straight away. Your partner should also tell her doctor straight away. You should not donate semen or sperm during treatment and for 7 days after the end of treatment. Blood donation and blood tests You should not donate blood during treatment and for 7 days after the end of treatment. Before and during the treatment with Imnovid you will have regular blood tests. This is because your medicine may cause a fall in the number of blood cells that help fight infection (white cells) and in the number of cells that help to stop bleeding (platelets). Your doctor should ask you to have a blood test: • before treatment • every week for the first 8 weeks of treatment • at least every month after that for as long as you are taking Imnovid. As a result of these tests, your doctor may change your dose of Imnovid or stop your treatment. The doctor may also change the dose or stop the medicine because of your general health. Children and adolescents Imnovid is not recommended for use in children and young people under 18 years. Other medicines and Imnovid Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. This is because Imnovid can affect the way some other medicines work. Also some other medicines can affect the way Imnovid works. In particular, tell your doctor, pharmacist or nurse before taking Imnovid if you are taking any of the following medicines: • some antifungals such as ketaconazole • some antibiotics (for example ciprofloxacin, enoxacin) • certain antidepressants such as fluvoxamine. Driving and using machines Some people feel tired, dizzy, faint, confused or less alert when taking Imnovid. If this happens to you, do not drive or operate tools or machinery. 63 Imnovid contains sodium This medicine contains less than 1 mmol sodium (23 mg) per capsule, therefore it is considered essentially ‘sodium-free’. 3. How to take Imnovid Imnovid must be given to you by a doctor with experience in treating multiple myeloma. Always take your medicines exactly as your doctor has told you. Check with your doctor, pharmacist or nurse if you are not sure. When to take Imnovid with other medicines Imnovid with bortezomib and dexamethasone • See the leaflets that come with bortezomib and dexamethasone for further information on their use and effects. • Imnovid, bortezomib and dexamethasone are taken in ‘treatment cycles’. Each cycle lasts 21 days (3 weeks). • Look at the chart below to see what to take on each day of the 3-week cycle: o Each day, look down the chart and find the correct day to see which medicines to take. o Some days, you take all 3 medicines, some days just 2 or 1 medicines, and some days none at all. IMN: Imnovid; BOR: Bortezomib; DEX: Dexamethasone Cycle 1 to 8 Cycle 9 and onwards Medicine name Medicine name Day IMN BOR DEX Day IMN BOR DEX 1 √ √ √ 1 √ √ √ 2 √ √ 2 √ √ 3 √ 3 √ 4 √ √ √ 4 √ 5 √ √ 5 √ 6 √ 6 √ 7 √ 7 √ 8 √ √ √ 8 √ √ √ 9 √ √ 9 √ √ 10 √ 10 √ 11 √ √ √ 11 √ 12 √ √ 12 √ 13 √ 13 √ 14 √ 14 √ 15 15 16 16 17 17 18 18 19 19 20 20 21 21 64 • After completing each 3-week cycle, start a new one. Imnovid with dexamethasone only • See the leaflet that comes with dexamethasone for further information on its use and effects. • Imnovid and dexamethasone are taken in ‘treatment cycles’. Each cycle lasts 28 days (4 weeks). • Look at the chart below to see what to take on each day of the 4-week cycle: o Each day, look down the chart and find the correct day to see which medicines to take. o Some days, you take both medicines, some days just 1 medicine, and some days none at all. IMN: Imnovid; DEX: Dexamethasone Medicine name Day IMN DEX 1 √ √ 2 √ 3 √ 4 √ 5 √ 6 √ 7 √ 8 √ √ 9 √ 10 √ 11 √ 12 √ 13 √ 14 √ 15 √ √ 16 √ 17 √ 18 √ 19 √ 20 √ 21 √ 22 √ 23 24 25 26 27 28 • After completing each 4-week cycle, start a new one. 65 How much Imnovid to take with other medicines Imnovid with bortezomib and dexamethasone • The recommended starting dose of Imnovid is 4 mg per day. • The recommended starting dose of bortezomib will be worked out by your doctor and based on your height and weight (1.3 mg/m2 body surface area). • The recommended starting dose of dexamethasone is 20 mg per day. However, if you are over 75, the recommended starting dose is 10 mg per day. Imnovid with dexamethasone only • The recommended dose of Imnovid is 4 mg per day. • The recommended starting dose of dexamethasone is 40 mg per day. However, if you are over 75, the recommended starting dose is 20 mg per day. Your doctor may need to reduce the dose of Imnovid, bortezomib or dexamethasone or stop one or more of these medicines based on the results of your blood tests, your general condition, other medic ines you may be taking (e.g. ciprofloxacin, enoxacin and fluvoxamine) and if you experience side effects (especially rash or swelling) from treatment. If you suffer from liver or kidney problems your doctor will check your condition very carefully whilst you are receiving this medicine. How to take Imnovid • Do not break, open or chew the capsules. If powder from a broken Imnovid capsule makes contact with the skin, wash the skin immediately and thoroughly with soap and water. • Swallow the capsules whole, preferably with water. • You can take the capsules either with or without food. • Take Imnovid at about the same time each day. To remove the capsule from the blister, press only one end of the capsule out to push it through the foil. Do not apply pressure on the centre of the capsule as this can cause it to break. Your doctor will advise you of how and when to take Imnovid if you have kidney problems and are receiving dialysis treatment. 66 Duration of the treatment with Imnovid You should continue the cycles of treatment until your doctor tells you to stop. If you take more Imnovid than you should If you take more Imnovid than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you. If you forget to take Imnovid If you forget to take Imnovid on a day when you should, take your next capsule as normal the next day. Do not increase the number of capsules you take to make up for not taking Imnovid the previous day. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects Stop taking Imnovid and see a doctor straight away if you notice any of the following serious side effects – you may need urgent medical treatment: • Fever, chills, sore throat, cough, mouth ulcers or any other signs of infection (due to less white blood cells, which fight infection). • Bleeding or bruising without a cause, including nosebleeds and bleeding from the bowels or stomach (due to effects on blood cells called ‘platelets’). • Rapid breathing, rapid pulse, fever and chills, passing very little to no urine, nausea and vomiting, confusion, unconsciousness (due to infection of blood called sepsis or septic shock). • Severe, persistent or bloody diarrhoea (possibly with stomach pain or fever) caused by bacteria called Clostridium difficile. • Chest pain, or leg pain and swelling, especially in your lower leg or calves (caused by blood clots). • Shortness of breath (from serious chest infection, inflammation of the lung, heart failure or blood clot). • Swelling of face, lips, tongue and throat, which may cause difficulty breathing (due to a serious type of allergic reaction called angioedema). • Certain types of skin cancer (squamous cell carcinoma and basal cell carcinoma), which can cause changes in the appearance of your skin or growths on your skin. If you notice any changes to your skin whilst taking Imnovid, tell your doctor as soon as possible. • Recurrence of hepatitis B infection, which can cause yellowing of the skin and eyes, dark brown- coloured urine, right-sided abdominal pain, fever and feeling nauseous or being sick. Tell your doctor straightaway if you notice any of these symptoms. Stop taking Imnovid and see a doctor straight away if you notice any of the serious side effects listed above – you may need urgent medical treatment. Other side effects Very common (may affect more than 1 in 10 people): • Shortness of breath (dyspnoea). 67 • Infections of the lungs (pneumonia and bronchitis). • Infections of the nose, sinuses and throat, caused by bacteria or viruses. • Low red blood cells, which may cause anaemia leading to tiredness and weakness. • Low blood levels of potassium (hypokalaemia), which may cause weakness, muscle cramps, muscle aches, palpitations, tingling or numbness, dyspnoea, mood changes. • High blood levels of sugar. • Loss of appetite. • Constipation, diarrhoea or nausea. • Being sick (vomiting). • Lack of energy. • Difficulty in falling asleep or staying asleep. • Dizziness, tremor. • Muscle spasm, muscle weakness. • Bone pain, back pain. • Numbness, tingling or burning sensation to the skin, pains in hands or feet (peripheral sensory neuropathy). • Swelling of the body, including swelling of the arms or legs. Common (may affect up to 1 in 10 people): • Fall. • Bleeding within the skull. • Decreased ability to move or feel (sensation) in your hands, arms, feet and legs because of nerve damage (peripheral sensorimotor neuropathy). • Numbness, itching, and a feeling of pins and needles on your skin (paraesthesia). • A spinning feeling in your head, making it difficult to stand up and move normally. • Swelling caused by fluid. • Hives (urticaria). • Rashes. • Itchy skin. • Shingles. • A fast and irregular heartbeat (atrial fibrillation). • Heart attack (chest pain spreading to the arms, neck, jaw, feeling sweaty and breathless, feeling sick or vomiting). • Chest pain, chest infection. • Increased blood pressure. • A fall in the number of red and white blood cells and platelets at the same time (pancytopenia) , which will make you more prone to bleeding and bruising. You may feel tired and weak, and short of breath and you are also more likely to get infections. • Decreased number of lymphocytes (one type of white blood cells) often caused by infection (lymphopenia). • Low blood levels of magnesium (hypomagnesaemia), which may cause tiredness, generalised weakness, muscle cramps, irritability and may result in low blood levels of calcium (hypocalcaemia), which may cause numbness and, or tingling of hands, feet, or lips, muscle cramps, muscle weakness, light-headedness, confusion. 68 • Low blood level of phosphate (hypophosphataemia), which may cause muscle weakness and irritability or confusion. • High blood level of calcium (hypercalcaemia), which may cause slowing reflexes and skeletal muscle weaknesses. • High blood levels of potassium, which may cause abnormal heart rhythm. • Low blood levels of sodium, which may cause tiredness and confusion, muscle twitching, fits (epileptic seizures) or coma. • High blood levels of uric acid, which may cause a form of arthritis called gout. • Low blood pressure, which may cause dizziness or fainting. • Flu-like symptoms (influenza). • Sore or dry mouth. • Changes in the way things taste. • Abdominal pain, swollen abdomen. • Feeling confused. • Feeling down (depressed mood). • Loss of consciousness, fainting. • Clouding of your eye (cataract). • Damage to the kidney. • Inability to pass urine. • Abnormal liver test. • Urinary tract infection, which may cause a burning sensation when passing urine, or a need to pass urine more often. • Pain in the pelvis. • Weight loss. Uncommon (may affect up to 1 in 100 people): • Stroke. • Inflammation of the liver (hepatitis) which can cause itchy skin, yellowing of the skin and the whites of the eyes (jaundice), pale coloured stools, dark coloured urine and abdominal pain. • The breakdown of cancer cells resulting in the release of toxic compounds into the bloodstream (tumour lysis syndrome). This can result in kidney problems. Not known (frequency cannot be estimated from the available data): • Widespread rash, high body temperature, enlarged lymph nodes and other body organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also known as DRESS or drug hypersensitivity syndrome, Toxic Epidermal Necrolysis or Stevens-Johnson Syndrome). Stop using pomalidomide if you develop these symptoms and contact your doctor or seek medical attention immediately. See also section 2. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 69 5. How to store Imnovid Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not use Imnovid if you notice any damage or signs of tampering to medicine packaging. Do not throw away any medicines via wastewater or household waste. Any unused medicine should be returned to the pharmacist at the end of treatment. These measures will help protect the environment. 6. Contents of the pack and other information What Imnovid contains • The active substance is pomalidomide. • The other ingredients are mannitol (E421), starch, pregelatinised, and sodium stearyl fumarate. Imnovid 1 mg hard capsule: • Each capsule contains 1 mg of pomalidomide. • The capsule shell contains: gelatin, titanium dioxide (E171), indigotine (E132) and yellow iron oxide (E172) and white and black ink. • The printing ink contains: shellac, titanium dioxide (E171), simeticone, propylene glycol (E1520) and ammonium hydroxide (E527) (white ink) and shellac, iron oxide black (E172), propylene glycol (E1520) and ammonium hydroxide (E527) (black ink). Imnovid 2 mg hard capsule: • Each capsule contains 2 mg of pomalidomide. • The capsule shell contains: gelatin, titanium dioxide (E171), indigotine (E132), yellow iron oxide (E172), erythrosin (E127) and white ink. • The printing ink contains: white ink - shellac, titanium dioxide (E171), simeticone, propylene glycol (E1520) and ammonium hydroxide (E527). Imnovid 3 mg hard capsule: • Each capsule contains 3 mg of pomalidomide. • The capsule shell contains: gelatin, titanium dioxide (E171), indigotine (E132), yellow iron oxide (E172) and white ink. • The printing ink contains: white ink - shellac, titanium dioxide (E171), simeticone, propylene glycol (E1520) and ammonium hydroxide (E527). Imnovid 4 mg hard capsule: • Each capsule contains 4 mg of pomalidomide. • The capsule shell contains: gelatin, titanium dioxide (E171), indigotine (E132), brilliant blue FCF (E133), and white ink. • The printing ink contains: white ink - shellac, titanium dioxide (E171), simeticone, propylene glycol (E1520) and ammonium hydroxide (E527). 70 What Imnovid looks like and contents of the pack Imnovid 1 mg hard capsules: Dark blue opaque cap and yellow opaque body, with “POML 1 mg” written on them. Imnovid 2 mg hard capsules: Dark blue opaque cap and orange opaque body, with “POML 2 mg” written on them. Imnovid 3 mg hard capsules: Dark blue opaque cap and green opaque body, with “POML 3 mg” written on them. Imnovid 4 mg hard capsules: Dark blue opaque cap and blue opaque body, with “POML 4 mg” written on them. Each pack contains 14 or 21 capsules. Not all pack sizes may be marketed. Marketing Authorisation Holder Celgene Europe B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands Manufacturer Celgene Distribution B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. http://www.ema.europa.eu/ 71 ANNEX IV CONCLUSIONS ON THE REQUEST FOR ONE-YEAR MARKETING PROTECTION PRESENTED BY THE EUROPEAN MEDICINES AGENCY 72 Conclusions presented by the European Medicines Agency on: • one-year marketing protection The CHMP reviewed the data submitted by the marketing authorisation holder, taking into account the provisions of Article 14(11) of Regulation (EC) No 726/2004, and considers that the new therapeutic indication brings significant clinical benefit in comparison with existing therapies as further explained in the European Public Assessment Report. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET CONCLUSIONS ON THE REQUEST FOR ONE-YEAR MARKETING PROTECTION PRESENTED BY THE EUROPEAN MEDICINES AGENCY

{'Title': '1. what imnovid is and what it is used for', 'Section_Content': "what imnovid is imnovid contains the active substance 'pomalidomide'. this medicine is related to thalidomide and belongs to a group of medicines which affect the immune system (the body's natural defences). what imnovid is used for imnovid is used to treat adults with a type of cancer called 'multiple myeloma'. imnovid is either used with: two other medicines - called 'bortezomib' (a type of chemotherapy medicine) and 'dexamethasone' (an anti-inflammatory medicine) in people who have had at least one other treatment - including lenalidomide. or 60 one other medicine - called 'dexamethasone' in people whose myeloma has become worse, despite having at least two other treatments - including lenalidomide and bortezomib. what is multiple myeloma multiple myeloma is a type of cancer which affects a certain type of white blood cell (called the 'plasma cell'). these cells grow out of control and accumulate in the bone marrow. this results in damage to the bones and kidneys. multiple myeloma generally cannot be cured. however, treatment can reduce the signs and symptoms of the disease, or make them disappear for a period of time. when this happens, it is called 'response'. how imnovid works imnovid works in a number of different ways: by stopping the myeloma cells developing by stimulating the immune system to attack the cancer cells by stopping the formation of blood vessels supplying the cancer cells. the benefit of using imnovid with bortezomib and dexamethasone when imnovid is used with bortezomib and dexamethasone, in people who have had at least one other treatment, it can stop multiple myeloma getting worse: on average, imnovid when used with bortezomib and dexamethasone stopped multiple myeloma from coming back for up to 11 months - compared with 7 months for those patients who only used bortezomib and dexamethasone. the benefit of using imnovid with dexamethasone when imnovid is used with dexamethasone, in people who have had at least two other treatments, it can stop multiple myeloma getting worse: on average, imnovid when used with dexamethasone stopped multiple myeloma from coming back for up to 4 months - compared with 2 months for those patients who used only dexamethasone.", 'Entity_Recognition': [{'Text': 'imnovid', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 5, 'BeginOffset': 55, 'EndOffset': 67, 'Score': 0.9878441095352173, 'Text': 'pomalidomide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Id': 6, 'BeginOffset': 98, 'EndOffset': 109, 'Score': 0.9924152493476868, 'Text': 'thalidomide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a group of medicines', 'Type': 'TREATMENT', 'BeginOffset': 125, 'EndOffset': 145}, {'Id': 27, 'BeginOffset': 280, 'EndOffset': 286, 'Score': 0.9120405912399292, 'Text': 'cancer', 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{'Title': '2. what you need to know before you take imnovid', 'Section_Content': 'do not take imnovid: if you are pregnant or think you may be pregnant or are planning to become pregnant this is because imnovid is expected to be harmful to an unborn child. (men and women taking this medicine must read the section "pregnancy, contraception and breast-feeding information for women and men" below). if you are able to become pregnant, unless you follow all the necessary measures to prevent you from becoming pregnant (see "pregnancy, contraception and breast-feeding information for women and men"). if you are able to become pregnant, your doctor will record with each prescription that the necessary measures have been taken and will provide you with this confirmation. if you are allergic to pomalidomide or any of the other ingredients of this medicine (listed in section 6). if you think you may be allergic, ask your doctor for advice. if you are uncertain whether any of the conditions above apply to you, talk to your doctor, pharmacist or nurse before taking imnovid. warnings and precautions talk to your doctor, pharmacist or nurse before taking imnovid if: you have ever had blood clots in the past. during the treatment with imnovid you have an increased risk of getting blood clots in your veins and arteries. your doctor may recommend you take additional treatments (e.g. warfarin) or lower the dose of imnovid to reduce the chance that you get blood clots. you have ever had an allergic reaction such as rash, itching, swelling, feeling dizzy or trouble breathing while taking related medicines called \'thalidomide\' or \'lenalidomide\'. you have had a heart attack, have heart failure, have difficulty breathing, or if you smoke, have high blood pressure or high cholesterol levels. you have a high total amount of tumour throughout the body, including your bone marrow. this could lead to a condition where the tumours break down and cause unusual levels of chemicals in the blood which can lead to kidney failure. you may also experience an uneven heartbeat. this condition is called tumour lysis syndrome. you have or have had neuropathy (nerve damage causing tingling or pain in your hands or feet). you have or have ever had hepatitis b infection. treatment with imnovid may cause the hepatitis b virus to become active again in patients who carry the virus, resulting in a recurrence of the infection. your doctor should check whether you have ever had hepatitis b infection. you experience or have experienced in the past a combination of any of the following symptoms: rash on face or extended rash, red skin, high fever, flu-like symptoms, enlarged lymph nodes (signs of severe skin reaction called drug reaction with eosinophilia and systemic symptoms (dress) or drug hypersensitivity syndrome, toxic epidermal necrolysis (ten) or stevens-johnson syndrome (sjs). see also section 4 "possible side effects"). it is important to note that patients with multiple myeloma treated with pomalidomide may develop additional types of cancer, therefore your doctor should carefully evaluate the benefit and risk when you are prescribed this medicine. at the end of the treatment you should return all unused capsules to the pharmacist. pregnancy, contraception and breast-feeding information for women and men the following must be followed as stated in the imnovid pregnancy prevention programme. women and men taking imnovid must not become pregnant or father a child. this is because pomalidomide is expected to harm the unborn baby. you and your partner should use effective methods of contraception while taking this medicine. women do not take imnovid if you are pregnant, think you may be pregnant or are planning to become pregnant. this is because this medicine is expected to harm the unborn baby. before starting the treatment, you should tell your doctor if you are able to become pregnant, even if you think this is unlikely. if you are able to become pregnant: you must use effective methods of contraception for at least 4 weeks before starting treatment, for the whole time you are taking treatment, and until at least 4 weeks after stopping treatment. talk to your doctor about the best method of contraception for you. each time your doctor writes a prescription for you, he will ensure you understand the necessary measures that have to be taken to prevent pregnancy. your doctor will arrange pregnancy tests before treatment, at least every 4 weeks during treatment, and at least 4 weeks after the treatment has finished. if you become pregnant despite the prevention measures: you must stop the treatment immediately and talk to your doctor straight away. breast-feeding it is not known if imnovid passes into human breast milk. tell your doctor if you are breast-feeding or intend to breast-feed. your doctor will advise if you should stop or continue breast-feeding. men imnovid passes into human semen. if your partner is pregnant or able to become pregnant, you must use condoms for the whole time you are taking treatment and for 7 days after the end of treatment. if your partner becomes pregnant while you are taking imnovid, tell your doctor straight away. your partner should also tell her doctor straight away. you should not donate semen or sperm during treatment and for 7 days after the end of treatment. blood donation and blood tests you should not donate blood during treatment and for 7 days after the end of treatment. before and during the treatment with imnovid you will have regular blood tests. this is because your medicine may cause a fall in the number of blood cells that help fight infection (white cells) and in the number of cells that help to stop bleeding (platelets). your doctor should ask you to have a blood test: before treatment every week for the first 8 weeks of treatment at least every month after that for as long as you are taking imnovid. as a result of these tests, your doctor may change your dose of imnovid or stop your treatment. the doctor may also change the dose or stop the medicine because of your general health. children and adolescents imnovid is not recommended for use in children and young people under 18 years. other medicines and imnovid tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. this is because imnovid can affect the way some other medicines work. also some other medicines can affect the way imnovid works. in particular, tell your doctor, pharmacist or nurse before taking imnovid if you are taking any of the following medicines: some antifungals such as ketaconazole some antibiotics (for example ciprofloxacin, enoxacin) certain antidepressants such as fluvoxamine. driving and using machines some people feel tired, dizzy, faint, confused or less alert when taking imnovid. if this happens to you, do not drive or operate tools or machinery. imnovid contains sodium this medicine contains less than 1 mmol sodium (23 mg) per capsule, therefore it is considered essentially \'sodium-free\'.', 'Entity_Recognition': [{'Text': 'imnovid', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 16, 'BeginOffset': 32, 'EndOffset': 40, 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{'Title': '3. how to take imnovid', 'Section_Content': "imnovid must be given to you by a doctor with experience in treating multiple myeloma. always take your medicines exactly as your doctor has told you. check with your doctor, pharmacist or nurse if you are not sure. when to take imnovid with other medicines imnovid with bortezomib and dexamethasone see the leaflets that come with bortezomib and dexamethasone for further information on their use and effects. imnovid, bortezomib and dexamethasone are taken in 'treatment cycles'. each cycle lasts 21 days (3 weeks). look at the chart below to see what to take on each day of the 3-week cycle: o each day, look down the chart and find the correct day to see which medicines to take. o some days, you take all 3 medicines, some days just 2 or 1 medicines, and some days none at all. imn: imnovid; bor: bortezomib; dex: dexamethasone cycle 1 to 8 cycle 9 and onwards medicine name medicine name day imn bor dex day imn bor dex 1 √ √ √ 1 √ √ √ 2 √ √ 2 √ √ 3 √ 3 √ 4 √ √ √ 4 √ 5 √ √ 5 √ 6 √ 6 √ 7 √ 7 √ 8 √ √ √ 8 √ √ √ 9 √ √ 9 √ √ 10 √ 10 √ 11 √ √ √ 11 √ 12 √ √ 12 √ 13 √ 13 √ 14 √ 14 √ 15 15 16 16 17 17 18 18 19 19 20 20 21 21 64 after completing each 3-week cycle, start a new one. imnovid with dexamethasone only see the leaflet that comes with dexamethasone for further information on its use and effects. imnovid and dexamethasone are taken in 'treatment cycles'. each cycle lasts 28 days (4 weeks). look at the chart below to see what to take on each day of the 4-week cycle: o each day, look down the chart and find the correct day to see which medicines to take. o some days, you take both medicines, some days just 1 medicine, and some days none at all. imn: imnovid; dex: dexamethasone medicine name day imn dex 1 √ √ 2 √ 3 √ 4 √ 5 √ 6 √ 7 √ 8 √ √ 9 √ 10 √ 11 √ 12 √ 13 √ 14 √ 15 √ √ 16 √ 17 √ 18 √ 19 √ 20 √ 21 √ 22 √ 23 24 25 26 27 28 after completing each 4-week cycle, start a new one. how much imnovid to take with other medicines imnovid with bortezomib and dexamethasone the recommended starting dose of imnovid is 4 mg per day. the recommended starting dose of bortezomib will be worked out by your doctor and based on your height and weight (1.3 mg/m2 body surface area). the recommended starting dose of dexamethasone is 20 mg per day. however, if you are over 75, the recommended starting dose is 10 mg per day. imnovid with dexamethasone only the recommended dose of imnovid is 4 mg per day. the recommended starting dose of dexamethasone is 40 mg per day. however, if you are over 75, the recommended starting dose is 20 mg per day. your doctor may need to reduce the dose of imnovid, bortezomib or dexamethasone or stop one or more of these medicines based on the results of your blood tests, your general condition, other medic ines you may be taking (e.g. ciprofloxacin, enoxacin and fluvoxamine) and if you experience side effects (especially rash or swelling) from treatment. if you suffer from liver or kidney problems your doctor will check your condition very carefully whilst you are receiving this medicine. how to take imnovid do not break, open or chew the capsules. if powder from a broken imnovid capsule makes contact with the skin, wash the skin immediately and thoroughly with soap and water. swallow the capsules whole, preferably with water. you can take the capsules either with or without food. take imnovid at about the same time each day. to remove the capsule from the blister, press only one end of the capsule out to push it through the foil. do not apply pressure on the centre of the capsule as this can cause it to break. your doctor will advise you of how and when to take imnovid if you have kidney problems and are receiving dialysis treatment. duration of the treatment with imnovid you should continue the cycles of treatment until your doctor tells you to stop. if you take more imnovid than you should if you take more imnovid than you should, talk to a doctor or go to a hospital straight away. take the medicine pack with you. if you forget to take imnovid if you forget to take imnovid on a day when you should, take your next capsule as normal the next day. do not increase the number of capsules you take to make up for not taking imnovid the previous day. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.", 'Entity_Recognition': [{'Text': 'imnovid', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 0, 'EndOffset': 7, 'Score': 0.42069298028945923, 'Text': 'imnovid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 21, 'BeginOffset': 69, 'EndOffset': 85, 'Score': 0.5825440883636475, 'Text': 'multiple myeloma', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.970255434513092}]}, {'Text': 'your medicines', 'Type': 'TREATMENT', 'BeginOffset': 99, 'EndOffset': 113}, {'Id': 1, 'BeginOffset': 229, 'EndOffset': 236, 'Score': 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects stop taking imnovid and see a doctor straight away if you notice any of the following serious side effects you may need urgent medical treatment: fever, chills, sore throat, cough, mouth ulcers or any other signs of infection (due to less white blood cells, which fight infection). bleeding or bruising without a cause, including nosebleeds and bleeding from the bowels or stomach (due to effects on blood cells called 'platelets'). rapid breathing, rapid pulse, fever and chills, passing very little to no urine, nausea and vomiting, confusion, unconsciousness (due to infection of blood called sepsis or septic shock). severe, persistent or bloody diarrhoea (possibly with stomach pain or fever) caused by bacteria called clostridium difficile. chest pain, or leg pain and swelling, especially in your lower leg or calves (caused by blood clots). shortness of breath (from serious chest infection, inflammation of the lung, heart failure or blood clot). swelling of face, lips, tongue and throat, which may cause difficulty breathing (due to a serious type of allergic reaction called angioedema). certain types of skin cancer (squamous cell carcinoma and basal cell carcinoma), which can cause changes in the appearance of your skin or growths on your skin. if you notice any changes to your skin whilst taking imnovid, tell your doctor as soon as possible. recurrence of hepatitis b infection, which can cause yellowing of the skin and eyes, dark brown- coloured urine, right-sided abdominal pain, fever and feeling nauseous or being sick. tell your doctor straightaway if you notice any of these symptoms. stop taking imnovid and see a doctor straight away if you notice any of the serious side effects listed above you may need urgent medical treatment. other side effects very common (may affect more than 1 in 10 people): shortness of breath (dyspnoea). infections of the lungs (pneumonia and bronchitis). infections of the nose, sinuses and throat, caused by bacteria or viruses. low red blood cells, which may cause anaemia leading to tiredness and weakness. low blood levels of potassium (hypokalaemia), which may cause weakness, muscle cramps, muscle aches, palpitations, tingling or numbness, dyspnoea, mood changes. high blood levels of sugar. loss of appetite. constipation, diarrhoea or nausea. being sick (vomiting). lack of energy. difficulty in falling asleep or staying asleep. dizziness, tremor. muscle spasm, muscle weakness. bone pain, back pain. numbness, tingling or burning sensation to the skin, pains in hands or feet (peripheral sensory neuropathy). swelling of the body, including swelling of the arms or legs. common (may affect up to 1 in 10 people): fall. bleeding within the skull. decreased ability to move or feel (sensation) in your hands, arms, feet and legs because of nerve damage (peripheral sensorimotor neuropathy). numbness, itching, and a feeling of pins and needles on your skin (paraesthesia). a spinning feeling in your head, making it difficult to stand up and move normally. swelling caused by fluid. hives (urticaria). rashes. itchy skin. shingles. a fast and irregular heartbeat (atrial fibrillation). heart attack (chest pain spreading to the arms, neck, jaw, feeling sweaty and breathless, feeling sick or vomiting). chest pain, chest infection. increased blood pressure. a fall in the number of red and white blood cells and platelets at the same time (pancytopenia) , which will make you more prone to bleeding and bruising. you may feel tired and weak, and short of breath and you are also more likely to get infections. decreased number of lymphocytes (one type of white blood cells) often caused by infection (lymphopenia). low blood levels of magnesium (hypomagnesaemia), which may cause tiredness, generalised weakness, muscle cramps, irritability and may result in low blood levels of calcium (hypocalcaemia), which may cause numbness and, or tingling of hands, feet, or lips, muscle cramps, muscle weakness, light-headedness, confusion. low blood level of phosphate (hypophosphataemia), which may cause muscle weakness and irritability or confusion. high blood level of calcium (hypercalcaemia), which may cause slowing reflexes and skeletal muscle weaknesses. high blood levels of potassium, which may cause abnormal heart rhythm. low blood levels of sodium, which may cause tiredness and confusion, muscle twitching, fits (epileptic seizures) or coma. high blood levels of uric acid, which may cause a form of arthritis called gout. low blood pressure, which may cause dizziness or fainting. flu-like symptoms (influenza). sore or dry mouth. changes in the way things taste. abdominal pain, swollen abdomen. feeling confused. feeling down (depressed mood). loss of consciousness, fainting. clouding of your eye (cataract). damage to the kidney. inability to pass urine. abnormal liver test. urinary tract infection, which may cause a burning sensation when passing urine, or a need to pass urine more often. pain in the pelvis. weight loss. uncommon (may affect up to 1 in 100 people): stroke. inflammation of the liver (hepatitis) which can cause itchy skin, yellowing of the skin and the whites of the eyes (jaundice), pale coloured stools, dark coloured urine and abdominal pain. the breakdown of cancer cells resulting in the release of toxic compounds into the bloodstream (tumour lysis syndrome). this can result in kidney problems. not known (frequency cannot be estimated from the available data): widespread rash, high body temperature, enlarged lymph nodes and other body organs involvement (drug reaction with eosinophilia and systemic symptoms which is also known as dress or drug hypersensitivity syndrome, toxic epidermal necrolysis or stevens-johnson syndrome). stop using pomalidomide if you develop these symptoms and contact your doctor or seek medical attention immediately. see also section 2. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'imnovid', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 27, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9642208814620972, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6504469513893127}]}, {'Text': 'serious side effects', 'Type': 'PROBLEM', 'BeginOffset': 92, 'EndOffset': 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'BeginOffset': 4818, 'EndOffset': 4832, 'Score': 0.9206219911575317, 'Text': 'depressed mood', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9248486161231995}]}, {'Id': 282, 'BeginOffset': 4835, 'EndOffset': 4856, 'Score': 0.9841952323913574, 'Text': 'loss of consciousness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.976798951625824}]}, {'Id': 283, 'BeginOffset': 4858, 'EndOffset': 4866, 'Score': 0.9775416254997253, 'Text': 'fainting', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.940132200717926}]}, {'Text': 'clouding of your eye (cataract', 'Type': 'PROBLEM', 'BeginOffset': 4868, 'EndOffset': 4898}, {'Text': 'damage to the kidney', 'Type': 'PROBLEM', 'BeginOffset': 4901, 'EndOffset': 4921}, {'Id': 287, 'BeginOffset': 4923, 'EndOffset': 4946, 'Score': 0.8804327249526978, 'Text': 'inability to pass urine', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9044067859649658}]}, {'Id': 288, 'BeginOffset': 4948, 'EndOffset': 4967, 'Score': 0.5986405611038208, 'Text': 'abnormal liver test', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 225, 'BeginOffset': 4957, 'EndOffset': 4962, 'Score': 0.9266886711120605, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 289, 'BeginOffset': 4969, 'EndOffset': 4992, 'Score': 0.965091347694397, 'Text': 'urinary tract infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.47349855303764343}, {'Name': 'DIAGNOSIS', 'Score': 0.47798997163772583}]}, {'Text': 'a burning sensation', 'Type': 'PROBLEM', 'BeginOffset': 5010, 'EndOffset': 5029}, {'Id': 291, 'BeginOffset': 5035, 'EndOffset': 5048, 'Score': 0.39790427684783936, 'Text': 'passing urine', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 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{'Id': 308, 'BeginOffset': 5624, 'EndOffset': 5644, 'Score': 0.7941575646400452, 'Text': 'enlarged lymph nodes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7446273565292358}]}, {'Text': 'other body organs involvement', 'Type': 'PROBLEM', 'BeginOffset': 5649, 'EndOffset': 5678}, {'Id': 309, 'BeginOffset': 5680, 'EndOffset': 5693, 'Score': 0.5816895961761475, 'Text': 'drug reaction', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6631329655647278}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9454312324523926, 'RelationshipScore': 0.43927010893821716, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 234, 'BeginOffset': 5633, 'EndOffset': 5644, 'Text': 'lymph nodes', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.5847405195236206, 'RelationshipScore': 0.9051011800765991, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 235, 'BeginOffset': 5655, 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{'Title': '5. how to store imnovid', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. do not use imnovid if you notice any damage or signs of tampering to medicine packaging. do not throw away any medicines via wastewater or household waste. any unused medicine should be returned to the pharmacist at the end of treatment. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'imnovid', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'any damage', 'Type': 'PROBLEM', 'BeginOffset': 309, 'EndOffset': 319}, {'Text': 'medicine packaging', 'Type': 'TREATMENT', 'BeginOffset': 345, 'EndOffset': 363}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 503, 'EndOffset': 512}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what imnovid contains the active substance is pomalidomide. the other ingredients are mannitol (e421), starch, pregelatinised, and sodium stearyl fumarate. imnovid 1 mg hard capsule: each capsule contains 1 mg of pomalidomide. the capsule shell contains: gelatin, titanium dioxide (e171), indigotine (e132) and yellow iron oxide (e172) and white and black ink. the printing ink contains: shellac, titanium dioxide (e171), simeticone, propylene glycol (e1520) and ammonium hydroxide (e527) (white ink) and shellac, iron oxide black (e172), propylene glycol (e1520) and ammonium hydroxide (e527) (black ink). imnovid 2 mg hard capsule: each capsule contains 2 mg of pomalidomide. the capsule shell contains: gelatin, titanium dioxide (e171), indigotine (e132), yellow iron oxide (e172), erythrosin (e127) and white ink. the printing ink contains: white ink - shellac, titanium dioxide (e171), simeticone, propylene glycol (e1520) and ammonium hydroxide (e527). imnovid 3 mg hard capsule: each capsule contains 3 mg of pomalidomide. the capsule shell contains: gelatin, titanium dioxide (e171), indigotine (e132), yellow iron oxide (e172) and white ink. the printing ink contains: white ink - shellac, titanium dioxide (e171), simeticone, propylene glycol (e1520) and ammonium hydroxide (e527). imnovid 4 mg hard capsule: each capsule contains 4 mg of pomalidomide. the capsule shell contains: gelatin, titanium dioxide (e171), indigotine (e132), brilliant blue fcf (e133), and white ink. the printing ink contains: white ink - shellac, titanium dioxide (e171), simeticone, propylene glycol (e1520) and ammonium hydroxide (e527). what imnovid looks like and contents of the pack imnovid 1 mg hard capsules: dark blue opaque cap and yellow opaque body, with "poml 1 mg" written on them. imnovid 2 mg hard capsules: dark blue opaque cap and orange opaque body, with "poml 2 mg" written on them. imnovid 3 mg hard capsules: dark blue opaque cap and green opaque body, with "poml 3 mg" written on them. imnovid 4 mg hard capsules: dark blue opaque cap and blue opaque body, with "poml 4 mg" written on them. each pack contains 14 or 21 capsules. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'imnovid', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 46, 'EndOffset': 58, 'Score': 0.9967862367630005, 'Text': 'pomalidomide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 86, 'EndOffset': 94, 'Score': 0.7208654284477234, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'starch', 'Type': 'TREATMENT', 'BeginOffset': 103, 'EndOffset': 109}, {'Text': 'pregelatinised', 'Type': 'TREATMENT', 'BeginOffset': 111, 'EndOffset': 125}, {'Id': 2, 'BeginOffset': 131, 'EndOffset': 154, 'Score': 0.998187243938446, 'Text': 'sodium stearyl fumarate', 'Category': 'MEDICATION', 'Type': 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4544B30A5E4E78127A7EFDDB2609CA65

https://www.ema.europa.eu/documents/product-information/nordimet-epar-product-information_en.pdf

Nordimet

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1 NAME OF THE MEDICINAL PRODUCT Nordimet 7.5 mg solution for injection in pre-filled pen Nordimet 10 mg solution for injection in pre-filled pen Nordimet 12.5 mg solution for injection in pre-filled pen Nordimet 15 mg solution for injection in pre-filled pen Nordimet 17.5 mg solution for injection in pre-filled pen Nordimet 20 mg solution for injection in pre-filled pen Nordimet 22.5 mg solution for injection in pre-filled pen Nordimet 25 mg solution for injection in pre-filled pen Nordimet 7.5 mg solution for injection in pre-filled syringe Nordimet 10 mg solution for injection in pre-filled syringe Nordimet 12.5 mg solution for injection in pre-filled syringe Nordimet 15 mg solution for injection in pre-filled syringe Nordimet 17.5 mg solution for injection in pre-filled syringe Nordimet 20 mg solution for injection in pre-filled syringe Nordimet 22.5 mg solution for injection in pre-filled syringe Nordimet 25 mg solution for injection in pre-filled syringe 2 QUALITATIVE AND QUANTITATIVE COMPOSITION One ml of solution contains 25 mg of methotrexate. Nordimet 7.5 mg solution for injection in pre-filled pen Each pre-filled pen contains 7.5 mg methotrexate in 0.3 mL Nordimet 10 mg solution for injection in pre-filled pen Each pre-filled pen contains 10 mg methotrexate in 0.4 mL Nordimet 12.5 mg solution for injection in pre-filled pen Each pre-filled pen contains 12.5 mg methotrexate in 0.5 mL Nordimet 15 mg solution for injection in pre-filled pen Each pre-filled pen contains 15 mg methotrexate in 0.6 mL Nordimet 17.5 mg solution for injection in pre-filled pen Each pre-filled pen contains 17.5 mg methotrexate in 0.7 mL Nordimet 20 mg solution for injection in pre-filled pen Each pre-filled pen contains 20 mg methotrexate in 0.8 mL Nordimet 22.5 mg solution for injection in pre-filled pen Each pre-filled pen contains 22.5 mg methotrexate in 0.9 mL Nordimet 25 mg solution for injection in pre-filled pen Each pre-filled pen contains 25 mg methotrexate in 1.0 mL Nordimet 7.5 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 7.5 mg methotrexate in 0.3 mL Nordimet 10 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 10 mg methotrexate in 0.4 mL 3 Nordimet 12.5 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 12.5 mg methotrexate in 0.5 mL Nordimet 15 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 15 mg methotrexate in 0.6 mL Nordimet 17.5 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 17.5 mg methotrexate in 0.7 mL Nordimet 20 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 20 mg methotrexate in 0.8 mL Nordimet 22.5 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 22.5 mg methotrexate in 0.9 mL Nordimet 25 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 25 mg methotrexate in 1.0 mL For the full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM Solution for injection. Clear, yellow solution with a pH of 8.0-9.0 and an osmolality of approximately 300 mOsm/kg. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications Nordimet is indicated for the treatment of - active rheumatoid arthritis in adult patients, - polyarthritic forms of severe, active juvenile idiopathic arthritis (JIA), when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate, - severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, psoralens and ultraviolet A (PUVA), and retinoids, and severe psoriatic arthritis in adult patients. 4.2 Posology and method of administration Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. Patients must be educated and trained in the proper injection technique when self-administering methotrexate. The first injection of Nordimet should be performed under direct medical supervision. 4 Important warning about the dosage of Nordimet In the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis,psoriasis and psoriatic arthritis requiring dosing once a week. Nordimet must only be used once a week. Dosage errors in the use of Nordimet can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully. When switching from oral use to subcutaneous use, a reduction in the dose may be required, due to the variable bioavailability of methotrexate after oral administration. Folic acid or folinic acid supplementation may be considered in accordance with current therapeutic guidelines. The overall duration of treatment is decided by the doctor. Posology Dosage in adult patients with rheumatoid arthritis The recommended initial dose is 7.5 mg of methotrexate once weekly, administered subcutaneously. Depending on the individual activity of the disease and patient tolerability, the initial dose may be increased. A weekly dose of 25 mg should in general not be exceeded. However, doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can be expected after approximately 4-8 weeks. Once the desired therapeutic result has been achieved, the dose should be reduced gradually to the lowest possible effective maintenance dose. Symptoms may return after treatment discontinuation. Methotrexate treatment of rheumatoid arthritis represents long-term treatment. Dosage in patients with psoriasis vulgaris and psoriatic arthritis It is recommended that a test dose of 5-10 mg be administered subcutaneously one week prior to initiation of therapy, in order to detect idiosyncratic adverse effects. The recommended initial dose is 7.5 mg methotrexate once weekly. The dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can generally be expected after approximately 2-6 weeks. Depending on the clinical picture and the changes of laboratory parameters, the therapy is then continued or discontinued. Once the desired therapeutic result has been achieved, dose should be reduced gradually to the lowest possible effective maintenance dose. In a few exceptional cases a higher dose than 25 mg might be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase. Methotrexate treatment of severe psoriasis vulgaris and psoriatic arthritis represents long-term treatment. Special populations Elderly Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occur with increased age (see sections 4.4, 4.5, 4.8 or 5.2) 5 Renal impairment Methotrexate should be used with caution in patients with impaired renal function (see sections 4.3 and 4.4). The dose should be adjusted as follows: Creatinine clearance (ml/min) Dose ≥ 60 100 % 30-59 50 % < 30 Nordimet must not be used Patients with hepatic impairment Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially when caused by alcohol. Methotrexate is contraindicated if bilirubin values are > 5 mg/dl (85.5 µmol/L) (see section 4.3). Use in patient with a third distribution space (pleural effusions, ascitis) As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space, dose reduction or, in some cases, discontinuation of methotrexate administration may be required (see sections 5.2 and 4.4). Paediatric population Dosage in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis The recommended dose is 10-15 mg/m² body surface area (BSA) per week. In therapy-refractory cases the weekly dose may be increased up to 20 mg/m² BSA per week. However, an increased monitoring frequency is indicated if the dose is increased. Parenteral administration is limited to subcutaneous injection. Patients with JIA should always be referred to a rheumatology unit specializing in the treatment of children/adolescents. The safety and efficacy of Nordimet in children < 3 years of age have not been established (see section 4.4). No data available. Method of administration It must be explicitly pointed out to the patient that Nordimet is applied only once a week. It is recommended to specify a certain day of the week as “day for injection”. Nordimet is for subcutaneous use (see section 6.6.). The medicinal product is for single use only. The solution is to be visually inspected prior to use. Only clear solutions practically free from particles should be used. Any contact of methotrexate with skin and mucosa is to be avoided. In case of contamination, the affected parts are to be rinsed immediately with plenty of water (see section 6.6). Please refer to the patient information leaflet for instructions on how to use the pre-filled pen or pre- filled syringe. 6 4.3 Contraindications - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Severe hepatic impairment, if serum if bilirubin is > 5 mg/dl (85.5 µmol/l) (see section 4.2). - Alcohol abuse. - Severe renal impairment (creatinine clearance less than 30 ml/min) (see sections 4.2 and 4.4). - Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia. - Immunodeficiency. - Serious, acute or chronic infections such as tuberculosis and HIV. - Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease. - Pregnancy and breast-feeding (see section 4.6). - Concurrent vaccination with live vaccines. 4.4 Special warnings and precautions for use Patients must be clearly advised that the therapy is to be administered once a week, and not every day. Incorrect administration of methotrexate can lead to severe, including potentially lethal adverse reactions. Healthcare professionals and patients should be clearly instructed. Patients receiving therapy should be appropriately monitored, so that signs of possible toxic effects or adverse reactions can be recognised and assessed without delay. Hence, methotrexate should be only administered by, or under the supervision of, doctors whose knowledge and experience include the use of antimetabolite therapy. Due to the risk of severe or even fatal toxic reactions, patients should be thoroughly informed by the doctor about the risks (including early signs and symptoms of toxicity) and recommended safety measures. They are to be informed about the necessity to immediately consult the physician if symptoms of intoxication occur, as well as about the subsequent necessary monitoring of symptoms of intoxication (including regular laboratory tests). Doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression. Skin and mucosal contact with methotrexate is to be avoided. In the case of contamination, the parts concerned should be rinsed with plenty of water. Fertility and reproduction Fertility Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy, and to cause impaired fertility, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy. Teratogenicity – Reproductive risk Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing potential (see section 4.6). The absence of pregnancy must be confirmed before Nordimet is used. If women of a sexually mature age are treated, effective contraception must be performed during treatment and for at least six months after. For contraception advice for men, see section 4.6. 7 Recommended examinations and safety measures Before initiating therapy or upon resuming therapy after a rest period Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest X-ray and renal function tests must be conducted. If clinically indicated, exclude tuberculosis and hepatitis. During therapy The tests below must be conducted every week during the first two weeks, then every two weeks for the next month; afterwards, depending on leukocyte count and stability of the patient, at least once monthly during the next six months and at least every three months thereafter. Increased monitoring frequency should also be considered when increasing the dose. Particularly elderly patients should be examined for early signs of toxicity in short intervals. - Examination of the oral cavity and throat for mucosal changes. - Complete blood count with differential blood count and platelets. Haematopoietic suppression induced by methotrexate may occur abruptly and at apparently safe doses. In the event of any significant drop in leukocytes or platelets, treatment must be discontinued immediately and appropriate supportive therapy instituted. Patients must be instructed to report all signs and symptoms suggestive of infection. In patients concomitantly taking haematotoxic medicinal products (e.g. leflunomide), the blood count and platelets should be closely monitored. - Liver function tests. Particular attention should be paid to the onset of liver toxicity. Treatment should not be initiated or should be discontinued if there are any abnormalities in liver function tests or liver biopsies, or if these develop during therapy. Such abnormalities should return to normal within two weeks; after which, treatment may be resumed at the discretion of the doctor. Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20 %. Persistent anomalies of liver-related enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity. Enzyme diagnostics does not allow any reliable prediction of the development of a morphologically detectable hepatotoxicity, i.e. even in case of normal transaminases, hepatic fibrosis only histologically identifiable or, more rarely, also hepatocirrhosis may be present. In rheumatological indications, there is no evidence to support use of liver biopsies in monitoring hepatotoxicity. For psoriasis patients the need of a liver biopsy prior to and during therapy is controversial. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. This assessment should differentiate between patients without any risk factors and patients with risk factors, e.g. excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic medicinal products or chemicals and prolonged methotrexate treatment or cumulative doses of 1.5 g or more. In the event of a constant increase in liver-related enzymes, consideration should be given to reducing the dose or discontinuing therapy. Due to the potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary and alcohol consumption should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products (e.g. leflunomide). 8 Increased caution should generally be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy hepatocirrhosis developed in isolated cases without intermittent increase in transaminases. - Renal function should be monitored via renal function tests and urinanalysis (see sections 4.2 and 4.3). If serum creatinine is increased, the dose should be reduced. As methotrexate is predominantly excreted via the renal route, increased concentrations can be expected in cases of renal impairment, which may result in severe adverse reactions. In cases of possible renal impairment (e.g. in elderly patients), closer monitoring is required. This particularly applies to the co-administration of medicinal products which affect methotrexate excretion, cause kidney damage (e.g. NSAIDs) or can potentially lead to haematopoietic disorders. In patients with impaired renal function, concomitant administration of NSAIDs is not recommended. Dehydration may also potentiate the toxicity of methotrexate. - Assessment of respiratory system. Questioning the patient with regard to possible pulmonary dysfunctions, if necessary lung function test. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough), thoracic pain and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea. In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis. Methotrexate should be discontinued in patients with pulmonary symptoms and a thorough investigation (including chest x-ray) should be made to exclude infection and tumours. If methotrexate induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted. Pulmonary diseases induced by methotrexate were not always completely reversible. Pulmonary symptoms require a quick diagnosis and discontinuation of methotrexate therapy. Pulmonary diseases induced by methotrexate, like pneumonitis, can occur acutely at any time of therapy, they were not always completely reversible and have been reported already at all doses (inclusive low doses of 7.5 mg/week). During methotrexate therapy, opportunistic infection can occur including pneumocystis jiroveci pneumonia, which may take a lethal course. If a patient presents with pulmonary symptoms, the possibility of pneumocystis jiroveci pneumonia should be taken into account. Special caution is required in patients with impaired pulmonary function. - Methotrexate may, due to its effect on the immune system, impair the response to vaccinations and interfere with the result of immunological tests. Concurrent vaccination using live vaccines must not be carried out. Particular caution should be exercised in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) due to possible activation. 9 Malignant lymphomas may occur in patients receiving low-dose methotrexate; in which case, methotrexate must be discontinued. If lymphomas should fail to regress spontaneously, initiation of cytotoxic therapy is required. In patients with pathological accumulation of liquid in body cavities (“third space”), such as ascites or pleural effusions, the plasma elimination half-life of methotrexate is prolonged. Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment. Conditions leading to dehydration such as emesis, diarrhoea or stomatitis, can increase the toxicity of methotrexate due to elevated levels of the active substance. In these cases use of methotrexate should be interrupted until the symptoms cease. Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate. Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-reaction). Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate. Concomitant administration of folate antagonists such as trimethoprim /sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances. Encephalopathy / Leukoencephalopathy have been reported in oncologic patients receiving methotrexate therapy and cannot be excluded for methotrexate therapy in non-oncologic indications. This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially “sodium-free“. 4.5 Interaction with other medicinal products and other forms of interaction In animal experiments non-steroidal anti-inflammatory drugs (NSAIDs) including salicylic acid caused reduction of tubular methotrexate secretion and consequently increased its toxic effects. However, in clinical studies, where NSAIDs and salicylic acid were given as concomitant medicinal products to patients with rheumatoid arthritis, no increase of adverse reactions was observed. Treatment of rheumatoid arthritis with such drugs can be continued during low-dose methotrexate therapy but only under close medical supervision. Regular alcohol consumption and administration of additional hepatotoxic medicinal products increase the probability of hepatotoxic effects of methotrexate. Patients taking potentially hepatotoxic and haematoxic medicinal products during methotrexate therapy (e.g. leflunomide, azathioprine, sulphasalazine, and retinoids) should be closely monitored for possibly increased hepatotoxicity. Alcohol consumption must be avoided during treatment with methotrexate. Administration of additional haematotoxic medicinal products (e.g. metamizole) increases the probability of severe haematoxic effects of methotrexate. One should be aware of pharmacokinetic interactions between methotrexate, anticonvulsant medicinal products (reduced methotrexate blood levels), and 5-fluorouracil (increased t½ of 5--fluorouracil). Salicylates, phenylbutazone, phenytoin, barbiturates, tranquillisers, oral contraceptives, tetracyclines, amidopyrine derivatives, sulfonamides and p-aminobenzoic acid displace methotrexate from serum albumin binding and thus increase bioavailability (indirect dose increase). Probenecid and mild organic acids may also reduce tubular methotrexate secretion, and thus cause indirect dose elevations, too. 10 Antibiotics, like penicillin, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur. Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics may reduce intestinal methotrexate absorption or interfere with the enterohepatic circulation, due to inhibition of the intestinal flora or suppression of bacterial metabolism. Under (pre-)treatment with substances that may have adverse effects on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine), the possibility of marked haematopoietic disorders should be considered. Co-administration of medicinal products which cause folate deficiency (e.g. sulphonamides, trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular caution should therefore also be exercised in the presence of existing folic acid deficiency. On the other hand, concomitant administration of folinic acid containing drugs or of vitamin preparations, which contain folic acid or derivatives, may impair methotrexate efficacy. A rise in the toxicity of methotrexate is generally not anticipated when methotrexate is used concomitantly with other antirheumatic agents (e.g. gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporin). Though the combination of methotrexate and sulfasalazine may enhance methotrexate efficacy by sulfasalazine related inhibition of folic acid synthesis, and thus may lead to an increased risk of adverse reactions, these were only observed in single patients within several trials. Co-administration of proton-pump inhibitors such as omeprazole or pantoprazole can lead to interactions: concomitant administration of methotrexate and omeprazole has led to a delay in the renal elimination of methotrexate. In combination with pantoprazole, inhibited renal elimination of the 7-hydroxymethotrexate metabolite, with myalgia and shivering, was reported in one case. Methotrexate may reduce theophylline clearance. Therefore, theophylline blood levels should be monitored under concomitant methotrexate administration. Excessive consumption of beverages containing caffeine or theophylline (coffee, soft drinks containing caffeine, black tea) should be avoided during methotrexate therapy since the efficacy of methotrexate may be reduced due to possible interaction between methotrexate and methylxanthines at adenosine receptors. The combined use of methotrexate and leflunomide may increase the risk for pancytopenia. Methotrexate leads to increased plasma levels of mercaptopurines. Therefore, the combination of these may require dose adjustment. Particularly in the case of orthopaedic surgery where susceptibility to infection is high, a combination of methotrexate with immune-modulating medicinal products must be used with caution. The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe unpredictable myelosuppression and stomatitis. Whilst this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided. Colestyramine can increase the non-renal elimination of methotrexate by interrupting the enterohepatic circulation. Delayed methotrexate clearance should be considered in combination with other cytostatic medicinal products. Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis. 11 On account of its possible effect on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to record the immune reaction). During methotrexate therapy concurrent vaccination with live vaccines must not be carried out (see sections 4.3 and 4.4). 4.6 Fertility, pregnancy and lactation Women of childbearing potential / contraception in females Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning. Contraception in males It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure. As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 6 months after cessation of methotrexate. Men should not donate semen during therapy or for 6 months following discontinuation of methotrexate. Pregnancy Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3). If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development. In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section 5.3). Methotrexate has been shown to have a teratogenic effect in humans; it has been reported to cause foetal death and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related). Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy. • Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low- dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate. • Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in in disease-matched patients treated with drugs other than methotrexate. Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but higher rates of spontaneous abortions and congenital malformations are expected. When methotrexate was discontinued prior to conception, normal pregnancies have been reported. 12 Breast-feeding As methotrexate is transferred into human milk and may cause toxicity in breast-feeding children, treatment is contraindicated during breast-feeding (see section 4.3). If use of methotrexate during the breast-feeding period should become necessary, breast-feeding is to be stopped prior to treatment. Fertility Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to be reversible after discontinuation of therapy in most cases. 4.7 Effects on ability to drive and use machines Nordimet has minor influence on the ability to drive and use machines. Central nervous system (CNS) symptoms, such as fatigue and confusion, can occur during treatment. 4.8 Undesirable effects Summary of the safety profile Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-Johnson syndrome. Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal disorders (e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite) and abnormal liver function tests (e.g. increased Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), bilirubin, alkaline phosphatase). Other frequently (common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus. The most relevant adverse reaction is suppression of the haematopoietic system and gastrointestinal disorders. List of adverse reactions Frequencies are defined using the following convention: very common (≥ 1/10) common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Infections and infestations Uncommon: Pharyngitis. Rare: Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis. Neoplasms benign, malignant and unspecified (including cysts and polyps) Very rare: lymphoma (see “description” below) Blood and lymphatic system disorders Common: Leukopenia, anaemia, thrombopenia. Uncommon: Pancytopenia. Very rare: Agranulocytosis, severe courses of bone marrow depression, lymphoproliferative disorders (see “description below”). Not known: Eosinophilia 13 Immune system disorders Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia. Metabolism and nutrition disorders Uncommon: Precipitation of diabetes mellitus. Psychiatric disorders Uncommon: Depression, confusion. Rare: Mood alterations. Nervous system disorders Common: Headache, tiredness, drowsiness. Uncommon: Dizziness. Very rare: Pain, muscular asthenia, paraesthesia/hypoaesthesia, changes in sense of taste (metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis. Not known: Encephalopathy/ Leukoencephalopathy. Eye disorders Rare: Visual disturbances. Very rare: Impaired vision, Retinopathy. Cardiac disorders Rare: Pericarditis, pericardial effusion, pericardial tamponade. Vascular disorders Rare: Hypotension, thromboembolic events Respiratory, thoracic and mediastinal disorders Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, shortness of breath and fever. Rare: Pulmonary fibrosis, Pneumocystis jiroveci pneumonia, shortness of breath and bronchial asthma, pleural effusion. Not known: Epistaxis, pulmonary alveolar haemorrhage. Gastrointestinal disorders Very common: Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain. Common: Oral ulcers, diarrhoea. Uncommon: Gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis. Rare: Gingivitis. Very rare: Haematemesis, haematorrhea, toxic megacolon. Hepatobiliary disorders (see section 4.4) Very common: Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and bilirubin). Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin. Rare: Acute hepatitis. Very rare: Hepatic failure. Skin and subcutaneous tissue disorders Common: Exanthema, erythema, pruritus. Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, skin ulcer, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticaria. Rare: Increased pigmentation, acne, petechiae, ecchymosis, allergic vasculitis. Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), increased pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia. Not known: Skin exfoliation / dermatitis exfoliative 14 Musculoskeletal and connective tissue disorders Uncommon: Arthralgia, myalgia, osteoporosis. Rare: Stress fracture. Not known: Osteonecrosis of jaw (secondary to lymphoproliferative disorders) Renal and urinary disorders Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition. Rare: Renal failure, oliguria, anuria, electrolyte disturbances. Not known: Proteinuria. Reproductive system and breast disorders Uncommon: Inflammation and ulceration of the vagina. Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal discharge. General disorders and administration site conditions Rare: Fever, wound-healing impairment. Not known: Asthenia, injection site necrosis, oedema. Description of selected adverse reactions Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma and other lymphoproliferative disorders which subsided in a number of cases once treatment with methotrexate had been discontinued. The appearance and degree of severity of undesirable effects depends on the dosage level and the frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is indispensable that patients are monitored regularly by the doctor at short intervals. Only mild local skin reactions (such as burning sensations, erythema, swelling, discolouration, pruritus, severe itching, pain) were observed with subcutaneous use, decreasing during therapy. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Symptoms of overdose The adverse toxic effects of methotrexate mainly affect the haematopoietic and gastrointestinal system. Symptoms include leukocytopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, bone marrow depression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration and gastrointestinal bleeding. Some patients showed no signs of overdose. There are reports of death due to sepsis, septic shock, renal failure and aplastic anaemia. Treatment of overdose Calcium folinate is the specific antidote for neutralising the adverse toxic effects of methotrexate. In the event of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered intravenously or intramuscularly within 1 hour, and dosing continued until serum level of methotrexate are below 10-7 mol/L. In the event of a massive overdose, hydration and urinary alkalisation may be required to prevent precipitation of methotrexate and/or its metabolites within the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective methotrexate clearance has been reported with acute, intermittent haemodialysis using a high-flux dialyser. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 15 In patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis or psoriasis vulgaris, administration of folic or folinic acid may reduce methotrexate toxicity (gastrointestinal symptoms, inflammation of oral mucosa, hair loss and increase of liver enzymes) (see section 4.5). Prior to using folic acid products, monitoring of vitamin B12 levels is recommended, since folic acid may mask an existing vitamin B12 deficiency, particularly in adults over 50 years of age. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, other immunosuppressants. ATC code: L04AX03 Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the management of psoriasis, psoriatic arthritis and chronic polyarthritis, is due to an anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to these effects. 5.2 Pharmacokinetic properties Absorption After oral application, methotrexate is absorbed from the gastrointestinal tract. When administered in low doses (7.5 mg/m2 to 80 mg/m2 BSA), methotrexate has a mean bioavailability of approximately 70%, although considerable inter- and intra-subject variations are possible (25-100%). Plasma peak concentrations are attained within 1-2 hours. Subcutaneous, intravenous and intramuscular administration demonstrated similar bioavailability. Distribution Approximately 50% of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations particularly in liver, kidneys and spleen in form of polyglutamates can be found, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the body fluids in minimal amounts; under high doses (300 mg/kg body weight), concentrations between 4 and 7 µg/ml have been measured in the body fluids. Average terminal half-life is 6-7 hours and demonstrates considerable variation (3-17 hours). Half-life may be prolonged to 4 times the normal length in patients with third spaces (pleural effusion, ascites). Biotransformation Approximately 10% of the administered methotrexate is metabolised intrahepatically. The major metabolite is 7-hydroxymethotrexate. Elimination Excretion takes place, mainly in unchanged form, primarily renal via glomerular filtration and active secretion in the proximal tubulus. Approx. 5-20% of methotrexate and 1-5% of 7- hydroxymethotrexate are eliminated via the bile. Pronounced enterohepatic blood flow exists. In case of renal insufficiency, elimination is delayed significantly. Impaired elimination in presence of hepatic insufficiency is not known. Methotrexate passes the placental barrier in rats and monkeys. 16 5.3 Preclinical safety data Chronic toxicity Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity. Mutagenic and carcinogenic potential Long-term studies in rats, mice and hamsters did not show any evidence of a tumorigenic potential of methotrexate. Methotrexate induces gene and chromosome mutations both in vitro and in vivo. A mutagenic effect is suspected in humans. Reproductive toxicology Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In rhesus monkeys, no malformations comparable to humans occurred. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Sodium hydroxide (for pH adjustment) Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store below 25°C. Keep the pre-filled pen and pre-filled syringe in the outer carton in order to protect from light. 6.5 Nature and contents of container Pre-filled pen Pre-filled pen with a 1 mL type I glass syringe with attached stainless steel needle and a chlorobutyl rubber plunger stopper. The pre-filled pens contain 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml or 1 ml of solution for injection. Each pack contains 1 pre-filled pen and one alcohol swab and multipacks containing 4 (4 packs of 1 or 1 pack of 4), 6 (6 packs of 1) and 12 (3 packs of 4) pre-filled pens and alcohol swabs. Pre-filled syringe 1 mL type I glass syringe with attached stainless steel needle, a chlorobutyl rubber plunger stopper and a needle guard to prevent needlestick injury and re-use. The pre-filled syringes contain 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml or 1 ml solution for injection. Each pack contains 1 pre-filled syringe and two alcohol swabs and multipacks containing 4 (4 packs of 1), 6 (6 packs of 1) and 12 (12 packs of 1) pre-filled syringes and alcohol swabs. Not all pack sizes may be marketed. 17 6.6 Special precautions for disposal and other handling Handling and disposal must be consistent with that of other cytotoxic preparations in accordance with local requirements. Pregnant health care personnel should not handle and/or administer methotrexate. Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with ample amount of water. Nordimet is for single use only and any unused solution must be discarded. Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic agents. 7. MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) Nordimet 7.5 mg solution for injection in pre-filled pen EU/1/16/1124/001 - 1 pack EU/1/16/1124/009 - 4 pack (4 packs of 1) EU/1/16/1124/010 - 6 pack EU/1/16/1124/057 - 4 pack (1 pack of 4) EU/1/16/1124/058 - 12 pack Nordimet 10 mg solution for injection in pre-filled pen EU/1/16/1124/002 - 1 pack EU/1/16/1124/011 - 4 pack (4 packs of 1) EU/1/16/1124/012 - 6 pack EU/1/16/1124/059 - 4 pack (1 pack of 4) EU/1/16/1124/060 - 12 pack Nordimet 12.5 mg solution for injection in pre-filled pen EU/1/16/1124/003 - 1 pack EU/1/16/1124/013 - 4 pack (4 packs of 1) EU/1/16/1124/014 - 6 pack EU/1/16/1124/061 - 4 pack (1 pack of 4) EU/1/16/1124/062 - 12 pack Nordimet 15 mg solution for injection in pre-filled pen EU/1/16/1124/004 - 1 pack EU/1/16/1124/015 - 4 pack (4 packs of 1) EU/1/16/1124/016 - 6 pack EU/1/16/1124/063 - 4 pack (1 pack of 4) EU/1/16/1124/064 - 12 pack 18 Nordimet 17.5 mg solution for injection in pre-filled pen EU/1/16/1124/005 - 1 pack EU/1/16/1124/017 - 4 pack (4 packs of 1) EU/1/16/1124/018 - 6 pack EU/1/16/1124/065 - 4 pack (1 pack of 4) EU/1/16/1124/066 - 12 pack Nordimet 20 mg solution for injection in pre-filled pen EU/1/16/1124/006 - 1 pack EU/1/16/1124/019 - 4 pack (4 packs of 1) EU/1/16/1124/020 - 6 pack EU/1/16/1124/067 - 4 pack (1 pack of 4) EU/1/16/1124/068 - 12 pack Nordimet 22.5 mg solution for injection in pre-filled pen EU/1/16/1124/007 - 1 pack EU/1/16/1124/021 - 4 pack (4 packs of 1) EU/1/16/1124/022 - 6 pack EU/1/16/1124/069 - 4 pack (1 pack of 4) EU/1/16/1124/070 - 12 pack Nordimet 25 mg solution for injection in pre-filled pen EU/1/16/1124/008 - 1 pack EU/1/16/1124/023 - 4 pack (4 packs of 1) EU/1/16/1124/024 - 6 pack EU/1/16/1124/071 - 4 pack (1 pack of 4) EU/1/16/1124/072 - 12 pack Nordimet 7.5 mg solution for injection in pre-filled syringe EU/1/16/1124/025 - 1 pack EU/1/16/1124/026 - 4 pack EU/1/16/1124/027 - 6 pack EU/1/16/1124/049 - 12 pack Nordimet 10 mg solution for injection in pre-filled syringe EU/1/16/1124/028 - 1 pack EU/1/16/1124/029 - 4 pack EU/1/16/1124/030 - 6 pack EU/1/16/1124/050 - 12 pack Nordimet 12.5 mg solution for injection in pre-filled syringe EU/1/16/1124/031 - 1 pack EU/1/16/1124/032 - 4 pack EU/1/16/1124/033 - 6 pack EU/1/16/1124/051 - 12 pack Nordimet 15 mg solution for injection in pre-filled syringe EU/1/16/1124/034 - 1 pack EU/1/16/1124/035 - 4 pack EU/1/16/1124/036 - 6 pack EU/1/16/1124/052 - 12 pack Nordimet 17.5 mg solution for injection in pre-filled syringe EU/1/16/1124/037 - 1 pack EU/1/16/1124/038 - 4 pack EU/1/16/1124/039 - 6 pack EU/1/16/1124/053 - 12 pack 19 Nordimet 20 mg solution for injection in pre-filled syringe EU/1/16/1124/040 - 1 pack EU/1/16/1124/041 - 4 pack EU/1/16/1124/042 - 6 pack EU/1/16/1124/054 - 12 pack Nordimet 22.5 mg solution for injection in pre-filled syringe EU/1/16/1124/043 - 1 pack EU/1/16/1124/044 - 4 pack EU/1/16/1124/045 - 6 pack EU/1/16/1124/055 - 12 pack Nordimet 25 mg solution for injection in pre-filled syringe EU/1/16/1124/046 - 1 pack EU/1/16/1124/047 - 4 pack EU/1/16/1124/048 - 6 pack EU/1/16/1124/056 - 12 pack 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 18 August 2016 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency (http://www.ema.europa.eu) http://www.ema.europa.eu/ 20 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 21 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Cenexi - Laboratoires Thissen S.A. Rue de la Papyrée 2-6 B-1420 Braine-L'Alleud Belgium QPharma AB Agneslundsvagen 27 P.O. Box 590 SE-201 25 Malmo Sweden The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date The MAH should implement the agreed targeted follow-up questionnaires for all medication errors resulting in overdose. From the date of notification of the Commission Decision* *Referral EMEA/H/A-31/1463 22 ANNEX III LABELLING AND PACKAGE LEAFLET 23 A. LABELLING 24 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 7.5 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.3 ml contains 7.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 7.5 mg/0.3 ml 1 pre-filled pen (0.3 ml) with pre-assembled needle and 1 alcohol swab. Component of a multipack, can’t be sold separately 4 pre-filled pens (0.3 ml) with pre-assembled needle and 4 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic: handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 25 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/009 4 pre-filled pens (4 packs of 1) EU/1/16/1124/010 6 pre-filled pens (6 packs of 1) EU/1/16/1124/058 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 7.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 26 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 27 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 7.5 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.3 ml contains 7.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 7.5 mg/0.3 ml 1 pre-filled syringe (0.3 ml) with pre-assembled needle with needle guard and 2 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic: handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 28 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/026 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/027 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/049 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 7.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 29 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 30 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 10 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.4 ml contains 10 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 10 mg/0.4 ml 1 pre-filled pen (0.4 ml) with pre-assembled needle and 1 alcohol swab. Component of a multipack, can’t be sold separately 4 pre-filled pens (0.4 ml) with pre-assembled needle and 4 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 31 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/011 4 pre-filled pens (4 packs of 1) EU/1/16/1124/012 6 pre-filled pens (6 packs of 1) EU/1/16/1124/060 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 10 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 32 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 33 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 10 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.4 ml contains 10 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 10 mg/0.4 ml 1 pre-filled syringe (0.4 ml) with pre-assembled needle with needle guard and 2 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 34 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/029 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/030 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/050 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 10 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 35 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 36 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 12.5 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.5 ml contains 12.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 12.5 mg/0.5 ml 1 pre-filled pen (0.5 ml) with pre-assembled needle and 1 alcohol swab. Component of a multipack, can’t be sold separately 4 pre-filled pens (0.5 ml) with pre-assembled needle and 4 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 37 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/013 4 pre-filled pens (4 packs of 1) EU/1/16/1124/014 6 pre-filled pens (6 packs of 1) EU/1/16/1124/062 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 12.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 38 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 39 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 12.5 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.5 ml contains 12.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 12.5 mg/0.5 ml 1 pre-filled syringe (0.5 ml) with pre-assembled needle with needle guard and 2 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 40 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/032 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/033 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/051 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 12.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 41 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 42 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 15 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.6 ml contains 15 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 15 mg/0.6 ml 1 pre-filled pen (0.6 ml) with pre-assembled needle and 1 alcohol swab. Component of a multipack, can’t be sold separately 4 pre-filled pens (0.6 ml) with pre-assembled needle and 4 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 43 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/015 4 pre-filled pens (4 packs of 1) EU/1/16/1124/016 6 pre-filled pens (6 packs of 1) EU/1/16/1124/064 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 15 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 44 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 45 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 15 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.6 ml contains 15 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 15 mg/0.6 ml 1 pre-filled syringe (0.6 ml) with pre-assembled needle with needle guard and 2 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 46 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/035 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/036 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/052 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 15 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 47 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 48 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 17.5 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.7 ml contains 17.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 17.5 mg/0.7 ml 1 pre-filled pen (0.7 ml) with pre-assembled needle and 1 alcohol swab. Component of a multipack, can’t be sold separately 4 pre-filled pens (0.7 ml) with pre-assembled needle and 4 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 49 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/017 4 pre-filled pens (4 packs of 1) EU/1/16/1124/018 6 pre-filled pens (6 packs of 1) EU/1/16/1124/066 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 17.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 50 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 51 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 17.5 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.7 ml contains 17.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 17.5 mg/0.7 ml 1 pre-filled syringe (0.7 ml) with pre-assembled needle with needle guard and 2 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 52 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/038 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/039 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/053 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 17.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 53 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 54 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 20 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.8 ml contains 20 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 20 mg/0.8 ml 1 pre-filled pen (0.8 ml) with pre-assembled needle and 1 alcohol swab. Component of a multipack, can’t be sold separately 4 pre-filled pens (0.8 ml) with pre-assembled needle and 4 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 55 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/019 4 pre-filled pens (4 packs of 1) EU/1/16/1124/020 6 pre-filled pens (6 packs of 1) EU/1/16/1124/068 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 56 16. INFORMATION IN BRAILLE Nordimet 20 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 57 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 20 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.8 ml contains 20 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 20 mg/0.8 ml 1 pre-filled syringe (0.8 ml) with pre-assembled needle and needle guard and 2 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 58 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/041 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/042 6 pre-filled syinges (6 packs of 1) EU/1/16/1124/054 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 20 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 59 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 60 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 22.5 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.9 ml contains 22.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 22.5 mg/0.9 ml 1 pre-filled pen (0.9 ml) with pre-assembled needle and 1 alcohol swab. Component of a multipack, can’t be sold separately 4 pre-filled pens (0.9 ml) with pre-assembled needle and 4 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 61 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/021 4 pre-filled pens (4 packs of 1) EU/1/16/1124/022 6 pre-filled pens (6 packs of 1) EU/1/16/1124/070 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 62 16. INFORMATION IN BRAILLE Nordimet 22.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 63 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 22.5 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.9 ml contains 22.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 22.5 mg/0.9 ml 1 pre-filled syringe (0.9 ml) with pre-assembled needle with needle guard and 2 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 64 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/044 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/045 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/055 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 22.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 65 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 66 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 25 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 1.0 ml contains 25 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 25 mg/1.0 ml 1 pre-filled pen (1 ml) with pre-assembled needle and 1 alcohol swab. Component of a multipack, can’t be sold separately 4 pre-filled pens (1 ml) with pre-assembled needle and 4 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 67 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/023 4 pre-filled pens (4 packs of 1) EU/1/16/1124/024 6 pre-filled pens (6 packs of 1) EU/1/16/1124/072 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 68 16. INFORMATION IN BRAILLE Nordimet 25 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 69 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON NO BLUE BOX IS INCLUDED 1. NAME OF THE MEDICINAL PRODUCT Nordimet 25 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 1.0 ml contains 25 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 25 mg/1.0 ml 1 pre-filled syringe (1 ml) with pre-assembled needle with needle guard and 2 alcohol swabs. Component of a multipack, can’t be sold separately 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 70 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/047 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/048 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/056 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 25 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 71 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 72 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 7.5 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.3 ml contains 7.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 7.5 mg/0.3 ml 1 pre-filled pen (0.3 ml) with pre-assembled needle and 1 alcohol swab Multipack: 4 (4 packs of 1) pre-filled pens (0.3 ml) with pre-assembled needle and alcohol swabs Multipack: 4 (1 pack of 4) pre-filled pens (0.3 ml) with pre-assembled needle and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled pens (0.3 ml) with pre-assembled needle and alcohol swabs Multipack: 12 (3 packs of 4) pre-filled pens (0.3 ml) with pre-assembled needle and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 73 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic: handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/001 1 pre-filled pen EU/1/16/1124/009 4 pre-filled pens (4 packs of 1) EU/1/16/1124/010 6 pre-filled pens (6 packs of 1) EU/1/16/1124/057 4 pre-filled pens (1 pack of 4) EU/1/16/1124/058 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 74 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 7.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 75 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 7.5 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.3 ml contains 7.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 7.5 mg/0.3 ml 1 pre-filled syringe (0.3 ml) with pre-assembled needle with needle guard and 2 alcohol swabs Multipack: 4 (4 packs of 1) pre-filled syringes (0.3 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled syringes (0.3 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 12 (12 packs of 1) pre-filled syringes (0.3 ml) with pre-assembled needle with needle guard and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 76 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic: handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/025 1 pre-filled syringe EU/1/16/1124/026 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/027 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/049 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 77 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 7.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 78 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 10 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.4 ml contains 10 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 10 mg/0.4 ml 1 pre-filled pen (0.4 ml) with pre-assembled needle and 1 alcohol swab Multipack: 4 (4 packs of 1) pre-filled pens (0.4 ml) with pre-assembled needle and alcohol swabs Multipack: 4 (1 pack of 4) pre-filled pens (0.4 ml) with pre-assembled needle and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled pens (0.4 ml) with pre-assembled needle and alcohol swabs Multipack: 12 (3 packs of 4) pre-filled pens (0.4 ml) with pre-assembled needle and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 79 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/002 1 pre-filled pen EU/1/16/1124/011 4 pre-filled pens (4 packs of 1) EU/1/16/1124/012 6 pre-filled pens (6 packs of 1) EU/1/16/1124/059 4 pre-filled pens (1 pack of 4) EU/1/16/1124/060 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 80 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 10 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 81 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 10 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.4 ml contains 10 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 10 mg/0.4 ml 1 pre-filled syringe (0.4 ml) with pre-assembled needle with needle guard and 2 alcohol swabs Multipack: 4 (4 packs of 1) pre-filled syringes (0.4 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled syringes (0.4 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 12 (12 packs of 1) pre-filled syringes (0.4 ml) with pre-assembled needle with needle guard and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 82 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/028 1 pre-filled syringe EU/1/16/1124/029 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/030 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/050 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 83 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 10 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 84 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 12.5 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.5 ml contains 12.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 12.5 mg/0.5 ml 1 pre-filled pen (0.5 ml) with pre-assembled needle and 1 alcohol swab Multipack: 4 (4 packs of 1) pre-filled pens (0.5 ml) with pre-assembled needle and alcohol swabs Multipack: 4 (1 pack of 4) pre-filled pens (0.5 ml) with pre-assembled needle and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled pens (0.5 ml) with pre-assembled needle and alcohol swabs Multipack: 12 (3 packs of 4) pre-filled pens (0.5 ml) with pre-assembled needle and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 85 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/003 1 pre-filled pen EU/1/16/1124/013 4 pre-filled pens (4 packs of 1) EU/1/16/1124/014 6 pre-filled pens (6 packs of 1) EU/1/16/1124/061 4 pre-filled pens (1 pack of 4) EU/1/16/1124/062 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 86 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 12.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 87 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 12.5 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.5 ml contains 12.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 12.5 mg/0.5 ml 1 pre-filled syringe (0.5 ml) with pre-assembled needle with needle guard and 2 alcohol swab Multipack: 4 (4 packs of 1) pre-filled syringes (0.5 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled syringes (0.5 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 12 (12 packs of 1) pre-filled syringes (0.5 ml) with pre-assembled needle with needle guard and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 88 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/031 1 pre-filled syringe EU/1/16/1124/032 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/033 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/051 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 89 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 12.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 90 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 15 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.6 ml contains 15 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 15 mg/0.6 ml 1 pre-filled pen (0.6 ml) with pre-assembled needle and 1 alcohol swab Multipack: 4 (4 packs of 1) pre-filled pens (0.6 ml) with pre-assembled needle and alcohol swabs Multipack: 4 (1 pack of 4) pre-filled pens (0.6 ml) with pre-assembled needle and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled pens (0.6 ml) with pre-assembled needle and alcohol swabs Multipack: 12 (3 packs of 4) pre-filled pens (0.6 ml) with pre-assembled needle and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 91 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/004 1 pre-filled pen EU/1/16/1124/015 4 pre-filled pens (4 packs of 1) EU/1/16/1124/016 6 pre-filled pens (6 packs of 1) EU/1/16/1124/063 4 pre-filled pens (1 pack of 4) EU/1/16/1124/064 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 92 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 15 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 93 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 15 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.6 ml contains 15 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 15 mg/0.6 ml 1 pre-filled syringe (0.6 ml) with pre-assembled needle with needle guard and 2 alcohol swabs Multipack: 4 (4 packs of 1) pre-filled syringes (0.6 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled syringes (0.6 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 12 (12 packs of 1) pre-filled syringes (0.6 ml) with pre-assembled needle with needle guard and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 94 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/034 1 pre-filled syringe EU/1/16/1124/035 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/036 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/052 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 95 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 15 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 96 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 17.5 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.7 ml contains 17.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 17.5 mg/0.7 ml 1 pre-filled pen (0.7 ml) with pre-assembled needle and 1 alcohol swab Multipack: 4 (4 packs of 1) pre-filled pens (0.7 ml) with pre-assembled needle and alcohol swabs Multipack: 4 (1 pack of 4) pre-filled pens (0.7 ml) with pre-assembled needle and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled pens (0.7 ml) with pre-assembled needle and alcohol swabs Multipack: 12 (3 packs of 4) pre-filled pens (0.7 ml) with pre-assembled needle and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 97 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/005 1 pre-filled pen EU/1/16/1124/017 4 pre-filled pens (4 packs of 1) EU/1/16/1124/018 6 pre-filled pens (6 packs of 1) EU/1/16/1124/065 4 pre-filled pens (1 pack of 4) EU/1/16/1124/066 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 98 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 17.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 99 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 17.5 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.7 ml contains 17.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 17.5 mg/0.7 ml 1 pre-filled syringe (0.7 ml) with pre-assembled needle with needle guard and 2 alcohol swabs Multipack: 4 (4 packs of 1) pre-filled syringes (0.7 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled syringes (0.7 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 12 (12 packs of 1) pre-filled syringes (0.7 ml) with pre-assembled needle with needle guard and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 100 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/037 1 pre-filled syringe EU/1/16/1124/038 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/039 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/053 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 101 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 17.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 102 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 20 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.8 ml contains 20 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 20 mg/0.8 ml 1 pre-filled pen (0.8 ml) with pre-assembled needle and 1 alcohol swab Multipack: 4 (4 packs of 1) pre-filled pens (0.8 ml) with pre-assembled needle and alcohol swabs Multipack: 4 (1 pack of 4) pre-filled pens (0.8 ml) with pre-assembled needle and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled pens (0.8 ml) with pre-assembled needle and alcohol swabs Multipack: 12 (3 packs of 4) pre-filled pens (0.8 ml) with pre-assembled needle and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 103 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/006 1 pre-filled pen EU/1/16/1124/019 4 pre-filled pens (4 packs of 1) EU/1/16/1124/020 6 pre-filled pens (6 packs of 1) EU/1/16/1124/067 4 pre-filled pens (1 pack of 4) EU/1/16/1124/068 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 104 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 20 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 105 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 20 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.8 ml contains 20 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 20 mg/0.8 ml 1 pre-filled syringe (0.8 ml) with pre-assembled needle with needle guard and 2 alcohol swabs Multipack: 4 (4 packs of 1) pre-filled syringes (0.8 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled syringes (0.8 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 12 (12 packs of 1) pre-filled syringes (0.8 ml) with pre-assembled needle with needle guard and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use. Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 106 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/040 1 pre-filled syringe EU/1/16/1124/041 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/042 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/054 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 107 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 20 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 108 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 22.5 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 0.9 ml contains 22.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 22.5 mg/0.9 ml 1 pre-filled pen (0.9 ml) with pre-assembled needle and 1 alcohol swab Multipack: 4 (4 packs of 1) pre-filled pens (0.9 ml) with pre-assembled needle and alcohol swabs Multipack: 4 (1 pack of 4) pre-filled pens (0.9 ml) with pre-assembled needle and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled pens (0.9 ml) with pre-assembled needle and alcohol swabs Multipack: 12 (3 packs of 4) pre-filled pens (0.9 ml) with pre-assembled needle and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 109 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/007 1 pre-filled pen EU/1/16/1124/021 4 pre-filled pens (4 packs of 1) EU/1/16/1124/022 6 pre-filled pens (6 packs of 1) EU/1/16/1124/069 4 pre-filled pens (1 pack of 4) EU/1/16/1124/070 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 110 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 22.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 111 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 22.5 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 0.9 ml contains 22.5 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 22.5 mg/0.9 ml 1 pre-filled syringe (0.9 ml) with pre-assembled needle with needle guard and 2 alcohol swabs Multipack: 4 (4 packs of 1) pre-filled syringes (0.9 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled syringes (0.9 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 12 (12 packs of 1) pre-filled syringes (0.9 ml) with pre-assembled needle with needle guard and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 112 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/043 1 pre-filled syringe EU/1/16/1124/044 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/045 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/055 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 113 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 22.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 114 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED PEN CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 25 mg solution for injection in pre-filled pen methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen of 1.0 ml contains 25 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 25 mg/1.0 ml 1 pre-filled pen (1 ml) with pre-assembled needle and 1 alcohol swab Multipack: 4 (4 packs of 1) pre-filled pens (1.0 ml) with pre-assembled needle and alcohol swabs Multipack: 4 (1 pack of 4) pre-filled pens (1.0 ml) with pre-assembled needle and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled pens (1.0 ml) with pre-assembled needle and alcohol swabs Multipack: 12 (3 packs of 4) pre-filled pens (1.0 ml) with pre-assembled needle and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 115 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/008 1 pre-filled pen EU/1/16/1124/023 4 pre-filled pens (4 packs of 1) EU/1/16/1124/024 6 pre-filled pens (6 packs of 1) EU/1/16/1124/071 4 pre-filled pens (1 pack of 4) EU/1/16/1124/072 12 pre-filled pens (3 packs of 4) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 116 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 25 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 117 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PRE-FILLED SYRINGE CARTON OUTER LABEL CONTAINS BLUE BOX 1. NAME OF THE MEDICINAL PRODUCT Nordimet 25 mg solution for injection in pre-filled syringe methotrexate 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe of 1.0 ml contains 25 mg methotrexate (25mg/ml) 3. LIST OF EXCIPIENTS Sodium chloride Sodium hydroxide Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 25 mg/1.0 ml 1 pre-filled syringe (1 ml) with pre-assembled needle with needle guard and 2 alcohol swabs Multipack: 4 (4 packs of 1) pre-filled syringes (1.0 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 6 (6 packs of 1) pre-filled syringes (1.0 ml) with pre-assembled needle with needle guard and alcohol swabs Multipack: 12 (12 packs of 1) pre-filled syringes (1.0 ml) with pre-assembled needle with needle guard and alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Methotrexate is injected once weekly. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 118 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic : handle with caution. Use only once a week on …………………………………………………………….. (include weekday of use in full) 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Store below 25°C. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused medicinal product or waste material should be disposed in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1124/046 1 pre-filled syringe EU/1/16/1124/047 4 pre-filled syringes (4 packs of 1) EU/1/16/1124/048 6 pre-filled syringes (6 packs of 1) EU/1/16/1124/056 12 pre-filled syringes (12 packs of 1) 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY 119 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Nordimet 25 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 120 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS for Blister - PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Nordimet 7.5 mg solution for injection methotrexate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. OTHER SC 7.5 mg / 0.3 ml Use only once a week 121 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS for Blister - PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Nordimet 10 mg solution for injection methotrexate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. OTHER SC 10 mg / 0.4 ml Use only once a week 122 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS for Blister - PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Nordimet 12.5 mg solution for injection methotrexate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. OTHER SC 12.5 mg / 0.5 ml Use only once a week 123 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS for Blister - PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Nordimet 15 mg solution for injection methotrexate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. OTHER SC 15 mg / 0.6 ml Use only once a week 124 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS for Blister - PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Nordimet 17.5 mg solution for injection methotrexate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. OTHER SC 17.5 mg / 0.7 ml Use only once a week 125 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS for Blister - PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Nordimet 20 mg solution for injection methotrexate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. OTHER SC 20 mg / 0.8 ml Use only once a week 126 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS for Blister - PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Nordimet 22.5 mg solution for injection methotrexate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. OTHER SC 22.5 mg / 0.9 ml Use only once a week 127 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS for Blister - PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Nordimet 25 mg solution for injection methotrexate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Nordic Group B.V. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. OTHER SC 25 mg / 1.0 ml Use only once a week 128 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN / PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Nordimet 7.5 mg solution for injection methotrexate SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 7.5 mg / 0.3 ml 6. OTHER 129 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN / PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Nordimet 10 mg solution for injection methotrexate SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10 mg / 0.4 ml 6. OTHER 130 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN / PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Nordimet 12.5 mg solution for injection methotrexate SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 12.5 mg / 0.5 ml 6. OTHER 131 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN / PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Nordimet 15 mg solution for injection methotrexate SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 15 mg / 0.6 ml 6. OTHER 132 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN / PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Nordimet 17.5 mg solution for injection methotrexate SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 17.5 mg / 0.7 ml 6. OTHER 133 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN / PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Nordimet 20 mg solution for injection methotrexate SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 20 mg / 0.8 ml 6. OTHER 134 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN / PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Nordimet 22.5 mg solution for injection methotrexate SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 22.5 mg / 0.9 ml 6. OTHER 135 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN / PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Nordimet 25 mg solution for injection methotrexate SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 25 mg / 1.0 ml 6. OTHER 136 B. PACKAGE LEAFLET 137 Package leaflet: Information for the user Nordimet 7.5 mg solution for injection in pre-filled pen Nordimet 10 mg solution for injection in pre-filled pen Nordimet 12.5 mg solution for injection in pre-filled pen Nordimet 15 mg solution for injection in pre-filled pen Nordimet 17.5 mg solution for injection in pre-filled pen Nordimet 20 mg solution for injection in pre-filled pen Nordimet 22.5 mg solution for injection in pre-filled pen Nordimet 25 mg solution for injection in pre-filled pen methotrexate Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Nordimet is and what it is used for 2. What you need to know before you use Nordimet 3. How to use Nordimet 4. Possible side effects 5. How to store Nordimet 6. Contents of the pack and other information 1. What Nordimet is and what it is used for Nordimet contains the active substance methotrexate which works by: - reducing inflammation or swelling, and - reducing the activity of the immune system (the body’s own defense mechanism). An overactive immune system has been linked to inflammatory diseases. Nordimet is a medicine used to treat a range of inflammatory diseases: - active rheumatoid arthritis in adults. Active rheumatoid arthritis is an inflammatory condition that affects the joints; - severe, active juvenile idiopathic arthritis in five or more joints (the condition is therefore called polyarthritic), in patients who have had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs); - a severe form of treatment resistant psoriasis (also called severe recalcitrant disabling psoriasis), in adult patients who have had an inadequate response to other treatments including phototherapy (light therapy), PUVA (ultraviolet light therapy), and retinoids (group of medicines derived from vitamin A). 138 2. What you need to know before you use Nordimet Do not use Nordimet if: - you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6) - you have severe kidney disease (your doctor will be able to tell you if you have severe kidney disease) - you have severe liver disease (your doctor will be able to tell you if you have severe liver disease) - you have disorders of the blood-forming system - your alcohol consumption is high - you have an impaired immune system - you have a severe or existing infection, e.g. tuberculosis or HIV - you have gastrointestinal ulcers - you are pregnant or breast-feeding (see section “Pregnancy, breast-feeding and fertility”) - you receive vaccinations with live vaccines at the same time. Warnings and precautions Acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with methotrexate. If you experience symptoms of spitting or coughing up blood you should contact your doctor immediately. Important warning about the dosing of Nordimet Methotrexate for the therapy of rheumatic diseases or diseases of the skin must only be used once weekly. Incorrect dosing of methotrexate may lead to serious adverse effects which may be fatal. Please read section 3 of this package leaflet very carefully. Talk to your doctor before using Nordimet if: - you have diabetes mellitus and are being treated with insulin - you have inactive, prolonged infections (e.g. tuberculosis, hepatitis B or C, shingles [herpes zoster]) - you have/had any liver or kidney disease - you have problems with lung function - you are severely overweight - you have abnormal accumulation of liquid in the abdomen or in the cavity between the lungs and chest wall (ascites, pleural effusions) - you are dehydrated or suffer from conditions leading to dehydration (e.g. dehydration as a result of vomiting, diarrhoea or inflammation of the mouth and lips) If you have experienced problems with your skin after radiation therapy (radiation induced dermatitis) or sun-burn, these conditions can reappear when taking Nordimet. Children, adolescents and elderly Dose instructions depend on the patient’s body weight. Use in children under 3 years of age is not recommended due to insufficient experience of using this medicine in this age group. Children, adolescents and the elderly being treated with Nordimet should be kept under close medical surveillance to identify possible side effects as early as possible. The dose for elderly patients should be lowered due to age-related reduced liver and kidney function. Special precautionary measures for treatment with Nordimet Methotrexate temporarily affects sperm and egg production, which is reversible in most cases. Methotrexate can cause miscarriage and severe birth defects. You must avoid becoming pregnant 139 when using methotrexate and for at least six months after treatment has stopped. See also section “Pregnancy, breast-feeding and fertility”. Skin changes caused by psoriasis can worsen during treatment with Nordimet if exposed to ultraviolet irradiation. Before the start of treatment and recommended follow-up examinations and precautions Before treatment is started your doctor may carry out blood tests, and also check how well your kidneys and liver are working. You may also have a chest X-ray. Further tests may also be done during and after treatment. Do not miss appointments for blood tests. If the results of any of these tests are abnormal, treatment will only be resumed when all readings are back to normal. Even when Nordimet is used at low doses, serious side effects can occur. Your doctor will carry out blood and urine tests to make sure that any side effects are identified quickly. Other medicines and Nordimet Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription and herbal or natural medicinal products. It is especially important to tell your doctor if you are taking: - other treatments for rheumatoid arthritis or psoriasis such as leflunomide, sulphasalazine (a medicine that besides arthritis and psoriasis is also used to treat ulcerative colitis), aspirin, phenylbutazone, or amidopyrine - alcohol (drinking alcohol should be avoided while you are taking Nordimet) - azathioprine (used to prevent rejection after an organ transplant) - retinoids (used to treat psoriasis and other skin disorders) - anticonvulsant medicines (used to prevent fits), such as phenytoin, valproate or carbamazepine - cancer treatments - barbiturates (sleeping injection) - tranquillisers - oral contraceptives - probenecid (used to treat gout) - antibiotics - pyrimethamine (which is used to prevent and treat malaria) - vitamin preparations containing folic acid - proton-pump inhibitors (medicines that reduce the production of gastric acid and that are used to treat severe heartburn or ulcers), such as omeprazole - theophylline (used to treat asthma) - any vaccination with a live vaccine (must be avoided), such as measles, mumps, influenza or yellow fever vaccines. Nordimet with food, drink and alcohol During treatment with Nordimet, you must not drink any alcohol and should avoid excessive consumption of coffee, soft drinks containing caffeine and black tea as this may enhance side effects or interfere with the efficacy of Nordimet. Also, make sure you drink plenty of liquids during treatment with Nordimet because dehydration (reduction in body water) can increase the toxicity of Nordimet. 140 Pregnancy, breast-feeding and fertility If you are pregnant or breast feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Pregnancy Do not use Nordimet during pregnancy or if you are trying to become pregnant. Methotrexate can cause birth defects, harm unborn babies or cause miscarriages. It is associated with malformations of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is very important that methotrexate is not given to pregnant patients or patients planning to become pregnant. In women of child-bearing age any possibility of pregnancy must be excluded with appropriate measures, e.g. a pregnancy test before starting treatment. You must avoid becoming pregnant whilst taking methotrexate and for at least 6 months after treatment is stopped by using reliable contraception throughout this time (see also section “Warnings and precautions”). If you do become pregnant during treatment or suspect you might be pregnant, speak to your doctor as soon as possible. You should be offered advice regarding the risk of harmful effects on the child through treatment. If you wish to become pregnant you should consult your doctor, who may refer you for specialist advice before the planned start of treatment. Breast-feeding Do not breast-feed during treatment because methotrexate passes into breast milk. If your doctor considers treatment with methotrexate absolutely necessary during the lactation period, you must stop breast-feeding. Male fertility The available evidence does not indicate an increased risk of malformations or miscarriage if the father takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded. Methotrexate may be genotoxic. This means that the medicine may cause genetic mutation. Methotrexate can affect sperm production with the potential to cause birth defects. Therefore, you should avoid fathering a child or to donate semen whilst taking methotrexate and for at least 6 months after treatment is stopped. Driving and using machines Side effects affecting the central nervous system, such as tiredness and dizziness, may occur during treatment with Nordimet. In some cases, the ability to drive vehicles and/or use machines may be impaired. If you feel tired or dizzy, you should not drive or use machines. Nordimet contains sodium This medicine contains less than 1 mmol sodium (23 mg) per dose, and so is essentially “sodium-free”. 3. How to use Nordimet Important warning about the dose of Nordimet Use Nordimet only once a week for the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis and psoriatic arthritis requiring dosing once a week. Using too much of Nordimet may be fatal. Please read section 3 of this leaflet very carefully. If you have any questions, please talk to your doctor or pharmacist before you take this medicine. Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. 141 Nordimet is administered once a week only. You and your doctor can decide on a suitable day each week to receive your injection. Incorrect administration of Nordimet can lead to severe side effects that may be fatal. The recommended dose is: Dose in patients with rheumatoid arthritis The recommended starting dose is 7.5 mg methotrexate once a week. The doctor may increase the dose if the used dose is not effective but tolerated well. The average weekly dose is 15-20 mg. Generally, a weekly dose of 25 mg should not be exceeded. Once Nordimet starts working, the doctor may reduce the dose gradually to the lowest possible effective maintenance dose. Generally, improvement of symptoms can be expected after 4-8 weeks of treatment. Symptoms may return if treatment with Nordimet is stopped. Dose in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis The doctor will calculate the dose required from the child’s body surface area (m2), and the dose is expressed as mg/m2. Use in children under < 3 years is not recommended due to insufficient experience in this age group. Use in adults with severe forms of psoriasis vulgaris or psoriatic arthritis Your doctor will give you a single test dose of 5-10 mg, in order to assess possible side effects. If the test dose is well tolerated, treatment will be continued after a week with a dose of approximately 7.5 mg. Response to treatment can generally be expected after 2-6 weeks. Depending on the effects of treatment and results of blood and urine tests, the therapy is then continued or stopped. Method and duration of administration Nordimet is given as injection under the skin (subcutaneously). It must be injected once weekly and it is recommended to always inject Nordimet on the same day of the week. At the start of your treatment, Nordimet may be injected by medical staff. However, your doctor may decide that you can learn how to inject Nordimet yourself. You will receive appropriate training for you to do this. Under no circumstances should you attempt to inject yourself, unless you have been trained to do so. The duration of treatment is determined by the treating physician. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris and psoriatic arthritis with Nordimet is a long-term treatment. How to give yourself an injection of Nordimet If you have difficulty handling the pen, ask your doctor or pharmacist. Do not try to inject yourself if you have not been trained on how to do so. If you are not sure what to do, talk to your doctor or nurse immediately. 142 Before injecting yourself with Nordimet - Check the expiry date on the medicine. Do not use if the date has passed. - Check the pen is not damaged and the medicine in it is a clear, yellow solution. If not, use another pen. - Check your last injection site to see if the last injection caused any redness, change in skin colour, swelling, oozing or is still painful, if so talk to your doctor or nurse. - Decide where you are going to inject the medicine. Change the place where you inject each time. Instructions on injecting yourself with Nordimet 1) Wash your hands thoroughly with soap and water. 2) Sit or lie in a relaxed, comfortable position. Make sure you can see the skin area you are going to inject. 3) The pen is pre-filled and ready to use. Visually inspect the pen. You should see a yellow fluid through the viewing window. You may see a small air bubble, this does not affect the injection and will not harm you. A droplet may appear at the tip of the needle. This is normal. 4) Choose an injection site and clean it with the enclosed alcohol swab. It requires 30-60 seconds to be effective. The skin on the front side abdominal wall and the skin at the front of the thigh are suitable as injection sites. 5) While holding the body of the pen, pull the cap off. Once you have taken the cap off, keep the pen in your hand. Do not allow the pen to touch anything else. This is to make sure that the pen is not accidentally activated and that the needle stays clean. 6) Make a fold in the skin by gently pinching the skin of the injection place with your forefinger and thumb. Make sure you hold the skin fold throughout the injection. 7) Move the pen towards the skin fold (site of injection) with the needle shield pointing directly at the site of injection. Place the yellow needle shield against the area of injection so that the entire rim of the needle shield is touching the skin. 143 8) Apply downward pressure on the pen on to your skin until you hear and feel a “click”. This activates the pen and the solution will inject automatically into the skin. 9) The injection lasts for a maximum of 10 seconds. You will feel and hear a second “click” once the injection is completed. 10) Wait another 2-3 seconds before removing the pen from your skin. The safety shield on the pen is now locked to prevent any needlestick injuries. You can now let go of the skin fold. 11) Visually inspect the pen through the viewing window. You should see green plastic. This means that all the fluid has been injected. Discard the used pen into the sharps bin provided. Close the container lid tightly and place the container out of reach of children. If you accidently get methotrexate on the surface of the skin or soft tissues you must rinse with plenty of water. 144 If you use more Nordimet than you should Follow the dose recommendations of your treating doctor. Do not change the dose without your doctor’s recommendation. If you suspect that you have used too much Nordimet, tell your doctor or contact the nearest hospital immediately. Take your medicine package and this leaflet with you if you go to a doctor or hospital. An overdose of methotrexate can lead to severe toxic reactions. Overdose symptoms may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomit that looks like coffee grounds, and decreased urinating. See also section 4. If you forget to use Nordimet Do not take a double dose to make up for a forgotten dose, but continue taking the prescribed dose as normal. Ask your doctor for advice. If you stop taking Nordimet You should not interrupt or discontinue Nordimet treatment before discussing with your doctor. If you suspect that you are experiencing side effects, contact your doctor immediately for advice. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor straight away if you get any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body). Serious side effects If you develop any of the following side effects, contact your doctor immediately: - inflammation of the lungs (symptoms may be general illness, dry, irritating cough, shortness of breath, breathlessness at rest, chest pain, or fever) - spitting or coughing blood - severe peeling or blistering of the skin - unusual bleeding (including vomiting blood) or bruising - severe diarrhoea - ulcers in mouth - black or tarry stools - blood in the urine or stools - tiny red spots on the skin - fever - yellowing of the skin (jaundice) - pain or difficulty in passing urine - thirst and/or frequent urination - fits (convulsions) - loss of consciousness - blurred or decreased vision 145 The following side effects have also been reported: Very common (may affect more than 1 in 10 people): loss of appetite, nausea (feeling sick), vomiting, tummy pain, inflammation and ulcers in the mouth and throat, and increase in liver enzymes. Common (may affect up to 1 in 10 people): Reduced blood cell formation with decrease in white and/or red blood cells and/or platelets (leukopenia, anaemia, thrombocytopenia), headache, tiredness, drowsiness, inflammation of the lungs (pneumonia) with dry, non-productive cough, shortness of breath and fever, diarrhoea, rash, reddening of the skin, itching. Uncommon (may affect up to 1 in 100 people): Decrease in the number of blood cells and platelets , dizziness, confusion, depression, fits, inflammation of blood vessels, lung damage, ulcers and bleeding in the digestive tract, liver disorders, diabetes, decreased blood protein, nettle rash, light sensitivity, brown skin, hair loss, increase of rheumatic nodules, shingles, painful psoriasis, joint or muscle pain, osteoporosis (reduction of bone mass), inflammation and ulcers of the bladder (possibly with blood in the urine), painful urination, severe allergic reactions, inflammation and ulcers of the vagina, slow wound healing. Rare (may affect up to 1 in 1,000 people): Inflammation of the sac around the heart, fluid in the sac around the heart, severe visual disturbance, mood fluctuations, low blood pressure, blood clots, sore throat, interruption of breathing, asthma, inflammation of the digestive tract, bloody stools, inflamed gums, abnormal digestion, acute hepatitis (inflammation of the liver), changed colour of nails, acne, red or purple spots due to vessel bleeding, bone fracture, kidney failure, decrease or absence of urine, electrolyte disturbances, defective sperm formation, menstruation disorders. Very rare (may affect up to 1 in 10,000 people): Infections, severe failure of the bone marrow, liver failure, swollen glands, sleeplessness, pain, muscle weakness, sensation of numbness or tingling / having less sensitivity to stimulation than normal, changes in sense of taste (metallic taste), inflammation of the lining of the brain causing paralysis or vomiting, red eyes, damage to the retina of the eye, fluid in the lungs, vomiting blood, cold sores, protein in the urine, fever, loss of sex drive, problems having an erection, infection around a fingernail, severe complications of the gastrointestinal tract, boils, small blood vessels in the skin, fungal infections, damage to the blood vessels of the skin, vaginal discharge, infertility, male breast enlargement (gynaecomastia), inflammation of the brain, lymphoproliferative disorders (excessive growth of white blood cells). Frequency not known (cannot be estimated from the available data): Bleeding from the lungs, bone damage in the jaw (secondary to excessive growth of white blood cells), tissue destruction at injection site, redness and shedding of skin, swelling. Only mild local skin reactions were observed with Nordimet and these decreased during therapy. Nordimet may cause a reduction in the number of white blood cells and your resistance to infection may be decreased. If you experience an infection with symptoms such as fever and serious deterioration of your general condition, or fever with local infection symptoms such as sore throat/sore pharynx/sore mouth or urinary problems you should see your doctor immediately. A blood test will be taken to check for possible reduction of white blood cells (agranulocytosis). It is important to tell your doctor that you are taking Nordimet. Methotrexate is known to cause bone disorders such as joint and muscle pain and osteoporosis. The frequency of these risks in children is not known. 146 Nordimet may cause serious (sometimes life-threatening) side effects. Your doctor will do tests to check for abnormalities developing in the blood (e.g. low white blood cells, low platelets, lymphoma) and changes in the kidney and the liver. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Nordimet Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the label of the pre-filled pen and the carton after EXP. The expiry date refers to the last day of that month. Store below 25°C. Keep the pen in the outer carton in order to protect from light. Do not use this medicine if you notice that the solution is not clear and contains particles. Nordimet is for single use only. Any used pen should be discarded. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Nordimet contains The active substance is methotrexate. 1 ml of solution contains 25 mg methotrexate. The other ingredients are sodium chloride, sodium hydroxide and water for injections. The following pens are available: Pre-filled pens of 0.3 ml containing 7.5 mg methotrexate. Pre-filled pens of 0.4 ml containing 10 mg methotrexate Pre-filled pens of 0.5 ml containing 12.5 mg methotrexate Pre-filled pens of 0.6 ml containing 15 mg methotrexate Pre-filled pens of 0.7 ml containing 17.5 mg methotrexate Pre-filled pens of 0.8 ml containing 20 mg methotrexate Pre-filled pens of 0.9 ml containing 22.5 mg methotrexate Pre-filled pens of 1.0 ml containing 25 mg methotrexate What Nordimet looks like and contents of the pack Nordimet pre-filled pens contain a clear, yellow solution for injection. The pre-filled pens are designed to prevent needlestick injury and reuse. Nordimet is available in packs containing 1 or 4 pre-filled pens of 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml or 1.0 ml solution for injection with attached needle and 1 or 4 alcohol swabs and in multipacks of 4 and 6 cartons, each containing 1 pre-filled pen solution for injection with attached needle and one alcohol swab. Nordimet is also available in multipacks containing 12 pre- filled pens in 3 cartons (4 pens and alcohol swabs per carton). Not all pack sizes may be marketed. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 147 Marketing Authorisation Holder Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands Manufacturer CENEXI - Laboratoires Thissen Rue de la Papyrée 2-6 B-1420 Braine-l’Alleud Belgium QPharma AB Agneslundsvagen 27 P.O. Box 590 SE-201 25 Malmo Sweden This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http//www.ema.europa.eu. 148 Package leaflet: Information for the user Nordimet 7.5 mg solution for injection in pre-filled syringe Nordimet 10 mg solution for injection in pre-filled syringe Nordimet 12.5 mg solution for injection in pre-filled syringe Nordimet 15 mg solution for injection in pre-filled syringe Nordimet 17.5 mg solution for injection in pre-filled syringe Nordimet 20 mg solution for injection in pre-filled syringe Nordimet 22.5 mg solution for injection in pre-filled syringe Nordimet 25 mg solution for injection in pre-filled syringe methotrexate Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Nordimet is and what it is used for 2. What you need to know before you use Nordimet 3. How to use Nordimet 4. Possible side effects 5. How to store Nordimet 6. Contents of the pack and other information 1. What Nordimet is and what it is used for Nordimet contains the active substance methotrexate which works by: - reducing inflammation or swelling, and - reducing the activity of the immune system (the body’s own defense mechanism). An overactive immune system has been linked to inflammatory diseases. Nordimet is a medicine used to treat a range of inflammatory diseases: - active rheumatoid arthritis in adults. Active rheumatoid arthritis is an inflammatory condition that affects the joints; - severe, active juvenile idiopathic arthritis in five or more joints (the condition is therefore called polyarthritic), in patients who have had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs); - a severe form of treatment resistant psoriasis (also called severe recalcitrant disabling psoriasis), in adult patients who have had an inadequate response to other treatments including phototherapy (light therapy), PUVA (ultraviolet light therapy), and retinoids (group of medicines derived from vitamin A). 149 2. What you need to know before you use Nordimet Do not use Nordimet if: - you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6) - you have severe kidney disease (your doctor will be able to tell you if you have severe kidney disease) - you have severe liver disease (your doctor will be able to tell you if you have severe liver disease) - you have disorders of the blood-forming system - your alcohol consumption is high - you have an impaired immune system - you have a severe or existing infection, e.g. tuberculosis or HIV - you have gastrointestinal ulcers - you are pregnant or breast-feeding (see section “Pregnancy, breast-feeding and fertility”) - you receive vaccinations with live vaccines at the same time. Warnings and precautions Acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with methotrexate. If you experience symptoms of spitting or coughing up blood you should contact your doctor immediately. Important warning about the dosing of Nordimet Methotrexate for the therapy of rheumatic diseases or diseases of the skin must only be used once weekly. Incorrect dosing of methotrexate may lead to serious adverse effects which may be fatal. Please read section 3 of this package leaflet very carefully. Talk to your doctor before using Nordimet if: - you have diabetes mellitus and are being treated with insulin - you have inactive, prolonged infections (e.g. tuberculosis, hepatitis B or C, shingles [herpes zoster]) - you have/had any liver or kidney disease - you have problems with lung function - you are severely overweight - you have abnormal accumulation of liquid in the abdomen or in the cavity between the lungs and chest wall (ascites, pleural effusions) - you are dehydrated or suffer from conditions leading to dehydration (e.g. dehydration as a result of vomiting, diarrhoea or inflammation of the mouth and lips) If you have experienced problems with your skin after radiation therapy (radiation induced dermatitis) or sun-burn, these conditions can reappear when taking Nordimet. Children, adolescents and elderly Dose instructions depend on the patient’s body weight. Use in children under 3 years of age is not recommended due to insufficient experience of using this medicine in this age group. Children, adolescents and the elderly being treated with Nordimet should be kept under close medical surveillance to identify possible side effects as early as possible. The dose for elderly patients should be lowered due to age-related reduced liver and kidney function. Special precautionary measures for treatment with Nordimet Methotrexate temporarily affects sperm and egg production, which is reversible in most cases. Methotrexate can cause miscarriage and severe birth defects. You must avoid becoming pregnant 150 when using methotrexate and for at least six months after treatment has stopped. See also section “Pregnancy, breast-feeding and fertility”. Skin changes caused by psoriasis can worsen during treatment with Nordimet if exposed to ultraviolet irradiation. Before the start of treatment and recommended follow-up examinations and precautions Before treatment is started your doctor may carry out blood tests, and also check how well your kidneys and liver are working. You may also have a chest X-ray. Further tests may also be done during and after treatment. Do not miss appointments for blood tests. If the results of any of these tests are abnormal, treatment will only be resumed when all readings are back to normal. Even when Nordimet is used at low doses, serious side effects can occur. Your doctor will carry out blood and urine tests to make sure that any side effects are identified quickly. Other medicines and Nordimet Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription and herbal or natural medicinal products. It is especially important to tell your doctor if you are taking: - other treatments for rheumatoid arthritis or psoriasis such as leflunomide, sulphasalazine (a medicine that besides arthritis and psoriasis is also used to treat ulcerative colitis), aspirin, phenylbutazone, or amidopyrine - alcohol (drinking alcohol should be avoided while you are taking Nordimet) - azathioprine (used to prevent rejection after an organ transplant) - retinoids (used to treat psoriasis and other skin disorders) - anticonvulsant medicines (used to prevent fits), such as phenytoin, valproate or carbamazepine - cancer treatments - barbiturates (sleeping injection) - tranquillisers - oral contraceptives - probenecid (used to treat gout) - antibiotics - pyrimethamine (which is used to prevent and treat malaria) - vitamin preparations containing folic acid - proton-pump inhibitors (medicines that reduce the production of gastric acid and that are used to treat severe heartburn or ulcers), such as omeprazole - theophylline (used to treat asthma) - any vaccination with a live vaccine (must be avoided), such as measles, mumps, influenza or yellow fever vaccines. Nordimet with food, drink and alcohol During treatment with Nordimet, you must not drink any alcohol and should avoid excessive consumption of coffee, soft drinks containing caffeine and black tea as this may enhance side effects or interfere with the efficacy of Nordimet. Also, make sure you drink plenty of liquids during treatment with Nordimet because dehydration (reduction in body water) can increase the toxicity of Nordimet. 151 Pregnancy, breast-feeding and fertility If you are pregnant or breast feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Pregnancy Do not use Nordimet during pregnancy or if you are trying to become pregnant. Methotrexate can cause birth defects, harm unborn babies or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is very important that methotrexate is not given to pregnant patients or patients planning to become pregnant. In women of child-bearing age any possibility of pregnancy must be excluded with appropriate measures, e.g. a pregnancy test before starting treatment. You must avoid becoming pregnant whilst taking methotrexate and for at least 6 months after treatment is stopped by using reliable contraception throughout this time (see also section “Warnings and precautions”). If you do become pregnant during treatment or suspect you might be pregnant, speak to your doctor as soon as possible. You should be offered advice regarding the risk of harmful effects on the child through treatment. If you wish to become pregnant you should consult your doctor, who may refer you for specialist advice before the planned start of treatment. Breast-feeding Do not breast-feed during treatment because methotrexate passes into breast milk. If your doctor considers treatment with methotrexate absolutely necessary during the lactation period, you must stop breast-feeding. Male fertility The available evidence does not indicate an increased risk of malformations or miscarriage if the father takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded. Methotrexate may be genotoxic. This means that the medicine may cause genetic mutation. Methotrexate can affect sperm production with the potential to cause birth defects. Therefore, you should avoid fathering a child or to donate semen whilst taking methotrexate and for at least 6 months after treatment is stopped. Driving and using machines Side effects affecting the central nervous system, such as tiredness and dizziness, may occur during treatment with Nordimet. In some cases, the ability to drive vehicles and/or use machines may be impaired. If you feel tired or dizzy, you should not drive or use machines. Nordimet contains sodium This medicine contains less than 1 mmol sodium (23 mg) per dose, and so is essentially “sodium-free”. 3. How to use Nordimet Important warning about the dose of Nordimet Use Nordimet only once a week for the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis,psoriasis and psoriatitic arthritis requiring dosing once a week. Using too much of Nordimet may be fatal. Please read section 3 of this leaflet very carefully. If you have any questions, please talk to your doctor or pharmacist before you take this medicine. Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. 152 Nordimet is administered once a week only. You and your doctor can decide on a suitable day each week to receive your injection. Incorrect administration of Nordimet can lead to severe side effects that may be fatal. The recommended dose is: Dose in patients with rheumatoid arthritis The recommended starting dose is 7.5 mg methotrexate once a week. The doctor may increase the dose if the used dose is not effective but tolerated well. The average weekly dose is 15-20 mg. Generally, a weekly dose of 25 mg should not be exceeded. Once Nordimet starts working, the doctor may reduce the dose gradually to the lowest possible effective maintenance dose. Generally, improvement of symptoms can be expected after 4-8 weeks of treatment. Symptoms may return if treatment with Nordimet is stopped. Dose in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis The doctor will calculate the dose required from the child’s body surface area (m2), and the dose is expressed as mg/m2. Use in children under < 3 years is not recommended due to insufficient experience in this age group. Use in adults with severe forms of psoriasis vulgaris or psoriatic arthritis Your doctor will give you a single test dose of 5-10 mg, in order to assess possible side effects. If the test dose is well tolerated, treatment will be continued after a week with a dose of approximately 7.5 mg. Response to treatment can generally be expected after 2-6 weeks. Depending on the effects of treatment and results of blood and urine tests, the therapy is then continued or stopped. Method and duration of administration Nordimet is given as injection under the skin (subcutaneously). It must be injected once weekly and it is recommended to always inject Nordimet on the same day of the week. At the start of your treatment, Nordimet may be injected by medical staff. However, your doctor may decide that you can learn how to inject Nordimet yourself. You will receive appropriate training for you to do this. Under no circumstances should you attempt to inject yourself, unless you have been trained to do so. The duration of treatment is determined by the treating physician. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris and psoriatic arthritis with Nordimet is a long-term treatment. How to give yourself an injection of Nordimet If you have difficulty handling the syringe, ask your doctor or pharmacist. Do not try to inject yourself if you have not been trained on how to do so. If you are not sure what to do, talk to your doctor or nurse immediately. 153 Before injecting yourself with Nordimet - Check the expiry date on the medicine. Do not use if the date has passed. - Check the syringe is not damaged and the medicine in it is a clear, yellow solution. If not, use another syringe. - Check your last injection site to see if the last injection caused any redness, change in skin colour, swelling, oozing or is still painful, if so talk to your doctor or nurse. - Decide where you are going to inject the medicine. Change the place where you inject each time. Instructions on injecting yourself with Nordimet 1) Wash your hands thoroughly with soap and water. 2) Sit or lie in a relaxed, comfortable position. Make sure you can see the skin area you are going to inject. 3) The syringe is pre-filled and ready to use. Open the blister pack by peeling back the top layer all the way off the blister pack as shown. 4) Precaution: DO NOT lift the product by the plunger or needle cover. Remove the syringe from the box by the body as shown in the picture below. 5) Visually inspect the syringe. You should see a yellow fluid through the viewing window. You may see a small air bubble, this does not affect the injection and will not harm you. 6) Choose an injection site and clean it with the enclosed alcohol swab. It requires 30-60 seconds to be effective. The skin on the front side abdominal wall and the skin at the front of the thigh are suitable as injection sites. 7) While holding the body of the syringe, pull the cap off. 154 Do not press on the plunger before injecting yourself to get rid of air bubbles. This can lead to a loss of the medicine. Once you have taken the cap off, keep the syringe in your hand. Do not allow the syringe to touch anything else. This is to make sure that the needle stays clean. 8) Hold the syringe in the hand you write with (like a pencil) and with your other hand, make a fold in the skin by gently pinching the skin of the injection place with your forefinger and thumb. Make sure you hold the skin fold throughout the injection. 9) Move the syringe towards the skin fold (site of injection) with the needle shield pointing directly at the site of injection. Insert the full length of the needle into the skin fold. 10) Press down on the plunger with your finger until the syringe is empty. This will send the medication under the skin. 11) Remove the needle by pulling it out straight. The safety shield on the syringe will automatically cover the needle to prevent any needlestick injuries. You can now let go of the skin fold. Note: the safety system allowing release of the safety shield, can only be activated when the syringe has been emptied by pressing the plunger all the way down. 155 12) Discard the used syringe into the sharps bin provided. Close the container lid tightly and place the container out of reach of children. If you accidently get methotrexate on the surface of the skin or soft tissues you must rinse with plenty of water. If you use more Nordimet than you should Follow the dose recommendations of your treating doctor. Do not change the dose without your doctor’s recommendation. If you suspect that you have used too much Nordimet, tell your doctor or contact the nearest hospital immediately. Take your medicine package and this leaflet with you if you go to a doctor or hospital. An overdose of methotrexate can lead to severe toxic reactions. Overdose symptoms may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomit that looks like coffee grounds, and decreased urinating. See also section 4. If you forget to use Nordimet Do not take a double dose to make up for a forgotten dose, but continue taking the prescribed dose as normal. Ask your doctor for advice. If you stop taking Nordimet You should not interrupt or discontinue Nordimet treatment before discussing with your doctor. If you suspect that you are experiencing side effects, contact your doctor immediately for advice. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor straight away if you get any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body). Serious side effects If you develop any of the following side effects, contact your doctor immediately: - inflammation of the lungs (symptoms may be general illness, dry, irritating cough, shortness of breath, breathlessness at rest, chest pain, or fever) - spitting or coughing blood - severe peeling or blistering of the skin - unusual bleeding (including vomiting blood) or bruising - severe diarrhoea - ulcers in mouth - black or tarry stools - blood in the urine or stools - tiny red spots on the skin - fever - yellowing of the skin (jaundice) - pain or difficulty in passing urine - thirst and/or frequent urination - fits (convulsions) - loss of consciousness - blurred or decreased vision 156 The following side effects have also been reported: Very common (may affect more than 1 in 10 people): loss of appetite, nausea (feeling sick), vomiting, tummy pain, inflammation and ulcers in the mouth and throat, and increase in liver enzymes. Common (may affect up to 1 in 10 people): Reduced blood cell formation with decrease in white and/or red blood cells and/or platelets (leukopenia, anaemia, thrombocytopenia), headache, tiredness, drowsiness, inflammation of the lungs (pneumonia) with dry, non-productive cough, shortness of breath and fever, diarrhoea, rash, reddening of the skin, itching. Uncommon (may affect up to 1 in 100 people): Decrease in the number of blood cells and platelets , dizziness, confusion, depression, fits, inflammation of blood vessels, lung damage, ulcers and bleeding in the digestive tract, liver disorders, diabetes, decreased blood protein, nettle rash, light sensitivity, brown skin, hair loss, increase of rheumatic nodules, shingles, painful psoriasis, joint or muscle pain, osteoporosis (reduction of bone mass), inflammation and ulcers of the bladder (possibly with blood in the urine), painful urination, severe allergic reactions, inflammation and ulcers of the vagina, slow wound healing. Rare (may affect up to 1 in 1,000 people): Inflammation of the sac around the heart, fluid in the sac around the heart, severe visual disturbance, mood fluctuations, low blood pressure, blood clots, sore throat, interruption of breathing, asthma, inflammation of the digestive tract, bloody stools, inflamed gums, abnormal digestion, acute hepatitis (inflammation of the liver), changed colour of nails, acne, red or purple spots due to vessel bleeding, bone fracture, kidney failure, decrease or absence of urine, electrolyte disturbances, defective sperm formation, menstruation disorders. Very rare (may affect up to 1 in 10,000 people): Infections, severe failure of the bone marrow, liver failure, swollen glands, sleeplessness, pain, muscle weakness, sensation of numbness or tingling / having less sensitivity to stimulation than normal, changes in sense of taste (metallic taste), inflammation of the lining of the brain causing paralysis or vomiting, red eyes, damage to the retina of the eye, fluid in the lungs, vomiting blood, cold sores, protein in the urine, fever, loss of sex drive, problems having an erection, infection around a fingernail, severe complications of the gastrointestinal tract, boils, small blood vessels in the skin, fungal infections, damage to the blood vessels of the skin, vaginal discharge, infertility, male breast enlargement (gynaecomastia), inflammation of the brain, lymphoproliferative disorders (excessive growth of white blood cells). Frequency not known (cannot be estimated from the available data): Bleeding from the lungs, bone damage in the jaw (secondary to excessive growth of white blood cells), tissue destruction at injection site, redness and shedding of skin, swelling. Only mild local skin reactions were observed with Nordimet and these decreased during therapy. Nordimet may cause a reduction in the number of white blood cells and your resistance to infection may be decreased. If you experience an infection with symptoms such as fever and serious deterioration of your general condition, or fever with local infection symptoms such as sore throat/sore pharynx/sore mouth or urinary problems you should see your doctor immediately. A blood test will be taken to check for possible reduction of white blood cells (agranulocytosis). It is important to tell your doctor that you are taking Nordimet. Methotrexate is known to cause bone disorders such as joint and muscle pain and osteoporosis. The frequency of these risks in children is not known. 157 Nordimet may cause serious (sometimes life-threatening) side effects. Your doctor will do tests to check for abnormalities developing in the blood (e.g. low white blood cells, low platelets, lymphoma) and changes in the kidney and the liver. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Nordimet Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the label of the pre-filled syringe and the carton after EXP. The expiry date refers to the last day of that month. Store below 25°C. Keep the syringe in the outer carton in order to protect from light. Do not use this medicine if you notice that the solution is not clear and contains particles. Nordimet is for single use only. Any used syringe should be discarded. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Nordimet contains The active substance is methotrexate. 1 ml of solution contains 25 mg methotrexate. The other ingredients are sodium chloride, sodium hydroxide and water for injections. The following syringes are available: Pre-filled syringes of 0.3 ml containing 7.5 mg methotrexate. Pre-filled syringes of 0.4 ml containing 10 mg methotrexate Pre-filled syringes of 0.5 ml containing 12.5 mg methotrexate Pre-filled syringes of 0.6 ml containing 15 mg methotrexate Pre-filled syringes of 0.7 ml containing 17.5 mg methotrexate Pre-filled syringes of 0.8 ml containing 20 mg methotrexate Pre-filled syringes of 0.9 ml containing 22.5 mg methotrexate Pre-filled syringes of 1.0 ml containing 25 mg methotrexate What Nordimet looks like and contents of the pack Nordimet pre-filled syringes contain a clear, yellow solution for injection. The pre-filled syringes contain a safety system designed to prevent needlestick injury and reuse. Nordimet is available in packs containing 1 pre-filled syringe of 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml or 1.0 ml solution for injection with attached needle with needle guard and two alcohol swabs and in multipacks of 4, 6 and 12 cartons, each containing 1 pre-filled syringe solution for injection with attached needle with needle guard and two alcohol swabs. Not all pack sizes may be marketed. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 158 Marketing Authorisation Holder Nordic Group B.V. Siriusdreef 41 2132 WT Hoofddorp The Netherlands Manufacturer CENEXI - Laboratoires Thissen Rue de la Papyrée 2-6 B-1420 Braine-l’Alleud Belgium This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http//www.ema.europa.eu. 159 Annex IV Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s) 160 Scientific conclusions Taking into account the PRAC Assessment Report on the PSUR(s) for methotrexate, the scientific conclusions of CHMP are as follows: In view of the available data on medication errors due to handling issues resulting from lack of training with parenteral products suitable for self-administration the PRAC concluded that the product information (Section 4.2 of the SmPC and Section 3 of the PL) of products containing methotrexate suitable for parenteral self-administration by patients (i.e. prefilled syringes and prefilled pens) should be amended accordingly. For products without any indication in oncology or extra-uterine pregnancy, the PRAC concluded that the existing wording in the product information (Section 4.5 of the SmPC) concerning the interaction between methotrexate and nitrous oxide should be amended to provide more clarity. In view of available data on skin exfoliation from the literature, spontaneous reports, including in some cases a close temporal relationship, and a positive de-challenge and/or re-challenge, the PRAC considers that a causal relationship between methotrexate and skin exfoliation / exfoliative dermatitis is established. The PRAC concluded that an update of section 4.8 of the SmPC to add the adverse reaction “skin exfoliation / dermatitis exfoliative” with a frequency “not known” was warranted for all methotrexate containing products. The PL should be amended accordingly. In view of available data on paraesthesia / hypoaesthesia (not restricted to extremities) from spontaneous reports, including in some cases a close temporal relationship, and a positive re- challenge, and existing product information the PRAC considers a causal relationship between methotrexate and paraesthesia / hypoaesthesia (not restricted to extremities) is at least a reasonable possibility. The PRAC concluded that an update of section 4.8 of the SmPC to add or amend the adverse reaction “paraesthesia / hypoaesthesia” not restricted to the extremities with a frequency of “very rare” was warranted for low dose methotrexate-containing products. The PL should be amended accordingly. In view of available data on oedema from spontaneous reports, including in some cases a close temporal relationship, and a positive de-challenge the PRAC considers a causal relationship between methotrexate and oedema is at least a reasonable possibility. The PRAC concluded that an update of section 4.8 of the SmPC to add the adverse reaction “oedema” with a frequency “not known” was warranted for low dose methotrexate-containing products. The PL should be amended accordingly. The CHMP agrees with the scientific conclusions made by the PRAC. Grounds for the variation to the terms of the marketing authorisation(s) On the basis of the scientific conclusions for methotrexate the CHMP is of the opinion that the benefit-risk balance of the medicinal products containing methotrexate is unchanged subject to the proposed changes to the product information. The CHMP recommends that the terms of the marketing authorisations should be varied. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what nordimet is and what it is used for', 'Section_Content': "nordimet contains the active substance methotrexate which works by: - reducing inflammation or swelling, and - reducing the activity of the immune system (the body's own defense mechanism). an overactive immune system has been linked to inflammatory diseases. nordimet is a medicine used to treat a range of inflammatory diseases: - active rheumatoid arthritis in adults. active rheumatoid arthritis is an inflammatory condition that affects the joints; - severe, active juvenile idiopathic arthritis in five or more joints (the condition is therefore called polyarthritic), in patients who have had an inadequate response to nonsteroidal anti-inflammatory drugs (nsaids); - a severe form of treatment resistant psoriasis (also called severe recalcitrant disabling psoriasis), in adult patients who have had an inadequate response to other treatments including phototherapy (light therapy), puva (ultraviolet light therapy), and retinoids (group of medicines derived from vitamin a).", 'Entity_Recognition': [{'Text': 'nordimet', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the active substance methotrexate', 'Type': 'TREATMENT', 'BeginOffset': 18, 'EndOffset': 51}, {'Text': 'reducing inflammation', 'Type': 'PROBLEM', 'BeginOffset': 70, 'EndOffset': 91}, {'Id': 10, 'BeginOffset': 95, 'EndOffset': 103, 'Score': 0.9960243701934814, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6667045950889587}]}, {'Id': 0, 'BeginOffset': 140, 'EndOffset': 153, 'Score': 0.7586780786514282, 'Text': 'immune system', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'an overactive immune system', 'Type': 'PROBLEM', 'BeginOffset': 190, 'EndOffset': 217}, {'Id': 12, 'BeginOffset': 237, 'EndOffset': 258, 'Score': 0.8649616837501526, 'Text': 'inflammatory diseases', 'Category': 'MEDICAL_CONDITION', 'Type': 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{'Title': '2. what you need to know before you use nordimet', 'Section_Content': 'do not use nordimet if: - you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6) - you have severe kidney disease (your doctor will be able to tell you if you have severe kidney disease) - you have severe liver disease (your doctor will be able to tell you if you have severe liver disease) - you have disorders of the blood-forming system - your alcohol consumption is high - you have an impaired immune system - you have a severe or existing infection, e.g. tuberculosis or hiv - you have gastrointestinal ulcers - you are pregnant or breast-feeding (see section "pregnancy, breast-feeding and fertility") - you receive vaccinations with live vaccines at the same time. warnings and precautions acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with methotrexate. if you experience symptoms of spitting or coughing up blood you should contact your doctor immediately. important warning about the dosing of nordimet methotrexate for the therapy of rheumatic diseases or diseases of the skin must only be used once weekly. incorrect dosing of methotrexate may lead to serious adverse effects which may be fatal. please read section 3 of this package leaflet very carefully. talk to your doctor before using nordimet if: - you have diabetes mellitus and are being treated with insulin - you have inactive, prolonged infections (e.g. tuberculosis, hepatitis b or c, shingles [herpes zoster]) - you have/had any liver or kidney disease - you have problems with lung function - you are severely overweight - you have abnormal accumulation of liquid in the abdomen or in the cavity between the lungs and chest wall (ascites, pleural effusions) - you are dehydrated or suffer from conditions leading to dehydration (e.g. dehydration as a result of vomiting, diarrhoea or inflammation of the mouth and lips) if you have experienced problems with your skin after radiation therapy (radiation induced dermatitis) or sun-burn, these conditions can reappear when taking nordimet. children, adolescents and elderly dose instructions depend on the patient\'s body weight. use in children under 3 years of age is not recommended due to insufficient experience of using this medicine in this age group. children, adolescents and the elderly being treated with nordimet should be kept under close medical surveillance to identify possible side effects as early as possible. the dose for elderly patients should be lowered due to age-related reduced liver and kidney function. special precautionary measures for treatment with nordimet methotrexate temporarily affects sperm and egg production, which is reversible in most cases. methotrexate can cause miscarriage and severe birth defects. you must avoid becoming pregnant 139 when using methotrexate and for at least six months after treatment has stopped. see also section "pregnancy, breast-feeding and fertility". skin changes caused by psoriasis can worsen during treatment with nordimet if exposed to ultraviolet irradiation. before the start of treatment and recommended follow-up examinations and precautions before treatment is started your doctor may carry out blood tests, and also check how well your kidneys and liver are working. you may also have a chest x-ray. further tests may also be done during and after treatment. do not miss appointments for blood tests. if the results of any of these tests are abnormal, treatment will only be resumed when all readings are back to normal. even when nordimet is used at low doses, serious side effects can occur. your doctor will carry out blood and urine tests to make sure that any side effects are identified quickly. other medicines and nordimet tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription and herbal or natural medicinal products. it is especially important to tell your doctor if you are taking: - other treatments for rheumatoid arthritis or psoriasis such as leflunomide, sulphasalazine (a medicine that besides arthritis and psoriasis is also used to treat ulcerative colitis), aspirin, phenylbutazone, or amidopyrine - alcohol (drinking alcohol should be avoided while you are taking nordimet) - azathioprine (used to prevent rejection after an organ transplant) - retinoids (used to treat psoriasis and other skin disorders) - anticonvulsant medicines (used to prevent fits), such as phenytoin, valproate or carbamazepine - cancer treatments - barbiturates (sleeping injection) - tranquillisers - oral contraceptives - probenecid (used to treat gout) - antibiotics - pyrimethamine (which is used to prevent and treat malaria) - vitamin preparations containing folic acid - proton-pump inhibitors (medicines that reduce the production of gastric acid and that are used to treat severe heartburn or ulcers), such as omeprazole - theophylline (used to treat asthma) - any vaccination with a live vaccine (must be avoided), such as measles, mumps, influenza or yellow fever vaccines. nordimet with food, drink and alcohol during treatment with nordimet, you must not drink any alcohol and should avoid excessive consumption of coffee, soft drinks containing caffeine and black tea as this may enhance side effects or interfere with the efficacy of nordimet. also, make sure you drink plenty of liquids during treatment with nordimet because dehydration (reduction in body water) can increase the toxicity of nordimet. pregnancy, breast-feeding and fertility if you are pregnant or breast feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. pregnancy do not use nordimet during pregnancy or if you are trying to become pregnant. methotrexate can cause birth defects, harm unborn babies or cause miscarriages. it is associated with malformations of the skull, face, heart and blood vessels, brain and limbs. therefore, it is very important that methotrexate is not given to pregnant patients or patients planning to become pregnant. in women of child-bearing age any possibility of pregnancy must be excluded with appropriate measures, e.g. a pregnancy test before starting treatment. you must avoid becoming pregnant whilst taking methotrexate and for at least 6 months after treatment is stopped by using reliable contraception throughout this time (see also section "warnings and precautions"). if you do become pregnant during treatment or suspect you might be pregnant, speak to your doctor as soon as possible. you should be offered advice regarding the risk of harmful effects on the child through treatment. if you wish to become pregnant you should consult your doctor, who may refer you for specialist advice before the planned start of treatment. breast-feeding do not breast-feed during treatment because methotrexate passes into breast milk. if your doctor considers treatment with methotrexate absolutely necessary during the lactation period, you must stop breast-feeding. male fertility the available evidence does not indicate an increased risk of malformations or miscarriage if the father takes methotrexate less than 30 mg/week. however, a risk cannot be completely excluded. methotrexate may be genotoxic. this means that the medicine may cause genetic mutation. methotrexate can affect sperm production with the potential to cause birth defects. therefore, you should avoid fathering a child or to donate semen whilst taking methotrexate and for at least 6 months after treatment is stopped. driving and using machines side effects affecting the central nervous system, such as tiredness and dizziness, may occur during treatment with nordimet. in some cases, the ability to drive vehicles and/or use machines may be impaired. if you feel tired or dizzy, you should not drive or use machines. 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{'Title': '3. how to use nordimet', 'Section_Content': 'important warning about the dose of nordimet use nordimet only once a week for the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis and psoriatic arthritis requiring dosing once a week. using too much of nordimet may be fatal. please read section 3 of this leaflet very carefully. if you have any questions, please talk to your doctor or pharmacist before you take this medicine. always use this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. nordimet is administered once a week only. you and your doctor can decide on a suitable day each week to receive your injection. incorrect administration of nordimet can lead to severe side effects that may be fatal. the recommended dose is: dose in patients with rheumatoid arthritis the recommended starting dose is 7.5 mg methotrexate once a week. the doctor may increase the dose if the used dose is not effective but tolerated well. the average weekly dose is 15-20 mg. generally, a weekly dose of 25 mg should not be exceeded. once nordimet starts working, the doctor may reduce the dose gradually to the lowest possible effective maintenance dose. generally, improvement of symptoms can be expected after 4-8 weeks of treatment. symptoms may return if treatment with nordimet is stopped. dose in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis the doctor will calculate the dose required from the child\'s body surface area (m2), and the dose is expressed as mg/m2. use in children under < 3 years is not recommended due to insufficient experience in this age group. use in adults with severe forms of psoriasis vulgaris or psoriatic arthritis your doctor will give you a single test dose of 5-10 mg, in order to assess possible side effects. if the test dose is well tolerated, treatment will be continued after a week with a dose of approximately 7.5 mg. response to treatment can generally be expected after 2-6 weeks. depending on the effects of treatment and results of blood and urine tests, the therapy is then continued or stopped. method and duration of administration nordimet is given as injection under the skin (subcutaneously). it must be injected once weekly and it is recommended to always inject nordimet on the same day of the week. at the start of your treatment, nordimet may be injected by medical staff. however, your doctor may decide that you can learn how to inject nordimet yourself. you will receive appropriate training for you to do this. under no circumstances should you attempt to inject yourself, unless you have been trained to do so. the duration of treatment is determined by the treating physician. treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris and psoriatic arthritis with nordimet is a long-term treatment. how to give yourself an injection of nordimet if you have difficulty handling the pen, ask your doctor or pharmacist. do not try to inject yourself if you have not been trained on how to do so. if you are not sure what to do, talk to your doctor or nurse immediately. before injecting yourself with nordimet - check the expiry date on the medicine. do not use if the date has passed. - check the pen is not damaged and the medicine in it is a clear, yellow solution. if not, use another pen. - check your last injection site to see if the last injection caused any redness, change in skin colour, swelling, oozing or is still painful, if so talk to your doctor or nurse. - decide where you are going to inject the medicine. change the place where you inject each time. instructions on injecting yourself with nordimet 1) wash your hands thoroughly with soap and water. 2) sit or lie in a relaxed, comfortable position. make sure you can see the skin area you are going to inject. 3) the pen is pre-filled and ready to use. visually inspect the pen. you should see a yellow fluid through the viewing window. you may see a small air bubble, this does not affect the injection and will not harm you. a droplet may appear at the tip of the needle. this is normal. 4) choose an injection site and clean it with the enclosed alcohol swab. it requires 30-60 seconds to be effective. the skin on the front side abdominal wall and the skin at the front of the thigh are suitable as injection sites. 5) while holding the body of the pen, pull the cap off. once you have taken the cap off, keep the pen in your hand. do not allow the pen to touch anything else. this is to make sure that the pen is not accidentally activated and that the needle stays clean. 6) make a fold in the skin by gently pinching the skin of the injection place with your forefinger and thumb. make sure you hold the skin fold throughout the injection. 7) move the pen towards the skin fold (site of injection) with the needle shield pointing directly at the site of injection. place the yellow needle shield against the area of injection so that the entire rim of the needle shield is touching the skin. 8) apply downward pressure on the pen on to your skin until you hear and feel a "click". this activates the pen and the solution will inject automatically into the skin. 9) the injection lasts for a maximum of 10 seconds. you will feel and hear a second "click" once the injection is completed. 10) wait another 2-3 seconds before removing the pen from your skin. the safety shield on the pen is now locked to prevent any needlestick injuries. you can now let go of the skin fold. 11) visually inspect the pen through the viewing window. you should see green plastic. this means that all the fluid has been injected. discard the used pen into the sharps bin provided. close the container lid tightly and place the container out of reach of children. if you accidently get methotrexate on the surface of the skin or soft tissues you must rinse with plenty of water. if you use more nordimet than you should follow the dose recommendations of your treating doctor. do not change the dose without your doctor\'s recommendation. if you suspect that you have used too much nordimet, tell your doctor or contact the nearest hospital immediately. take your medicine package and this leaflet with you if you go to a doctor or hospital. an overdose of methotrexate can lead to severe toxic reactions. overdose symptoms may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomit that looks like coffee grounds, and decreased urinating. see also section 4. if you forget to use nordimet do not take a double dose to make up for a forgotten dose, but continue taking the prescribed dose as normal. ask your doctor for advice. if you stop taking nordimet you should not interrupt or discontinue nordimet treatment before discussing with your doctor. if you suspect that you are experiencing side effects, contact 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor straight away if you get any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body). serious side effects if you develop any of the following side effects, contact your doctor immediately: - inflammation of the lungs (symptoms may be general illness, dry, irritating cough, shortness of breath, breathlessness at rest, chest pain, or fever) - spitting or coughing blood - severe peeling or blistering of the skin - unusual bleeding (including vomiting blood) or bruising - severe diarrhoea - ulcers in mouth - black or tarry stools - blood in the urine or stools - tiny red spots on the skin - fever - yellowing of the skin (jaundice) - pain or difficulty in passing urine - thirst and/or frequent urination - fits (convulsions) - loss of consciousness - blurred or decreased vision 145 the following side effects have also been reported: very common (may affect more than 1 in 10 people): loss of appetite, nausea (feeling sick), vomiting, tummy pain, inflammation and ulcers in the mouth and throat, and increase in liver enzymes. common (may affect up to 1 in 10 people): reduced blood cell formation with decrease in white and/or red blood cells and/or platelets (leukopenia, anaemia, thrombocytopenia), headache, tiredness, drowsiness, inflammation of the lungs (pneumonia) with dry, non-productive cough, shortness of breath and fever, diarrhoea, rash, reddening of the skin, itching. uncommon (may affect up to 1 in 100 people): decrease in the number of blood cells and platelets , dizziness, confusion, depression, fits, inflammation of blood vessels, lung damage, ulcers and bleeding in the digestive tract, liver disorders, diabetes, decreased blood protein, nettle rash, light sensitivity, brown skin, hair loss, increase of rheumatic nodules, shingles, painful psoriasis, joint or muscle pain, osteoporosis (reduction of bone mass), inflammation and ulcers of the bladder (possibly with blood in the urine), painful urination, severe allergic reactions, inflammation and ulcers of the vagina, slow wound healing. rare (may affect up to 1 in 1,000 people): inflammation of the sac around the heart, fluid in the sac around the heart, severe visual disturbance, mood fluctuations, low blood pressure, blood clots, sore throat, interruption of breathing, asthma, inflammation of the digestive tract, bloody stools, inflamed gums, abnormal digestion, acute hepatitis (inflammation of the liver), changed colour of nails, acne, red or purple spots due to vessel bleeding, bone fracture, kidney failure, decrease or absence of urine, electrolyte disturbances, defective sperm formation, menstruation disorders. very rare (may affect up to 1 in 10,000 people): infections, severe failure of the bone marrow, liver failure, swollen glands, sleeplessness, pain, muscle weakness, sensation of numbness or tingling / having less sensitivity to stimulation than normal, changes in sense of taste (metallic taste), inflammation of the lining of the brain causing paralysis or vomiting, red eyes, damage to the retina of the eye, fluid in the lungs, vomiting blood, cold sores, protein in the urine, fever, loss of sex drive, problems having an erection, infection around a fingernail, severe complications of the gastrointestinal tract, boils, small blood vessels in the skin, fungal infections, damage to the blood vessels of the skin, vaginal discharge, infertility, male breast enlargement (gynaecomastia), inflammation of the brain, lymphoproliferative disorders (excessive growth of white blood cells). frequency not known (cannot be estimated from the available data): bleeding from the lungs, bone damage in the jaw (secondary to excessive growth of white blood cells), tissue destruction at injection site, redness and shedding of skin, swelling. only mild local skin reactions were observed with nordimet and these decreased during therapy. nordimet may cause a reduction in the number of white blood cells and your resistance to infection may be decreased. if you experience an infection with symptoms such as fever and serious deterioration of your general condition, or fever with local infection symptoms such as sore throat/sore pharynx/sore mouth or urinary problems you should see your doctor immediately. a blood test will be taken to check for possible reduction of white blood cells (agranulocytosis). it is important to tell your doctor that you are taking nordimet. methotrexate is known to cause bone disorders such as joint and muscle pain and osteoporosis. the frequency of these risks in children is not known. nordimet may cause serious (sometimes life-threatening) side effects. your doctor will do tests to check for abnormalities developing in the blood (e.g. low white blood cells, low platelets, lymphoma) and changes in the kidney and the liver. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'nordimet', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 21, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9653276205062866, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7972280383110046}]}, {'Text': 'any sudden wheeziness', 'Type': 'PROBLEM', 'BeginOffset': 134, 'EndOffset': 155}, {'Id': 24, 'BeginOffset': 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'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9862252473831177, 'RelationshipScore': 0.995681881904602, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 139, 'BeginOffset': 3502, 'EndOffset': 3515, 'Text': 'blood vessels', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 221, 'BeginOffset': 3548, 'EndOffset': 3559, 'Score': 0.969170093536377, 'Text': 'infertility', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6956374049186707}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9862252473831177, 'RelationshipScore': 0.603486180305481, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 139, 'BeginOffset': 3502, 'EndOffset': 3515, 'Text': 'blood vessels', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'male breast enlargement', 'Type': 'PROBLEM', 'BeginOffset': 3561, 'EndOffset': 3584}, {'Text': 'gynaecomastia)', 'Type': 'PROBLEM', 'BeginOffset': 3586, 'EndOffset': 3600}, {'Text': 'inflammation of the brain', 'Type': 'PROBLEM', 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'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 254, 'BeginOffset': 4330, 'EndOffset': 4342, 'Score': 0.5098017454147339, 'Text': 'sore pharynx', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5411865711212158}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9929959177970886, 'RelationshipScore': 0.6476317048072815, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 235, 'BeginOffset': 4323, 'EndOffset': 4329, 'Text': 'throat', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9846593141555786, 'RelationshipScore': 0.646848201751709, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 236, 'BeginOffset': 4335, 'EndOffset': 4342, 'Text': 'pharynx', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 255, 'BeginOffset': 4343, 'EndOffset': 4353, 'Score': 0.732523500919342, 'Text': 'sore mouth', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6358491778373718}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9929959177970886, 'RelationshipScore': 0.8538196086883545, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 235, 'BeginOffset': 4323, 'EndOffset': 4329, 'Text': 'throat', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 256, 'BeginOffset': 4357, 'EndOffset': 4373, 'Score': 0.8260691165924072, 'Text': 'urinary problems', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6935747861862183}]}, {'Text': 'a blood test', 'Type': 'TEST', 'BeginOffset': 4414, 'EndOffset': 4426}, {'Id': 257, 'BeginOffset': 4476, 'EndOffset': 4493, 'Score': 0.4902242422103882, 'Text': 'white blood cells', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6402544379234314}]}, {'Id': 258, 'BeginOffset': 4495, 'EndOffset': 4510, 'Score': 0.9131758809089661, 'Text': 'agranulocytosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9038504362106323}]}, {'Id': 244, 'BeginOffset': 4579, 'EndOffset': 4591, 'Score': 0.9591796398162842, 'Text': 'methotrexate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 259, 'BeginOffset': 4610, 'EndOffset': 4624, 'Score': 0.9676987528800964, 'Text': 'bone disorders', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8931840658187866}]}, {'Id': 260, 'BeginOffset': 4633, 'EndOffset': 4654, 'Score': 0.36440667510032654, 'Text': 'joint and muscle pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7091770172119141}]}, {'Id': 240, 'BeginOffset': 4643, 'EndOffset': 4649, 'Score': 0.9891451001167297, 'Text': 'muscle', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 261, 'BeginOffset': 4659, 'EndOffset': 4671, 'Score': 0.9992011189460754, 'Text': 'osteoporosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9385046362876892}]}, {'Id': 262, 'BeginOffset': 4677, 'EndOffset': 4686, 'Score': 0.4179285168647766, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 263, 'BeginOffset': 4784, 'EndOffset': 4796, 'Score': 0.8727337121963501, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6840687990188599}]}, {'Id': 277, 'BeginOffset': 4818, 'EndOffset': 4823, 'Score': 0.36168232560157776, 'Text': 'tests', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 264, 'BeginOffset': 4837, 'EndOffset': 4850, 'Score': 0.7871865630149841, 'Text': 'abnormalities', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6545943021774292}]}, {'Text': 'the blood (e.g. low white blood cells', 'Type': 'PROBLEM', 'BeginOffset': 4865, 'EndOffset': 4902}, {'Id': 266, 'BeginOffset': 4904, 'EndOffset': 4917, 'Score': 0.7004210352897644, 'Text': 'low platelets', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6123349666595459}]}, {'Id': 267, 'BeginOffset': 4919, 'EndOffset': 4927, 'Score': 0.9357675909996033, 'Text': 'lymphoma', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8796973824501038}]}, {'Text': 'changes in the kidney and the liver', 'Type': 'PROBLEM', 'BeginOffset': 4933, 'EndOffset': 4968}, {'Id': 269, 'BeginOffset': 4983, 'EndOffset': 4995, 'Score': 0.9525356292724609, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7386535406112671}]}, {'Id': 270, 'BeginOffset': 5011, 'EndOffset': 5023, 'Score': 0.9263832569122314, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7530642747879028}]}, {'Id': 271, 'BeginOffset': 5087, 'EndOffset': 5099, 'Score': 0.9583445191383362, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6454603672027588}]}, {'Id': 272, 'BeginOffset': 5148, 'EndOffset': 5160, 'Score': 0.8725186586380005, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7092121839523315}]}, {'Id': 273, 'BeginOffset': 5214, 'EndOffset': 5225, 'Score': 0.40836578607559204, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6187501549720764}]}, {'Id': 274, 'BeginOffset': 5239, 'EndOffset': 5251, 'Score': 0.8666620850563049, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7439308166503906}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 5307, 'EndOffset': 5320}]}

{'Title': '5. how to store nordimet', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label of the pre-filled pen and the carton after exp. the expiry date refers to the last day of that month. store below 25. keep the pen in the outer carton in order to protect from light. do not use this medicine if you notice that the solution is not clear and contains particles. nordimet is for single use only. any used pen should be discarded. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'nordimet', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '25.', 'Type': 'NUMBER', 'BeginOffset': 249, 'EndOffset': 252}, {'Text': 'the pen in the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 258, 'EndOffset': 285}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 329, 'EndOffset': 342}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what nordimet contains the active substance is methotrexate. 1 ml of solution contains 25 mg methotrexate. the other ingredients are sodium chloride, sodium hydroxide and water for injections. the following pens are available: pre-filled pens of 0.3 ml containing 7.5 mg methotrexate. pre-filled pens of 0.4 ml containing 10 mg methotrexate pre-filled pens of 0.5 ml containing 12.5 mg methotrexate pre-filled pens of 0.6 ml containing 15 mg methotrexate pre-filled pens of 0.7 ml containing 17.5 mg methotrexate pre-filled pens of 0.8 ml containing 20 mg methotrexate pre-filled pens of 0.9 ml containing 22.5 mg methotrexate pre-filled pens of 1.0 ml containing 25 mg methotrexate what nordimet looks like and contents of the pack nordimet pre-filled pens contain a clear, yellow solution for injection. the pre-filled pens are designed to prevent needlestick injury and reuse. nordimet is available in packs containing 1 or 4 pre-filled pens of 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml or 1.0 ml solution for injection with attached needle and 1 or 4 alcohol swabs and in multipacks of 4 and 6 cartons, each containing 1 pre-filled pen solution for injection with attached needle and one alcohol swab. nordimet is also available in multipacks containing 12 pre- filled pens in 3 cartons (4 pens and alcohol swabs per carton). not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'nordimet', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 47, 'EndOffset': 59, 'Score': 0.996619462966919, 'Text': 'methotrexate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9570043087005615, 'RelationshipScore': 0.9904138445854187, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 61, 'EndOffset': 65, 'Text': '1 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 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860E463689856EBCE34DA2F48D8F5CBC

https://www.ema.europa.eu/documents/product-information/arikayce-liposomal-product-information_en.pdf

Arikayce liposomal

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT ARIKAYCE liposomal 590 mg nebuliser dispersion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains amikacin sulfate equivalent to 590 mg amikacin in a liposomal formulation. The mean delivered dose per vial is approximately 312 mg of amikacin. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Nebuliser dispersion White, milky, aqueous, nebuliser dispersion. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications ARIKAYCE liposomal is indicated for the treatment of non-tuberculous mycobacterial (NTM) lung infections caused by Mycobacterium avium Complex (MAC) in adults with limited treatment options who do not have cystic fibrosis (see sections 4.2, 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration ARIKAYCE liposomal treatment should be initiated and managed by physicians experienced in the treatment of non-tuberculous lung disease due to Mycobacterium avium Complex. ARIKAYCE liposomal should be used in conjunction with other antibacterial agents active against Mycobacterium avium Complex lung infections. Posology The recommended dose is one vial (590 mg) administered once daily, by oral inhalation. Duration of treatment Treatment with inhaled liposomal amikacin, as part of a combination antibacterial regimen, should be continued for 12 months after sputum culture conversion. Treatment with inhaled liposomal amikacin should not continue beyond a maximum of 6 months if sputum culture conversion (SCC) has not been confirmed by then. The maximum duration of treatment with inhaled liposomal amikacin should not exceed 18 months. Missed doses If a daily dose of amikacin is missed, the next dose should be administered the next day. A double dose should not be given to make up for the missed dose. Elderly No dose adjustment is required. 3 Hepatic impairment Inhaled liposomal amikacin has not been studied in patients with hepatic impairment. No dose adjustments based on hepatic impairment are required since amikacin is not hepatically metabolised. Renal impairment Inhaled liposomal amikacin has not been studied in patients with renal impairment. Use is contraindicated in severe renal impairment (see sections 4.3 and 4.4). Paediatric population The safety and efficacy of inhaled liposomal amikacin in paediatric patients below 18 years of age have not been established. No data are available. Method of administration Inhalation use Inhaled liposomal amikacin must only be used with the Lamira Nebuliser System (nebuliser handset, aerosol head and controller). For instructions for use, see section 6.6. It must not be administered by any other route or using any other type of inhalation delivery system. ARIKAYCE liposomal is administered only using a Lamira Nebuliser System. Like all other nebulised treatments, the amount delivered to the lungs will depend upon patient factors. Under recommended in vitro testing with the adult breathing pattern (500 mL tidal volume, 15 breaths per minute, and inhalation: exhalation ration of 1:1), the mean delivered dose from the mouthpiece was approximately 312 mg of amikacin (approximately 53% of label claim) with an average drug delivery rate of 22.3 mg/min assuming the nebulisation time of 14 minutes. The average mass median aerodynamic diameter (MMAD) of the nebulised aerosol droplets is about 4.7 µm with D10 of 2.4 µm and D90 of 9.0 µm as determined using the next generation impactor method. 4.3 Contraindications Hypersensitivity to the active substance, to any aminoglycoside antibacterial agent, or to any of the excipients listed in section 6.1. Hypersensitivity to soya. Co-administration with any aminoglycoside administered via any route of administration. Severe renal impairment. 4.4 Special warnings and precautions for use Anaphylaxis and hypersensitivity reactions Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking inhaled liposomal amikacin. Before therapy with inhaled liposomal amikacin is instituted, an evaluation for previous hypersensitivity reactions to aminoglycosides should take place. If anaphylaxis or a hypersensitivity reaction occurs, inhaled liposomal amikacin should be discontinued and appropriate supportive measures should be instituted. 4 Allergic alveolitis Allergic alveolitis and pneumonitis have been reported with the use of inhaled liposomal amikacin in clinical studies (see section 4.8). If allergic alveolitis occurs, treatment with inhaled liposomal amikacin should be discontinued and patients should be treated as medically appropriate. Bronchospasm Bronchospasm has been reported with the use of inhaled liposomal amikacin in clinical studies. In patients with a history of reactive airway disease, asthma or bronchospasm, inhaled liposomal amikacin should be administered after using a short-acting bronchodilator. If there is evidence of bronchospasm due to inhaled liposomal amikacin inhalation, the patient may be pre-treated with bronchodilators (see section 4.8). Exacerbation of underlying pulmonary disease In clinical trials, exacerbation of underlying pulmonary disease (chronic obstructive pulmonary disease, infective exacerbation of chronic obstructive pulmonary disease, infective exacerbation of bronchiectasis) was reported with a higher frequency in patients treated with inhaled liposomal amikacin compared with patients not receiving inhaled liposomal amikacin. Caution should be exercised when initiating inhaled liposomal amikacin in patients presenting with these underlying conditions. Discontinuation of treatment with inhaled liposomal amikacin should be considered if signs of exacerbation are observed. Ototoxicity In clinical trials, ototoxicity, (including deafness, dizziness, presyncope, tinnitus, and vertigo) was reported with a higher frequency in patients treated with inhaled liposomal amikacin compared with patients not receiving inhaled liposomal amikacin. Tinnitus was the most commonly reported ototoxicity related adverse reaction. Auditory and vestibular function should be monitored periodically in all patients and frequent monitoring is advised in patients with known or suspected auditory or vestibular dysfunction. If ototoxicity occurs during treatment, consideration should be given to discontinuing inhaled liposomal amikacin. Nephrotoxicity Nephrotoxicity was reported in clinical trials in patients treated with inhaled liposomal amikacin. Renal function should be monitored periodically during treatment in all patients and frequent monitoring is advised in patients with pre-existing renal dysfunction. Consideration should be given to stopping inhaled liposomal amikacin in patients who develop evidence of nephrotoxicity on treatment. Use in patients with severe renal impairment is contraindicated (see section 4.3). Neuromuscular blockade In clinical trials, neuromuscular disorders (reported as muscle weakness, neuropathy peripheral and balance disorder) have been reported with inhaled liposomal amikacin. Aminoglycosides may aggravate muscle weakness because of a curare-like effect at the neuromuscular junction. Use of 5 inhaled liposomal amikacin in patients with myasthenia gravis is not recommended. Patients with any known or suspected neuromuscular disorders should be closely monitored. Co-administration with other medicinal products Co-administration of inhaled liposomal amikacin with other aminoglycosides is contraindicated (see section 4.3). Co-administration with any other medicinal product affecting auditory function, vestibular function or renal function (including diuretics) is not recommended. 4.5 Interaction with other medicinal products and other forms of interaction No clinical drug interaction studies have been conducted with inhaled liposomal amikacin. Pharmacodynamic interactions Use of inhaled liposomal amikacin with any aminoglycoside administered by any route is contraindicated (see section 4.3). Concurrent and/or sequential use of inhaled liposomal amikacin is not recommended with other medicinal products with neurotoxic, nephrotoxic or ototoxic potential that can enhance aminoglycoside toxicity (e.g. diuretic compounds such as ethacrynic acid, furosemide or intravenous mannitol) (see section 4.4). 4.6 Fertility, pregnancy and lactation Pregnancy There are no data from the use of inhaled liposomal amikacin in pregnant women. Systemic exposure to amikacin following inhalation of inhaled liposomal amikacin is expected to be low compared to parenteral administration of amikacin. There are limited data from the use of aminoglycosides in pregnant women. Aminoglycosides can cause foetal harm. Aminoglycosides cross the placenta, and there have been reports of total, irreversible, bilateral congenital deafness in children, whose mothers received streptomycin during pregnancy. Although adverse reactions on the foetus or newborns have not been reported in pregnant women treated with other aminoglycosides, the potential for harm exists. Animal reproductive toxicity studies have not been conducted with inhaled amikacin. In reproductive toxicity studies in mice, rats and rabbits with amikacin administered parenterally, no foetal malformations were reported. As a precautionary measure, it is preferable to avoid the use of inhaled liposomal amikacin during pregnancy. Breast-feeding There is no information regarding the presence of amikacin in human milk. However, systemic exposure to inhaled liposomal amikacin following inhalation is expected to be low compared to parenteral administration of amikacin. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from inhaled liposomal amikacin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. 6 Fertility No fertility studies were conducted with inhaled liposomal amikacin. 4.7 Effects on ability to drive and use machines Amikacin has minor influence on the ability to drive and use machines. The administration of inhaled liposomal amikacin can cause dizziness and other vestibular disturbances (see section 4.8). Patients should be advised not to drive or operate machinery while using inhaled liposomal amikacin. 4.8 Undesirable effects Summary of the safety profile The most commonly reported respiratory adverse reactions were dysphonia (42.6%), cough (30.9%), dyspnoea (14.4%), haemoptysis (10.9%), oropharyngeal pain (9.2%), and bronchospasm (2.2%). Other commonly reported non-respiratory adverse reactions included fatigue (7.2%), diarrhoea (6.4%), infective exacerbation of bronchiectasis (6.2%), and nausea (5.9%). Most common serious adverse reactions included Chronic Obstructive Pulmonary Disease (COPD) (1.5%), haemoptysis (1.2%), and infective exacerbation of bronchiectasis (1.0%). Tabulated list of adverse reactions Adverse drug reactions in Table 1 are listed according to system organ classes in MedDRA based on clinical trials and post marketing data. Within each system organ class, the following definitions apply to the frequency terminology used hereafter: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known: (cannot be estimated from the available data). Table 1 – Summary of adverse reactions System Organ Class Adverse reactions Frequency category Infections and infestations Infective exacerbation of bronchiectasis Common Laryngitis Common Oral candidiasis Common Immune system disorders Anaphylactic reactions Not known Hypersensitivity reactions Not known Psychiatric disorders Anxiety Uncommon Nervous system disorders Headache Common Dizziness Common Dysgeusia Common Aphonia Common Balance disorder Common Ear and labyrinth disorders Tinnitus Common Deafness Common Respiratory, thoracic and mediastinal Dysphonia Very common disorders Dyspnoea Very common Cough Very common Haemoptysis Very common 7 System Organ Class Adverse reactions Frequency category Oropharyngeal pain Common Allergic alveolitis Common Chronic Obstructive Pulmonary Disease Common Wheezing Common Productive cough Common Sputum increased Common Bronchospasm Common Pneumonitis Common Vocal cord inflammation Common Throat irritation Common Gastrointestinal disorders Diarrhoea Common Nausea Common Vomiting Common Dry mouth Common Decrease of appetite Common Skin and subcutaneous tissue disorders Rash Common Pruritus Common Musculoskeletal and connective tissue disorders Myalgia Common Arthralgia Common Renal and urinary disorders Renal impairment Common General disorders and administration site conditions Fatigue Common Pyrexia Common Chest discomfort Common Investigations Weight decreased Common Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Adverse reactions specifically associated with overdose of inhaled liposomal amikacin have not been identified in clinical trials. Overdose in subjects with pre-existing impaired renal function, deafness or vestibular disturbance, or impaired neuromuscular transmission may develop worsening of the pre- existing disorder. In the event of an overdose inhaled liposomal amikacin should be stopped immediately. Where rapid removal of amikacin is indicated to prevent target organ damage, for example in subjects with renal impairment, peritoneal dialysis or haemodialysis will accelerate the extraction of amikacin from blood. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 8 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antibacterials for systemic use, other aminoglycosides. ATC code: J01GB06 Mechanism of action Amikacin binds to a specific receptor protein on the 30S subunit of bacterial ribosomes and interferes with an initiation complex between mRNA (messenger RNA) and the 30S subunit resulting in inhibition of protein synthesis. Resistance The mechanism of resistance to amikacin in mycobacteria has been linked to mutations in the rrs gene of the 16S rRNA. Clinical experience The efficacy of inhaled liposomal amikacin was evaluated in study INS-212, a randomised, open-label study in adult patients with non-tuberculous mycobacterial lung infections caused by MAC. Patients who had not achieved sputum culture conversion (SCC) while being treated with Multiple Drug Regimen(s) (MDR) for at least 6 months before study entry were randomised to receive ARIKAYCE in addition to their MDR treatment or to continue with MDR alone. Patients achieving SCC, defined as 3 consecutive negative MAC sputum cultures by month 6 on treatment continued therapy for up to 12 months after achieving SCC. Those not achieving SCC by month 6 were discontinued from the study at month 8. A total of 335 patients were randomised and dosed (ARIKAYCE liposomal + MDR n = 223; MDR alone n = 112) (Safety population). Median duration of prior MDR treatment was 2.6 years and 2.4 years in the ARIKAYCE liposomal + MDR and MDR alone group, respectively. Patients were stratified per smoking status (current smoker or not) and MDR use at screening (on treatment or off treatment for at least 3 months prior to screening). The primary endpoint was durable SCC defined as the proportion of randomised patients that had achieved SCC by month 6 on treatment and had no positive solid media culture or no more than two broth media cultures by 3 months off treatment. Sixty-five (29.0%) and 10 (8.9%) patients achieved SCC by month 6 on treatment in the ARIKAYCE liposomal + MDR and the MDR group, respectively (p< 0.0001). Of these, based on the primary analysis durable SCC at 3 months off treatment was achieved by 16.1% [36/224] vs. 0% [0/112]; p- value <0.0001. In a post-hoc analysis that eliminated patients with negative cultures (solid media or broth) at study baseline and which counted any post-treatment positive culture (solid media or broth) as positive, 30/224 (13.4%) in the ARIKAYCE liposomal + MDR group and 0/112 (0%) in the MDR group achieved durable SCC at 3 months off treatment. Respective rates at 12 months off treatment were 25/224 (11%) vs. 0/112 (0%). Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with inhaled liposomal amikacin in one or more subsets of the paediatric population in NTM lung infection (see section 4.2 for information on paediatric use). 9 5.2 Pharmacokinetic properties Absorption Sputum concentrations Following once daily inhalation of 590 mg inhaled liposomal amikacin in MAC patients, sputum concentrations at 1 to 4 hours post-inhalation were 1720, 884, and 1300 µg/g at 1, 3, and 6 months, respectively. High variability in amikacin concentrations was observed (CV% > 100%). After 48 to 72 hours post-inhalation, amikacin sputum concentrations decreased to approximately 5% of those at 1 to 4 hours post-inhalation. Serum concentrations Following daily inhalation of 590 mg ARIKAYCE in MAC patients, at steady state, the median serum AUC0-24 was 16.7 µg *hr/mL (range: 4.31 to 55.6 µg *hr/mL; n = 53) and the median serum Cmax was 1.81 µg/mL (range: 0.482 to 6.87 μg/mL; n = 53). Distribution Amikacin is ≤ 10% bound to serum proteins. The mean total apparent volume of distribution has been estimated to be approximately 5.0 L/kg. Biotransformation Amikacin is not metabolised. Elimination Amikacin is excreted in the urine unchanged, primarily by glomerular filtration. The median apparent terminal serum half-life of amikacin after inhalation of ARIKAYCE liposomal ranged from approximately 3.29 to 14.0 hrs. A population pharmacokinetic analysis for ARIKAYCE liposomal in 53 subjects with NTM lung disease aged 20 to 84 years indicated that amikacin clearance is 34 L/h. The only clinical covariate identified to be predictive of amikacin clearance was body weight. 5.3 Preclinical safety data Carcinogenicity In a 2-year inhalation carcinogenicity study with inhaled liposomal amikacin in rats at doses of 5, 15, and 45 mg/kg/day, squamous cell carcinoma was observed in the lungs of 2 of 120 rats (0/60 males and 2/60 females) administered the highest dose tested (45 mg/kg/day). This ARIKAYCE dose was 6-fold greater than the clinical dose when normalised on a lung weight basis. No squamous cell carcinoma was observed at the mid-dose of 15 mg/kg/day, which was 2-fold greater than the clinical dose when normalised on a lung weight basis. The squamous cell carcinomas may be the result of a high lung burden of particulates from inhaled liposomal amikacin in the rat lung. The relevance of the lung tumour findings with regards to humans receiving inhaled liposomal amikacin is unknown. In dogs administered inhaled liposomal amikacin daily by inhalation for 9 months at doses up to 30 mg/kg/day, no preneoplastic or neoplastic changes were observed in the lungs (approximately 3 to 11 times the recommended human dose based on lung weight). Genotoxicity No evidence of mutagenicity or genotoxicity was observed in a battery of in vitro and in vivo genotoxicity studies with liposomal amikacin formulations (in vitro microbial mutagenesis test, in vitro mouse lymphoma mutation assay, in vitro chromosomal aberration study, and an in vivo micronucleus study in rats). 10 Reproductive and development toxicity Animal reproductive toxicology studies have not been conducted with inhaled amikacin. In non-GLP reproduction toxicology studies in mice and rats with parenterally administered amikacin, no effect of fertility or foetal toxicity was reported. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Cholesterol Dipalmitoylphosphatidylcholine (DPPC) Sodium chloride Sodium hydroxide (for pH adjustment) Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store in a refrigerator (2 °C – 8 °C). Do not freeze. ARIKAYCE can be stored at room temperature below 25 °C for up to 4 weeks. 6.5 Nature and contents of container Each 10 mL clear, Type I borosilicate glass vial is sealed with a bromobutyl rubber stopper and aluminium seal with a flip-tear off cap. Pack-size of 28 vials. The carton also contains the Lamira Nebuliser Handset and 4 aerosol heads. 6.6 Special precautions for disposal and other handling Discard any vial that has been frozen. Once at room temperature, any unused medicine must be discarded at the end of 4 weeks. If the current dose is refrigerated, the vial of ARIKAYCE liposomal should be removed from the refrigerator and be allowed to come to room temperature. Prepare ARIKAYCE liposomal by shaking the vial vigorously until the contents appear uniform and well mixed. Open the vial of ARIKAYCE liposomal by flipping up the plastic top of the vial, then pulling downward to loosen the metal ring. Carefully remove the metal ring and remove the rubber stopper. Pour the content of the ARIKAYCE liposomal vial into the medicine reservoir of the Lamira Nebuliser Handset. ARIKAYCE liposomal is administered by oral inhalation via nebulisation using the Lamira Nebuliser System. ARIKAYCE liposomal should only be used with the Lamira Nebuliser System (nebuliser 11 handset, aerosol head, and controller). ARIKAYCE should not be used with any other type of inhalation delivery system. Do not put other medicinal products in the Lamira Nebuliser Handset. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Insmed Netherlands B.V. Stadsplateau 7 3521 AZ Utrecht Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1469/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 12 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 13 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Almac Pharma Services (Ireland) Ltd. Finnabair Industrial Estate, Dundalk, Co. Louth, A91 P9KD, Ireland B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web- portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures The MAH has developed a patient alert card which will be included in the outer carton. The wording of the alert card is part of the labelling - please see Annex III, A. LABELLING. The purpose of the alert card is to inform patients that the use of ARIKAYCE liposomal may be associated with the development of allergic alveolitis. 14 ANNEX III LABELLING AND PACKAGE LEAFLET 15 A. LABELLING 16 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON FOR 28 VIALS CONTAINED IN 4 INNER CARTONS 1. NAME OF THE MEDICINAL PRODUCT ARIKAYCE liposomal 590 mg nebuliser dispersion amikacin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains amikacin sulfate equivalent to 590 mg amikacin in a liposomal formulation. The mean delivered dose per vial is approximately 312 mg of amikacin. 3. LIST OF EXCIPIENTS Excipients: cholesterol, dipalmitoylphosphatidylcholine (DPPC), sodium chloride, sodium hydroxide and water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Nebuliser dispersion 28 vials 4 Lamira aerosol heads 1 Lamira Nebuliser Handset 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Inhalation use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 17 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Unopened vials can be stored at room temperature below 25 °C for up to 4 weeks. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Insmed Netherlands B.V. Stadsplateau 7 3521 AZ Utrecht Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1469/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Arikayce 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 18 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON WITH TRAY FOR 7 VIALS AND 1 LAMIRA AEROSOL HEAD 1. NAME OF THE MEDICINAL PRODUCT ARIKAYCE liposomal 590 mg nebuliser dispersion amikacin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains amikacin sulfate equivalent to 590 mg amikacin in a liposomal formulation. The mean delivered dose per vial is approximately 312 mg of amikacin. 3. LIST OF EXCIPIENTS Excipients: cholesterol, dipalmitoylphosphatidylcholine (DPPC), sodium chloride, sodium hydroxide and water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Nebuliser dispersion 7 vials 1 Lamira aerosol head 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Inhalation use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE See vial for batch number and expiry date 19 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Unopened vials can be stored at room temperature up to 25 °C for up to 4 weeks. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Insmed Netherlands B.V. Stadsplateau 7 3521 AZ Utrecht Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1469/001 13. BATCH NUMBER See vial for batch number and expiry date 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 20 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ARIKAYCE liposomal 590 mg nebuliser dispersion amikacin 2. METHOD OF ADMINISTRATION Inhalation use 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10 mL 6. OTHER 21 PARTICULARS TO APPEAR ON THE PATIENT ALERT CARD 1. OTHER Front side PATIENT ALERT CARD Important safety information ARIKAYCE liposomal 590 mg (amikacin) Insmed Reverse side ARIKAYCE liposomal (amikacin) may cause serious side effects. These may happen any time during treatment. You may experience more than one side effect at the same time. ARIKAYCE liposomal may be associated with the development of an allergic lung condition (allergic alveolitis) CONTACT YOUR DOCTOR IMMEDIATELY if you develop any signs or symptoms such as: • Fever, cough, worsening breathlessness, weight loss • Lung condition gets worse, affecting your breathing or overall health Your doctor may give you other medicines to prevent more severe complications and reduce your symptoms. Your doctor may decide to stop treatment. Important • Do not attempt to diagnose or treat side effects yourself. • Please keep this card with you at all times, especially when you travel, whenever you go to the Emergency department, or when you must see another doctor. • Be sure to notify any health care professional you see that you are being treated with ARIKAYCE liposomal and show them this card. • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed on this card. ARIKAYCE liposomal start date 22 B. PACKAGE LEAFLET 23 Package leaflet: Information for the patient ARIKAYCE liposomal 590 mg nebuliser dispersion amikacin Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What ARIKAYCE liposomal is and what it is used for 2. What you need to know before you use ARIKAYCE liposomal 3. How to use ARIKAYCE liposomal 4. Possible side effects 5. How to store ARIKAYCE liposomal 6. Contents of the pack and other information 7. Instructions for use 1. What ARIKAYCE liposomal is and what it is used for ARIKAYCE liposomal is an antibiotic that contains the active ingredient amikacin. Amikacin belongs to a group of antibiotics called aminoglycosides which stop the growth of certain bacteria that cause infections. ARIKAYCE liposomal is used by inhalation to treat lung infection caused by Mycobacterium avium Complex in adults with limited treatment options who do not have cystic fibrosis. 2. What you need to know before you use ARIKAYCE liposomal Do not use ARIKAYCE liposomal - if you are allergic to amikacin or other aminoglycosides, soya or any of the other ingredients of this medicine (listed in section 6) - if you are taking any other aminoglycosides (oral or for injection) - if you have very poor kidney function Warnings and precautions Talk to your doctor or pharmacist before using ARIKAYCE liposomal if: - you use a bronchodilator (“reliever”) for breathing problems, as you will be asked to use that first, before using ARIKAYCE liposomal; - you have kidney problems; you may need to have a kidney test before starting treatment; - you have hearing difficulties, ringing or buzzing in the ears (tinnitus) or balance problems including spinning sensation, lack of coordinated muscle movements, dizziness or light- headedness. You may have to have a hearing test before starting or during treatment, if you have any hearing problems; - you suffer from other lung diseases; - you have a disease that causes muscle weakness and fatigue, such as myasthenia gravis. 24 Talk to your doctor immediately if, whilst using ARIKAYCE liposomal you experience any of the below: - loss of consciousness, skin rash, fever, worsening or new problems with your breathing; - worsening of kidney problems; - ear problems like ringing in your ears or loss of hearing. See section 4. Children and adolescents ARIKAYCE liposomal should not be given to children and adolescents less than 18 years old. Other medicines and ARIKAYCE liposomal Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Special care is needed if you are taking other medicines, as some could interact with ARIKAYCE liposomal, for example: - diuretics (“water tablets”) such as ethacrynic acid, furosemide, or mannitol - other medicines that can affect your kidneys, hearing, balance or reduce muscle strength Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, the use of ARIKAYCE liposomal should be avoided. Ask your doctor or pharmacist for advice before using this medicine. If you become pregnant while using ARIKAYCE liposomal, inform your doctor. He will advise whether to stop using ARIKAYCE liposomal. It is not known if amikacin passes into breast milk in humans. If you are breastfeeding, your doctor will advise you whether to stop breast-feeding or stop treatment with this medicine. Driving and using machines ARIKAYCE liposomal can cause dizziness and other vestibular disturbances, such as vertigo and balance disorders. You are advised not to drive or operate machinery while inhaling ARIKAYCE liposomal. If you have questions, please talk to your doctor. 3. How to use ARIKAYCE liposomal Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. The recommended dose is one vial of ARIKAYCE liposomal inhaled in your mouth once a day, using the Lamira Nebuliser. After 6 months of treatment your doctor will advise whether to continue or to stop treatment. The maximum duration of treatment is 18 months. Taking ARIKAYCE liposomal If you use a bronchodilator (“reliever”), use that first, before using ARIKAYCE liposomal. Each vial is for single use only. - Only use ARIKAYCE liposomal with the Lamira Nebuliser Handset and aerosol head connected to a Lamira Control Unit. See section 7 for how to use the medicine together with the Lamira Nebuliser System. - Do not use ARIKAYCE liposomal with any other type of handset or aerosol head. - Do not put other medicines in the Lamira Nebuliser Handset. - Do not drink the liquid in the vial. - Read the instructions for use, which are provided at the end of this leaflet. 25 How and when do you replace the Lamira Nebuliser Handset? One Lamira Nebuliser Handset should be used for one 28-day treatment course. The aerosol head should be replaced weekly. There are 4 aerosol heads provided in each ARIKAYCE liposomal carton. Please refer to the manufacturer’s instructions for use for cleaning and storage advice. If you use more ARIKAYCE liposomal than you should Tell your doctor immediately if you are concerned that you may have used too much of this medicine. If you forget to use ARIKAYCE liposomal If you forget to take your medicine, take it as soon as possible on the day of the missed dose. Do not take more than one dose on the same day to make up for a forgotten dose. If you stop using ARIKAYCE liposomal You must tell your doctor if you decide to stop using ARIKAYCE liposomal for any reason. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor immediately if: - you experience any hypersensitivity or severe allergic reactions when taking ARIKAYCE liposomal (e.g. with low blood pressure, loss of consciousness, severe skin rash or severe wheezing and breathlessness). The frequency of these side effects is not known. - you experience worsening of your usual lung problems or new problems with your breathing (e.g. breathlessness or wheezing). This may be a sign of severe inflammation in the lungs that requires treatment and may mean you should stop taking ARIKAYCE liposomal. The frequency of these severe side effects is common to very common. Other side effects: Tell your doctor or pharmacist if you experience any of the following: Very common side effects (may affect more than 1 in 10 people) - Difficulty in speaking - Difficulty in breathing - Cough - Coughing up blood Common side effects (may affect up to 1 in 10 people) - Infection causing worsening of your lung condition - Increase in mucus coughed up from lungs - Chesty cough - Wheezing - Throat irritation - Sore throat - Loss of voice - Thrush (a fungal infection) in the mouth - Pain in the mouth - Change in your sense of taste - Lung inflammation - Headache - Dizziness - Feeling unsteady - Diarrhoea - Feeling sick (nausea) 26 - Being sick (vomiting) - Dry mouth - Decrease of appetite - Itching of the skin - Deafness - Ringing in your ears - Kidney problems including poor kidney function - Joint pain - Muscle pain - Rash - Tiredness - Discomfort in chest - Fever - Loss of weight Uncommon side effect (may affect up to 1 in 100 people) - Anxiety Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store ARIKAYCE liposomal Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the vial after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2 °C – 8 °C). Do not freeze, discard any vial that has been frozen. If the dose you want to use is refrigerated, remove the vial from the refrigerator and allow it to come to room temperature before using it. Alternatively, ARIKAYCE liposomal can be stored at room temperature below 25 °C, but only for up to 4 weeks. Once at room temperature, any unused medicinal product must be discarded at the end of 4 weeks. This medicine is a milky white liquid in a clear vial. Do not use if you notice change in colour or any small lumps floating in the vial. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What ARIKAYCE liposomal contains - The active substance is amikacin. Each vial contains amikacin sulfate equivalent to 590 mg amikacin in a liposomal formulation. The mean delivered dose per vial is approximately 312 mg of amikacin. - The other ingredients are cholesterol, dipalmitoylphosphatidylcholine (DPPC), sodium chloride, sodium hydroxide and water for injections. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 27 What ARIKAYCE liposomal looks like and contents of the pack ARIKAYCE liposomal is a white to off-white, milky nebuliser dispersion in a 10 mL glass vial sealed with a rubber stopper and a metal seal with a flip tear-off cap. The 28 vials are provided in a carton for a 28-day supply; one vial per day. One ARIKAYCE liposomal carton contains 4 inner cartons, each containing 7 vials and one aerosol head. The 28-day supply pack also contains 1 Lamira Nebuliser Handset. Marketing Authorisation Holder Insmed Netherlands B.V. Stadsplateau 7 3521 AZ Utrecht Netherlands Manufacturer Almac Pharma Services (Ireland) Ltd. Finnabair Industrial Estate, Dundalk, Co. Louth, A91 P9KD, Ireland This leaflet was last revised in {month/YYYY}. Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 28 7. Instructions for use ARIKAYCE liposomal is for oral inhalation use with the Lamira Nebuliser System. Before using your Lamira Nebuliser System, be sure you read and understand the detailed information in the full Instructions for Use that come with the Lamira Nebuliser System. These will provide more complete information about how to put together (assemble), prepare, use, clean, and disinfect your Lamira Nebuliser System. Wash your hands with soap and water and dry them well. Assemble the handset including the connection to the controller as illustrated in the full Instructions for Use. Preparing the medicine for use: 1. It is recommended that the vial be removed from the refrigerator at least 45 minutes before use to allow it to come to room temperature. Do not use other medicines in the Lamira Nebuliser Handset. 2. Shake the ARIKAYCE liposomal vial vigorously, until the medicine looks the same throughout and well mixed. 3. Lift orange cap from vial and put aside (Figure 1). Figure 1 4. Grip the metal ring on top of the vial and pull it down gently until one side breaks away from the vial (Figure 2). Figure 2 5. Pull the metal band from around the vial top in a circular motion until it comes off completely from the vial (Figure 3). 29 Figure 3 6. Put aside the metal ring after it is detached. Carefully remove the rubber stopper (Figure 4). Figure 4 7. Pour the contents of the ARIKAYCE liposomal vial into the medicine’s reservoir of the Lamira Nebuliser Handset (Figure 5). Figure 5 8. Close the medication reservoir (Figure 6). Figure 6 9. Sit in a relaxed, upright position. This makes inhaling easier and helps the medicine get into your lungs. 30 10. Insert the mouthpiece and take slow, deep breaths. Then, breathe normally in and out through the mouthpiece until your treatment is complete. Treatment should take about 14 minutes but could take up to 20 minutes. Be sure to hold the handset level throughout the treatment (Figure 7). Figure 7 SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to use arikayce liposomal', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. the recommended dose is one vial of arikayce liposomal inhaled in your mouth once a day, using the lamira nebuliser. after 6 months of treatment your doctor will advise whether to continue or to stop treatment. the maximum duration of treatment is 18 months. taking arikayce liposomal if you use a bronchodilator ("reliever"), use that first, before using arikayce liposomal. each vial is for single use only. - only use arikayce liposomal with the lamira nebuliser handset and aerosol head connected to a lamira control unit. see section 7 for how to use the medicine together with the lamira nebuliser system. - do not use arikayce liposomal with any other type of handset or aerosol head. - do not put other medicines in the lamira nebuliser handset. - do not drink the liquid in the vial. - read the instructions for use, which are provided at the end of this leaflet. how and when do you replace the lamira nebuliser handset? one lamira nebuliser handset should be used for one 28-day treatment course. the aerosol head should be replaced weekly. there are 4 aerosol heads provided in each arikayce liposomal carton. please refer to the manufacturer\'s instructions for use for cleaning and storage advice. if you use more arikayce liposomal than you should tell your doctor immediately if you are concerned that you may have used too much of this medicine. if you forget to use arikayce liposomal if you forget to take your medicine, take it as soon as possible on the day of the missed dose. do not take more than one dose on the same day to make up for a forgotten dose. if you stop using arikayce liposomal you must tell your doctor if you decide to stop using arikayce liposomal for any reason. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'arikayce liposomal', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Text': 'arikayce liposomal inhaled', 'Type': 'TREATMENT', 'BeginOffset': 142, 'EndOffset': 168}, {'Text': 'the lamira nebuliser', 'Type': 'TREATMENT', 'BeginOffset': 201, 'EndOffset': 221}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 229, 'EndOffset': 230}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 241, 'EndOffset': 250}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 306, 'EndOffset': 315}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 341, 'EndOffset': 350}, {'Text': '18', 'Type': 'NUMBER', 'BeginOffset': 354, 'EndOffset': 356}, {'Id': 7, 'BeginOffset': 372, 'EndOffset': 390, 'Score': 0.6957833766937256, 'Text': 'arikayce liposomal', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a bronchodilator', 'Type': 'TREATMENT', 'BeginOffset': 402, 'EndOffset': 418}, {'Id': 9, 'BeginOffset': 462, 'EndOffset': 480, 'Score': 0.3118346631526947, 'Text': 'arikayce liposomal', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 527, 'EndOffset': 545, 'Score': 0.4332682192325592, 'Text': 'arikayce liposomal', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.3238605260848999, 'RelationshipScore': 0.9999932050704956, 'RelationshipType': 'FORM', 'Id': 12, 'BeginOffset': 562, 'EndOffset': 571, 'Text': 'nebuliser', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.6010236740112305, 'RelationshipScore': 0.9991395473480225, 'RelationshipType': 'FORM', 'Id': 13, 'BeginOffset': 584, 'EndOffset': 591, 'Text': 'aerosol', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the lamira nebuliser handset', 'Type': 'TREATMENT', 'BeginOffset': 551, 'EndOffset': 579}, {'Text': 'aerosol head', 'Type': 'TREATMENT', 'BeginOffset': 584, 'EndOffset': 596}, {'Text': 'a lamira control unit', 'Type': 'TREATMENT', 'BeginOffset': 610, 'EndOffset': 631}, {'Text': '7', 'Type': 'NUMBER', 'BeginOffset': 645, 'EndOffset': 646}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 662, 'EndOffset': 674}, {'Text': 'the lamira nebuliser system', 'Type': 'TREATMENT', 'BeginOffset': 689, 'EndOffset': 716}, {'Text': 'arikayce liposomal', 'Type': 'TREATMENT', 'BeginOffset': 731, 'EndOffset': 749}, {'Text': 'other medicines', 'Type': 'TREATMENT', 'BeginOffset': 811, 'EndOffset': 826}, {'Text': 'the lamira nebuliser handset', 'Type': 'TREATMENT', 'BeginOffset': 830, 'EndOffset': 858}, {'Text': 'the lamira nebuliser handset', 'Type': 'TREATMENT', 'BeginOffset': 1007, 'EndOffset': 1035}, {'Text': 'one lamira nebuliser handset', 'Type': 'TREATMENT', 'BeginOffset': 1037, 'EndOffset': 1065}, {'Text': 'the aerosol head', 'Type': 'TREATMENT', 'BeginOffset': 1114, 'EndOffset': 1130}, {'Text': '4 aerosol heads', 'Type': 'TREATMENT', 'BeginOffset': 1168, 'EndOffset': 1183}, {'Text': 'each arikayce liposomal carton', 'Type': 'TREATMENT', 'BeginOffset': 1196, 'EndOffset': 1226}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1453, 'EndOffset': 1466}, {'Id': 25, 'BeginOffset': 1489, 'EndOffset': 1507, 'Score': 0.33962175250053406, 'Text': 'arikayce liposomal', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'your medicine', 'Type': 'TREATMENT', 'BeginOffset': 1530, 'EndOffset': 1543}, {'Text': 'arikayce liposomal', 'Type': 'TREATMENT', 'BeginOffset': 1702, 'EndOffset': 1720}, {'Text': 'arikayce liposomal', 'Type': 'TREATMENT', 'BeginOffset': 1775, 'EndOffset': 1793}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1858, 'EndOffset': 1871}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor immediately if: - you experience any hypersensitivity or severe allergic reactions when taking arikayce liposomal (e.g. with low blood pressure, loss of consciousness, severe skin rash or severe wheezing and breathlessness). the frequency of these side effects is not known. - you experience worsening of your usual lung problems or new problems with your breathing (e.g. breathlessness or wheezing). this may be a sign of severe inflammation in the lungs that requires treatment and may mean you should stop taking arikayce liposomal. the frequency of these severe side effects is common to very common. other side effects: tell your doctor or pharmacist if you experience any of the following: very common side effects (may affect more than 1 in 10 people) - difficulty in speaking - difficulty in breathing - cough - coughing up blood common side effects (may affect up to 1 in 10 people) - infection causing worsening of your lung condition - increase in mucus coughed up from lungs - chesty cough - wheezing - throat irritation - sore throat - loss of voice - thrush (a fungal infection) in the mouth - pain in the mouth - change in your sense of taste - lung inflammation - headache - dizziness - feeling unsteady - diarrhoea - feeling sick (nausea) 26 - being sick (vomiting) - dry mouth - decrease of appetite - itching of the skin - deafness - ringing in your ears - kidney problems including poor kidney function - joint pain - muscle pain - rash - tiredness - discomfort in chest - fever - loss of weight uncommon side effect (may affect up to 1 in 100 people) - anxiety reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in 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{'Title': '5. how to store arikayce liposomal', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the vial after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not freeze, discard any vial that has been frozen. if the dose you want to use is refrigerated, remove the vial from the refrigerator and allow it to come to room temperature before using it. alternatively, arikayce liposomal can be stored at room temperature below 25 , but only for up to 4 weeks. once at room temperature, any unused medicinal product must be discarded at the end of 4 weeks. this medicine is a milky white liquid in a clear vial. do not use if you notice change in colour or any small lumps floating in the vial. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'arikayce liposomal', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 226, 'EndOffset': 227}, {'Text': 'arikayce liposomal', 'Type': 'TREATMENT', 'BeginOffset': 441, 'EndOffset': 459}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 500, 'EndOffset': 502}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 524, 'EndOffset': 525}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 620, 'EndOffset': 621}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 629, 'EndOffset': 642}, {'Text': 'a milky white liquid', 'Type': 'PROBLEM', 'BeginOffset': 646, 'EndOffset': 666}, {'Id': 0, 'BeginOffset': 709, 'EndOffset': 725, 'Score': 0.6215984225273132, 'Text': 'change in colour', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6345242857933044}]}, {'Text': 'any small lumps', 'Type': 'PROBLEM', 'BeginOffset': 729, 'EndOffset': 744}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what arikayce liposomal contains - the active substance is amikacin. each vial contains amikacin sulfate equivalent to 590 mg amikacin in a liposomal formulation. the mean delivered dose per vial is approximately 312 mg of amikacin. - the other ingredients are cholesterol, dipalmitoylphosphatidylcholine (dppc), sodium chloride, sodium hydroxide and water for injections. what arikayce liposomal looks like and contents of the pack arikayce liposomal is a white to off-white, milky nebuliser dispersion in a 10 ml glass vial sealed with a rubber stopper and a metal seal with a flip tear-off cap. the 28 vials are provided in a carton for a 28-day supply; one vial per day. one arikayce liposomal carton contains 4 inner cartons, each containing 7 vials and one aerosol head. the 28-day supply pack also contains 1 lamira nebuliser handset.', 'Entity_Recognition': [{'Text': 'arikayce liposomal', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 59, 'EndOffset': 67, 'Score': 0.8038963079452515, 'Text': 'amikacin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 88, 'EndOffset': 104, 'Score': 0.9779244065284729, 'Text': 'amikacin sulfate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '590', 'Type': 'NUMBER', 'BeginOffset': 119, 'EndOffset': 122}, {'Id': 3, 'BeginOffset': 126, 'EndOffset': 134, 'Score': 0.9435141682624817, 'Text': 'amikacin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.972525954246521, 'RelationshipScore': 0.9990677237510681, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 119, 'EndOffset': 125, 'Text': '590 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'a liposomal formulation', 'Type': 'TREATMENT', 'BeginOffset': 138, 'EndOffset': 161}, {'Text': '312', 'Type': 'NUMBER', 'BeginOffset': 213, 'EndOffset': 216}, {'Id': 6, 'BeginOffset': 223, 'EndOffset': 231, 'Score': 0.8163942098617554, 'Text': 'amikacin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9924985766410828, 'RelationshipScore': 0.9999934434890747, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 213, 'EndOffset': 219, 'Text': '312 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'cholesterol, dipalmitoylphosphatidylcholine (dppc)', 'Type': 'TREATMENT', 'BeginOffset': 261, 'EndOffset': 311}, {'Id': 9, 'BeginOffset': 313, 'EndOffset': 328, 'Score': 0.9996635913848877, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.46534648537635803, 'RelationshipScore': 0.9998041987419128, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 11, 'BeginOffset': 361, 'EndOffset': 371, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 10, 'BeginOffset': 330, 'EndOffset': 346, 'Score': 0.9987976551055908, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.46534648537635803, 'RelationshipScore': 0.9990315437316895, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 11, 'BeginOffset': 361, 'EndOffset': 371, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 361, 'EndOffset': 371}, {'Text': 'the pack arikayce liposomal', 'Type': 'TREATMENT', 'BeginOffset': 424, 'EndOffset': 451}, {'Text': 'milky nebuliser dispersion', 'Type': 'TREATMENT', 'BeginOffset': 477, 'EndOffset': 503}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 509, 'EndOffset': 511}, {'Text': 'a rubber stopper', 'Type': 'TREATMENT', 'BeginOffset': 538, 'EndOffset': 554}, {'Text': 'a metal seal', 'Type': 'TREATMENT', 'BeginOffset': 559, 'EndOffset': 571}, {'Text': 'a flip tear', 'Type': 'TREATMENT', 'BeginOffset': 577, 'EndOffset': 588}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 602, 'EndOffset': 604}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 642, 'EndOffset': 644}, {'Text': 'one arikayce liposomal carton', 'Type': 'TREATMENT', 'BeginOffset': 675, 'EndOffset': 704}, {'Text': '4 inner cartons', 'Type': 'TREATMENT', 'BeginOffset': 714, 'EndOffset': 729}, {'Text': '7', 'Type': 'NUMBER', 'BeginOffset': 747, 'EndOffset': 748}, {'Text': 'the 28-day supply pack', 'Type': 'TREATMENT', 'BeginOffset': 777, 'EndOffset': 799}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 781, 'EndOffset': 783}, {'Text': '1 lamira nebuliser handset', 'Type': 'TREATMENT', 'BeginOffset': 814, 'EndOffset': 840}]}

2FACB377F58985B93B438528E7B24319

https://www.ema.europa.eu/documents/product-information/gazyvaro-epar-product-information_en.pdf

Gazyvaro

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Gazyvaro 1,000 mg concentrate for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One vial of 40 mL concentrate contains 1,000 mg obinutuzumab, corresponding to a concentration before dilution of 25 mg/mL. Obinutuzumab is a Type II humanised anti-CD20 monoclonal antibody of the IgG1 subclass derived by humanisation of the parental B-Ly1 mouse antibody and produced in the Chinese Hamster Ovary cell line by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion. Clear, colourless to slightly brownish liquid. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Chronic lymphocytic leukaemia (CLL) Gazyvaro in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine based therapy (see section 5.1). Follicular lymphoma (FL) Gazyvaro in combination with chemotherapy, followed by Gazyvaro maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced FL (see section 5.1) Gazyvaro in combination with bendamustine followed by Gazyvaro maintenance is indicated for the treatment of patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen. 4.2 Posology and method of administration Gazyvaro should be administered under the close supervision of an experienced physician and in an environment where full resuscitation facilities are immediately available. Posology Prophylaxis and premedication for tumour lysis syndrome (TLS) Patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 109/L) and/or renal impairment (CrCl < 70 mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or suitable alternative treatment such as urate oxidase (e.g. rasburicase), starting 12-24 hours prior to 3 start of Gazyvaro infusion as per standard practice (see section 4.4). Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate. Prophylaxis and premedication for infusion related reactions (IRRs) Premedication to reduce the risk of IRRs is outlined in Table 1 (see also section 4.4). Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below. Hypotension, as a symptom of IRRs, may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration (see section 4.4). Table 1 Premedication to be administered before Gazyvaro infusion to reduce the risk of IRRs in patients with CLL and FL (see section 4.4) Day of treatment cycle Patients requiring premedication Premedication Administration Cycle 1: Day 1 for CLL and FL All patients Intravenous corticosteroid1,4 (mandatory for CLL, recommended for FL) Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusion Anti-histaminic medicine3 Cycle 1: Day 2 for CLL only All patients Intravenous corticosteroid1 (mandatory) Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusion Anti-histaminic medicine3 All subsequent infusions for CLL and FL Patients with no IRR during the previous infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusion Patients with an IRR (Grade 1 or 2) with the previous infusion Oral analgesic/anti-pyretic2 Anti-histaminic medicine3 Patients with a Grade 3 IRR with the previous infusion OR Patients with lymphocyte counts >25 x 109/L prior to next treatment Intravenous corticosteroid1,4 Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 Anti-histaminic medicine3 At least 30 minutes before Gazyvaro infusion 1100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone should not be used as it has not been effective in reducing rates of IRR. 2 e.g. 1,000 mg acetaminophen/paracetamol 3 e.g. 50 mg diphenhydramine 4.If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyvaro, the corticosteroid can be administered as an oral medicinal product if given at least 60 minutes prior to Gazyvaro, in which case additional IV corticosteroid as premedication is not required. 4 Dose Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil1) For patients with CLL the recommended dose of Gazyvaro in combination with chlorambucil is shown in Table 2. Cycle 1 The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered over Day 1 and Day 2, (or Day 1 continued), and on Day 8 and Day 15 of the first 28 day treatment cycle. Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 900 mg for Day 2). If the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the second bag must be administered the following day. Cycles 2 – 6 The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered on Day 1 of each cycle. Table 2 Dose of Gazyvaro to be administered during 6 treatment cycles each of 28 days duration for patients with CLL Cycle Day of treatment Dose of Gazyvaro Cycle 1 Day 1 100 mg Day 2 (or Day 1 continued) 900 mg Day 8 1,000 mg Day 15 1,000 mg Cycles 2-6 Day 1 1,000 mg 1See section 5.1 for information on chlorambucil dose Duration of treatment Six treatment cycles, each of 28 day duration. Delayed or missed doses If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyvaro should be maintained between doses. Follicular lymphoma For patients with FL, the recommended dose of Gazyvaro in combination with chemotherapy is shown in Table 3. 5 Patients with previously untreated follicular lymphoma Induction (in combination with chemotherapy2) Gazyvaro should be administered with chemotherapy as follows: • Six 28-day cycles in combination with bendamustine2 or, • Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyvaro alone or, • Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone(CVP). Maintenance Patients who achieve a complete or partial response to induction treatment with Gazyvaro in combination with chemotherapy (CHOP or CVP or bendamustine) should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first). Patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen Induction (in combination with bendamustine2) Gazyvaro should be administered in six 28-day cycles in combination with bendamustine2. Maintenance Patients who achieved a complete or partial response to induction treatment (i.e. the initial 6 treatment cycles) with Gazyvaro in combination with bendamustine or have stable disease should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first). Table 3 Follicular lymphoma: Dose of Gazyvaro to be administered during induction treatment, followed by maintenance treatment Cycle Day of treatment Dose of Gazyvaro Cycle 1 Day 1 1,000 mg Day 8 1,000 mg Day 15 1,000 mg Cycles 2–6 or 2–8 Day 1 1,000 mg Maintenance Every 2 months for 2 years or until disease progression (whichever occurs first) 1,000 mg 2See section 5.1 for information on bendamustine dose 6 Duration of treatment Induction treatment of approximately six months (six treatment cycles of Gazyvaro, each of 28 day duration when combined with bendamustine, or eight treatment cycles of Gazyvaro, each of 21 day duration when combined with CHOP or CVP) followed by maintenance once every 2 months for 2 years or until disease progression (whichever occurs first). Delayed or missed doses If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not omit it or wait until the next planned dose. If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, requiring delay of treatment, these doses should be given after resolution of toxicity. In such instances, all subsequent visits and the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1. During maintenance, maintain the original dosing schedule for subsequent doses. Dose modifications during treatment (all indications) No dose reductions of Gazyvaro are recommended. For management of symptomatic adverse events (including IRRs), see paragraph below (Management of IRRs or section 4.4). Special populations Elderly No dose adjustment is required in elderly patients (see section 5.2). Renal impairment No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30-89 mL/min) (see section 5.2). The safety and efficacy of Gazyvaro has not been established in patients with severe renal impairment (CrCl < 30 mL/min) (see sections 4.8 and 5.2). Hepatic impairment The safety and efficacy of Gazyvaro in patients with impaired hepatic function has not been established. No specific dose recommendations can be made. Paediatric population The safety and efficacy of Gazyvaro in children and adolescents aged below 18 years has not been established. No data are available. Method of administration Gazyvaro is for intravenous use. It should be given as an intravenous infusion through a dedicated line after dilution (see section 6.6). Gazyvaro infusions should not be administered as an intravenous push or bolus. For instructions on dilution of Gazyvaro before administration, see section 6.6. Instructions on the rate of infusion are shown in Tables 4-5. 7 Table 4 Chronic lymphocytic leukaemia: Standard infusion rate in the absence of IRRs/hypersensitivity and recommendations in case an IRR occurred with previous infusion Cycle Day of treatment Rate of infusion The infusion rate may be escalated provided that the patient can tolerate it. For management of IRRs that occur during the infusion, refer to “Management of IRRs”. Cycle 1 Day 1 (100 mg) Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate. Day 2 (or Day 1 continued) (900 mg) If no IRR occurred during the previous infusion, administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. If the patient experienced an IRR during the previous infusion, start with administration at 25 mg/hr. The rate of infusion can be escalated in increments up to 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. Day 8 (1,000 mg) If no IRR occurred during the previous infusion, when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If the patient experienced an IRR during the previous infusion administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. Day 15 (1,000 mg) Cycles 2-6 Day 1 (1,000 mg) 8 Table 5 Follicular lymphoma: Standard infusion rate in the absence of IRRs /hypersensitivity and recommendations in case an IRR occurred with previous infusion Cycle Day of treatment Rate of infusion The infusion rate may be escalated provided that the patient can tolerate it. For management of IRRs that occur during the infusion, refer to “Management of IRRs”. Cycle 1 Day 1 (1,000 mg) Administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Day 8 (1,000 mg) If no IRR or if an IRR Grade 1 occurred during the previous infusion when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If the patient experienced an IRR of Grade 2 or higher during the previous infusion administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Day 15 (1,000 mg) Cycles 2–6 or 2–8 Day 1 (1,000 mg) Maintenance Every 2 months for 2 years or until disease progression (whichever occurs first) Management of IRRs (all indications) Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Gazyvaro as outlined below (see also section 4.4). • Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued. • Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 and 5). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further. The infusion must be stopped and therapy permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR. • Grade 1-2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 and 5). For CLL patients receiving the Day 1 (Cycle 1) dose split over the two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further. 9 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file. Based on a subgroup analysis in previously untreated follicular lymphoma, the efficacy in FLIPI low risk (0-1) patients is currently inconclusive (see section 5.1). A therapy choice for these patients should carefully consider the overall safety profile of Gazyvaro plus chemotherapy and the patient-specific situation. Infusion related reactions The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyvaro were IRRs, which occurred predominantly during infusion of the first 1,000 mg. IRRs may be related to cytokine release syndrome which has also been reported in Gazyvaro treated patients. In CLL patients who received the combined measures for prevention of IRRs (adequate corticosteroid, oral analgesic/anti-histamine, omission of antihypertensive medicine in the morning of the first infusion, and the Cycle 1 Day 1 dose administered over 2 days) as described in section 4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which were based on a relatively small number of patients) were similar before and after mitigation measures were implemented. Mitigation measures to reduce IRRs should be followed (see section 4.2). The incidence and severity of infusion related symptoms decreased substantially after the first 1,000 mg was infused, with most patients having no IRRs during subsequent administrations of Gazyvaro (see section 4.8). In the majority of patients, irrespective of indication, IRRs were mild to moderate and could be managed by the slowing or temporary halting of the first infusion, but severe and life-threatening IRRs requiring symptomatic treatment have also been reported. IRRs may be clinically indistinguishable from immunoglobulin E (IgE) mediated allergic reactions (e.g. anaphylaxis). Patients with a high tumour burden and/or high circulating lymphocyte count in CLL [> 25 x 109/L] may be at increased risk of severe IRRs. Patients with renal impairment (CrCl < 50 mL/min) and patients with both Cumulative Illness Rating Scale (CIRS) > 6 and CrCl < 70 mL/min are more at risk of IRRs, including severe IRRs (see section 4.8). For management of IRRs see section 4.2 Posology and method of administration. Patients must not receive further Gazyvaro infusions if they experience: • acute life-threatening respiratory symptoms, • a Grade 4 (i.e. life threatening) IRR or, • a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a subsequent infusion). Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine. Hypersensitivity reactions Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. serum sickness) have been reported in patients treated with Gazyvaro. Hypersensitivity may be difficult to clinically distinguish from IRRs. Hypersensitivity symptoms can occur after previous exposure and very rarely with the first infusion. If a hypersensitivity reaction is suspected during or after an infusion, the 10 infusion must be stopped and treatment permanently discontinued. Patients with known hypersensitivity to obinutuzumab must not be treated (see section 4.3). Tumour lysis syndrome (TLS) TLS has been reported with Gazyvaro. Patients who are considered to be at risk of TLS (e.g. patients with a high tumour burden and/or a high circulating lymphocyte count [> 25 x 109/L] and/or renal impairment [CrCl < 70 mL/min]) should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urate oxidate (e.g. rasburicase) starting 12-24 hours prior to the infusion of Gazyvaro as per standard practice (see section 4.2). All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. Neutropenia Severe and life-threatening neutropenia including febrile neutropenia has been reported during treatment with Gazyvaro. Patients who experience neutropenia should be closely monitored with regular laboratory tests until resolution. If treatment is necessary it should be administered in accordance with local guidelines and the administration of granulocyte-colony stimulating factors (G-CSF) should be considered. Any signs of concomitant infection should be treated as appropriate. Dose delays should be considered in case of severe or life-threatening neutropenia. It is strongly recommended that patients with severe neutropenia lasting more than 1 week receive antimicrobial prophylaxis throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungal prophylaxis should also be considered (see section 4.2). Late onset neutropenia (occurring >28 days after the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment has been completed/stopped) may occur. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of neutropenia (see section 4.8). Thrombocytopenia Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with Gazyvaro. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of thrombocytopenia (see section 4.8). Fatal haemorrhagic events have also been reported in Cycle 1 in patients treated with Gazyvaro. A clear relationship between thrombocytopenia and haemorrhagic events has not been established. Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests should be performed until the event resolves, and dose delays should be considered in case of severe or life-threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional practice is at the discretion of the treating physician. Use of any concomitant therapies which could possibly worsen thrombocytopenia-related events, such as platelet inhibitors and anticoagulants, should also be taken into consideration, especially during the first cycle. Worsening of pre-existing cardiac conditions In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (see section 4.8). These events may occur as part of an IRR and can be fatal. Therefore patients with a history of cardiac disease should be monitored closely. In addition these patients should be hydrated with caution in order to prevent a potential fluid overload. 11 Infections Gazyvaro should not be administered in the presence of an active infection and caution should be exercised when considering the use of Gazyvaro in patients with a history of recurring or chronic infections. Serious bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Gazyvaro therapy. Fatal infections have been reported. Patients (CLL) with both CIRS > 6 and CrCl < 70 mL/min are more at risk of infections, including severe infections (see section 4.8). In the follicular lymphoma studies, a high incidence of infections was observed in all phases of the studies, including follow-up, with the highest incidence seen in the maintenance phase. During the follow-up phase, Grade 3-5 infections are observed more in patients who received Gazyvaro plus bendamustine in the induction phase. Hepatitis B reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies including Gazyvaro (see section 4.8). HBVscreening should be performed in all patients before initiation of treatment with Gazyvaro. At a minimum this should include hepatitis B surface antigen (HBsAg) status and hepatitis B core antibody (HBcAb) status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with Gazyvaro. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation. Progressive multifocal leukoencephalopathy (PML) Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with Gazyvaro (see section 4.8). The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. The symptoms of PML are nonspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. muscular weakness, paralysis and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptoms regarded as “cortical” (e.g. aphasia or visual-spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture (cerebrospinal fluid testing for John Cunningham viral DNA). Therapy with Gazyvaro should be withheld during the investigation of potential PML and permanently discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be considered. The patient should be referred to a neurologist for the evaluation and treatment of PML. Immunisation The safety of immunisation with live or attenuated viral vaccines following Gazyvaro therapy has not been studied and vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery. Exposure in utero to obinutuzumab and vaccination of infants with live virus vaccines Due to the potential depletion of B-cells in infants of mothers who have been exposed to Gazyvaro during pregnancy, infants should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell count has recovered. The safety and timing of vaccination should be discussed with the infant’s physician (see section 4.6). 12 4.5 Interaction with other medicinal products and other forms of interaction No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyvaro with bendamustine, CHOP, fludarabine and cyclophosphamide (FC), and chlorambucil. A risk for interactions with other concomitantly used medicinal products cannot be excluded. Pharmacokinetic interactions Obinutuzumab is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450), uridine diphosphate glucuronyltransferase (UGT) enzymes and transporters such as P-glycoprotein. Therefore, no pharmacokinetic interaction is expected with medicinal products known to be metabolised by these enzyme systems. Co-administration with Gazyvaro had no effect on the pharmacokinetics of bendamustine, FC, chlorambucil or the individual components of CHOP. In addition, there were no apparent effects of bendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of Gazyvaro. Pharmacodynamic interactions Vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery because of the immunosuppressive effect of obinutuzumab (see section 4.4). The combination of obinutuzumab with chlorambucil, bendamustine, CHOP or CVP may increase the risk of neutropenia (see section 4.4). 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential must use effective contraception during and for 18 months after treatment with Gazyvaro. Pregnancy A reproduction study in cynomolgus monkeys showed no evidence of embryofoetal toxicity or teratogenic effects but resulted in a complete depletion of B-lymphocytes in offspring. B-cell counts returned to normal levels in the offspring, and immunologic function was restored within 6 months of birth. Serum concentrations of obinutuzumab in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that obinutuzumab crosses the placenta (see section 5.3). There are no data from the use of obinutuzumab in pregnant women. Gazyvaro should not be administered to pregnant women unless the possible benefit outweighs the potential risk. In case of exposure during pregnancy, depletion of B-cells may be expected in infants due to the pharmacological properties of the product. Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to Gazyvaro during pregnancy until the infant’s B-cell levels are within normal ranges (see section 4.4). Breast-feeding Animal studies have shown secretion of obinutuzumab in breast milk (see section 5.3). Since human immunoglobulin G (IgG) is secreted in human milk and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue breast-feeding during Gazyvaro therapy and for 18 months after the last dose of Gazyvaro. 13 Fertility No specific studies in animals have been performed to evaluate the effect of obinutuzumab on fertility. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies in cynomolgus monkeys (see section 5.3). 4.7 Effects on ability to drive and use machines Gazyvaro has no or negligible influence on the ability to drive and use machines. IRRs are very common during the first infusion of Gazyvaro, and patients experiencing infusion related symptoms should be advised not to drive or use machines until symptoms abate. 4.8 Undesirable effects Summary of the safety profile The adverse drug reactions (ADRs) described in this section were identified during induction, maintenance and follow up for indolent Non-Hodgkin lymphoma (iNHL) including FL; treatment and follow up for CLL in the three pivotal clinical studies: • BO21004/CLL11 (N=781): Patients with previously untreated CLL • BO21223/GALLIUM (N=1390): Patients with previously untreated iNHL (86% of the patients had FL) • GAO4753g/GADOLIN (N=409): Patients with iNHL (81% of the patients had FL) who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen. These trials investigated Gazyvaro in combination with chlorambucil for CLL and with bendamustine, CHOP or CVP followed by Gazyvaro maintenance therapy for iNHL. The studies BO21223/GALLIUM and GAO4753g/GADOLIN enrolled patients with iNHL including FL. Therefore, in order to provide the most comprehensive safety information, the analysis of ADRs presented in the following has been performed on the entire study population (i.e. iNHL). Table 6 summarises the ADRs of the pivotal studies (BO21004/CLL11, BO21223/GALLIUM GAO4753g/GADOLIN) that occurred at a higher incidence (difference of ≥ 2%) compared to the relevant comparator arm in at least one pivotal study in: • Patients with CLL receiving Gazyvaro plus chlorambucil compared with chlorambucil alone or rituximab plus chlorambucil (study BO21004/CLL11) • Patients with previously untreated iNHL receiving Gazyvaro plus chemotherapy (bendamustine, CHOP, CVP) followed by Gazyvaro maintenance in patients achieving a response, compared to rituximab plus chemotherapy followed by rituximab maintenance in patients achieving a response (study BO21223/GALLIUM) • Patients with iNHL who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen receiving Gazyvaro plus bendamustine, followed by Gazyvaro maintenance in some patients, compared to bendamustine alone (study GAO4753g/GADOLIN) The incidences presented in Table 6 (all grades and Grades 3-5) are the highest incidence of that ADR reported from any of the three studies. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 14 Tabulated list of adverse reactions Table 6 Summary of ADRs reported with a higher incidence (difference of ≥2% versus the comparator arm) in patients# receiving Gazyvaro + chemotherapy* System organ class Frequency All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL) Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL) Infections and infestations Very common Upper respiratory tract infection, sinusitis§,urinary tract infection, pneumonia§ ,herpes zoster§, nasopharyngitis Common Oral herpes, rhinitis, pharyngitis, lung infection, influenza Urinary tract infection, pneumonia, lung infection, upper respiratory tract infection, sinusitis, herpes zoster Uncommon Nasopharyngitis, rhinitis, influenza, oral herpes Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Squamous cell carcinoma of skin, Basal cell carcinoma Squamous cell carcinoma of skin, Basal cell carcinoma Blood and lymphatic system disorders Very common Neutropenia§, thrombocytopenia, anaemia, leukopenia Neutropenia, thrombocytopenia Common Febrile neutropenia Anaemia, leukopenia, febrile neutropenia Metabolism and nutrition disorders Common Tumour lysis syndrome, hyperuricaemia, hypokalaemia Tumour lysis syndrome, hypokalaemia Uncommon Hyperuricaemia Psychiatric disorders Very common Insomnia Common Depression, anxiety Uncommon Insomnia, depression, anxiety Nervous system disorders Very common Headache Uncommon Headache Cardiac disorders Common Atrial fibrillation Atrial fibrillation Vascular disorders Common Hypertension Hypertension Respiratory, thoracic and mediastinal disorders Very common Cough§ Common Nasal congestion, rhinorrhoea, oropharyngeal pain Uncommon Cough, oropharyngeal pain Gastrointestinal disorders Very common Diarrhoea, constipation§ Common Dyspepsia, haemorrhoids Diarrhoea Uncommon Constipation, haemorrhoids Skin and subcutaneous tissue disorders Very common Alopecia, pruritus Common Eczema Uncommon Pruritus 15 System organ class Frequency All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL) Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL) Musculoskeletal and connective tissue disorders Very common Arthralgia§, back pain, pain in extremity Common Musculoskeletal chest pain, bone pain Pain in extremity Uncommon Arthralgia, back pain, musculoskeletal chest pain, bone pain Renal and Urinary Disorders Common Dysuria, urinary incontinence Uncommon Dysuria, urinary incontinence General disorders and administration site conditions Very common Pyrexia, Asthenia, fatigue Common Chest pain Pyrexia, asthenia, fatigue Uncommon Chest pain Investigations Common White blood cell count decreased, neutrophil count decreased, weight increased White blood cell count decreased, neutrophil count decreased Injury, poisoning and procedural complications Very common IRRs IRRs #with a higher incidence (difference of ≥ 2% between the treatment arms). Only the highest frequency observed in the trials is reported (based on studies BO21004/previously untreated CLL, BO21223/previously untreated advanced iNHL and GAO4753g/rituximab refractory iNHL) † No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms * Chemotherapy: Chlorambucil in CLL; bendamustine, CHOP, CVP in iNHL including FL § observed also during maintenance treatment with at least 2% higher incidence in Gazyvaro arm (BO21223) In study GAO4753g/GADOLIN, patients in the bendamustine arm received 6 months of induction treatment only, whereas after the induction period, patients in the Gazyvaro plus bendamustine arm continued with Gazyvaro maintenance treatment. During the maintenance period in study GAO4753g/GADOLIN, the most common adverse reactions were cough (20%), neutropenia (13%), upper respiratory infections (12%), sinusitis (10%), diarrhoea (10%), bronchitis (10%), nausea (9%), fatigue (9%), IRRs (8%), urinary tract infections (7%), nasopharyngitis (7%), pyrexia (7%), arthralgia (6%), vomiting (6%), rash (6%), pneumonia (5%), dyspnea (5%) and pain in extremity (5%). The most common Grade 3-5 adverse reactions were neutropenia (10%), febrile neutropenia (2%) and anaemia, thrombocytopenia, pneumonia, sepsis, upper respiratory tract infection, and urinary tract infection (all at 1%). The profile of adverse reactions in patients with FL was consistent with the overall iNHL population in both studies. Description of selected adverse reactions The incidences presented in the following sections if referring to iNHL are the highest incidence of that ADR reported from either pivotal study (BO21223/GALLIUM, GAO4753g/GADOLIN). Infusion related reactions Most frequently reported (≥ 5%) symptoms associated with an IRR were nausea, vomiting, diarrhoea, headache, dizziness, fatigue, chills, pyrexia, hypotension, flushing, hypertension, tachycardia, dyspnoea, and chest discomfort. Respiratory symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and cardiac symptoms such as atrial fibrillation have also been reported (see section 4.4). 16 Chronic Lymphocytic Leukaemia The incidence of IRRs was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm. The incidence of IRRs was 66% with the infusion of the first 1,000 mg of Gazyvaro (20% of patients experiencing a Grade 3-4 IRR). Overall, 7% of patients experienced an IRR leading to discontinuation of Gazyvaro. The incidence of IRRs with subsequent infusions was 3% with the second 1,000 mg dose and 1% thereafter. No Grade 3-5 IRRs were reported beyond the first 1,000 mg infusions of Cycle 1. In patients who received the recommended measures for prevention of IRRs as described in section 4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which occurred in relatively few patients) were similar before and after mitigation measures were implemented. Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma Grade 3-4 IRRs occurred in 12% of patients. In Cycle 1, the overall incidence of IRRs was higher in patients receiving Gazyvaro plus chemotherapy compared to patients in the comparator arm. In patients receiving Gazyvaro plus chemotherapy, the incidence of IRRs was highest on Day 1 and gradually decreased with subsequent infusions. This decreasing trend continued during maintenance therapy with Gazyvaro alone. Beyond Cycle 1 the incidence of IRRs in subsequent infusions was comparable between the Gazyvaro and the relevant comparator arms. Overall, 4% of patients experienced an infusion related reaction leading to discontinuation of Gazyvaro. Neutropenia and infections Chronic Lymphocytic Leukaemia The incidence of neutropenia was higher in the Gazyvaro plus chlorambucil arm (41%) compared to the rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use of granulocyte-colony stimulating factors. The incidence of infection was 38% in the Gazyvaro plus chlorambucil arm and 37% in the rituximab plus chlorambucil arm (with Grade 3-5 events reported in 12% and 14%, respectively and fatal events reported in < 1% in both treatment arms). Cases of prolonged neutropenia (2% in the Gazyvaro plus chlorambucil arm and 4% in the rituximab plus chlorambucil arm) and late onset neutropenia (16% in the Gazyvaro plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported (see section 4.4). Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma In the Gazyvaro plus chemotherapy arm, the incidence of Grade 1-4 neutropenia (50%) was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia was 3% and 8%, respectively. The incidence of infection was 81% in the Gazyvaro plus chemotherapy arm (with Grade 3-5 events reported in 22% of patients and fatal events reported in 3% of patients). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections (see section 4.4). Thrombocytopenia and haemorrhagic events Chronic Lymphocytic Leukaemia The incidence of thrombocytopenia was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm (16% vs. 7%) especially during the first cycle. Four percent of patients treated with Gazyvaro plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours after the Gazyvaro infusion) (see section 4.4). The overall incidence of haemorrhagic events was similar in the Gazyvaro treated arm and in the rituximab treated arm. The number of fatal haemorrhagic events was balanced between the treatment arms; however, all of the events in patients 17 treated with Gazyvaro were reported in Cycle 1. No Grade 5 events of thrombocytopenia were reported. A clear relationship between thrombocytopenia and haemorrhagic events has not been established. Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma The incidence of thrombocytopenia was 15%. Thrombocytopenia occurred more frequently in Cycle 1 in the Gazyvaro plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end of infusion (acute thrombocytopenia) was more frequently observed in patients in the Gazyvaro plus chemotherapy arm than in the comparator arm. The incidence of haemorrhagic events was similar across all treatment arms. Haemorrhagic events and Grade 3-5 haemorrhagic events occurred in 12% and 4% of patients, respectively. While fatal haemorrhagic events occurred in less than 1% of patients; none of the fatal adverse events occurred in Cycle 1. Special populations Elderly Chronic Lymphocytic Leukaemia In the pivotal BO21004/CLL11 study, 46% (156 out of 336) of patients with CLL treated with Gazyvaro plus chlorambucil were 75 years or older (median age was 74 years). These patients experienced more serious adverse events and adverse events leading to death than those patients < 75 years of age. Indolent Non Hodgkin Lymphoma including Follicular Lymphoma In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, patients 65 years or older experienced more serious adverse events and adverse events leading to withdrawal or death than patients < 65 years of age. Renal impairment Chronic Lymphocytic Leukaemia In the pivotal BO21004/CLL11 study, 27% (90 out of 336) of patients treated with Gazyvaro plus chlorambucil had moderate renal impairment (CrCl < 50 mL/min). These patients experienced more serious adverse events and adverse events leading to death than patients with a CrCl ≥ 50 mL/min (see section 4.2, 4.4 and 5.2). Patients with a CrCl < 30 mL/min were excluded from the study (see section 5.1). Indolent Non Hodgkin Lymphoma including Follicular Lymphoma In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, 5% (35 out of 698) and 7% (14 out of 204) of patients treated with Gazyvaro, respectively, had moderate renal impairment (CrCL < 50 mL/min). These patients experienced more serious adverse events, G rade 3 to 5 adverse events and adverse events leading to treatment withdrawal (patients in BO21223 only) than patients with a CrCl ≥ 50 mL/min (see section 4.2 and 5.2). Patients with a CrCl < 40 mL/min were excluded from the studies (see section 5.1). Additional safety information from clinical studies experience Progressive multifocal leukoencephalopathy PML has been reported in patients treated with Gazyvaro (see section 4.4). 18 Hepatitis B reactivation Cases of hepatitis B reactivation have been reported in patients treated with Gazyvaro (see section 4.4). Gastro-Intestinal Perforation Cases of gastro-intestinal perforation have been reported in patients receiving Gazyvaro, mainly in iNHL. In the pivotal studies in iNHL up to 1% of patients experienced gastrointestinal perforation. Worsening of pre-existing cardiac conditions Cases of arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (see section 4.4). These events may occur as part of an IRR and can be fatal. Laboratory abnormalities Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed shortly after the first infusion of Gazyvaro. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose No experience with overdose is available from human clinical studies. In clinical studies with Gazyvaro, doses ranging from 50 mg up to and including 2,000 mg per infusion have been administered. The incidence and intensity of adverse reactions reported in these studies did not appear to be dose dependent. Patients who experience overdose should have immediate interruption or reduction of their infusion and be closely supervised. Consideration should be given to the need for regular monitoring of blood cell count and for increased risk of infections while patients are B-cell depleted. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC15 Mechanism of action Obinutuzumab is a recombinant monoclonal humanised and glycoengineered Type II anti-CD20 antibody of the IgG1 isotype. It specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes, but not on haematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. Glycoengineering of the Fc part of obinutuzumab results in higher affinity for FcɣRIII receptors on immune effector cells such as natural killer (NK) cells, macrophages and monocytes as compared to non-glycoengineered antibodies. https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc 19 In nonclinical studies, obinutuzumab induces direct cell death and mediates antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) through recruitment of FcɣRIII positive immune effector cells. In addition, in vivo, obinutuzumab mediates a low degree of complement dependent cytotoxicity (CDC). Compared to Type I antibodies, obinutuzumab, a Type II antibody, is characterised by an enhanced direct cell death induction with a concomitant reduction in CDC at an equivalent dose. Obinutuzumab, as a glycoengineered antibody, is characterised by enhanced ADCC and ADCP compared to non-glycoengineered antibodies at an equivalent dose. In animal models obinutuzumab mediates potent B-cell depletion and antitumour efficacy. In the pivotal clinical study in patients with CLL (BO21004/CLL11), 91% (40 out of 44) of evaluable patients treated with Gazyvaro were B-cell depleted (defined as CD19+ B-cell counts < 0.07 x 109/L) at the end of treatment period and remained depleted during the first 6 months of follow up. Recovery of B-cells was observed within 12-18 months of follow up in 35% (14 out of 40) of patients without progressive disease and 13% (5 out of 40) with progressive disease. In the pivotal clinical study in patients with iNHL (GAO4753/GADOLIN), 97% (171 out of 176) of evaluable patients treated with Gazyvaro were B-cell depleted at the end of the treatment period, and 97% (61 out of 63) remained depleted for more than 6 months from the last dose. Recovery of B-cells was observed within 12-18 months of follow-up in 11% (5 out of 46) of evaluable patients. Clinical efficacy and safety Chronic Lymphocytic Leukaemia A Phase III international, multicentre, open label, randomised, two-stage, three-arm clinical study (BO21004/CLL11) investigating the efficacy and safety of Gazyvaro plus chlorambucil (GClb) compared to rituximab plus chlorambucil (RClb) or chlorambucil (Clb) alone was conducted in patients with previously untreated CLL with comorbidities. Prior to enrolment, patients had to have documented CD20+ CLL, and one or both of the following measures of coexisting medical conditions: comorbidity score (CIRS) of greater than 6 or reduced renal function as measured by CrCl < 70 mL/min. Patients with inadequate liver function (National Cancer Institute – Common Terminology Criteria for Adverse Events Grade 3 liver function tests (AST, ALT > 5 x ULN for > 2 weeks; bilirubin > 3 x ULN) and renal function (CrCl < 30 mL/min) were excluded. Patients with one or more individual organ/system impairment score of 4 as assessed by the CIRS definition, excluding eyes, ears, nose, throat and larynx organ system, were excluded. A total of 781 patients were randomised 2:2:1 to receive Gazyvaro plus chlorambucil, rituximab plus chlorambucil or chlorambucil alone. Stage 1a compared Gazyvaro plus chlorambucil to chlorambucil alone in 356 patients and Stage 2 compared Gazyvaro plus chlorambucil to rituximab plus chlorambucil in 663 patients. In the majority of patients, Gazyvaro was given intravenously as a 1,000 mg initial dose administered on Day 1, Day 8 and Day 15 of the first treatment cycle. In order to reduce the rate of infusion related reactions in patients, an amendment was implemented and 140 patients received the first Gazyvaro dose administered over 2 days (Day 1 [100 mg] and Day 2 [900 mg]) (see section 4.2 and 4.4). For each subsequent treatment cycle (Cycles 2 to 6), patients received Gazyvaro 1,000 mg on Day 1 only. Chlorambucil was given orally at 0.5 mg/kg body weight on Day 1 and Day 15 of all treatment cycles (1 to 6). The demographics data and baseline characteristics were well balanced between the treatment arms. The majority of patients were Caucasian (95%) and male (61%). The median age was 73 years, with 44% being 75 years or older. At baseline, 22% of patients had Binet Stage A, 42% had Binet Stage B and 36% had Binet Stage C. 20 The median comorbidity score was 8 and 76% of the patients enrolled had a comorbidity score above 6. The median estimated CrCl was 62 mL/min and 66% of all patients had a CrCl < 70 mL/min. Forty-two percent of patients enrolled had both a CrCl < 70 mL/min and a comorbidity score of > 6. Thirty-four percent of patients were enrolled on comorbidity score alone, and 23% of patients were enrolled with only impaired renal function. The most frequently reported coexisting medical conditions (using a cut off of 30% or higher), in the MedDRA body systems are: Vascular disorders (73%), Cardiac disorders (46%), Gastrointestinal disorders (38%), Metabolism and nutrition disorders (40%), Renal and urinary disorders (38%), Musculoskeletal and connective tissue disorders (33%). Efficacy results for patients with previously untreated CLL are summarised in Table 7. Kaplan-Meier curves for progression-free survival (PFS) and Overall Survival (OS) are shown in Figures 1-4. Table 7 Summary of efficacy from BO21004/CLL11 study Stage 1a Stage 2 Chlorambucil N=118 Gazyvaro + chlorambucil N= 238 Rituximab + chlorambucil N= 330 Gazyvaro + chlorambucil N= 333 22.8 months median observation time g 18.7 months median observation time g Primary endpoint Investigator-assessed PFS (PFS-INV)a Number (%) of patients with event 96 (81.4%) 93 (39.1%) 199 (60.3%) 104 (31.2%) Median time to event (months) 11.1 26.7 15.2 26.7 Hazard ratio (95% CI) 0.18 [0.13; 0.24] 0.39 [0.31; 0.49] p-value (Log-Rank test, stratifiedb) < 0.0001 < 0.0001 Key secondary endpoints IRC-assessed PFS (PFS-IRC)a Number (%) of patients with event 90 (76.3%) 89 (37.4%) 183 (55.5%) 103 (30.9%) Median time to event (months) 11.2 27.2 14.9 26.7 Hazard ratio (95% CI) 0.19 [0.14; 0.27] 0.42 [0.33; 0.54] p-value (Log-Rank test, stratifiedb) < 0.0001 < 0.0001 End of treatment response rate No. of patients included in the analysis 118 238 329 333 Responders (%) 37 (31.4%) 184 (77.3%) 214 (65.0%) 261 (78.4%) Non-responders (%) 81 (68.6%) 54 (22.7%) 115 (35.0%) 72 (21.6%) Difference in response rate, (95% CI) 45.95 [35.6; 56.3] 13.33 [6.4; 20.3] p-value (Chi-squared Test) < 0.0001 0.0001 No. of complete respondersc (%) 0 (0.0%) 53 (22.3%) 23 (7.0%) 69 (20.7%) Molecular remission at end of treatmentd No. of patients included in the analysis 90 168 244 239 MRD negativee (%) 0 (0%) 45 (26.8%) 6 (2.5%) 61 (25.5%) MRD positivef (%) 90 (100%) 123 (73.2%) 238 (97.5%) 178 (74.5%) Difference in MRD rates, (95% CI) 26.79 [19.5; 34.1] 23.06 [17.0; 29.1] 21 Stage 1a Stage 2 Chlorambucil N=118 Gazyvaro + chlorambucil N= 238 Rituximab + chlorambucil N= 330 Gazyvaro + chlorambucil N= 333 22.8 months median observation time g 18.7 months median observation time g Event free survival No. (%) of patients with event 103 (87.3%) 104 (43.7%) 208 (63.0 %) 118 (35.4 %) Median time to event (months) 10.8 26.1 14.3 26.1 Hazard ratio (95% CI) 0.19 [0.14; 0.25] 0.43 [0.34; 0.54] p-value (Log-Rank test, stratifiedb) < 0.0001 < 0.0001 Time to new anti-leukaemic therapy No. (%) of patients with event 65 (55.1%) 51 (21.4%) 86 (26.1%) 55 (16.5%) Median time to event (months) 14.8 NR 30.8 NR Hazard ratio (95% CI) 0.24 [0.16; 0.35] 0.59 [0.42; 0.82] p-value (Log-Rank test, stratifiedb) < 0.0001 < 0.0018 Overall survival No. (%) of patients with event 57 (48.3%) 93 (39.1%) 147 (44.5%) 121 (36.3%) Median time to event (months) 66.7 NR 73.1 NR Hazard ratio (95% CI) 0.68 [0.49; 0.94] 0.76 [0.60; 0.97] p-value (Log-Rank test, stratifiedb) 0.0196 0.0245 IRC: Independent Review Committee; PFS: progression-free survival; HR: Hazard Ratio; CI: Confidence Intervals, MRD: Minimal Residual Disease, NR = Not reached a Defined as the time from randomisation to the first occurrence of progression, relapse or death from any cause as assessed by the investigator b stratified by Binet stage at baseline c Includes 11 patients in the GClb arm with a complete response with incomplete marrow recovery d Blood and bone marrow combined e MRD negativity is defined as a result below 0.0001 f Includes MRD positive patients and patients who progressed or died before the end of treatment g Median observation time for overall survival (OS) data corresponds to 62.5 months median observation time in Stage 1a and to 59.4 months median observation time in Stage 2. Results of subgroup analyses Results of the progression free survival (PFS) subgroup analysis (i.e. sex, age, Binet stages, CrCl, CIRS score, beta2-microglobulin, IGVH status, chromosomal abnormalities, lymphocyte count at baseline) were consistent with the results seen in the overall Intent-to-Treat population. The risk of disease progression or death was reduced in the GClb arm compared to the RClb arm and Clb arm in all subgroups except in the subgroup of patients with deletion 17p. In the small subgroup of patients with deletion 17p, only a positive trend was observed compared to Clb (HR=0.42, p=0.0892); no benefit was observed compared to RClb. For subgroups, reduction of the risk of disease progression or death ranged from 92% to 58% for GClb versus Clb and 72% to 29% for GClb versus RClb. 22 Figure 1 Kaplan-Meier curve of Investigator assessed PFS from Stage 1a in patients with CLL (Study BO21004/CLL11) Figure 2 Kaplan-Meier curve of OS from Stage 1a in patients with CLL (Study BO21004/CLL11) 23 Figure 3 Kaplan-Meier curve of investigator assessed PFS from Stage 2 in patients with CLL (Study BO21004/CLL11) Figure 4 Kaplan-Meier curve of OS from Stage 2 in patients with CLL (Study BO21004/CLL11) Quality of life In the QLQC30 and QLQ-CLL-16 questionnaires conducted during the treatment period, no substantial difference in any of the subscales was observed. Data during follow up, especially for the chlorambucil alone arm, is limited. However, no notable differences in quality of life during follow up have been identified to date. 24 Health-related quality of life assessments, specific to fatigue through treatment period, show no statistically significant difference suggesting that the addition of Gazyvaro to a chlorambucil regimen does not increase the experience of fatigue for patients. Follicular lymphoma Previously untreated follicular lymphoma (study BO21223/GALLIUM) In a phase III, open label, multicentre, randomised clinical study (BO21223/GALLIUM), 1202 patients with previously untreated Grade 1-3a advanced (stage II bulky disease, stage III/IV) FL were evaluated. Patients with FL Grade 3b were excluded from the study. Patients were randomised to 1:1 to receive either Gazyvaro (n=601 patients) or rituximab (n=601 patients) in combination with chemotherapy (bendamustine, CHOP or CVP), followed by Gazyvaro or rituximab maintenance in patients achieving a complete or partial response. Gazyvaro was given by intravenous infusion as a dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on Day 1 of subsequent cycles. In total, six cycles of Gazyvaro (every 28 days) were given in combination with six cycles of bendamustine, and a total of eight cycles of Gazyvaro (every 21 days) were given in combination with six cycles of CHOP or eight cycles of CVP. Gazyvaro was administered prior to chemotherapy. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (Cycles 1-6) at 90 mg/m2/day when given in combination with Gazyvaro. Standard dosing of CHOP and CVP was given. Following Cycles 6-8, in combination with chemotherapy, responding patients received Gazyvaro maintenance therapy every 2 months until disease progression or for up to 2 years. The demographic data and baseline characteristics of the patient population were well balanced between the treatment arms; median age was 59 years, 81% were Caucasian, 53% were female, 79% had a FLIPI score of ≥ 2 and 7% had Stage II (bulky), 35% had Stage III and 57% had Stage IV disease, 44% had bulky disease (> 7 cm), 34% had at least one B-symptom at baseline and 97% had an ECOG performance status of 0-1 at baseline. Fifty-seven percent received bendamustine, 33% received CHOP, and 10% received CVP chemotherapy. Efficacy results for patients with previously untreated FL are summarised in Table 8. Kaplan-Meier curves for progression-free survival (PFS) are shown in Figure 5. 25 Table 8 Summary of efficacy in patients with previously untreated FL from BO21223/ GALLIUM study Rituximab + Chemotherapy followed by rituximab maintenance N=601 Gazyvaro +Chemotherapy followed by Gazyvaro maintenance N=601 Median observation time 34 months Median observation time 35 months Primary Endpoint Investigator-assessed PFS§ (PFS-INV) Number (%) of patients with event 144 (24.0%) 101 (16.8%) HR [95% CI] 0.66 [0.51, 0.85] p-value (Log-Rank test, stratified*) 0.0012 3 year PFS estimate [95% CI] 73.3 [68.8, 77.2] 80.0 [75.9, 83.6] Key Endpoints IRC-assessed PFS (PFS-IRC) Number (%) of patients with event 125 (20.8%) 93 (15.5%) HR [95% CI] 0.71 [0.54, 0.93] p-value (Log-Rank test, stratified*) 0.0138 Time to next anti-lymphoma therapy# Number (%) of patients with event 111 (18.5%) 80 (13.3%) HR [95% CI] 0.68 [0.51, 0.91] p-value (Log-Rank test, stratified*) 0.0094 Overall Survival# No. (%) of patients with event 46 (7.7%) 35 (5.8%) HR [95% CI] 0.75 [0.49, 1.17] ¶ p-value (Log-Rank test, stratified*) 0.21¶ Overall Response Rate** at End of Induction‡ (INV-assessed, CT) # Responders (%) (CR, PR) 522 (86.9%) 532 (88.5%) Difference in response rate (%) [95% CI] 1.7% [-2.1%, 5.5%] p-value (Cochran-Mantel-Haenszel test) 0.33 Complete Response (CR) 143 (23.8%) 117 (19.5%) Partial Response (PR) 379 (63.1%) 415 (69.1%) IRC: Independent Review Committee; PFS: progression-free survival; HR: Hazard Ratio; CI: Confidence Interval * Stratification factors were chemotherapy regimen, FLIPI risk group for follicular lymphoma, geographic region § Significance level at this efficacy interim analysis: 0.012 ¶ Data Not Yet Mature. Median was not reached at time of analysis # not adjusted for multiplicity **Assessed as per modified Cheson 2007 criteria ‡ End of Induction = end of induction phase, does not include monotherapy maintenance 26 Figure 5 Kaplan-Meier curve of INV-assessed progression-free survival in patients with previously untreated FL (Study BO21223/GALLIUM) R-Chemo: Rituximab plus chemotherapy, G-Chemo: Gazyvaro plus chemotherapy, HR: hazard ratio, CI: confidence interval Results of subgroup analyses Results of subgroup analyses (not adjusted for multiplicity) were, in general, consistent with the results seen in the FL population, supporting the robustness of the overall result. The subgroups evaluated included IPI, FLIPI, Bulky Disease, B Symptoms at baseline, Ann Arbor Stage and ECOG at baseline. In patients with FLIPI score 0-1 (low risk), no difference between Gazyvaro plus chemotherapy and rituximab plus chemotherapy was observed (INV-assessed PFS HR 1.17 (95%CI 0.63;2.19, 40 PFS events). This subgroup comprised 21% (253/1202) of the FL ITT population and experienced 16.3% (40/245) of the PFS events. In addition, exploratory subgroup analyses of PFS across chemotherapy regimens (bendamustine, CHOP and CVP) were consistent with the results seen in the Gazyvaro plus chemotherapy population. The observed HRs by chemotherapy subgroup were as follows; CHOP (n = 398): HR 0.77 (95% CI: 0.50, 1.20), CVP (n = 118): HR 0.63 (95% CI: 0.32, 1.21), and bendamustine (n = 686): HR 0.61 (95% CI: 0.43, 0.86). Patient Reported Outcomes Based on the FACT-Lym questionnaire collected during treatment and follow-up phases, patients in both treatment arms experienced clinically meaningful improvements in lymphoma-related symptoms as defined by a ≥ 3 point increase from baseline in the Lymphoma subscale, a ≥ 6 point increase from baseline in the FACT Lym TOI and a ≥ 7 point increase from baseline in the FACT Lym Total score. EQ-5D utility scores were similar at baseline, during treatment and follow-up. No meaningful differences were seen between the arms in HRQOL or health status measures. Due to the open label design the patient reported outcomes should be interpreted with caution. Patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen (study GAO4753g/GADOLIN). In a phase III, open label, multicentre, randomised clinical study (GAO4753g/GADOLIN), 396 patients with iNHL who had no response during treatment or who progressed within 6 months following the last dose of rituximab or a rituximab-containing regimen (including rituximab monotherapy as part of induction or maintenance treatment) were evaluated. Patients were randomised 1:1 to receive either bendamustine (B) alone (n = 202) or Gazyvaro in combination with bendamustine 27 (G+B) (n = 194) for 6 cycles, each of 28 days duration. Patients in the G+B arm who did not have disease progression (i.e. patients with a complete response (CR), partial response (PR) or stable disease (SD)) at the end of induction continued receiving Gazyvaro maintenance once every two months for two years or until disease progression (whichever occurred first). Patients were stratified according to region, iNHL subtype (follicular versus non-follicular), rituximab-refractory type (whether refractory to prior rituximab monotherapy or rituximab in combination with chemotherapy) and the number of prior therapies (≤ 2 versus > 2). The demographic data and baseline characteristics were well balanced between the treatment arms (median age 63 years, the majority were Caucasian [88%] and male [58%]). The majority of patients had follicular lymphoma (81%). The median time from initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10); 44% of patients had received 1 prior therapy and 34% of patients had received 2 prior therapies. Gazyvaro was given by intravenous infusion as a dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on Day 1 of Cycles 2-6, and in patients who did not have disease progression, once every two months for two years or until disease progression (whichever occurs first). Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (Cycles 1-6) at 90 mg/m2/day when given in combination with Gazyvaro or 120 mg/m2/day when given alone. In patients treated with G+ B, 79.4% received all six treatment cycles compared to 66.7% of patients in the B arm. The primary analysis, based on independent Review Committee (IRC) assessment demonstrated a statistically significant - 45% reduction in the risk of disease progression or death, in patients with iNHL receiving G+B followed by Gazyvaro maintenance, compared with patients receiving bendamustine alone. The reduction in the risk of disease progression or death seen in the iNHL population is driven by the subset of patients with FL. The majority of the patients in study GAO4753g had FL (81.1%). Efficacy results from the primary analysis in the FL population are shown in Table 9 and Figures 6 and 8. 11.6% of the patients had marginal zone lymphoma (MZL) and 7.1% had small lymphocytic lymphoma (SLL). In the non-FL population the HR for IRC-assessed PFS was 0.94 [95% CI: 0.49, 1.90]. No definitive conclusions could be drawn on efficacy in the MZL and SLL sub-populations. At final analysis, the median observation time was 45.9 months (range: 0-100.9 months) for FL patients in the B arm and 57.3 months (range: 0.4-97.6 months) for patients in the G+B arm, representing an additional 25.6 months and 35.2 months of median follow-up in B and G+B arms, respectively, since the primary analysis. Only Investigator (INV) assessed endpoints were reported at final analysis since IRC assessments did not continue. Overall, the investigator assessed efficacy results were consistent with what was observed in the primary analysis. The overall survival (OS) in patients with FL was stable with longer follow-up (see Figure 7); the HR for risk of death was 0.71 (95%CI: 0.51, 0.98). 28 Table 9 Summary of primary efficacy analysis in patients with FL# from GAO4753g/GADOLIN study Bendamustine N=166 Gazyvaro + Bendamustine followed by Gazyvaro maintenance N=155 Median observation time: 20 months Median observation time: 22 months Primary Endpoint in FL population IRC-assessed PFS (PFS-IRC) Number (%) of patients with event 90 (54.2%) 54 (34.8%) Median time to event (months, 95% CI) 13.8 (11.4, 16.2) NR (22.5,-) HR (95% CI) 0.48 (0.34, 0.68) p-value (Log-Rank test, stratified*) < 0.0001 Secondary Endpoints Investigator-assessed PFS (PFS-INV) Number (%) of patients with event 102 (61.4%) 62 (40.0%) Median time to event (months, 95% CI) 13.7 (11.0, 15.5) 29.2 (17.5,-) HR (95% CI) 0.48 (0.35, 0.67) p-value (Log-Rank test, stratified*) < 0.0001 Best Overall Response (BOR) (IRC-assessed)§ No. of patients included in the analysis 161 153 Responders (%) (CR/PR) 124 (77.0%) 122 (79.7%) Difference in response rate (95% CI) 2.72 (-6.74, 12.18) p-value (Cochran-Mantel-Haenszel test) 0.6142 Complete Responders (%) 31 (19.3%) 24 (15.7%) Partial Responders (%) 93 (57.8%) 98 (64.1%) Stable Disease (%) 18 (11.2%) 13 (8.5%) 29 Duration of response (DOR) (IRC- assessed) No of patients included in the analysis 127 122 No. (%) of patients with event 74 (58.3%) 36 (29.5%) Median duration (months) of DOR (95% CI) 11.9 (8.8, 13.6) NR (25.4,-) HR (95% CI) 0.36 (0.24, 0.54) Overall Survival No. (%) of patients with event 36 (21.7%) 25 (16.1%) Median time to event (months) NR NR HR (95% CI) 0.71 (0.43, 1.19) p-value (Log-Rank test, stratified*) 0.1976 IRC: Independent Review Committee; PFS: progression-free survival; HR: Hazard Ratio; CI: Confidence Intervals, NR = Not Reached # Patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen *Stratification factors for analysis were refractory type (rituximab monotherapy vs. rituximab + chemotherapy) and prior therapies (≤ 2 vs > 2). Follicular versus non-follicular was also a stratification factor for the study but is not applicable in the subgroup analysis of patients with FL. § Best response within 12 months of start of treatment Figure 6 Kaplan-Meier curve of IRC-assessed PFS in patients with FL # (Study GAO4753g/GADOLIN) # Patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen 30 Figure 7 Kaplan-Meier curve of Overall Survival in FL patients at Final Analysis (Study GAO4753g/GADOLIN) Results of subgroup analyses Results of subgroup analyses were in general consistent with the results seen in the FL population, supporting the robustness of the overall result. Figure 8 IRC-assessed PFS by patient subgroup in FL *# (Study GAO4753g/GADOLIN) *pre-specified analyses performed on the intent to treat (ITT) population were repeated on the FL population; analysis of double refractory (i.e. unresponsive to or disease progression during or within 6 months of the last dose of an alkylating agent-based regimen) status was exploratory. # Patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen 31 Patient-reported Outcomes Due to the open label design the patient reported outcomes should be interpreted with caution. Based on the FACT-Lym questionnaire and EQ-5D index scale collected during the treatment and during follow-up periods, health-related quality of life was generally maintained in the pivotal study with no meaningful difference between the arms. However, in patients with FL the addition of Gazyvaro to bendamustine delayed the time to worsening of health-related quality of life as measured by the FACT-Lym TOI score by 2.2 months (median 5.6 versus 7.8 months for B and G+B respectively HR = 0.83; 95% CI: 0.60, 1.13). Immunogenicity Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, assay robustness to quantities of Gazyvaro/antibody in the circulation, sample handling, timing of sample collection, concomitant medicines and underlying disease. For these reasons, comparison of incidence of antibodies to Gazyvaro with the incidence of antibodies to other products may be misleading. Patients in the CLL pivotal study BO21004/CLL11 were tested at multiple time-points for anti-therapeutic antibodies (ATA) to Gazyvaro. In patients treated with Gazyvaro 8 out of 140 patients in the randomised phase and 2 out of 6 in the run in phase tested positive for ATA at 12 months of follow up. Of these patients, none experienced anaphylactic or hypersensitivity reactions that were considered related to ATA, nor was clinical response affected. No post-baseline HAHA (Human Anti-Human Antibody) were observed in patients with iNHL treated in study GAO4753g/GADOLIN. In study BO21223/GALLIUM, 1/565 patient (0.2% of patients with a post-baseline assessment) developed HAHA at induction completion. While the clinical significance of HAHA is not known, a potential correlation between HAHA and clinical course cannot be ruled out. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Gazyvaro in all subsets of the paediatric population in CLLand FL (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties A population pharmacokinetic (PK) model was developed to analyse the PK data in 469 iNHL, 342 CLL and 130 diffuse large B-cell lymphoma (DLBCL) patients from Phase I, Phase II and Phase III studies who received obinutuzumab alone or in combination with chemotherapy. Absorption Obinutuzumab is administered intravenously, therefore absorption is not applicable. There have been no studies performed with other routes of administration. From the population PK model, after the Cycle 6 Day 1 infusion in CLL patients, the estimated median Cmax value was 465.7 μg/mL and AUC(τ) value was 8961 μg•d/mL and in iNHL patients the estimated median Cmax value was 539.3 μg/mL and AUC(τ) value was 10956 μg•day/mL. Distribution Following intravenous administration, the volume of distribution of the central compartment (2.98 L in patients with CLL and 2.97 in patients with iNHL), approximates serum volume, which indicates distribution is largely restricted to plasma and interstitial fluid. 32 Biotransformation The metabolism of obinutuzumab has not been directly studied. Antibodies are mostly cleared by catabolism. Elimination The clearance of obinutuzumab was approximately 0.11 L/day in CLL patients and 0.08 L/day in iNHL patients with a median elimination t½ of 26.4 days in CLL patients and 36.8 days in iNHL patients. Obinutuzumab elimination comprises two parallel pathways which describe clearance, a linear clearance pathway and a non-linear clearance pathway which changes as a function of time. During the initial treatment, the non-linear time-varying clearance pathway is dominant and is consequently the major clearance pathway. As treatment continues, the impact of this pathway diminishes and the linear clearance pathway predominates. This is indicative of target mediated drug disposition (TMDD), where the initial abundance of CD20 cells causes a rapid removal of obinutuzumab from the circulation. However, once the majority of CD20 cells are bound with obinutuzumab, the impact of TMDD on PK is minimised. Pharmacokinetic/pharmacodynamic relationship(s) In the population pharmacokinetic analysis, gender was found to be a covariate which explains some of the inter-patient variability, with a 22% greater steady state clearance (CLss) and a 19% greater volume of distribution (V) in males. However, results from the population analysis have shown that the differences in exposure are not significant (with an estimated median AUC and Cmax in CLL patients of 11282 µg•d/mL and 578.9 µg/mL in females and 8451 µg•d/mL and 432.5 µg/mL in males, respectively at Cycle 6 and AUC and Cmax in iNHL of 13172 µg•d/mL and 635.7 µg/mL in females and 9769 µg•d/mL and 481.3 µg/mL in males, respectively), indicating that there is no need to dose adjust based on gender. Elderly The population pharmacokinetic analysis of obinutuzumab showed that age did not affect the pharmacokinetics of obinutuzumab. No significant difference was observed in the pharmacokinetics of obinutuzumab among patients < 65 years (n=375), patients between 65-75 years (n=265) and patients > 75 years (n=171). Paediatric population No studies have been conducted to investigate the pharmacokinetics of obinutuzumab in paediatric patients. Renal impairment The population pharmacokinetic analysis of obinutuzumab showed that creatinine clearance does not affect pharmacokinetics of obinutuzumab. Pharmacokinetics of obinutuzumab in patients with mild creatinine clearance (CrCl 50-89 mL/min, n=464) or moderate (CrCl 30 to 49 mL/min, n=106) renal impairment were similar to those in patients with normal renal function (CrCl ≥ 90 mL/min, n=383). Pharmacokinetic data in patients with severe renal impairment (CrCl 15-29 mL/min) is limited (n=8), therefore no dose recommendations can be made. Hepatic impairment No formal pharmacokinetic study has been conducted in patients with hepatic impairment. 33 5.3 Preclinical safety data No studies have been performed to establish the carcinogenic potential of obinutuzumab. No specific studies in animals have been performed to evaluate the effect of obinutuzumab on fertility. In repeat-dose toxicity studies in cynomolgus monkeys obinutuzumab had no adverse effects on male and female reproductive organs. An enhanced pre and postnatal development (ePPND) toxicity study in pregnant cynomolgus monkeys showed no evidence of teratogenic effects. However, weekly obinutuzumab dosing from post-coitum day 20 to delivery resulted in complete depletion of B-cells in infant monkeys at weekly intravenous obinutuzumab doses of 25 and 50 mg/kg (2-5 times the clinical exposure based on Cmax and AUC). Offspring exposure on day 28 post-partum suggests that obinutuzumab can cross the blood-placenta barrier. Concentrations in infant serum on day 28 post-partum were in the range of concentrations in maternal serum, whereas concentrations in milk on the same day were very low (less than 0.5% of the corresponding maternal serum levels) suggesting that exposure of infants must have occurred in utero. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months post-partum. In a 26-week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanised antibody in cynomolgus monkeys (0.7-6 times the clinical exposure based on Cmax and AUC at steady state after weekly administration of 5, 25, and 50 mg/kg). Findings included acute anaphylactic or anaphylactoid reactions and an increased prevalence of systemic inflammation and infiltrates consistent with immune-complex mediated hypersensitivity reactions, such as arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation. These reactions led to unscheduled termination of 6/36 animals treated with obinutuzumab during dosing and recovery phases; these changes were partially reversible. No renal toxicity with a causal relationship to obinutuzumab has been observed in humans. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Histidine Histidine hydrochloride monohydrate Trehalose dihydrate Poloxamer 188 Water for injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial 3 years. After dilution After dilution, chemical and physical stability have been demonstrated in sodium chloride 9 mg/mL (0.9%) solution for injection at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C followed by 48 hours (including infusion time) at ≤ 30°C. 34 From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated aseptic conditions. 6.4 Special precautions for storage Store in a refrigerator (2°C-8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 40 mL concentrate in a 50 mL vial (clear Type I glass) with stopper (butyl rubber). Pack size of 1 vial. 6.6 Special precautions for disposal and other handling Instructions for dilution Gazyvaro should be prepared by a healthcare professional using aseptic technique. Do not shake the vial. Use a sterile needle and syringe to prepare Gazyvaro. For CLL cycles 2 – 6 and all FL cycles Withdraw 40 mL of concentrate from the vial and dilute in polyvinyl chloride (PVC) or non-PVC polyolefin infusion bags containing sodium chloride 9 mg/mL (0.9%) solution for injection. CLL only – Cycle 1 To ensure differentiation of the two infusion bags for the initial 1,000 mg dose, it is recommended to utilise bags of different sizes to distinguish between the 100 mg dose for Cycle 1 Day 1 and the 900 mg dose for Cycle 1 Day 1 (continued) or Day 2. To prepare the 2 infusion bags, withdraw 40 mL of concentrate from the vial and dilute 4 mL into a 100 mL PVC or non-PVC polyolefin infusion bag and the remaining 36 mL in a 250 mL PVC or non-PVC polyolefin infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection. Clearly label each infusion bag. For storage conditions of the infusion bags see section 6.3. Dose of Gazyvaro to be administered Required amount of Gazyvaro concentrate Size of PVC or non-PVC polyolefin infusion bag 100 mg 4 mL 100 mL 900 mg 36 mL 250 mL 1000 mg 40 mL 250 mL Do not use other diluents such as glucose (5%) solution (see section 6.2). The bag should be gently inverted to mix the solution in order to avoid excessive foaming. The diluted solution should not be shaken or frozen. Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration. 35 No incompatibilities have been observed between Gazyvaro, in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of Gazyvaro with sodium chloride 9 mg/mL (0.9%) solution for injection, and: • PVC, polyethylene (PE), polypropylene or polyolefin bags • PVC, polyurethane (PUR) or PE infusion sets • optional inline filters with product contact surfaces of polyethersulfone (PES), a 3-way stopcock infusion aid made from polycarbonate (PC), and catheters made from polyetherurethane (PEU). Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Roche Registration GmbH Emil-Barell-Strasse 1 79639 Grenzach-Wyhlen Germany 8. MARKETING AUTHORISATION NUMBER(S) EU/1/14/937/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 23 July 2014 Date of latest renewal: 02 April 2019 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 36 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 37 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Roche Diagnostics GmbH Nonnenwald 2 82377 Penzberg GERMANY Name and address of the manufacturer responsible for batch release Roche Pharma AG Emil-Barell-Strasse 1 79639 Grenzach-Wyhlen GERMANY B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorization holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. 38 ANNEX III LABELLING AND PACKAGE LEAFLET 39 A. LABELLING 40 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Gazyvaro 1,000 mg concentrate for solution for infusion obinutuzumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of 40 mL concentrate contains 1,000 mg obinutuzumab, corresponding to a concentration before dilution of 25 mg/mL 3. LIST OF EXCIPIENTS HistidineHistidine hydrochloride monohydrate Trehalose dihydrate Poloxamer 188 Water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion 1,000 mg/40 mL 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use For intravenous use after dilution Do not shake the vial 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 41 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator Do not freeze Keep the vial in the outer carton in order to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Roche Registration GmbH Emil-Barell-Strasse 1 79639 Grenzach-Wyhlen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/937/001 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 42 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Gazyvaro 1,000 mg concentrate for solution for infusion obinutuzumab Intravenous use 2. METHOD OF ADMINISTRATION For intravenous use after dilution 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1,000 mg/40 mL 6. OTHER 43 B. PACKAGE LEAFLET 44 Package leaflet: Information for the patient Gazyvaro 1,000 mg concentrate for solution for infusion obinutuzumab Read all of this leaflet carefully before you start using this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or nurse. • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Gazyvaro is and what it is used for 2. What you need to know before you are given Gazyvaro 3. How Gazyvaro is given 4. Possible side effects 5. How to store Gazyvaro 6. Content of the pack and other information 1. What Gazyvaro is and what it is used for What Gazyvaro is Gazyvaro contains the active substance obinutuzumab, which belongs to a group of medicines called “monoclonal antibodies”. Antibodies work by attaching themselves to specific targets in your body. What Gazyvaro is used for Gazyvaro can be used in adults to treat two different types of cancer • Chronic lymphocytic leukaemia (also called “CLL”) - Gazyvaro is used in patients who have not had any treatment for CLL before and who have other illnesses which make it unlikely that they would be able to tolerate a full dose of a different medicine used to treat CLL called fludarabine. - Gazyvaro is used together with another medicine for cancer called chlorambucil. • Follicular lymphoma (also called “FL”) - Gazyvaro is used in patients who have not had any treatment for FL - Gazyvaro is used in patients who have had at least one treatment with a medicine called rituximab before and whose FL has come back or got worse during or after this treatment. - At the start of treatment for FL, Gazyvaro is used together with other medicines for cancer. - Gazyvaro can then be used on its own for up to 2 years as a “maintenance treatment”. How Gazyvaro works • CLL and FL are types of cancer that affect white blood cells called “B-lymphocytes”. The affected “B-lymphocytes” multiply too quickly and live too long. Gazyvaro binds to targets on the surface of the affected “B-lymphocyte” cells and causes them to die. • When Gazyvaro is given to patients with CLL or FL together with other medicines for cancer - this slows down the time it takes for their disease to get worse. 45 2. What you need to know before you are given Gazyvaro You must not be given Gazyvaro if: • you are allergic to obinutuzumab or any of the other ingredients of this medicine (listed in section 6). If you are not sure talk to your doctor or nurse before being given Gazyvaro. Warnings and precautions Talk to your doctor or nurse before you are given Gazyvaro if: • you have an infection, or have had an infection in the past which lasted a long time or keeps coming back • you have ever taken, or been given, medicines which affect your immune system (such as chemotherapy or immunosuppressants) • you are taking medicines for high blood pressure or medicines used to thin your blood – your doctor might need to alter how you take these • you have ever had heart problems • you have ever had brain problems (such as memory problems, difficulty moving or feeling sensations in your body, eyesight problems) • you have ever had breathing problems or lung problems • you have ever had “hepatitis B” - a type of liver disease • you are due to have a vaccine or you know you may need to have one in the near future. If any of the above apply to you (or you are not sure), talk to your doctor or nurse before you are given Gazyvaro. Pay attention to the following side effects Gazyvaro can cause some serious side effects that you need to tell your doctor or nurse about straight away. These include: Infusion related reactions • Tell your doctor or nurse straight away if you get any of the infusion related reactions listed at the start of section 4. Infusion related reactions can happen during the infusion or up to 24 hours after the infusion. • If you get an infusion related reaction, you may require additional treatment, or the infusion may need to be slowed down or stopped. When these symptoms go away, or improve, the infusion can be continued. These reactions are more likely to happen with the first infusion. Your doctor may decide to stop treatment with Gazyvaro if you have a severe infusion related reaction. • Before each infusion of Gazyvaro, you will be given medicines which help to reduce possible infusion related reactions or “tumour lysis syndrome”. Tumour lysis syndrome is a potentially life-threatening complication, caused by chemical changes in the blood due to the breakdown of dying cancer cells (see section 3). Progressive multifocal leukoencephalopathy (also called “PML”) • PML is a very rare and life-threatening brain infection that has been reported in very few patients having treatment with Gazyvaro. • Tell your doctor or nurse straight away if you have memory loss, trouble speaking, difficulty walking or problems with your eyesight. 46 • If you had any of these symptoms before treatment with Gazyvaro, tell your doctor straight away if you notice any changes in them. You may need medical treatment. Infections • Tell your doctor or nurse straight away if you get any signs of infection after your Gazyvaro treatment (see "Infections" in section 4). Children and adolescents Do not give Gazyvaro to children or young people under 18 years of age. This is because there is no information about its use in these age groups. Other medicines and Gazyvaro Tell your doctor or nurse if you are taking, have recently taken or might start taking any other medicines. This includes medicines obtained without a prescription and herbal medicines. Pregnancy • Tell your doctor or nurse if you are pregnant, think you might be pregnant or are planning to have a baby. They will help you weigh up the benefit of continuing Gazyvaro against the risk to your baby. • If you become pregnant during treatment with Gazyvaro, tell your doctor or nurse as soon as possible. This is because treatment with Gazyvaro may affect yours or the baby’s health. Breast-feeding • Do not breast-feed during treatment with Gazyvaro or for 18 months after stopping treatment with Gazyvaro. This is because small amounts of the medicine may pass into your breast milk. Contraception • Use an effective method of contraception while being treated with Gazyvaro. • Continue to use effective contraception for 18 months after stopping treatment with Gazyvaro. Driving and using machines Gazyvaro is not likely to affect your ability to drive, cycle or use any tools or machines. However, if you get an infusion related reaction, (see section 4), do not drive, cycle or use any tools or machines until the reaction stops. 3. How Gazyvaro is given How Gazyvaro is given Gazyvaro is given under the supervision of a doctor experienced in such treatment. It is given into a vein as a drip (intravenous infusion) over several hours. The Gazyvaro treatment Chronic lymphocytic leukaemia • You will be given 6 treatment cycles of Gazyvaro in combination with another medicine for cancer called chlorambucil. Each cycle lasts 28 days. 47 • On Day 1 of your first cycle, you will be given part of your first Gazyvaro dose of 100 milligrams (mg) very slowly. Your doctor/nurse will monitor you carefully for infusion related reactions. • If you do not have an infusion related reaction following the small part of your first dose, you may be given the rest of your first dose (900 mg) on the same day. • If you do have an infusion related reaction following the small part of your first dose, you will be given the rest of your first dose on Day 2. A typical schedule is shown below. Cycle 1 - this will include three doses of Gazyvaro in the 28 days: • Day 1 – part of your first dose (100 mg) • Day 2 or Day 1 (continued) – remainder of first dose 900 mg • Day 8 – full dose (1,000 mg) • Day 15 – full dose (1,000 mg) Cycles 2, 3, 4, 5 and 6 this will be just one dose of Gazyvaro in the 28 days: • Day 1 – full dose (1,000 mg). Follicular lymphoma • You will be given 6 or 8 treatment cycles of Gazyvaro in combination with other medicines for cancer - each cycle lasts 28 or 21 days depending on which other cancer medicines are given together with Gazyvaro. • This induction phase will be followed by a “maintenance phase” - during this time you will be given Gazyvaro every 2 months for up to 2 years as long as your disease does not progress. Based on your disease status after the initial treatment cycles your doctor will decide whether you will receive treatment in the maintenance phase. • A typical schedule is shown below. Induction phase Cycle 1 - this will include three doses of Gazyvaro in the 28 or 21 days depending on which other cancer medicines are given together with Gazyvaro: • Day 1 - full dose (1,000 mg) • Day 8 - full dose (1,000 mg) • Day 15 - full dose (1,000 mg). Cycles 2-6 or 2-8 - this will be just one dose of Gazyvaro in the 28 or 21 days depending on which other cancer medicines are given together with Gazyvaro: • Day 1 - full dose (1,000 mg). Maintenance phase • Full dose (1,000 mg) once every 2 months for up to 2 years as long as your disease does not progress. Medicines given before each infusion Before each infusion of Gazyvaro, you will be given medicines to lessen the chance of getting infusion related reactions or tumour lysis syndrome. These may include: • fluids • medicines to reduce a fever • medicines to reduce pain (analgesics) • medicines to reduce inflammation (corticosteroids) • medicines to reduce an allergic reaction (anti-histamines) 48 • medicine to prevent tumour lysis syndrome (such as allopurinol). If you miss a Gazyvaro treatment If you miss your appointment, make another one as soon as possible. This is because for this medicine to be as effective as possible, it is important to follow the dosing schedule. If you have any further questions on the use of this medicine, ask your doctor or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects have been reported with this medicine: Serious side effects Infusion related reactions Tell your doctor or nurse straight away if you get any of the following symptoms during your infusion or up to 24 hours after having your infusion: Most frequently reported: • nausea • fatigue • dizziness • headache • diarrhoea • fever, flushing or chills • vomiting • shortness of breath • low or high blood pressure • heart beating very fast • chest discomfort Less frequently reported: • irregular heartbeat • swelling of the throat or airway • wheezing, difficulty breathing, tight chest or throat irritation If you get any of the above, tell your doctor or nurse straight away. Progressive multifocal leukoencephalopathy PML is a very rare and life-threatening brain infection that has been reported with Gazyvaro. Tell your doctor or nurse straight away if you have • memory loss • trouble speaking • difficulty walking • problems with your eyesight If you had any of these symptoms before treatment with Gazyvaro, tell your doctor straight away if you notice any changes in them. You may need medical treatment. 49 Infections You may be more likely to get an infection during and after treatment with Gazyvaro. Often these are colds, but there have been cases of more severe infections. A type of liver disease called “hepatitis B” has also been reported to reoccur in patients who have had hepatitis B in the past. Tell your doctor or nurse straight away if you get any signs of infection during and after your Gazyvaro treatment. These include: • fever • cough • chest pain • fatigue • painful rash • sore throat • burning pain when passing urine • feeling weak or generally unwell If you had recurring or chronic infections before the start of Gazyvaro treatment, tell your doctor about it. Other side effects Tell your doctor or nurse if you notice any of the following side effects: Very common (may affect more than 1 in 10 people) • fever • lung infection • headache • joint pain, back pain • feeling weak • feeling tired • pain in arms and legs • diarrhoea, constipation • sleeplessness • hair loss, itchiness • urinary tract infection, nose and throat inflammation, shingles • changes in blood tests: - anaemia (low levels of red blood cells) - low levels of all types of white blood cell (combined) - low levels of neutrophils (a type of white blood cell) - low level of platelets (a type of blood cell that helps your blood to clot) • infection of upper airways (infection of nose, pharynx, larynx and sinuses), cough Common (may affect up to 1 in 10 people) • cold sores • depression, anxiety • flu (influenza) • weight increase • runny or blocked nose • eczema • pain in mouth or throat • muscle and bone pain in your chest • skin cancer (squamous cell carcinoma, basal cell carcinoma) • bone pain • irregular heart beat (atrial fibrillation) 50 • problems with urinating, urinary incontinence • high blood pressure • problems with digestion (e.g. heartburn), haemorrhoids • changes shown in blood tests: - low levels of lymphocytes (a type of white blood cells), fever associated with low levels of neutrophils (a type of white blood cells) - increase in potassium, phosphate or uric acid - which can cause kidney problems (part of tumour lysis syndrome) - decrease in potassium Uncommon (may affect up to 1 in 100 people) ● a hole in the stomach or intestines (gastrointestinal perforation, especially in cases where the cancer affects the gastrointestinal tubes) Tell your doctor or nurse if you notice any of the side effects listed above. Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Gazyvaro Gazyvaro will be stored by the healthcare professionals at the hospital or clinic. The storage details are as follows: • Keep this medicine out of the sight and reach of children. • Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month. • Store in a refrigerator (2 °C-8 °C). Do not freeze. • Keep the container in the outer carton in order to protect from light. Medicines should not be disposed of via wastewater or household waste. Your healthcare professional will throw away any medicines that are no longer being used. These measures will help protect the environment. 6. Contents of the pack and other information What Gazyvaro contains • The active substance is obinutuzumab: 1,000 mg/40 mL per vial corresponding to a concentration before dilution of 25 mg/mL. • The other ingredients are histidine, histidine hydrochloride monohydrate, trehalose dihydrate, poloxamer 188 and water for injections. What Gazyvaro looks like and contents of the pack Gazyvaro is a concentrate for solution for infusion and is a colourless to slightly brown liquid. Gazyvaro is available in a pack containing 1 glass vial. https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc 51 Marketing Authorisation Holder Roche Registration GmbH Emil-Barell-Strasse 1 79639 Grenzach-Wyhlen Germany Manufacturer Roche Pharma AG Emil-Barell-Strasse 1 D-79639 Grenzach-Wyhlen Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien N.V. Roche S.A. Tél/Tel: +32 (0) 2 525 82 11 Lietuva UAB “Roche Lietuva” Tel: +370 5 2546799 България Рош България ЕООД Тел: +359 2 818 44 44 Luxembourg/Luxemburg (Voir/siehe Belgique/Belgien) Česká republika Roche s. r. o. Tel: +420 - 2 20382111 Magyarország Roche (Magyarország) Kft. Tel: +36 - 23 446 800 Danmark Roche a/s Tlf: +45 - 36 39 99 99 Malta (See Ireland) Deutschland Roche Pharma AG Tel: +49 (0) 7624 140 Nederland Roche Nederland B.V. Tel: +31 (0) 348 438050 Eesti Roche Eesti OÜ Tel: + 372 - 6 177 380 Norge Roche Norge AS Tlf: +47 - 22 78 90 00 Ελλάδα Roche (Hellas) A.E. Τηλ: +30 210 61 66 100 Österreich Roche Austria GmbH Tel: +43 (0) 1 27739 España Roche Farma S.A. Tel: +34 - 91 324 81 00 Polska Roche Polska Sp.z o.o. Tel: +48 - 22 345 18 88 France Roche Tél: +33 (0)1 47 61 40 00 Portugal Roche Farmacêutica Química, Lda Tel: +351 - 21 425 70 00 Hrvatska Roche d.o.o. Tel: + 385 1 47 22 333 România Roche România S.R.L. Tel: +40 21 206 47 01 52 Ireland Roche Products (Ireland) Ltd. Tel: +353 (0) 1 469 0700 Slovenija Roche farmacevtska družba d.o.o. Tel: +386 - 1 360 26 00 Ísland Roche a/s c/o Icepharma hf Sími: +354 540 8000 Slovenská republika Roche Slovensko, s.r.o. Tel: +421 - 2 52638201 Italia Roche S.p.A. Tel: +39 - 039 2471 Suomi/Finland Roche Oy Puh/Tel: +358 (0) 10 554 500 Kύπρος Γ.Α.Σταμάτης & Σια Λτδ. Τηλ: +357 - 22 76 62 76 Sverige Roche AB Tel: +46 (0) 8 726 1200 Latvija Roche Latvija SIA Tel: +371 - 6 7039831 United Kingdom Roche Products Ltd. Tel: +44 (0) 1707 366000 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ 53 --------------------------------------------------------------------------------------------------------------------------- The following information is intended for healthcare professionals only: Posology Gazyvaro should be administered under the close supervision of an experienced physician and in an environment where full resuscitation facilities are immediately available. Prophylaxis and premedication for tumour lysis syndrome (TLS) Patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 109/L) and/or renal impairment (CrCl < 70 mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or suitable alternative such as a urate oxidase (e.g. rasburicase) starting 12-24 hours prior to start of Gazyvaro infusion as per standard practice. All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed. Prophylaxis and premedication for infusion related reactions (IRRs) Premedication to reduce the risk of IRRs is outlined in Table 1. Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below. Hypotension, as a symptom of IRRs, may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration. 54 Table 1 Premedication to be administered before Gazyvaro infusion to reduce the risk of IRRsin CLL and FL patients Day of treatment cycle Patients requiring premedication Premedication Administration Cycle 1: Day 1 for CLL and FL All patients Intravenous corticosteroid1,4 (mandatory for CLL, recommended for FL) Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusion Anti-histaminic medicine3 Cycle 1: Day 2 for CLL only All patients Intravenous corticosteroid1 (mandatory) Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusion Anti-histaminic medicine3 All subsequent infusions for CLL and FL Patients with no IRR during the previous infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusion Patients with an IRR (Grade 1 or 2) with the previous infusion Oral analgesic/anti-pyretic2 Anti-histaminic medicine3 Patients with a Grade 3 IRR with the previous infusion OR Patients with lymphocyte counts >25 x 109/L prior to next treatment Intravenous corticosteroid1,4 Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 Anti-histaminic medicine3 At least 30 minutes before Gazyvaro infusion 1100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone should not be used as it has not been effective in reducing rates of IRR. 2 e.g. 1,000 mg acetaminophen/paracetamol 3 e.g. 50 mg diphenhydramine 4.If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyvaro, the corticosteroid can be administered as an oral medicinal productif given at least 60 minutes prior to Gazyvaro, in which case additional IV corticosteroid as premedication is not required. Dose Chronic lymphocytic leukaemia (in combination with chlorambucil1) For patients with CLL the recommended dose of Gazyvaro in combination with chlorambucil is shown in Table 2. Cycle 1 The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered over Day 1 and Day 2 (or Day 1 continued), and on Day 8 and Day 15 of the first 28 day treatment cycle. Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 900 mg for Day 2). If the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the second bag must be administered the following day. 55 Cycles 2 – 6 The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered on Day 1 of each cycle. Table 2 Dose of Gazyvaro to be administered during 6 treatment cycles each of 28 days duration for patients with CLL Cycle Day of treatment Dose of Gazyvaro Cycle 1 Day 1 100 mg Day 2 (or Day 1 continued) 900 mg Day 8 1,000 mg Day 15 1,000 mg Cycles 2-6 Day 1 1,000 mg 1 Chlorambucil is given orally at 0.5 mg/kg body weight on Day 1 and Day 15 of all treatment cycles Duration of treatment Six treatment cycles, each of 28 day duration. Follicular lymphoma For patients with FL, the recommended dose of Gazyvaro in combination with chemotherapy is shown in Table 3. Patients with previously untreated follicular lymphoma Induction (in combination with chemotherapy2) Gazyvaro should be administered with chemotherapy as follows: • Six 28-day cycles in combination with bendamustine2 or • Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyvaro alone or • Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone (CVP). Maintenance Patients who achieve a complete or partial response to induction treatment with Gazyvaro in combination with chemotherapy should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first). Patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen Induction (in combination with bendamustine2) Gazyvaro should be administered in six 28-day cycles in combination with bendamustine2. 56 Maintenance Patients who achieved a complete or partial response to induction treatment (i.e. the initial 6 treatment cycles) with Gazyvaro in combination with bendamustine or have stable disease should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first). Table 3 Follicular lymphoma: Dose of Gazyvaro to be administered during induction treatment, followed by maintenance treatment Cycle Day of treatment Dose of Gazyvaro Cycle 1 Day 1 1,000 mg Day 8 1,000 mg Day 15 1,000 mg Cycles 2–6 or 2-8 Day 1 1,000 mg Maintenance Every 2 months for 2 years or until disease progression (whichever occurs first) 1,000 mg 2 Bendamustine is given intravenously on Days 1 and 2 of all treatment cycles (Cycles 1-6) at 90 mg/m2/day; CHOP and CVP according to standard regimens Duration of treatment Induction treatment of approximately six months (six treatment cycles of Gazyvaro, each of 28 day duration when combined with bendamustine, or eight treatment cycles of Gazyvaro, each of 21 day duration when combined with CHOP or CVP) followed by maintenance once every 2 months for 2 years or until disease progression (whichever occurs first). Method of administration Gazyvaro is for intravenous use. It should be given as an intravenous infusion through a dedicated line after dilution. Gazyvaro infusions should not be administered as an intravenous push or bolus. For instructions on dilution of Gazyvaro before administration, see below. Instructions on the rate of infusion are shown in Tables 4 and 5. 57 Chronic Lymphocytic Leukaemia Table 4 Chronic lymphocytic leukaemia: Standard infusion rate in the absence of IRRs/hypersensitivity and recommendations in case an IRR occurred with previous infusion Cycle Day of treatment Rate of infusion The infusion rate may be escalated provided that the patient can tolerate it. For management IRRs that occur during the infusion, refer to “Management of IRRs”. Cycle 1 Day 1 (100 mg) Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate. Day 2 (or Day 1 continued) (900 mg) If no IRR occurred during the previous infusion, administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. If the patient experienced an IRR during the previous infusion, start with administration at 25 mg/hr. The rate of infusion can be escalated in increments up to 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. Day 8 (1,000 mg) If no IRR occurred during the previous infusion when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If the patient experienced an IRR during the previous infusion administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50mg/hr every 30 minutes to a maximum rate of 400 mg/hr. Day 15 (1,000 mg) Cycles 2-6 Day 1 (1,000 mg) 58 Follicular lymphoma (FL) Table 5 Follicular lymphoma: Standard infusion rate in the absence of IRR/hypersensitivity and recommendations in case an IRR occurred with previous infusion Cycle Day of treatment Rate of infusion The infusion rate may be escalated provided that the patient can tolerate it. For management of IRRs that occur during the infusion, refer to “Management of IRRs”. Cycle 1 Day 1 (1,000 mg) Administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Day 8 (1,000 mg) If no IRR or if an IRR Grade 1 occurred during the previous infusion when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If the patient experienced an IRR of Grade 2 or higher during the previous infusion administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Day 15 (1,000 mg) Cycles 2–6 or 2–8 Day 1 (1,000 mg) Maintenance Every 2 months for 2 years or until disease progression (whichever occurs first) Management of IRRs (all indications) Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Gazyvaro as outlined below. • Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued. • Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 and 5). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further. The infusion must be stopped and therapy permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR. 59 • Grade 1-2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 and 5). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further. Instructions for dilution Gazyvaro should be prepared by a healthcare professional using aseptic technique. Do not shake the vial. Use a sterile needle and syringe to prepare Gazyvaro. For CLL cycles 2 – 6 and all FL cycles Withdraw 40 mL of concentrate from the vial and dilute in polyvinyl chloride (PVC) or non-PVC polyolefin infusion bags containing sodium chloride 9 mg/mL (0.9%) solution for injection. CLL only – Cycle 1 To ensure differentiation of the two infusion bags for the initial 1,000 mg dose, it is recommended to utilise bags of different sizes to distinguish between the 100 mg dose for Cycle 1 Day 1 and the 900 mg dose for Cycle 1 Day 1 (continued) or Day 2. To prepare the 2 infusion bags, withdraw 40 mL of concentrate from the vial and dilute 4 mL into a 100 mL PVC or non-PVC polyolefin infusion bag and the remaining 36 mL in a 250 mL PVC or non-PVC polyolefin infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection. Clearly label each infusion bag. Dose of Gazyvaro to be administered Required amount of Gazyvaro concentrate Size of PVC or non-PVC polyolefin infusion bag 100 mg 4 mL 100 mL 900 mg 36 mL 250 mL 1,000 mg 40 mL 250 mL No incompatibilities have been observed between Gazyvaro, in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of Gazyvaro with sodium chloride 9 mg/mL (0.9%) solution for injection, and: • PVC, polyethylene (PE), polypropylene or polyolefin bags • PVC, polyurethane (PUR) or PE infusion sets • optional inline filters with product contact surfaces of polyethersulfone (PES), a 3-way stopcock infusion aid made from polycarbonate (PC), and catheters made from polyetherurethane (PEU). Do not use other diluents such as glucose (5%) solution. The bag should be gently inverted to mix the solution in order to avoid excessive foaming. The diluted solution should not be shaken or frozen. Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration. After dilution, chemical and physical stability have been demonstrated in sodium chloride 9 mg/mL (0.9%) solution for injection at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C followed by 48 hours (including infusion time) at ≤ 30°C. From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated aseptic conditions. 60 Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what gazyvaro is and what it is used for', 'Section_Content': 'what gazyvaro is gazyvaro contains the active substance obinutuzumab, which belongs to a group of medicines called "monoclonal antibodies". antibodies work by attaching themselves to specific targets in your body. what gazyvaro is used for gazyvaro can be used in adults to treat two different types of cancer chronic lymphocytic leukaemia (also called "cll") - gazyvaro is used in patients who have not had any treatment for cll before and who have other illnesses which make it unlikely that they would be able to tolerate a full dose of a different medicine used to treat cll called fludarabine. - gazyvaro is used together with another medicine for cancer called chlorambucil. follicular lymphoma (also called "fl") - gazyvaro is used in patients who have not had any treatment for fl - gazyvaro is used in patients who have had at least one treatment with a medicine called rituximab before and whose fl has come back or got worse during or after this treatment. - at the start of treatment for fl, gazyvaro is used together with other medicines for cancer. - gazyvaro can then be used on its own for up to 2 years as a "maintenance treatment". how gazyvaro works cll and fl are types of cancer that affect white blood cells called "b-lymphocytes". the affected "b-lymphocytes" multiply too quickly and live too long. gazyvaro binds to targets on the surface of the affected "b-lymphocyte" cells and causes them to die. when gazyvaro is given to patients with cll or fl together with other medicines for cancer - this slows down the time it takes for their disease to get worse.', 'Entity_Recognition': [{'Text': 'gazyvaro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 13, 'Score': 0.8366816639900208, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 17, 'EndOffset': 25, 'Score': 0.863460898399353, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 56, 'EndOffset': 68, 'Score': 0.9944045543670654, 'Text': 'obinutuzumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5708677172660828}]}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 98, 'EndOffset': 107}, {'Id': 3, 'BeginOffset': 219, 'EndOffset': 227, 'Score': 0.7135759592056274, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 240, 'EndOffset': 248, 'Score': 0.984473705291748, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'cancer chronic lymphocytic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 303, 'EndOffset': 339}, {'Id': 18, 'BeginOffset': 354, 'EndOffset': 357, 'Score': 0.9851505160331726, 'Text': 'cll', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9535477161407471}]}, {'Id': 31, 'BeginOffset': 362, 'EndOffset': 370, 'Score': 0.33080780506134033, 'Text': 'gazyvaro', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'NAME', 'Traits': []}, {'Id': 19, 'BeginOffset': 426, 'EndOffset': 429, 'Score': 0.9837884902954102, 'Text': 'cll', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9455022215843201}]}, {'Text': 'other illnesses', 'Type': 'PROBLEM', 'BeginOffset': 450, 'EndOffset': 465}, {'Text': 'a different medicine', 'Type': 'TREATMENT', 'BeginOffset': 540, 'EndOffset': 560}, {'Id': 21, 'BeginOffset': 575, 'EndOffset': 578, 'Score': 0.9638224840164185, 'Text': 'cll', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.967474639415741}]}, {'Id': 6, 'BeginOffset': 586, 'EndOffset': 597, 'Score': 0.9883205890655518, 'Text': 'fludarabine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 32, 'BeginOffset': 601, 'EndOffset': 609, 'Score': 0.1939057558774948, 'Text': 'gazyvaro', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'NAME', 'Traits': []}, {'Id': 22, 'BeginOffset': 653, 'EndOffset': 659, 'Score': 0.9434288740158081, 'Text': 'cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9658709168434143}]}, {'Id': 8, 'BeginOffset': 667, 'EndOffset': 679, 'Score': 0.9379633665084839, 'Text': 'chlorambucil', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 23, 'BeginOffset': 681, 'EndOffset': 700, 'Score': 0.9309547543525696, 'Text': 'follicular lymphoma', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9685714840888977}]}, {'Id': 33, 'BeginOffset': 722, 'EndOffset': 730, 'Score': 0.8828075528144836, 'Text': 'gazyvaro', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'NAME', 'Traits': []}, {'Text': 'fl - 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{'Title': '2. what you need to know before you are given gazyvaro', 'Section_Content': 'you must not be given gazyvaro if: you are allergic to obinutuzumab or any of the other ingredients of this medicine (listed in section 6). if you are not sure talk to your doctor or nurse before being given gazyvaro. warnings and precautions talk to your doctor or nurse before you are given gazyvaro if: you have an infection, or have had an infection in the past which lasted a long time or keeps coming back you have ever taken, or been given, medicines which affect your immune system (such as chemotherapy or immunosuppressants) you are taking medicines for high blood pressure or medicines used to thin your blood your doctor might need to alter how you take these you have ever had heart problems you have ever had brain problems (such as memory problems, difficulty moving or feeling sensations in your body, eyesight problems) you have ever had breathing problems or lung problems you have ever had "hepatitis b" - a type of liver disease you are due to have a vaccine or you know you may need to have one in the near future. if any of the above apply to you (or you are not sure), talk to your doctor or nurse before you are given gazyvaro. pay attention to the following side effects gazyvaro can cause some serious side effects that you need to tell your doctor or nurse about straight away. these include: infusion related reactions tell your doctor or nurse straight away if you get any of the infusion related reactions listed at the start of section 4. infusion related reactions can happen during the infusion or up to 24 hours after the infusion. if you get an infusion related reaction, you may require additional treatment, or the infusion may need to be slowed down or stopped. when these symptoms go away, or improve, the infusion can be continued. these reactions are more likely to happen with the first infusion. your doctor may decide to stop treatment with gazyvaro if you have a severe infusion related reaction. before each infusion of gazyvaro, you will be given medicines which help to reduce possible infusion related reactions or "tumour lysis syndrome". tumour lysis syndrome is a potentially life-threatening complication, caused by chemical changes in the blood due to the breakdown of dying cancer cells (see section 3). progressive multifocal leukoencephalopathy (also called "pml") pml is a very rare and life-threatening brain infection that has been reported in very few patients having treatment with gazyvaro. tell your doctor or nurse straight away if you have memory loss, trouble speaking, difficulty walking or problems with your eyesight. if you had any of these symptoms before treatment with gazyvaro, tell your doctor straight away if you notice any changes in them. you may need medical treatment. infections tell your doctor or nurse straight away if you get any signs of infection after your gazyvaro treatment (see "infections" in section 4). children and adolescents do not give gazyvaro to children or young people under 18 years of age. this is because there is no information about its use in these age groups. other medicines and gazyvaro tell your doctor or nurse if you are taking, have recently taken or might start taking any other medicines. this includes medicines obtained without a prescription and herbal medicines. pregnancy tell your doctor or nurse if you are pregnant, think you might be pregnant or are planning to have a baby. they will help you weigh up the benefit of continuing gazyvaro against the risk to your baby. if you become pregnant during treatment with gazyvaro, tell your doctor or nurse as soon as possible. this is because treatment with gazyvaro may affect yours or the baby\'s health. breast-feeding do not breast-feed during treatment with gazyvaro or for 18 months after stopping treatment with gazyvaro. this is because small amounts of the medicine may pass into your breast milk. contraception use an effective method of contraception while being treated with gazyvaro. continue to use effective contraception for 18 months after stopping treatment with gazyvaro. driving and using machines gazyvaro is not likely to affect your ability to drive, cycle or use any tools or machines. however, if you get an infusion related reaction, (see section 4), do not drive, cycle or use any tools or machines until the reaction stops.', 'Entity_Recognition': [{'Text': 'gazyvaro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 5, 'BeginOffset': 22, 'EndOffset': 30, 'Score': 0.9888455271720886, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.4193369150161743}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 43, 'EndOffset': 51}, {'Id': 6, 'BeginOffset': 55, 'EndOffset': 67, 'Score': 0.9928702712059021, 'Text': 'obinutuzumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this 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{'Title': '3. how gazyvaro is given', 'Section_Content': 'how gazyvaro is given gazyvaro is given under the supervision of a doctor experienced in such treatment. it is given into a vein as a drip (intravenous infusion) over several hours. the gazyvaro treatment chronic lymphocytic leukaemia you will be given 6 treatment cycles of gazyvaro in combination with another medicine for cancer called chlorambucil. each cycle lasts 28 days. on day 1 of your first cycle, you will be given part of your first gazyvaro dose of 100 milligrams (mg) very slowly. your doctor/nurse will monitor you carefully for infusion related reactions. if you do not have an infusion related reaction following the small part of your first dose, you may be given the rest of your first dose (900 mg) on the same day. if you do have an infusion related reaction following the small part of your first dose, you will be given the rest of your first dose on day 2. a typical schedule is shown below. cycle 1 - this will include three doses of gazyvaro in the 28 days: day 1 part of your first dose (100 mg) day 2 or day 1 (continued) remainder of first dose 900 mg day 8 full dose (1,000 mg) day 15 full dose (1,000 mg) cycles 2, 3, 4, 5 and 6 this will be just one dose of gazyvaro in the 28 days: day 1 full dose (1,000 mg). follicular lymphoma you will be given 6 or 8 treatment cycles of gazyvaro in combination with other medicines for cancer - each cycle lasts 28 or 21 days depending on which other cancer medicines are given together with gazyvaro. this induction phase will be followed by a "maintenance phase" - during this time you will be given gazyvaro every 2 months for up to 2 years as long as your disease does not progress. based on your disease status after the initial treatment cycles your doctor will decide whether you will receive treatment in the maintenance phase. a typical schedule is shown below. induction phase cycle 1 - this will include three doses of gazyvaro in the 28 or 21 days depending on which other cancer medicines are given together with gazyvaro: day 1 - full dose (1,000 mg) day 8 - full dose (1,000 mg) day 15 - full dose (1,000 mg). cycles 2-6 or 2-8 - this will be just one dose of gazyvaro in the 28 or 21 days depending on which other cancer medicines are given together with gazyvaro: day 1 - full dose (1,000 mg). maintenance phase full dose (1,000 mg) once every 2 months for up to 2 years as long as your disease does not progress. medicines given before each infusion before each infusion of gazyvaro, you will be given medicines to lessen the chance of getting infusion related reactions or tumour lysis syndrome. these may include: fluids medicines to reduce a fever medicines to reduce pain (analgesics) medicines to reduce inflammation (corticosteroids) medicines to reduce an allergic reaction (anti-histamines) 48 medicine to prevent tumour lysis syndrome (such as allopurinol). if you miss a gazyvaro treatment if you miss your appointment, make another 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the following side effects have been reported with this medicine: serious side effects infusion related reactions tell your doctor or nurse straight away if you get any of the following symptoms during your infusion or up to 24 hours after having your infusion: most frequently reported: nausea fatigue dizziness headache diarrhoea fever, flushing or chills vomiting shortness of breath low or high blood pressure heart beating very fast chest discomfort less frequently reported: irregular heartbeat swelling of the throat or airway wheezing, difficulty breathing, tight chest or throat irritation if you get any of the above, tell your doctor or nurse straight away. progressive multifocal leukoencephalopathy pml is a very rare and life-threatening brain infection that has been reported with gazyvaro. tell your doctor or nurse straight away if you have memory loss trouble speaking difficulty walking problems with your eyesight if you had any of these symptoms before treatment with gazyvaro, tell your doctor straight away if you notice any changes in them. you may need medical treatment. infections you may be more likely to get an infection during and after treatment with gazyvaro. often these are colds, but there have been cases of more severe infections. a type of liver disease called "hepatitis b" has also been reported to reoccur in patients who have had hepatitis b in the past. tell your doctor or nurse straight away if you get any signs of infection during and after your gazyvaro treatment. these include: fever cough chest pain fatigue painful rash sore throat burning pain when passing urine feeling weak or generally unwell if you had recurring or chronic infections before the start of gazyvaro treatment, tell your doctor about it. other side effects tell your doctor or nurse if you notice any of the following side effects: very common (may affect more than 1 in 10 people) fever lung infection headache joint pain, back pain feeling weak feeling tired pain in arms and legs diarrhoea, constipation sleeplessness hair loss, itchiness urinary tract infection, nose and throat inflammation, shingles changes in blood tests: - anaemia (low levels of red blood cells) - low levels of all types of white blood cell (combined) - low levels of neutrophils (a type of white blood cell) - low level of platelets (a type of blood cell that helps your blood to clot) infection of upper airways (infection of nose, pharynx, larynx and sinuses), cough common (may affect up to 1 in 10 people) cold sores depression, anxiety flu (influenza) weight increase runny or blocked nose eczema pain in mouth or throat muscle and bone pain in your chest skin cancer (squamous cell carcinoma, basal cell carcinoma) bone pain irregular heart beat (atrial fibrillation) 50 problems with urinating, urinary incontinence high blood pressure problems with digestion (e.g. heartburn), haemorrhoids changes shown in blood tests: - low levels of lymphocytes (a type of white blood cells), fever associated with low levels of neutrophils (a type of white blood cells) - increase in potassium, phosphate or uric acid - which can cause kidney problems (part of tumour lysis syndrome) - decrease in potassium uncommon (may affect up to 1 in 100 people) a hole in the stomach or intestines (gastrointestinal perforation, especially in cases where the cancer affects the gastrointestinal tubes) tell your doctor or nurse if you notice any of the side effects listed above. reporting of side effects if you get any side effects, talk to your doctor or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': 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'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.6818856000900269, 'RelationshipScore': 0.9999988079071045, 'RelationshipType': 'TEST_VALUE', 'Id': 171, 'BeginOffset': 3159, 'EndOffset': 3167, 'Text': 'increase', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 173, 'BeginOffset': 3182, 'EndOffset': 3191, 'Score': 0.5573211908340454, 'Text': 'phosphate', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.6818856000900269, 'RelationshipScore': 0.9990094900131226, 'RelationshipType': 'TEST_VALUE', 'Id': 171, 'BeginOffset': 3159, 'EndOffset': 3167, 'Text': 'increase', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 174, 'BeginOffset': 3195, 'EndOffset': 3204, 'Score': 0.45358750224113464, 'Text': 'uric acid', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.6818856000900269, 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{'Title': '5. how to store gazyvaro', 'Section_Content': 'gazyvaro will be stored by the healthcare professionals at the hospital or clinic. the storage details are as follows: keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 -8 ). do not freeze. keep the container in the outer carton in order to protect from light. medicines should not be disposed of via wastewater or household waste. your healthcare professional will throw away any medicines that are no longer being used. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'gazyvaro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 0, 'EndOffset': 8, 'Score': 0.3590685725212097, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 189, 'EndOffset': 202}, {'Text': '-8', 'Type': 'NUMBER', 'BeginOffset': 347, 'EndOffset': 349}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 390, 'EndOffset': 406}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 439, 'EndOffset': 448}, {'Text': 'any medicines', 'Type': 'TREATMENT', 'BeginOffset': 555, 'EndOffset': 568}]}

{'Title': '6. content of the pack and other information', 'Section_Content': 'what gazyvaro contains the active substance is obinutuzumab: 1,000 mg/40 ml per vial corresponding to a concentration before dilution of 25 mg/ml. the other ingredients are histidine, histidine hydrochloride monohydrate, trehalose dihydrate, poloxamer 188 and water for injections. what gazyvaro looks like and contents of the pack gazyvaro is a concentrate for solution for infusion and is a colourless to slightly brown liquid. gazyvaro is available in a pack containing 1 glass vial.', 'Entity_Recognition': [{'Text': 'gazyvaro', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 13, 'Score': 0.6227300763130188, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 47, 'EndOffset': 59, 'Score': 0.9930883049964905, 'Text': 'obinutuzumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.6354219317436218, 'RelationshipScore': 0.9999841451644897, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 61, 'EndOffset': 69, 'Text': '1,000 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8544449210166931, 'RelationshipScore': 0.9999940395355225, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 70, 'EndOffset': 75, 'Text': '40 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'STRENGTH', 'Score': 0.48379847407341003, 'RelationshipScore': 0.9980206489562988, 'RelationshipType': 'STRENGTH', 'Id': 4, 'BeginOffset': 137, 'EndOffset': 145, 'Text': '25 mg/ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 61, 'EndOffset': 66}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 137, 'EndOffset': 139}, {'Id': 5, 'BeginOffset': 173, 'EndOffset': 182, 'Score': 0.9043720364570618, 'Text': 'histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 184, 'EndOffset': 219, 'Score': 0.9854885935783386, 'Text': 'histidine hydrochloride monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5020003914833069}]}, {'Id': 7, 'BeginOffset': 221, 'EndOffset': 240, 'Score': 0.9651886224746704, 'Text': 'trehalose dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.44187596440315247}], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5098876357078552, 'RelationshipScore': 0.7398839592933655, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 9, 'BeginOffset': 270, 'EndOffset': 280, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 8, 'BeginOffset': 242, 'EndOffset': 251, 'Score': 0.7918940186500549, 'Text': 'poloxamer', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.4508414566516876}], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5098876357078552, 'RelationshipScore': 0.9995893836021423, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 9, 'BeginOffset': 270, 'EndOffset': 280, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '188', 'Type': 'NUMBER', 'BeginOffset': 252, 'EndOffset': 255}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 270, 'EndOffset': 280}, {'Id': 10, 'BeginOffset': 287, 'EndOffset': 295, 'Score': 0.7561898231506348, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'the pack gazyvaro', 'Type': 'TREATMENT', 'BeginOffset': 323, 'EndOffset': 340}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 375, 'EndOffset': 383}, {'Text': 'a colourless to slightly brown liquid', 'Type': 'PROBLEM', 'BeginOffset': 391, 'EndOffset': 428}, {'Id': 12, 'BeginOffset': 430, 'EndOffset': 438, 'Score': 0.7948921322822571, 'Text': 'gazyvaro', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 473, 'EndOffset': 474}]}

08B331006615DBC9DCA92C36C72E1C49

https://www.ema.europa.eu/documents/product-information/bemfola-epar-product-information_en.pdf

Bemfola

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Bemfola 75 IU/0.125 mL solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of the solution contains 600 IU (equivalent to 44 micrograms) of follitropin alfa*. Each pre- filled pen delivers 75 IU (equivalent to 5.5 micrograms) in 0.125 mL. * recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection). Clear colourless solution. The pH of the solution is 6.7 - 7.3. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications In adult women • Anovulation (including polycystic ovarian syndrome, PCOS) in women who have been unresponsive to treatment with clomiphene citrate. • Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT). • Follitropin alfa in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/L. In adult men • Follitropin alfa is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hCG) therapy. 4.2 Posology and method of administration Treatment should be initiated under the supervision of a physician experienced in the treatment of fertility disorders. Patients must be provided with the correct number of pens for their treatment course and educated to use the proper injection techniques. Posology 3 The dose recommendations given for follitropin alfa are those in use for urinary FSH. Clinical assessment of follitropin alfa indicates that its daily doses, regimens of administration and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below. Comparative clinical trials have shown that on average patients require a lower cumulative dose and shorter treatment duration with follitropin alfa compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of follitropin alfa than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation (see section 5.1). Women with anovulation (including polycystic ovarian syndrome) Follitropin alfa may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle. A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and/or estrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle. When an optimal response is obtained, a single injection of 250 micrograms of recombinant human chorionic gonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa injection. The patient is recommended to have coitus on the day of, and the day following hCG administration. Alternatively intrauterine insemination (IUI) may be performed. If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle. Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies A commonly used regimen for superovulation involves the administration of 150-225 IU of follitropin alfa daily commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum estrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days). A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last follitropin alfa injection to induce final follicular maturation. Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, follitropin alfa is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU follitropin alfa are administered for the first 7 days. The dose is then adjusted according to the ovarian response. Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter. Women with anovulation resulting from severe LH and FSH deficiency In LH and FSH deficient women (hypogonadotropic hypogonadism), the objective of follitropin alfa therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the 4 oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). Follitropin alfa should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous estrogen secretion, treatment can commence at any time. A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and estrogen response. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks. When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following hCG administration. Alternatively, IUI may be performed. Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum. If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle. Men with hypogonadotropic hypogonadism Follitropin alfa should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. Special populations Elderly population There is no relevant use of follitropin alfa in the elderly population. The safety and efficacy of follitropin alfa in elderly patients have not been established. Renal or hepatic impairment The safety, efficacy and pharmacokinetics of follitropin alfa in patients with renal or hepatic impairment have not been established. Paediatric population There is no relevant use of follitropin alfa in the paediatric population. Method of administration Bemfola is intended for subcutaneous use. The first injection of Bemfola should be performed under direct medical supervision. Self-administration of Bemfola should only be performed by patients who are well motivated, adequately trained and have access to expert advice. As the Bemfola pre-filled pen with the single-dose cartridge is intended for only one injection, clear instructions should be provided to the patients to avoid misuse of the single dose presentation. For instructions on the administration with the pre-filled pen, see section 6.6 and the package leaflet. 4.3 Contraindications 5 • hypersensitivity to the active substance or to any of the excipients listed in section 6.1; • tumours of the hypothalamus or pituitary gland; • ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome; • gynaecological haemorrhages of unknown aetiology; • ovarian, uterine or mammary carcinoma. Follitropin alfa must not be used when an effective response cannot be obtained, such as in cases of: • primary ovarian failure; • malformations of sexual organs incompatible with pregnancy; • fibroid tumours of the uterus incompatible with pregnancy; • primary testicular insufficiency. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of the ovarian response with ultrasound, alone or preferably in combination with measurement of serum estradiol levels, on a regular basis. There may be a degree of inter-patient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women. Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be thoroughly investigated and putative contraindications for pregnancy must be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and should be treated accordingly. Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests. In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments. No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) 6 A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment. In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities. The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction. Independent risk factors for developing OHSS include polycystic ovarian syndrome, high absolute or rapidly rising serum estradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or > 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of ≥ 14 mm in diameter in anovulation; ≥ 20 follicles of ≥ 12 mm in diameter in ART). Adherence to the recommended follitropin alfa dose and to the regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as estradiol measurements are recommended to early identify risk factors. There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as a serum estradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or ≥ 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Therefore patients should be followed for at least two weeks after hCG administration. In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy In patients undergoing ovulation induction, the incidence of a multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes. To minimise the risk of a multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of a multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. Pregnancy loss 7 The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception. Ectopic pregnancy Women with a history of tubal disease are at risk of ectopic pregnancy, regardless of whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART was reported to be higher than in the general population. Reproductive system neoplasms There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. Congenital malformation The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies. Thromboembolic events In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events. Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of follitropin alfa with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of follitropin alfa needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during follitropin alfa therapy. 4.6 Fertility, pregnancy and lactation Pregnancy There is no indication for use of follitropin alfa during pregnancy. Data on a limited number of exposed pregnant women (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of follitropin alfa. No teratogenic effect has been observed in animal studies (see section 5.3). In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of follitropin alfa. Breast-feeding 8 Follitropin alfa is not indicated during breast-feeding. Fertility Follitropin alfa is indicated for use in infertility (see section 4.1). 4.7 Effects on ability to drive and use machines Follitropin alfa is expected to have no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection). Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4). Thromboembolism may occur very rarely (see section 4.4). List of adverse reactions The adverse reactions are ranked under heading of frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Treatment in women Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Nervous system disorders Very common: Headache Vascular disorders Very rare: Thromboembolism (both in association with and separate from OHSS) Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Gastrointestinal disorders Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea Reproductive system and breast disorders Very common: Ovarian cysts Common: Mild or moderate OHSS (including associated symptomatology) 9 Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4) Rare: Complication of severe OHSS General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Treatment in men Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Skin and subcutaneous tissue disorders Common: Acne Reproductive system and breast disorders Common: Gynaecomastia, Varicocele General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Investigations Common: Weight gain Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The effects of an overdose of follitropin alfa are unknown, nevertheless, there is a possibility that OHSS may occur (see section 4.4). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 10 Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG. Clinical efficacy and safety in women In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation. In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) follitropin alfa (n = 130) urinary FSH (n = 116) Number of oocytes retrieved 11.0 ± 5.9 8.8 ± 4.8 Days of FSH stimulation required 11.7 ± 1.9 14.5 ± 3.3 Total dose of FSH required (number of FSH 75 IU ampoules) 27.6 ± 10.2 40.7 ± 13.6 Need to increase the dose (%) 56.2 85.3 Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men In men deficient in FSH, follitropin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis. 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine. Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity in addition to those already stated in the other sections of this SmPC. Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (≥ 40 IU/kg/day) for extended periods, through reduced fecundity. http://www.ema.europa.eu/� 11 Given in high doses (≥ 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being teratogenic, and dystocia similar to that observed with urinary menopausal gonadotropin (hMG). However, since follitropin alfa is not indicated in pregnancy, these data are of limited clinical relevance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Poloxamer 188 Sucrose Methionine Disodium phosphate dihydrate Sodium dihydrogen phosphate dihydrate Phosphoric acid Water for injections 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years Once opened, the medicinal product should be injected immediately. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Before opening and within its shelf life, the medicinal product may be removed from the refrigerator, and without being refrigerated again, may be stored for up to 3 months at or below 25°C. The medicinal product must be discarded if it has not been used after 3 months. Store in the original package in order to protect from light. 6.5 Nature and contents of container 1.5 mL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a rubber inlay, assembled in a pre-filled pen. Each cartridge contains 0.125 mL solution for injection Pack sizes of 1, 5 and 10 pre-filled pens including one disposable needle and alcohol swab per pen. One needle and one alcohol swab to be used with the pen for administration. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The solution should not be administered if it contains particles or is not clear. Bemfola 75 IU/0.125 mL (5.5 micrograms/0.125 mL) is not designed to allow the cartridge to be removed. Discard used pen and needle immediately after injection. 12 Any unused medicinal product or waste material should be disposed of in accordance with local requirements. For instructions on the administration with the pre-filled pen, see the package leaflet. 7. MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 8. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/001 EU/1/13/909/006 EU/1/13/909/007 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 27/03/2014 Date of latest renewal: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/� 13 1. NAME OF THE MEDICINAL PRODUCT Bemfola 150 IU/0.25 mL solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of the solution contains 600 IU (equivalent to 44 micrograms) of follitropin alfa*. Each pre- filled pen delivers 150 IU (equivalent to 11 micrograms) in 0.25 mL. * recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection). Clear colourless solution. The pH of the solution is 6.7 - 7.3. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications In adult women • Anovulation (including polycystic ovariansyndrome, PCOS) in women who have been unresponsive to treatment with clomiphene citrate. • Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT). • Follitropin alfa in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/L. In adult men • Follitropin alfa is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hCG) therapy. 4.2 Posology and method of administration Treatment should be initiated under the supervision of a physician experienced in the treatment of fertility disorders. Patients must be provided with the correct number of pens for their treatment course and educated to use the proper injection techniques. Posology 14 The dose recommendations given for follitropin alfa are those in use for urinary FSH. Clinical assessment of follitropin alfa indicates that its daily doses, regimens of administration and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below. Comparative clinical trials have shown that on average patients require a lower cumulative dose and shorter treatment duration with follitropin alfa compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of follitropin alfa than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation (see section 5.1). Women with anovulation (including polycystic ovarian syndrome) Follitropin alfa may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle. A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and/or estrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle. When an optimal response is obtained, a single injection of 250 micrograms of recombinant human chorionic gonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed. If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle. Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies A commonly used regimen for superovulation involves the administration of 150-225 IU of follitropin alfa daily commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum estrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days). A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last follitropin alfa injection to induce final follicular maturation. Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, follitropin alfa is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU follitropin alfa are administered for the first 7 days. The dose is then adjusted according to the ovarian response. Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter. Women with anovulation resulting from severe LH and FSH deficiency In LH and FSH deficient women (hypogonadotropic hypogonadism), the objective of follitropin alfa therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the 15 oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). Follitropin alfa should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous estrogen secretion, treatment can commence at any time. A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and estrogen response. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks. When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration. Alternatively, IUI may be performed. Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum. If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle. Men with hypogonadotropic hypogonadism Follitropin alfa should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. Special populations Elderly population There is no relevant use of follitropin alfa in the elderly population. The safety and efficacy of follitropin alfa in elderly patients have not been established. Renal or hepatic impairment The safety, efficacy and pharmacokinetics of follitropin alfa in patients with renal or hepatic impairment have not been established. Paediatric population There is no relevant use of follitropin alfa in the paediatric population. Method of administration Bemfola is intended for subcutaneous use. The first injection of Bemfola should be performed under direct medical supervision. Self-administration of Bemfola should only be performed by patients who are well motivated, adequately trained and have access to expert advice. As the Bemfola pre-filled pen with the single-dose cartridge is intended for only one injection, clear instructions should be provided to the patients to avoid misuse of the single dose presentation. For instructions on the administration with the pre-filled pen, see section 6.6 and the package leaflet. 4.3 Contraindications 16 • hypersensitivity to the active substance or to any of the excipients listed in section 6.1; • tumours of the hypothalamus or pituitary gland; • ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome; • gynaecological haemorrhages of unknown aetiology; • ovarian, uterine or mammary carcinoma. Follitropin alfa must not be used when an effective response cannot be obtained, such as in case of: • primary ovarian failure; • malformations of sexual organs incompatible with pregnancy; • fibroid tumours of the uterus incompatible with pregnancy; • primary testicular insufficiency. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of the ovarian response with ultrasound, alone or preferably in combination with measurement of serum estradiol levels, on a regular basis. There may be a degree of inter-patient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women. Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be thoroughly investigated and putative contraindications for pregnancy must be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and should be treated accordingly. Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests. In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments. No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) 17 A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment. In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities. The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction. Independent risk factors for developing OHSS include polycystic ovarian syndrome, high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or > 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of ≥ 14 mm in diameter in anovulation; ≥ 20 follicles of ≥ 12 mm in diameter in ART). Adherence to the recommended follitropin alfa dose and to the regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as estradiol measurements are recommended to early identify risk factors. There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as a serum estradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or ≥ 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Therefore patients should be followed for at least two weeks after hCG administration. In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy In patients undergoing ovulation induction, the incidence of a multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes. To minimise the risk of a multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. Pregnancy loss 18 The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception. Ectopic pregnancy Women with a history of tubal disease are at risk of ectopic pregnancy, regardless of whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART was reported to be higher than in the general population. Reproductive system neoplasms There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. Congenital malformation The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies. Thromboembolic events In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events. Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of follitropin alfa with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of follitropin alfa needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during follitropin alfa therapy. 4.6 Fertility, pregnancy and lactation Pregnancy There is no indication for use of follitropin alfa during pregnancy. Data on a limited number of exposed pregnant women (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of follitropin alfa. No teratogenic effect has been observed in animal studies (see section 5.3). In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of follitropin alfa. Breast-feeding 19 Follitropin alfa is not indicated during breastfeeding. Fertility Follitropin alfa is indicated for use in infertility (see section 4.1). 4.7 Effects on ability to drive and use machines Follitropin alfa is expected to have no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection). Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4). Thromboembolism may occur very rarely (see section 4.4). List of adverse reactions The adverse reactions are ranked under heading of frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Treatment in women Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Nervous system disorders Very common: Headache Vascular disorders Very rare: Thromboembolism (both in association with and separate from OHSS) Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Gastrointestinal disorders Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea Reproductive system and breast disorders Very common: Ovarian cysts Common: Mild or moderate OHSS (including associated symptomatology) Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4) 20 Rare: Complication of severe OHSS General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Treatment in men Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Skin and subcutaneous tissue disorders Common: Acne Reproductive system and breast disorders Common: Gynaecomastia, Varicocele General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Investigations Common: Weight gain Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The effects of an overdose of follitropin alfa are unknown, nevertheless, there is a possibility that OHSS may occur (see section 4.4). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� http://www.ema.europa.eu/� 21 Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG. Clinical efficacy and safety in women In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation. In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) follitropin alfa (n = 130) urinary FSH (n = 116) Number of oocytes retrieved 11.0 ± 5.9 8.8 ± 4.8 Days of FSH stimulation required 11.7 ± 1.9 14.5 ± 3.3 Total dose of FSH required (number of FSH 75 IU ampoules) 27.6 ± 10.2 40.7 ± 13.6 Need to increase the dose (%) 56.2 85.3 Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men In men deficient in FSH, follitropin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis. 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine. Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steadystate within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity in addition to those already stated in the other sections of this SmPC. Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (≥ 40 IU/kg/day) for extended periods, through reduced fecundity. Given in high doses (≥ 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being teratogenic, and dystocia similar to that observed with urinary menopausal gonadotropin 22 (hMG). However, since follitropin alfa is not indicated in pregnancy, these data are of limited clinical relevance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Poloxamer 188 Sucrose Methionine Disodium phosphate dihydrate Sodium dihydrogen phosphate dihydrate Phosphoric acid Water for injections 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years Once opened, the medicinal product should be injected immediately. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Before opening and within its shelf life, the medicinal product may be removed from the refrigerator, and without being refrigerated again, may be stored for up to 3 months at or below 25°C. The medicinal product must be discarded if it has not been used after 3 months. Store in the original package in order to protect from light. 6.5 Nature and contents of container 1.5 mL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a rubber inlay, assembled in a pre-filled pen.. Each cartridge contains 0.25 mL solution for injection. Pack sizes of 1, 5 and 10 pre-filled pens including one disposable needle and alcohol swab per pen. One needle and one alcohol swab to be used with the pen for administration. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The solution should not be administered if it contains particles or is not clear. Bemfola 150 IU/0.25 mL (11 micrograms/0.25 mL) is not designed to allow the cartridge to be removed. Discard used pen and needle immediately after injection. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 23 For instructions on the administration with the pre-filled pen, see the package leaflet. 7. MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 8. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/002 EU/1/13/909/008 EU/1/13/909/009 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 27/03/2014 Date of latest renewal: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/� 24 1. NAME OF THE MEDICINAL PRODUCT Bemfola 225 IU/0.375 mL solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of the solution contains 600 IU (equivalent to 44 micrograms) of follitropin alfa*. Each pre- filled pen delivers 225 IU (equivalent to 16.5 micrograms) in 0.375 mL. * recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection). Clear colourless solution. The pH of the solution is 6.7 - 7.3. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications In adult women • Anovulation (including polycystic ovariansyndrome, PCOS) in women who have been unresponsive to treatment with clomiphene citrate. • Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT). • Follitropin alfa in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/L. In adult men • Follitropin alfa is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hCG) therapy. 4.2 Posology and method of administration Treatment should be initiated under the supervision of a physician experienced in the treatment of fertility disorders. Patients must be provided with the correct number of pens for their treatment course and educated to use the proper injection techniques. Posology 25 The dose recommendations given for follitropin alfa are those in use for urinary FSH. Clinical assessment of follitropin alfa indicates that its daily doses, regimens of administration and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below. Comparative clinical trials have shown that on average patients require a lower cumulative dose and shorter treatment duration with follitropin alfa compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of follitropin alfa than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation (see section 5.1). Women with anovulation (including polycystic ovarian syndrome) Follitropin alfa may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle. A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and/or estrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle. When an optimal response is obtained, a single injection of 250 micrograms of recombinant human chorionic gonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed. If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle. Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies A commonly used regimen for superovulation involves the administration of 150-225 IU of follitropin alfa daily commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum estrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days). A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last follitropin alfa injection to induce final follicular maturation. Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, follitropin alfa is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU follitropin alfa are administered for the first 7 days. The dose is then adjusted according to the ovarian response. Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter. Women with anovulation resulting from severe LH and FSH deficiency In LH and FSH deficient women (hypogonadotropic hypogonadism), the objective of follitropin alfa therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the 26 oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). Follitropin alfa should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous estrogen secretion, treatment can commence at any time. A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and estrogen response. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks. When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following hCG administration. Alternatively, IUI may be performed. Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum. If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle. Men with hypogonadotropic hypogonadism Follitropin alfa should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. Special populations Elderly population There is no relevant use of follitropin alfa in the elderly population. The safety and efficacy of follitropin alfa in elderly patients have not been established. Renal or hepatic impairment The safety, efficacy and pharmacokinetics of follitropin alfa in patients with renal or hepatic impairment have not been established. Paediatric population There is no relevant use of follitropin alfa in the paediatric population. Method of administration Bemfola is intended for subcutaneous use. The first injection of Bemfola should be performed under direct medical supervision. Self-administration of Bemfola should only be performed by patients who are well motivated, adequately trained and have access to expert advice. As the Bemfola pre-filled pen with the single-dose cartridge is intended for only one injection, clear instructions should be provided to the patients to avoid misuse of the single dose presentation. For instructions on the administration with the pre-filled pen, see section 6.6 and the package leaflet. 4.3 Contraindications 27 • hypersensitivity to the active substance or to any of the excipients listed in section 6.1; • tumours of the hypothalamus or pituitary gland; • ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome; • gynaecological haemorrhages of unknown aetiology; • ovarian, uterine or mammary carcinoma. Follitropin alfa must not be used when an effective response cannot be obtained, such as in case of: • primary ovarian failure; • malformations of sexual organs incompatible with pregnancy; • fibroid tumours of the uterus incompatible with pregnancy; • primary testicular insufficiency. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of the ovarian response with ultrasound, alone or preferably in combination with measurement of serum estradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women. Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be thoroughly investigated and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and should be treated accordingly. Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests. In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments. No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) 28 A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment. In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities. The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction. Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or > 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of ≥ 14 mm in diameter in anovulation; ≥ 20 follicles of ≥ 12 mm in diameter in ART). Adherence to the recommended follitropin alfa dose and to the regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors. There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as a serum estradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or ≥ 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Therefore patients should be followed for at least two weeks after hCG administration. In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy In patients undergoing ovulation induction, the incidence of a multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes. To minimise the risk of a multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. Pregnancy loss 29 The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception. Ectopic pregnancy Women with a history of tubal disease are at risk of ectopic pregnancy, regardless of whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART was reported to be higher than in the general population. Reproductive system neoplasms There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. Congenital malformation The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies. Thromboembolic events In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events. Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of follitropin alfa with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of follitropin alfa needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during follitropin alfa therapy. 4.6 Fertility, pregnancy and lactation Pregnancy There is no indication for use of follitropin alfa during pregnancy. Data on a limited number of exposed pregnant women (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of follitropin alfa. No teratogenic effect has been observed in animal studies (see section 5.3). In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of follitropin alfa. Breastfeeding 30 Follitropin alfa is not indicated during breastfeeding. Fertility Follitropin alfa is indicated for use in infertility (see section 4.1). 4.7 Effects on ability to drive and use machines Follitropin alfa is expected to have no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection). Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4). Thromboembolism may occur very rarely (see section 4.4). List of adverse reactions The adverse reactions are ranked under heading of frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Treatment in women Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Nervous system disorders Very common: Headache Vascular disorders Very rare: Thromboembolism(both in association with and separate from OHSS Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Gastrointestinal disorders Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea Reproductive system and breast disorders Very common: Ovarian cysts Common: Mild or moderate OHSS (including associated symptomatology) 31 Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4) Rare: Complication of severe OHSS General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Treatment in men Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Skin and subcutaneous tissue disorders Common: Acne Reproductive system and breast disorders Common: Gynaecomastia, Varicocele General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Investigations Common: Weight gain Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The effects of an overdose of follitropin alfa are unknown, nevertheless, there is a possibility that OHSS may occur (see section 4.4). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 32 Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG. Clinical efficacy and safety in women In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation. In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) follitropin alfa (n = 130) urinary FSH (n = 116) Number of oocytes retrieved 11.0 ± 5.9 8.8 ± 4.8 Days of FSH stimulation required 11.7 ± 1.9 14.5 ± 3.3 Total dose of FSH required (number of FSH 75 IU ampoules) 27.6 ± 10.2 40.7 ± 13.6 Need to increase the dose (%) 56.2 85.3 Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men In men deficient in FSH, follitropin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis. 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine. Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity in addition to those already stated in the other sections of this SmPC. Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (≥ 40 IU/kg/day) for extended periods, through reduced fecundity. http://www.ema.europa.eu/� 33 Given in high doses (≥ 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being teratogenic, and dystocia similar to that observed with urinary menopausal gonadotropin (hMG). However, since follitropin alfa is not indicated in pregnancy, these data are of limited clinical relevance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Poloxamer 188 Sucrose Methionine Disodium phosphate dihydrate Sodium dihydrogen phosphate dihydrate Phosphoric acid Water for injections 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years Once opened, the medicinal product should be injected immediately. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Before opening and within its shelf life, the medicinal product may be removed from the refrigerator, and without being refrigerated again, may be stored for up to 3 months at or below 25°C. The medicinal product must be discarded if it has not been used after 3 months. Store in the original package in order to protect from light. 6.5 Nature and contents of container 1.5 mL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a rubber inlay, assembled in a pre-filled pen. Each cartridge contains 0.375 mL solution for injection. Pack sizes of 1, 5 and 10 pre-filled pens including one disposable needle and alcohol swab per pen. One needle and one alcohol swab to be used with the pen for administration. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The solution should not be administered if it contains particles or is not clear. Bemfola 225 IU/0.375 mL (16.5 micrograms/0.375 mL) is not designed to allow the cartridge to be removed. Discard used pen and needle immediately after injection. 34 Any unused medicinal product or waste material should be disposed of in accordance with local requirements. For instructions on the administration with the pre-filled pen, see the package leaflet. 7. MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 8. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/003 EU/1/13/909/010 EU/1/13/909/011 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 27/03/2014 Date of latest renewal: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/� 35 1. NAME OF THE MEDICINAL PRODUCT Bemfola 300 IU/0.50 mL solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of the solution contains 600 IU (equivalent to 44 micrograms) of follitropin alfa*. Each pre- filled pen delivers 300 IU (equivalent to 22 micrograms) in 0.5 mL. * recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection). Clear colourless solution. The pH of the solution is 6.7 - 7.3. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications In adult women • Anovulation (including polycystic ovarian syndrome, PCOs) in women who have been unresponsive to treatment with clomiphene citrate. • Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT). • Follitropin alfa in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/L. In adult men • Follitropin alfa is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hCG) therapy. 4.2 Posology and method of administration Treatment should be initiated under the supervision of a physician experienced in the treatment of fertility disorders. Patients must be provided with the correct number of pens for their treatment course and educated to use the proper injection techniques. Posology 36 The dose recommendations given for follitropin alfa are those in use for urinary FSH. Clinical assessment of follitropin alfa indicates that its daily doses, regimens of administration and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below. Comparative clinical trials have shown that on average patients require a lower cumulative dose and shorter treatment duration with follitropin alfa compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of follitropin alfa than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation (see section 5.1). Women with anovulation (including polycystic ovarian syndrome) Follitropin alfa may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle. A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and/or estrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle. When an optimal response is obtained, a single injection of 250 micrograms of recombinant human chorionic gonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed. If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle. Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies A commonly used regimen for superovulation involves the administration of 150-225 IU of follitropin alfa daily commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum estrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days). A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last follitropin alfa injection to induce final follicular maturation. Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, follitropin alfa is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU follitropin alfa are administered for the first 7 days. The dose is then adjusted according to the ovarian response. Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter. Women with anovulation resulting from severe LH and FSH deficiency In LH and FSH deficient women (hypogonadotropic hypogonadism), the objective of follitropin alfa therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the 37 oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). Follitropin alfa should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous estrogen secretion, treatment can commence at any time. A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and estrogen response. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks. When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following hCG administration. Alternatively, IUI may be performed. Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum. If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle. Men with hypogonadotropic hypogonadism Follitropin alfa should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. Special populations Elderly population There is no relevant use of follitropin alfa in the elderly population. The safety and efficacy of follitropin alfa in elderly patients have not been established. Renal or hepatic impairment The safety, efficacy and pharmacokinetics of follitropin alfa in patients with renal or hepatic impairment have not been established. Paediatric population There is no relevant use of follitropin alfa in the paediatric population. Method of administration Bemfola is intended for subcutaneous use. The first injection of Bemfola should be performed under direct medical supervision. Self-administration of Bemfola should only be performed by patients who are well motivated, adequately trained and have access to expert advice. As the Bemfola pre-filled pen with the single-dose cartridge is intended for only one injection, clear instructions should be provided to the patients to avoid misuse of the single dose presentation. For instructions on the administration with the pre-filled pen, see section 6.6 and the package leaflet. 4.3 Contraindications 38 • hypersensitivity to the active substance or to any of the excipients listed in section 6.1; • tumours of the hypothalamus or pituitary gland; • ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome; • gynaecological haemorrhages of unknown aetiology; • ovarian, uterine or mammary carcinoma. Follitropin alfa must not be used when an effective response cannot be obtained, such as in case of: • primary ovarian failure; • malformations of sexual organs incompatible with pregnancy; • fibroid tumours of the uterus incompatible with pregnancy; • primary testicular insufficiency. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of the ovarian response with ultrasound, alone or preferably in combination with measurement of serum estradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women. Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be assessed thoroughly investigated and putative contraindications for pregnancy must be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and should be treated accordingly. Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests. In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments. No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. 39 Ovarian Hyperstimulation Syndrome (OHSS) A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment. In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities. The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction. Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or > 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of ≥ 14 mm in diameter in anovulation; ≥ 20 follicles of ≥ 12 mm in diameter in ART). Adherence to the recommended follitropin alfa dose and to the regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors. There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as a serum estradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or ≥ 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Therefore patients should be followed for at least two weeks after hCG administration. In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy In patients undergoing ovulation induction, the incidence of a multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes. To minimise the risk of a multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. 40 Pregnancy loss The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception. Ectopic pregnancy Women with a history of tubal disease are at risk of ectopic pregnancy, regardless of whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART was reported to be higher than in the general population. Reproductive system neoplasms There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. Congenital malformation The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies. Thromboembolic events In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events. Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of follitropin alfa with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of follitropin alfa needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during follitropin alfa therapy. 4.6 Fertility, pregnancy and lactation Pregnancy There is no indication for use of follitropin alfa during pregnancy. Data on a limited number of exposed pregnant women (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of follitropin alfa. No teratogenic effect has been observed in animal studies (see section 5.3). In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of follitropin alfa. 41 Breast-feeding Follitropin alfa is not indicated during breast-feeding. Fertility Follitropin alfa is indicated for use in infertility (see section 4.1). 4.7 Effects on ability to drive and use machines Follitropin alfa is expected to have no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection). Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4). Thromboembolism may occur very rarely (see section 4.4). List of adverse reactions The adverse reactions are ranked under heading of frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Treatment in women Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Nervous system disorders Very common: Headache Vascular disorders Very rare: Thromboembolism (both in association with and separate from OHSS. Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Gastrointestinal disorders Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea Reproductive system and breast disorders Very common: Ovarian cysts 42 Common: Mild or moderate OHSS (including associated symptomatology) Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4) Rare: Complication of severe OHSS General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Treatment in men Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Skin and subcutaneous tissue disorders Common: Acne Reproductive system and breast disorders Common: Gynaecomastia, Varicocele General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Investigations Common: Weight gain Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The effects of an overdose of follitropin alfa are unknown, nevertheless, there is a possibility that OHSS may occur (see section 4.4). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 43 Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG. Clinical efficacy and safety in women In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation. In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) follitropin alfa (n = 130) urinary FSH (n = 116) Number of oocytes retrieved 11.0 ± 5.9 8.8 ± 4.8 Days of FSH stimulation required 11.7 ± 1.9 14.5 ± 3.3 Total dose of FSH required (number of FSH 75 IU ampoules) 27.6 ± 10.2 40.7 ± 13.6 Need to increase the dose (%) 56.2 85.3 Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men In men deficient in FSH, follitropin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis. 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine. Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steadystate within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity in addition to those already stated in other sections of this SmPC. Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (≥ 40 IU/kg/day) for extended periods, through reduced fecundity. http://www.ema.europa.eu/� 44 Given in high doses (≥ 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being teratogenic, and dystocia similar to that observed with urinary menopausal gonadotropin (hMG). However, since follitropin alfa is not indicated in pregnancy, these data are of limited clinical relevance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Poloxamer 188 Sucrose Methionine Disodium phosphate dihydrate Sodium dihydrogen phosphate dihydrate Phosphoric acid Water for injections 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years Once opened, the medicinal product should be injected immediately. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Before opening and within its shelf life, the medicinal product may be removed from the refrigerator, and without being refrigerated again, may be stored for up to 3 months at or below 25°C. The medicinal product must be discarded if it has not been used after 3 months. Store in the original package in order to protect from light. 6.5 Nature and contents of container 1.5 mL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a rubber inlay, assembled in a pre-filled pen. Each cartridge contains 0.5 mL solution for injection. Pack sizes of 1, 5 and 10 pre-filled pens including one disposable needle and alcohol swab per pen. One needle and one alcohol swab to be used with the pen for administration. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The solution should not be administered if it contains particles or is not clear. Bemfola 300 IU/0.50 mL (22 micrograms/0.5 mL) is not designed to allow the cartridge to be removed. Discard used pen and needle immediately after injection. 45 Any unused medicinal product or waste material should be disposed of in accordance with local requirements. For instructions on the administration with the pre-filled pen, see the package leaflet. 7. MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 8. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/004 EU/1/13/909/012 EU/1/13/909/013 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 27/03/2014 Date of latest renewal: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/� 46 1. NAME OF THE MEDICINAL PRODUCT Bemfola 450 IU/0.75 mL solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of the solution contains 600 IU (equivalent to 44 micrograms) of follitropin alfa*. Each pre- filled pen delivers 450 IU (equivalent to 33 micrograms) in 0.75 mL. * recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection). Clear colourless solution. The pH of the solution is 6.7 - 7.3. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications In adult women • Anovulation (including polycystic ovarian snydrome, PCOS) in women who have been unresponsive to treatment with clomiphene citrate. • Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT). • Follitropin alfa in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/L. In adult men • Follitropin alfa is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hCG) therapy. 4.2 Posology and method of administration Treatment should be initiated under the supervision of a physician experienced in the treatment of fertility disorders. Patients must be provided with the correct number of pens for their treatment course and educated to use the proper injection techniques. Posology 47 The dose recommendations given for follitropin alfa are those in use for urinary FSH. Clinical assessment of follitropin alfa indicates that its daily doses, regimens of administration and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below. Comparative clinical trials have shown that on average patients require a lower cumulative dose and shorter treatment duration with follitropin alfa compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of follitropin alfa than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation (see section 5.1). Women with anovulation (including polycystic ovarian syndrome) Follitropin alfa may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle. A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and/or estrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle. When an optimal response is obtained, a single injection of 250 micrograms of recombinant human chorionic gonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed. If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle. Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies A commonly used regimen for superovulation involves the administration of 150-225 IU of follitropin alfa daily commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum estrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days). A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last follitropin alfa injection to induce final follicular maturation. Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, follitropin alfa is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU follitropin alfa are administered for the first 7 days. The dose is then adjusted according to the ovarian response. Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter. Women with anovulation resulting from severe LH and FSH deficiency In LH and FSH deficient women (hypogonadotropic hypogonadism), the objective of follitropin alfa therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the 48 oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). Follitropin alfa should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous estrogen secretion, treatment can commence at any time. A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and estrogen response. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks. When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following hCG administration. Alternatively, IUI may be performed. Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum. If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle. Men with hypogonadotropic hypogonadism Follitropin alfa should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. Special populations Elderly population There is no relevant use of follitropin alfa in the elderly population. The safety and efficacy of follitropin alfa in elderly patients have not been established. Renal or hepatic impairment The safety, efficacy and pharmacokinetics of follitropin alfa in patients with renal or hepatic impairment have not been established. Paediatric population There is no relevant use of follitropin alfa in the paediatric population. Method of administration Bemfola is intended for subcutaneous use. The first injection of Bemfola should be performed under direct medical supervision. Self-administration of Bemfola should only be performed by patients who are well motivated, adequately trained and have access to expert advice. As the Bemfola pre-filled pen with the single-dose cartridge is intended for only one injection, clear instructions should be provided to the patients to avoid misuse of the single dose presentation. For instructions on the administration with the pre-filled pen, see section 6.6 and the package leaflet. 4.3 Contraindications 49 • hypersensitivity to the active substance or to any of the excipients listed in section 6.1; • tumours of the hypothalamus or pituitary gland; • ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome; • gynaecological haemorrhages of unknown aetiology; • ovarian, uterine or mammary carcinoma. Follitropin alfa must not be used when an effective response cannot be obtained, such as in case of: • primary ovarian failure; • malformations of sexual organs incompatible with pregnancy; • fibroid tumours of the uterus incompatible with pregnancy; • primary testicular insufficiency. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of the ovarian response with ultrasound, alone or preferably in combination with measurement of serum estradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women. Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be thoroughly investigated and putative contraindications for pregnancy must be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and should be treated accordingly. Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests. In clinicaltrials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments. No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) 50 A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment. In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities. The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction. Independent risk factors for developing OHSS include polycystic ovarian syndrome, high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or > 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of ≥ 14 mm in diameter in anovulation; ≥ 20 follicles of ≥ 12 mm in diameter in ART). Adherence to the recommended follitropin alfa dose and to the regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors. There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as serum oestradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or ≥ 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Therefore patients should be followed for at least two weeks after hCG administration. In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy In patients undergoing ovulation induction, the incidence of a multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes. To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of a multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. Pregnancy loss 51 The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception. Ectopic pregnancy Women with a history of tubal disease are at risk of ectopic pregnancy, regardless of whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART was reported to be higher than in the general population. Reproductive system neoplasms There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. Congenital malformation The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies. Thromboembolic events In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events. Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of follitropin alfa with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of follitropin alfa needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during follitropin alfa therapy. 4.6 Fertility, pregnancy and lactation Pregnancy There is no indication for use of follitropin alfa during pregnancy. Data on a limited number of exposed pregnant women (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of follitropin alfa. No teratogenic effect has been observed in animal studies (see section 5.3). In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of follitropin alfa. Breastfeeding 52 Follitropin alfa is not indicated during breastfeeding. Fertility Follitropin alfa is indicated for use in infertility (see section 4.1). 4.7 Effects on ability to drive and use machines Follitropin alfa is expected to have no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection). Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4). Thromboembolism may occur very rarely, usually associated with severe OHSS (see section 4.4). List of adverse reactions The adverse reactions are ranked under heading of frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Treatment in women Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Nervous system disorders Very common: Headache Vascular disorders Very rare: Thromboembolism, (both in association with and separate from OHSS. Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Gastrointestinal disorders Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea Reproductive system and breast disorders Very common: Ovarian cysts Common: Mild or moderate OHSS (including associated symptomatology) 53 Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4) Rare: Complication of severe OHSS General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Treatment in men Immune system disorders Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Respiratory, thoracic and mediastinal disorders Very rare: Exacerbation or aggravation of asthma Skin and subcutaneous tissue disorders Common: Acne Reproductive system and breast disorders Common: Gynaecomastia, Varicocele General disorders and administration site conditions Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Investigations Common: Weight gain Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The effects of an overdose of follitropin alfa are unknown, nevertheless, there is a possibility that OHSS may occur (see section 4.4). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 54 Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG. Clinical efficacy and safety in women In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation. In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) follitropin alfa (n = 130) urinary FSH (n = 116) Number of oocytes retrieved 11.0 ± 5.9 8.8 ± 4.8 Days of FSH stimulation required 11.7 ± 1.9 14.5 ± 3.3 Total dose of FSH required (number of FSH 75 IU ampoules) 27.6 ± 10.2 40.7 ± 13.6 Need to increase the dose (%) 56.2 85.3 Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men In men deficient in FSH, follitropin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis. 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine. Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steadystate within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity in addition to those already stated in the other sections of this SmPC. Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (≥ 40 IU/kg/day) for extended periods, through reduced fecundity. http://www.ema.europa.eu/� 55 Given in high doses (≥ 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being teratogenic, and dystocia similar to that observed with urinary menopausal gonadotropin (hMG). However, since follitropin alfa is not indicated in pregnancy, these data are of limited clinical relevance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Poloxamer 188 Sucrose Methionine Disodium phosphate dihydrate Sodium dihydrogen phosphate dihydrate Phosphoric acid Water for injections 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years Once opened, the medicinal product should be injected immediately. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Before opening and within its shelf life, the medicinal product may be removed from the refrigerator, and without being refrigerated again, may be stored for up to 3 months at or below 25°C. The medicinal product must be discarded if it has not been used after 3 months. Store in the original package in order to protect from light. 6.5 Nature and contents of container 1.5 mL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a rubber inlay, assembled in a pre-filled pen. Each cartridge contains 0.75 mL solution for injection. Pack sizes of 1, 5 and 10 pre-filled pens including one disposable needle and alcohol swab per pen. One needle and one alcohol swab to be used with the pen for administration. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The solution should not be administered if it contains particles or is not clear. Bemfola 450 IU/0.75 mL (33 micrograms/0.75 mL) is not designed to allow the cartridge to be removed. Discard used pen and needle immediately after injection. 56 Any unused medicinal product or waste material should be disposed of in accordance with local requirements. For instructions on the administration with the pre-filled pen, see the package leaflet. 7. MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 8. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/005 EU/1/13/909/014 EU/1/13/909/015 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 27/03/2014 Date of latest renewal: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/� 57 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 58 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Polymun Scientific Immunbiologische Forschung GmbH Donaustraße 99 Klosterneuburg 3400 Austria Name and address of the manufacturer responsible for batch release Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal products subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web- portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 59 ANNEX III LABELLING AND PACKAGE LEAFLET 60 A. LABELLING 61 PARTICULARS TO APPEAR ON THE OUTER PACKAGING BOX OF 1, 5 OR 10 PRE-FILLED PENS 1. NAME OF THE MEDICINAL PRODUCT Bemfola 75 IU/0.125 mL solution for injection in pre-filled pen follitropin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled pen delivers 75 IU follitropin alfa, equivalent to 5.5 micrograms per 0.125 mL. Each mL of the solution contains 600 IU equivalent to 44 micrograms. 3. LIST OF EXCIPIENTS Poloxamer 188, sucrose, methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, phosphoric acid and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled pen 1 injection needle 1 alcohol swab 5 pre-filled pens 5 injection needles 5 alcohol swabs 10 pre-filled pens 10 injection needles 10 alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 62 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. Within its shelf-life, the unopened product may be stored at or below 25°C for up to 3 months without being refrigerated again and must be discarded if it has not been used after 3 months. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/001 EU/1/13/909/006 EU/1/13/909/007 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Bemfola 75 IU/0.125 mL 63 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 64 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Bemfola 75 IU/0.125 mL injection follitropin alfa SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.125 mL 6. OTHER 65 PARTICULARS TO APPEAR ON THE OUTER PACKAGING BOX OF 1, 5 OR 10 PRE-FILLED PENS 1. NAME OF THE MEDICINAL PRODUCT Bemfola 150 IU/0.25 mL solution for injection in pre-filled pen follitropin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled pen delivers 150 IU follitropin alfa, equivalent to 11 micrograms per 0.25 mL. Each mL of the solution contains 600 IU equivalent to 44 micrograms. 3. LIST OF EXCIPIENTS Poloxamer 188, sucrose, methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, phosphoric acid and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled pen 1 injection needle 1 alcohol swab 5 pre-filled pens 5 injection needles 5 alcohol swabs 10 pre-filled pens 10 injection needles 10 alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 66 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. Within its shelf-life, the unopened product may be stored at or below 25°C for up to 3 months without being refrigerated again and must be discarded if it has not been used after 3 months. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/002 EU/1/13/909/008 EU/1/13/909/009 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Bemfola 150 IU/0.25 mL 67 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 68 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Bemfola 150 IU/0.25 mL injection follitropin alfa SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.25 mL 6. OTHER 69 PARTICULARS TO APPEAR ON THE OUTER PACKAGING BOX OF 1, 5 OR 10 PRE-FILLED PENS 1. NAME OF THE MEDICINAL PRODUCT Bemfola 225 IU/0.375 mL solution for injection in pre-filled pen follitropin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled pen delivers 225 IU follitropin alfa, equivalent to 16.5 micrograms per 0.375 mL. Each mL of the solution contains 600 IU equivalent to 44 micrograms. 3. LIST OF EXCIPIENTS Poloxamer 188, sucrose, methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, phosphoric acid and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled pen 1 injection needle 1 alcohol swab 5 pre-filled pens 5 injection needles 5 alcohol swabs 10 pre-filled pens 10 injection needles 10 alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 70 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. Within its shelf-life, the unopened product may be stored at or below 25°C for up to 3 months without being refrigerated again and must be discarded if it has not been used after 3 months. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/003 EU/1/13/909/010 EU/1/13/909/011 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Bemfola 225 IU/0.375 mL 71 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 72 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Bemfola 225 IU/0.375 mL injection follitropin alfa SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.375 mL 6. OTHER 73 PARTICULARS TO APPEAR ON THE OUTER PACKAGING BOX OF 1, 5 OR 10 PRE-FILLED PENS 1. NAME OF THE MEDICINAL PRODUCT Bemfola 300 IU/0.5 mL solution for injection in pre-filled pen follitropin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled pen delivers 300 IU follitropin alfa, equivalent to 22 micrograms per 0.5 mL. Each mL of the solution contains 600 IU equivalent to 44 micrograms. 3. LIST OF EXCIPIENTS Poloxamer 188, sucrose, methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, phosphoric acid and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled pen 1 injection needle 1 alcohol swab 5 pre-filled pens 5 injection needles 5 alcohol swabs 10 pre-filled pens 10 injection needles 10 alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 74 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. Within its shelf-life, the unopened product may be stored at or below 25°C for up to 3 months without being refrigerated again and must be discarded if it has not been used after 3 months. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/004 EU/1/13/909/012 EU/1/13/909/013 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Bemfola 300 IU/0.5 mL 75 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 76 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Bemfola 300 IU/0.5 mL injection follitropin alfa SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.5 mL 6. OTHER 77 PARTICULARS TO APPEAR ON THE OUTER PACKAGING BOX OF 1, 5 OR 10 PRE-FILLED PENS 1. NAME OF THE MEDICINAL PRODUCT Bemfola 450 IU/0.75 mL solution for injection in pre-filled pen follitropin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled pen delivers 450 IU follitropin alfa, equivalent to 33 micrograms per 0.75 mL. Each mL of the solution contains 600 IU equivalent to 44 micrograms. 3. LIST OF EXCIPIENTS Poloxamer 188, sucrose, methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, phosphoric acid and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled pen 1 injection needle 1 alcohol swab 5 pre-filled pens 5 injection needles 5 alcohol swabs 10 pre-filled pens 10 injection needles 10 alcohol swabs 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 78 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. Within its shelf-life, the unopened product may be stored at or below 25°C for up to 3 months without being refrigerated again and must be discarded if it has not been used after 3 months. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/005 EU/1/13/909/014 EU/1/13/909/015 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Bemfola 450 IU/0.75 mL 79 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 80 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED PEN LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Bemfola 450 IU/0.75 mL injection follitropin alfa SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.75 mL 6. OTHER 81 B. PACKAGE LEAFLET 82 Package leaflet: Information for the user Bemfola 75 IU/0.125 mL solution for injection in pre-filled pen Bemfola 150 IU/0.25 mL solution for injection in pre-filled pen Bemfola 225 IU/0.375 mL solution for injection in pre-filled pen Bemfola 300 IU/0.50 mL solution for injection in pre-filled pen Bemfola 450 IU/0.75 mL solution for injection in pre-filled pen follitropin alfa Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects,talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Bemfola is and what it is used for 2. What you need to know before you use Bemfola 3. How to use Bemfola 4. Possible side effects 5. How to store Bemfola 6. Contents of the pack and other information 1. What Bemfola is and what it is used for What Bemfola is This medicine contains the active substance follitropin alfa, which is almost identical to a natural hormone produced by your body called “follicle-stimulating hormone” (FSH). FSH is a gonadotropin, a type of hormone that plays an important role in human fertility and reproduction. In women, FSH is needed for the growth and development of the sacs (follicles) in the ovaries that contain the egg cells. In men, FSH is needed for the production of sperm. What Bemfola is used for In adult women, Bemfola is used: • to help release an egg from the ovary (ovulation) in women that cannot ovulate and that did not respond to treatment with a medicine called “clomiphene citrate”. • together with another medicine called “lutropin alfa” (“luteinising hormone” or LH) to help release an egg from the ovary (ovulation) in women that are not ovulating because their body is producing very little gonadotropins (FSH and LH). • to help develop several follicles (each containing an egg) in women undergoing assisted reproductive technology procedures (procedures that may help you to become pregnant) such as “in vitro fertilisation”, “gamete intra-fallopian transfer” or “zygote intra-fallopian transfer”. In adult men, Bemfola is used: • together with another medicine called “human chorionic gonadotropin” (hCG) to help produce sperm in men that are infertile due to a low level of certain hormones. 2. What you need to know before you use Bemfola 83 You and your partner’s fertility should be evaluated before the treatment is started by a doctor experienced in treating fertility disorders. Do not use Bemfola • if you are allergic to follicle stimulating hormone or any of the other ingredients of this medicine (listed in section 6). • if you have a tumour in your hypothalamus or pituitary gland (both are parts of the brain). • If you are a woman: - with large ovaries or sacs of fluids within the ovaries (ovarian cysts) of unknown origin. - with unexplained vaginal bleeding. - with cancer in your ovaries, womb or breasts. - with a condition that usually makes normal pregnancy impossible, such as ovarian failure (early menopause), or malformed reproductive organs. • If you are a man: - with damaged testicles that cannot be healed. Do not use Bemfola if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before using this medicine. Warnings and precautions Porphyria Tell your doctor before you start treatment, if you or any member of your family have porphyria (an inability to break down porphyrins that may be passed on from parents to children). Tell your doctor straight away if: • your skin becomes fragile and easily blistered, especially skin that has been frequently in the sun, and/or • you have stomach, arm or leg pain. In case of the above events your doctor may recommend that you stop treatment. Ovarian Hyper-Stimulation Syndrome (OHSS) If you are a woman, this medicine increases your risk of developing OHSS. This is when your follicles develop too much and become large cysts. If you get lower abdominal pain, gain any weight rapidly, feel sick or are vomiting or if you have difficulty in breathing, talk to your doctor straight away who might ask you to stop using this medicine (see section 4). In case you are not ovulating, and if the recommended dose and schedule of administration are adhered to, the occurrence of OHSS is less likely. Bemfola treatment seldom causes severe OHSS unless the medicine that is used for final follicular maturation (containing human chorionic gonadotropin, hCG) is administered. If you are developing OHSS your doctor may not give you any hCG in this treatment cycle and you may be told not to have sex or to use a barrier contraceptive method for at least four days. Multiple pregnancy When using Bemfola, you have a higher risk of being pregnant with more than one child at the same time (“multiple pregnancy”, mostly twins), than if you conceive naturally. A multiple pregnancy may lead to medical complications for you and your babies. You can reduce the risk of multiple pregnancy by using the right dose of Bemfola at the right times. When undergoing assisted reproductive technology the risk of having a multiple pregnancy is related to your age, the quality and the number of fertilised eggs or embryos placed inside you. Miscarriage When undergoing assisted reproductive technology or stimulation of your ovaries to produce eggs, you are more likely to have a miscarriage than the average woman. Blood clotting problems (thromboembolic events) 84 If you had in the past or recently blood clots in the leg or in the lung, or a heart attack or stroke, or if those happened in your family, then you might have a higher risk that these problems occur or become worse with Bemfola treatment. Men with too much FSH in their blood If you are a man, having too much FSH in your blood can be a sign of damaged testicles. Bemfola usually does not work if you have this problem. If your doctor decides to try Bemfola treatment, to monitor the treatment, they may ask you to provide semen for analysis 4 to 6 months after starting treatment. Children and adolescents Bemfola is not indicated for use in children and adolescents under 18 years of age. Other medicines and Bemfola Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. • If you use Bemfola with other medicines which help ovulation (such as hCG or clomiphene citrate), this may increase the response of your follicles. • If you use Bemfola at the same time as a “gonadotropin-releasing hormone” (GnRH) agonist or antagonist (these medicines reduce your sex hormone levels and stop you ovulating) you may need a higher dose of Bemfola to produce follicles. Pregnancy and breast-feeding Do not use Bemfola if you are pregnant or breast-feeding. Driving and using machines It is not expected that this medicine will affect your ability to drive and use machines. Bemfola contains sodium This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium- free”. 3. How to use Bemfola Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Using this medicine • Bemfola is intended to be given by injection just under the skin (subcutaneously). Use the pre- filled pen only once then it should be disposed of in a safe manner. Do not administered the solution if it contains particles or is not clear. • The first injection of Bemfola should be given under supervision of your doctor. • Your doctor or nurse will show you how to use the Bemfola pre-filled pen to inject the medicine. • If you administer Bemfola to yourself, please carefully read and follow the “Instructions for Use”. These instructions can be found at the end of the package leaflet. How much to use Your doctor will decide how much medicine you will use and how often. The doses described below are stated in International Units (IU) and millilitres (mL). Women If you are not ovulating and have irregular or no periods 85 • Bemfola is usually given every day. • If you have irregular periods, start using Bemfola within the first 7 days of your menstrual cycle. If you do not have periods you can start using the medicine on any convenient day. • The usual starting dose of Bemfola is 75 to 150 IU (0.12 to 0.25 mL) each day. • Your dose of Bemfola may be increased every 7 or every 14 days by 37.5 to 75 IU, until you get the desired response or your doctor tells you to stop, see below. • The maximum daily dose of Bemfola is usually not higher than 225 IU (0.375 mL). • When you get the desired response, you will be given a single injection of 250 micrograms of “recombinant hCG” (r-hCG, an hCG made in a laboratory by a special DNA technique), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after your last Bemfola injection. The best time to have sex is on the day of the hCG injection and the day after. If your doctor cannot see a desired response after 4 weeks, that treatment cycle with Bemfola should be stopped. For the following treatment cycle, your doctor will give you a higher starting dose of Bemfola than before. If your body responds too strongly, your treatment will be stopped and you will not be given any hCG (see section 2, OHSS). For the following cycle, your doctor will give you a lower dose of Bemfola than before. If you are not ovulating, have no periods and have been diagnosed with very low levels of FSH and LH hormones • The usual starting dose of Bemfola is 75 to 150 IU (0.12 to 0.25 mL) together with 75 IU (0.12 mL) of lutropin alfa. • You will use these two medicines each day for up to five weeks. • Your dose of Bemfola may be increased every 7 or every 14 days by 37.5 to 75 IU, until you get the desired response. • When you get the desired response, you will be given a single injection of 250 micrograms of “recombinant hCG” (r-hCG, an hCG made in a laboratory by a special DNA technique), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after your last injections of Bemfola and lutropin alfa. The best time to have sex is on the day of the hCG injection and the day after. Alternatively, intrauterine insemination may be performed by placing the sperm into the womb cavity. If your doctor cannot see a response after 5 weeks, that treatment cycle with Bemfola should be stopped. For the following cycle, your doctor will give you a higher starting dose of Bemfola than before. If your body responds too strongly, your treatment with Bemfola will be stopped and you will not be given any hCG (see section 2, OHSS). For the following cycle, your doctor will give you a lower dose of Bemfola than before. If you need to develop several eggs for collection prior to any assisted reproductive technology • The usual starting dose of Bemfola is 150 to 225 IU (0.25 to 0.37 mL) each day, from day 2 or 3 of your treatment cycle. • Bemfola dose may be increased, depending on your response. The maximum daily dose is 450 IU (0.75 mL). • Treatment is continued until your eggs have developed to a desired point. This usually takes about 10 days but can take any time between 5 and 20 days. Your doctor will use blood tests and/or an ultrasound machine to check when this is. • When your eggs are ready, you will be given a single injection of 250 micrograms “recombinant hCG” (r-hCG, an hCG made in a laboratory by a special recombinant DNA technique), or 86 5,000 IU to 10,000 IU of hCG, 24 to 48 hours after the last Bemfola injection. This gets your eggs ready for collection. In other cases, your doctor may first stop you from ovulating by using a gonadotropin-releasing hormone (GnRH) agonist or antagonist. Then Bemfola is started approximately two weeks after start of agonist treatment. The Bemfola and GnRH agonist are then both given until your follicles develop as desired. For example, after two weeks of GnRH agonist treatment, 150 to 225 IU Bemfola is administered for 7 days. The dose is then adjusted according to your ovarian response. When GnRH antagonist is used, it is administered from the 5th or 6th day of Bemfola treatment and continued until ovulation induction. Men • The usual dose of Bemfola is 150 IU (0.25 mL) together with hCG. • You will use these two medicines three times a week for at least 4 months. • If you have not responded to treatment after 4 months, your doctor may suggest that you continue using these two medicines for at least 18 months. If you use more Bemfola than you should The effects of taking too much Bemfola are unknown. Nevertheless one could expect Ovarian Hyper- Stimulation Syndrome (OHSS) to occur, which is described in section 4. However the OHSS will only occur if hCG is also administered (see section 2, under ‘OHSS’). If you forget to use Bemfola If you forget to use Bemfola, do not take a double dose to make up for a forgotten dose. Please talk to your doctor as soon as you notice that you forgot a dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects in women • Lower abdominal pain together with nausea or vomiting may be the symptoms of Ovarian Hyper-Stimulation Syndrome (OHSS). This may indicate that the ovaries over-reacted to the treatment and that large ovarian cysts developed (see also section 2 “Take special care with Bemfola”). This side effect is common (may affect up to 1 in 10 people). • OHSS may become severe with clearly enlarged ovaries, decreased urine production, weight gain, difficulty in breathing and/or possible fluid accumulation in your stomach or chest. This side effect is uncommon (may affect up to 1 in 100 people). • Complications of OHSS such as twisting of ovaries or blood clotting may occur rarely (may affect up to 1 in 1,000 people). • Serious blood clotting complications (thromboembolic events) sometimes independent of OHSS may be found very rarely (may affect up to 1 in 10,000 people). This could cause chest pain, breathlessness, stroke or heart attack (see also section 2 under ‘Blood clotting problems’). Serious side effects in men and women • Allergic reactions such as rash, red skin, hives, swelling of your face with difficulty breathing can sometimes be serious. This side effect is very rare If you notice any of the above-listed side effects you should immediately contact your doctor, who might ask you to stop using Bemfola. 87 Other side effects in women Very common (may affect more than 1 in 10 people): • Sacs of fluid within the ovaries (ovarian cysts) • Headache • Local reactions at the injection site, such as pain, redness, bruising, swelling and/or irritation Common (may affect up to 1 in 10 people): • Abdominal pain • Feeling sick, vomiting, diarrhoea, abdominal cramps and bloating Very rare (may affect up to 1 in 10,000 people): • Allergic reactions such as rash, red skin, hives, swelling of your face with difficulty breathing may occur. These reactions can sometimes be serious. • Your asthma may get worse Other side effects in men Very common (may affect more than 1 in 10 people): • Local reactions at the injection site, such as pain, redness, bruising, swelling and/or irritation Common (may affect up to 1 in 10 people): • Swelling of the veins above and behind the testicles (varicocele). • Breast development, acne or weight gain. Very rare (may affect up to 1 in 10,000 people): • Allergic reactions such as rash, red skin, hives, swelling of your face with difficulty in breathing may occur. These reactions can sometimes be serious. • Your asthma may get worse. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Bemfola Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date, which is stated on the pen label and carton after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the original package in order to protect from light. Within its shelf life, the unopened pen may be stored at or below 25°C for up to 3 months without being refrigerated again and must be discarded if it has not been used after 3 months. Do not use this medicine if you notice any visible signs of deterioration, if the liquid contains particles or is not clear. Once opened, the medicine should be injected immediately. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc� 88 Do not throw any medicines away via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Bemfola contains • The active substance is follitropin alfa. • Bemfola 75 IU/0.125 mL: Each cartridge contains 75 IU (equivalent to 5.5 micrograms) follitropin alfa in 0.125 mL solution. • Bemfola 150 IU/0.25 mL: Each cartridge contains 150 IU (equivalent to 11 micrograms) follitropin alfa in 0.25 mL solution. • Bemfola 225 IU/0.375 mL: Each cartridge contains 225 IU (equivalent to 16.5 micrograms) follitropin alfa in 0.375 mL solution. • Bemfola 300 IU/0.50 mL: Each cartridge contains 300 IU (equivalent to 22 micrograms) follitropin alfa in 0.50 mL solution. • Bemfola 450 IU/0.75 mL: Each cartridge contains 450 IU (equivalent to 33 micrograms) follitropin alfa in 0.75 mL solution. • Each mL of the solution contains 600 IU (equivalent to 44 micrograms) follitropin alfa. • The other ingredients are poloxamer 188, sucrose, methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, phosphoric acid and water for injections. What Bemfola looks like and contents of the pack • Bemfola is presented as a clear, colourless liquid for injection in a pre-filled pen (injection). • Bemfola is supplied in packs with 1, 5 or 10 pre-filled pens, 1, 5 or 10 disposable needles and 1, 5 or 10 alcohol swabs. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Gedeon Richter Plc. Gyömrői út 19-21. 1103 Budapest Hungary This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/� 89 Bemfola 75 IU/0.125 mL pre-filled pen Bemfola 150 IU/0.25 mL pre-filled pen Bemfola 225 IU/0.375 mL pre-filled pen Bemfola 300 IU/0.50 mL pre-filled pen Bemfola 450 IU/0.75 mL pre-filled pen Instructions for use CONTENTS 1. How to use the Bemfola pre-filled pen 2. Before you start using your pre-filled pen 3. Getting your pre-filled pen ready for injection 4. Setting the dose 5. Injecting the dose 6. After the injection 1. How to use the Bemfola pre-filled pen • Before starting to use your pre-filled pen, please read these instructions and the package leaflet the whole way through first. • Only use this pen for you – do not let anyone else use it. • The numbers on the dose display are measured in International Units or IU. Your doctor will have told you how many IU to inject each day. • Your doctor/pharmacist will tell you how many Bemfola pens you need to use for your complete treatment course. • Give yourself the injection around the same time each day. 2. Before you start using your pre-filled pen 2.1. Wash your hands • It is important that your hands and the things you use to get your pen ready are as clean as possible. 2.2. Find a clean area • A good place is a clean table or surface. 3. Getting your pre-filled pen ready for injection The different parts of your pen 90 Perform the injection every day around the same time. Take the pen out of the fridge 5 to 10 minutes before using it. Note: Please check that the medicine is not frozen. 91 Remove the peel tab from the injection needle. Hold the pen by its sides and attach the needle by clicking it into place. Do not twist it on. You will hear a click when it is securely fixed. Caution: Do not push the dosage knob in while attaching the needle. Remove the outer needle cap. Keep it for later. You will need it after the injection. Remove the inner needle cap. 92 4. Setting the dose Hold the pen so that the needle is pointing upright. Gently tap the pen so that any large air bubbles rise to the top. Still holding the pen upright, push the dosage knob in until the activation bar with the small arrow disappears. You should also hear a click, and some liquid will splash out (this is normal).The pen is now ready to set the dose. If no liquid splashes out, the pen should not be used. Turn the dosage knob until your prescribed dose is in line with the display window. Note: The pen is now ready for injection. Caution: Do not push the dosage knob in any further, at this point. 93 5. Injecting the dose Now you are ready to immediately give yourself the injection: Your doctor or nurse will have already advised you where to inject (e.g. tummy, front of thigh). To minimise skin irritation, select a different injection site each day. Clean the injection site with the alcohol swab using a circular motion. Lightly pinch the skin of the injection area. Hold the pen at approximately a right angle and insert the needle completely in a steady movement. Caution: Do not push the dosage knob, while inserting the needle. Push in the dosage knob slowly and continuously until it stops, and the dose bar has disappeared. Do not remove the needle immediately, wait for 5 seconds, before pulling it out. After the withdrawal of the needle: clean the skin with an alcohol swab using a circular motion. 94 6. After the injection Replace the outer needle cap onto the needle carefully. Throw away the packaging box, inner needle cap, peel tab, alcohol swab and the instructions for use in the normal household waste. Do not throw away any medicines via your sink, toilet or in your household waste. The used pen needs to be discarded in a sharps container and returned to the pharmacy for a correct disposal. Ask your pharmacist how to dispose of medicines you no longer use. SUMMARY OF PRODUCT CHARACTERISTICS For the full list of excipients, see section 6.1. In adult women In adult men Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of t... Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be thoroughly investigated and putative contraindications for pregnancy must be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficienc... Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of... In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably wit... No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can... The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical ev... Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy To minimise the risk of a multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of a multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurre... Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction 4.6 Fertility, pregnancy and lactation 4.7 Effects on ability to drive and use machines 4.8 Undesirable effects 4.9 Overdose 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian folli... In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements perf... In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to tri... In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of d... 5.3 Preclinical safety data 6.1 List of excipients 6.2 Incompatibilities 6.3 Shelf life 6.4 Special precautions for storage 6.5 Nature and contents of container 6.6 Special precautions for disposal and other handling For the full list of excipients, see section 6.1. In adult women In adult men Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of t... Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be thoroughly investigated and putative contraindications for pregnancy must be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficienc... Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of... In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably wit... No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can... The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical ev... Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy To minimise the risk of a multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurre... Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction 4.6 Fertility, pregnancy and lactation 4.7 Effects on ability to drive and use machines 4.8 Undesirable effects 4.9 Overdose 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian folli... In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements perf... In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to tri... In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of d... 5.3 Preclinical safety data 6.1 List of excipients 6.2 Incompatibilities 6.3 Shelf life 6.4 Special precautions for storage 6.5 Nature and contents of container 6.6 Special precautions for disposal and other handling For the full list of excipients, see section 6.1. In adult women In adult men Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of t... Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be thoroughly investigated and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyper... Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of... In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably wit... No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can... The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical ev... Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy To minimise the risk of a multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurre... Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction 4.6 Fertility, pregnancy and lactation 4.7 Effects on ability to drive and use machines 4.8 Undesirable effects 4.9 Overdose 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian folli... In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements perf... In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to tri... In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of d... 5.3 Preclinical safety data 6.1 List of excipients 6.2 Incompatibilities 6.3 Shelf life 6.4 Special precautions for storage 6.5 Nature and contents of container 6.6 Special precautions for disposal and other handling For the full list of excipients, see section 6.1. In adult women In adult men Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of t... Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be assessed thoroughly investigated and putative contraindications for pregnancy must be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical ... Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of... In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably wit... No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can... The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical ev... Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy To minimise the risk of a multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurre... Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction 4.6 Fertility, pregnancy and lactation 4.7 Effects on ability to drive and use machines 4.8 Undesirable effects 4.9 Overdose 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian folli... In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements perf... In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to tri... In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of d... 5.3 Preclinical safety data 6.1 List of excipients 6.2 Incompatibilities 6.3 Shelf life 6.4 Special precautions for storage 6.5 Nature and contents of container 6.6 Special precautions for disposal and other handling For the full list of excipients, see section 6.1. In adult women In adult men Follitropin alfa is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of t... Porphyria Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment. Treatment in women Before starting treatment, the reason for the couple's infertility must be thoroughly investigated and putative contraindications for pregnancy must be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficienc... Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dose and regimen of... In clinicaltrials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with... No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG. Ovarian Hyperstimulation Syndrome (OHSS) In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can... The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical ev... Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started. Multiple pregnancy To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended. In patients undergoing ART procedures the risk of a multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age. The patients should be advised of the potential risk of multiple births before starting treatment. In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurre... Treatment in men Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained. Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction 4.6 Fertility, pregnancy and lactation 4.7 Effects on ability to drive and use machines 4.8 Undesirable effects 4.9 Overdose 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05. Bemfola is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Pharmacodynamic effects In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian folli... In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements perf... In clinical trials comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to tri... In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH. Table 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies) Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed. Clinical efficacy and safety in men 5.2 Pharmacokinetic properties Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and is eliminated from the body with a terminal half-life of about one day. The steady state volume of d... 5.3 Preclinical safety data 6.1 List of excipients 6.2 Incompatibilities 6.3 Shelf life 6.4 Special precautions for storage 6.5 Nature and contents of container 6.6 Special precautions for disposal and other handling A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT ANNEX III LABELLING AND PACKAGE LEAFLET A. LABELLING 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 5. METHOD AND ROUTE(S) OF ADMINISTRATION 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/001 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE 4. BATCH NUMBER 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 5. METHOD AND ROUTE(S) OF ADMINISTRATION 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/002 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE 4. BATCH NUMBER 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 5. METHOD AND ROUTE(S) OF ADMINISTRATION 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/003 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE 4. BATCH NUMBER 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 5. METHOD AND ROUTE(S) OF ADMINISTRATION 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/004 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE 4. BATCH NUMBER 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 5. METHOD AND ROUTE(S) OF ADMINISTRATION 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/909/005 13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE 4. BATCH NUMBER 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER B. PACKAGE LEAFLET You and your partner’s fertility should be evaluated before the treatment is started by a doctor experienced in treating fertility disorders. This leaflet was last revised in

{'Title': '1. what bemfola is and what it is used for', 'Section_Content': 'what bemfola is this medicine contains the active substance follitropin alfa, which is almost identical to a natural hormone produced by your body called "follicle-stimulating hormone" (fsh). fsh is a gonadotropin, a type of hormone that plays an important role in human fertility and reproduction. in women, fsh is needed for the growth and development of the sacs (follicles) in the ovaries that contain the egg cells. in men, fsh is needed for the production of sperm. what bemfola is used for in adult women, bemfola is used: to help release an egg from the ovary (ovulation) in women that cannot ovulate and that did not respond to treatment with a medicine called "clomiphene citrate". together with another medicine called "lutropin alfa" ("luteinising hormone" or lh) to help release an egg from the ovary (ovulation) in women that are not ovulating because their body is producing very little gonadotropins (fsh and lh). to help develop several follicles (each containing an egg) in women undergoing assisted reproductive technology procedures (procedures that may help you to become pregnant) such as "in vitro fertilisation", "gamete intra-fallopian transfer" or "zygote intra-fallopian transfer". in adult men, bemfola is used: together with another medicine called "human chorionic gonadotropin" (hcg) to help produce sperm in men that are infertile due to a low level of certain hormones.', 'Entity_Recognition': [{'Text': 'bemfola', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 16, 'EndOffset': 29}, {'Text': 'the active substance follitropin alfa', 'Type': 'TREATMENT', 'BeginOffset': 39, 'EndOffset': 76}, {'Text': 'a gonadotropin', 'Type': 'TREATMENT', 'BeginOffset': 199, 'EndOffset': 213}, {'Text': 'a type of hormone', 'Type': 'TREATMENT', 'BeginOffset': 215, 'EndOffset': 232}, {'Text': 'fsh', 'Type': 'TREATMENT', 'BeginOffset': 309, 'EndOffset': 312}, {'Text': 'the growth', 'Type': 'PROBLEM', 'BeginOffset': 327, 'EndOffset': 337}, {'Text': 'the sacs (follicles) in the ovaries', 'Type': 'PROBLEM', 'BeginOffset': 357, 'EndOffset': 392}, {'Text': 'the production of sperm', 'Type': 'PROBLEM', 'BeginOffset': 447, 'EndOffset': 470}, {'Id': 1, 'BeginOffset': 562, 'EndOffset': 567, 'Score': 0.621220052242279, 'Text': 'ovary', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 637, 'EndOffset': 646}, {'Text': 'a medicine', 'Type': 'TREATMENT', 'BeginOffset': 652, 'EndOffset': 662}, {'Text': '"clomiphene citrate', 'Type': 'TREATMENT', 'BeginOffset': 670, 'EndOffset': 689}, {'Text': 'another medicine', 'Type': 'TREATMENT', 'BeginOffset': 706, 'EndOffset': 722}, {'Text': '"lutropin alfa"', 'Type': 'TREATMENT', 'BeginOffset': 730, 'EndOffset': 745}, {'Text': 'luteinising hormone"', 'Type': 'TREATMENT', 'BeginOffset': 748, 'EndOffset': 768}, {'Id': 2, 'BeginOffset': 808, 'EndOffset': 813, 'Score': 0.6062977910041809, 'Text': 'ovary', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'very little gonadotropins', 'Type': 'PROBLEM', 'BeginOffset': 890, 'EndOffset': 915}, {'Text': 'several follicles', 'Type': 'PROBLEM', 'BeginOffset': 946, 'EndOffset': 963}, {'Text': 'assisted reproductive technology procedures', 'Type': 'TREATMENT', 'BeginOffset': 1009, 'EndOffset': 1052}, {'Text': 'procedures', 'Type': 'TREATMENT', 'BeginOffset': 1054, 'EndOffset': 1064}, {'Id': 6, 'BeginOffset': 1093, 'EndOffset': 1101, 'Score': 0.9930069446563721, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9420676231384277}]}, {'Text': 'another medicine', 'Type': 'TREATMENT', 'BeginOffset': 1254, 'EndOffset': 1270}, {'Text': '"human chorionic gonadotropin"', 'Type': 'TREATMENT', 'BeginOffset': 1278, 'EndOffset': 1308}, {'Text': 'infertile', 'Type': 'PROBLEM', 'BeginOffset': 1353, 'EndOffset': 1362}, {'Text': 'a low level of certain hormones', 'Type': 'PROBLEM', 'BeginOffset': 1370, 'EndOffset': 1401}]}

{'Title': '2. what you need to know before you use bemfola', 'Section_Content': 'you and your partner\'s fertility should be evaluated before the treatment is started by a doctor experienced in treating fertility disorders. do not use bemfola if you are allergic to follicle stimulating hormone or any of the other ingredients of this medicine (listed in section 6). if you have a tumour in your hypothalamus or pituitary gland (both are parts of the brain). if you are a woman: - with large ovaries or sacs of fluids within the ovaries (ovarian cysts) of unknown origin. - with unexplained vaginal bleeding. - with cancer in your ovaries, womb or breasts. - with a condition that usually makes normal pregnancy impossible, such as ovarian failure (early menopause), or malformed reproductive organs. if you are a man: - with damaged testicles that cannot be healed. do not use bemfola if any of the above applies to you. if you are not sure, talk to your doctor or pharmacist before using this medicine. warnings and precautions porphyria tell your doctor before you start treatment, if you or any member of your family have porphyria (an inability to break down porphyrins that may be passed on from parents to children). tell your doctor straight away if: your skin becomes fragile and easily blistered, especially skin that has been frequently in the sun, and/or you have stomach, arm or leg pain. in case of the above events your doctor may recommend that you stop treatment. ovarian hyper-stimulation syndrome (ohss) if you are a woman, this medicine increases your risk of developing ohss. this is when your follicles develop too much and become large cysts. if you get lower abdominal pain, gain any weight rapidly, feel sick or are vomiting or if you have difficulty in breathing, talk to your doctor straight away who might ask you to stop using this medicine (see section 4). in case you are not ovulating, and if the recommended dose and schedule of administration are adhered to, the occurrence of ohss is less likely. bemfola treatment seldom causes severe ohss unless the medicine that is used for final follicular maturation (containing human chorionic gonadotropin, hcg) is administered. if you are developing ohss your doctor may not give you any hcg in this treatment cycle and you may be told not to have sex or to use a barrier contraceptive method for at least four days. multiple pregnancy when using bemfola, you have a higher risk of being pregnant with more than one child at the same time ("multiple pregnancy", mostly twins), than if you conceive naturally. a multiple pregnancy may lead to medical complications for you and your babies. you can reduce the risk of multiple pregnancy by using the right dose of bemfola at the right times. when undergoing assisted reproductive technology the risk of having a multiple pregnancy is related to your age, the quality and the number of fertilised eggs or embryos placed inside you. miscarriage when undergoing assisted reproductive technology or stimulation of your ovaries to produce eggs, you are more likely to have a miscarriage than the average woman. blood clotting problems (thromboembolic events) 84 if you had in the past or recently blood clots in the leg or in the lung, or a heart attack or stroke, or if those happened in your family, then you might have a higher risk that these problems occur or become worse with bemfola treatment. men with too much fsh in their blood if you are a man, having too much fsh in your blood can be a sign of damaged testicles. bemfola usually does not work if you have this problem. if your doctor decides to try bemfola treatment, to monitor the treatment, they may ask you to provide semen for analysis 4 to 6 months after starting treatment. children and adolescents bemfola is not indicated for use in children and adolescents under 18 years of age. other medicines and bemfola tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. if you use bemfola with other medicines which help ovulation (such as hcg or clomiphene citrate), this may increase the response of your follicles. if you use bemfola at the same time as a "gonadotropin-releasing hormone" (gnrh) agonist or antagonist (these medicines reduce your sex hormone levels and stop you ovulating) you may need a higher dose of bemfola to produce follicles. pregnancy and breast-feeding do not use bemfola if you are pregnant or breast-feeding. driving and using machines it is not expected that this medicine will affect your ability to drive and use machines. bemfola contains sodium this medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially "sodium- free".', 'Entity_Recognition': [{'Text': 'bemfola', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 60, 'EndOffset': 73}, {'Id': 15, 'BeginOffset': 121, 'EndOffset': 140, 'Score': 0.841837465763092, 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{'Title': '3. how to use bemfola', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. using this medicine bemfola is intended to be given by injection just under the skin (subcutaneously). use the pre- filled pen only once then it should be disposed of in a safe manner. do not administered the solution if it contains particles or is not clear. the first injection of bemfola should be given under supervision of your doctor. your doctor or nurse will show you how to use the bemfola pre-filled pen to inject the medicine. if you administer bemfola to yourself, please carefully read and follow the "instructions for use". these instructions can be found at the end of the package leaflet. how much to use your doctor will decide how much medicine you will use and how often. the doses described below are stated in international units (iu) and millilitres (ml). women if you are not ovulating and have irregular or no periods 85 bemfola is usually given every day. if you have irregular periods, start using bemfola within the first 7 days of your menstrual cycle. if you do not have periods you can start using the medicine on any convenient day. the usual starting dose of bemfola is 75 to 150 iu (0.12 to 0.25 ml) each day. your dose of bemfola may be increased every 7 or every 14 days by 37.5 to 75 iu, until you get the desired response or your doctor tells you to stop, see below. the maximum daily dose of bemfola is usually not higher than 225 iu (0.375 ml). when you get the desired response, you will be given a single injection of 250 micrograms of "recombinant hcg" (r-hcg, an hcg made in a laboratory by a special dna technique), or 5,000 to 10,000 iu of hcg, 24 to 48 hours after your last bemfola injection. the best time to have sex is on the day of the hcg injection and the day after. if your doctor cannot see a desired response after 4 weeks, that treatment cycle with bemfola should be stopped. for the following treatment cycle, your doctor will give you a higher starting dose of bemfola than before. if your body responds too strongly, your treatment will be stopped and you will not be given any hcg (see section 2, ohss). for the following cycle, your doctor will give you a lower dose of bemfola than before. if you are not ovulating, have no periods and have been diagnosed with very low levels of fsh and lh hormones the usual starting dose of bemfola is 75 to 150 iu (0.12 to 0.25 ml) together with 75 iu (0.12 ml) of lutropin alfa. you will use these two medicines each day for up to five weeks. your dose of bemfola may be increased every 7 or every 14 days by 37.5 to 75 iu, until you get the desired response. when you get the desired response, you will be given a single injection of 250 micrograms of "recombinant hcg" (r-hcg, an hcg made in a laboratory by a special dna technique), or 5,000 to 10,000 iu of hcg, 24 to 48 hours after your last injections of bemfola and lutropin alfa. the best time to have sex is on the day of the hcg injection and the day after. alternatively, intrauterine insemination may be performed by placing the sperm into the womb cavity. if your doctor cannot see a response after 5 weeks, that treatment cycle with bemfola should be stopped. for the following cycle, your doctor will give you a higher starting dose of bemfola than before. if your body responds too strongly, your treatment with bemfola will be stopped and you will not be given any hcg (see section 2, ohss). for the following cycle, your doctor will give you a lower dose of bemfola than before. if you need to develop several eggs for collection prior to any assisted reproductive technology the usual starting dose of bemfola is 150 to 225 iu (0.25 to 0.37 ml) each day, from day 2 or 3 of your treatment cycle. bemfola dose may be increased, depending on your response. the maximum daily dose is 450 iu (0.75 ml). treatment is continued until your eggs have developed to a desired point. this usually takes about 10 days but can take any time between 5 and 20 days. your doctor will use blood tests and/or an ultrasound machine to check when this is. when your eggs are ready, you will be given a single injection of 250 micrograms "recombinant hcg" (r-hcg, an hcg made in a laboratory by a special recombinant dna technique), or 86 5,000 iu to 10,000 iu of hcg, 24 to 48 hours after the last bemfola injection. this gets your eggs ready for collection. in other cases, your doctor may first stop you from ovulating by using a gonadotropin-releasing hormone (gnrh) agonist or antagonist. then bemfola is started approximately two weeks after start of agonist treatment. the bemfola and gnrh agonist are then both given until your follicles develop as desired. for example, after two weeks of gnrh agonist treatment, 150 to 225 iu bemfola is administered for 7 days. the dose is then adjusted according to your ovarian response. when gnrh antagonist is used, it is administered from the 5th or 6th day of bemfola treatment and continued until ovulation induction. men the usual dose of bemfola is 150 iu (0.25 ml) together with hcg. you will use these two medicines three times a week for at least 4 months. if you have not responded to treatment after 4 months, your doctor may suggest that you continue using these two medicines for at least 18 months. if you use more bemfola than you should the effects of taking too much bemfola are unknown. nevertheless one could expect ovarian hyper- stimulation syndrome (ohss) to occur, which is described in section 4. however the ohss will only occur if hcg is also administered (see section 2, under \'ohss\'). if you forget to use bemfola if you forget to use bemfola, do not take a double dose to make up for a forgotten dose. please talk to your doctor as soon as you notice that you forgot a dose. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects in women lower abdominal pain together with nausea or vomiting may be the symptoms of ovarian hyper-stimulation syndrome (ohss). this may indicate that the ovaries over-reacted to the treatment and that large ovarian cysts developed (see also section 2 "take special care with bemfola"). this side effect is common (may affect up to 1 in 10 people). ohss may become severe with clearly enlarged ovaries, decreased urine production, weight gain, difficulty in breathing and/or possible fluid accumulation in your stomach or chest. this side effect is uncommon (may affect up to 1 in 100 people). complications of ohss such as twisting of ovaries or blood clotting may occur rarely (may affect up to 1 in 1,000 people). serious blood clotting complications (thromboembolic events) sometimes independent of ohss may be found very rarely (may affect up to 1 in 10,000 people). this could cause chest pain, breathlessness, stroke or heart attack (see also section 2 under \'blood clotting problems\'). serious side effects in men and women allergic reactions such as rash, red skin, hives, swelling of your face with difficulty breathing can sometimes be serious. this side effect is very rare if you notice any of the above-listed side effects you should immediately contact your doctor, who might ask you to stop using bemfola. other side effects in women very common (may affect more than 1 in 10 people): sacs of fluid within the ovaries (ovarian cysts) headache local reactions at the injection site, such as pain, redness, bruising, swelling and/or irritation common (may affect up to 1 in 10 people): abdominal pain feeling sick, vomiting, diarrhoea, abdominal cramps and bloating very rare (may affect up to 1 in 10,000 people): allergic reactions such as rash, red skin, hives, swelling of your face with difficulty breathing may occur. these reactions can sometimes be serious. your asthma may get worse other side effects in men very common (may affect more than 1 in 10 people): local reactions at the injection site, such as pain, redness, bruising, swelling and/or irritation common (may affect up to 1 in 10 people): swelling of the veins above and behind the testicles (varicocele). breast development, acne or weight gain. very rare (may affect up to 1 in 10,000 people): allergic reactions such as rash, red skin, hives, swelling of your face with difficulty in breathing may occur. these reactions can sometimes be serious. your asthma may get worse. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 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{'Title': '5. how to store bemfola', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date, which is stated on the pen label and carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 - 8). do not freeze. store in the original package in order to protect from light. within its shelf life, the unopened pen may be stored at or below 25 for up to 3 months without being refrigerated again and must be discarded if it has not been used after 3 months. do not use this medicine if you notice any visible signs of deterioration, if the liquid contains particles or is not clear. once opened, the medicine should be injected immediately. do not throw any medicines away via wastewater or household waste. ask your pharmacist how to dispose of medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'bemfola', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 392, 'EndOffset': 394}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 405, 'EndOffset': 406}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 499, 'EndOffset': 500}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 520, 'EndOffset': 533}, {'Text': 'deterioration', 'Type': 'PROBLEM', 'BeginOffset': 569, 'EndOffset': 582}, {'Text': 'the liquid contains particles', 'Type': 'PROBLEM', 'BeginOffset': 587, 'EndOffset': 616}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 647, 'EndOffset': 659}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 797, 'EndOffset': 806}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 826, 'EndOffset': 840}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what bemfola contains the active substance is follitropin alfa. bemfola 75 iu/0.125 ml: each cartridge contains 75 iu (equivalent to 5.5 micrograms) follitropin alfa in 0.125 ml solution. bemfola 150 iu/0.25 ml: each cartridge contains 150 iu (equivalent to 11 micrograms) follitropin alfa in 0.25 ml solution. bemfola 225 iu/0.375 ml: each cartridge contains 225 iu (equivalent to 16.5 micrograms) follitropin alfa in 0.375 ml solution. bemfola 300 iu/0.50 ml: each cartridge contains 300 iu (equivalent to 22 micrograms) follitropin alfa in 0.50 ml solution. bemfola 450 iu/0.75 ml: each cartridge contains 450 iu (equivalent to 33 micrograms) follitropin alfa in 0.75 ml solution. each ml of the solution contains 600 iu (equivalent to 44 micrograms) follitropin alfa. the other ingredients are poloxamer 188, sucrose, methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, phosphoric acid and water for injections. what bemfola looks like and contents of the pack bemfola is presented as a clear, colourless liquid for injection in a pre-filled pen (injection). bemfola is supplied in packs with 1, 5 or 10 pre-filled pens, 1, 5 or 10 disposable needles and 1, 5 or 10 alcohol swabs. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'bemfola', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 46, 'EndOffset': 62, 'Score': 0.9896915555000305, 'Text': 'follitropin alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8266546726226807, 'RelationshipScore': 0.9667745232582092, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 72, 'EndOffset': 77, 'Text': '75 iu', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.793348491191864, 'RelationshipScore': 0.8826727867126465, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 78, 'EndOffset': 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284AEF4A93DF6030B4AB6CEC34042E38

https://www.ema.europa.eu/documents/product-information/epoetin-alfa-hexal-epar-product-information_en.pdf

Epoetin Alfa Hexal

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 1,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 2,000 IU/1 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 3,000 IU/0.3 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 4,000 IU/0.4 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 5,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 6,000 IU/0.6 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 7,000 IU/0.7 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 8,000 IU/0.8 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 9,000 IU/0.9 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 10,000 IU/1 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 20,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 30,000 IU/0.75 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 40,000 IU/1 mL solution for injection in a pre-filled syringe 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Epoetin alfa HEXAL 1,000 IU/0.5 mL solution for injection in a pre-filled syringe Each mL of solution contains 2,000 IU of epoetin alfa* corresponding to 16.8 micrograms per mL A pre-filled syringe of 0.5 mL contains 1,000 international units (IU) corresponding to 8.4 micrograms epoetin alfa. * Epoetin alfa HEXAL 2,000 IU/1 mL solution for injection in a pre-filled syringe Each mL of solution contains 2,000 IU of epoetin alfa* corresponding to 16.8 micrograms per mL A pre-filled syringe of 1 mL contains 2,000 international units (IU) corresponding to 16.8 micrograms epoetin alfa. * Epoetin alfa HEXAL 3,000 IU/0.3 mL solution for injection in a pre-filled syringe Each mL of solution contains 10,000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL A pre-filled syringe of 0.3 mL contains 3,000 international units (IU) corresponding to 25.2 micrograms epoetin alfa. * Epoetin alfa HEXAL 4,000 IU/0.4 mL solution for injection in a pre-filled syringe Each mL of solution contains 10,000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL A pre-filled syringe of 0.4 mL contains 4,000 international units (IU) corresponding to 33.6 micrograms epoetin alfa. * Epoetin alfa HEXAL 5,000 IU/0.5 mL solution for injection in a pre-filled syringe Each mL of solution contains 10,000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL A pre-filled syringe of 0.5 mL contains 5,000 international units (IU) corresponding to 42.0 micrograms epoetin alfa. * Epoetin alfa HEXAL 6,000 IU/0.6 mL solution for injection in a pre-filled syringe Each mL of solution contains 10,000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL A pre-filled syringe of 0.6 mL contains 6,000 international units (IU) corresponding to 50.4 micrograms epoetin alfa. * Epoetin alfa HEXAL 7,000 IU/0.7 mL solution for injection in a pre-filled syringe Each mL of solution contains 10,000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL A pre-filled syringe of 0.7 mL contains 7,000 international units (IU) corresponding to 58.8 micrograms epoetin alfa. * 3 Epoetin alfa HEXAL 8,000 IU/0.8 mL solution for injection in a pre-filled syringe Each mL of solution contains 10,000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL A pre-filled syringe of 0.8 mL contains 8,000 international units (IU) corresponding to 67.2 micrograms epoetin alfa. * Epoetin alfa HEXAL 9,000 IU/0.9 mL solution for injection in a pre-filled syringe Each mL of solution contains 10,000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL A pre-filled syringe of 0.9 mL contains 9,000 international units (IU) corresponding to 75.6 micrograms epoetin alfa. * Epoetin alfa HEXAL 10,000 IU/1 mL solution for injection in a pre-filled syringe Each mL of solution contains 10,000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL A pre-filled syringe of 1 mL contains 10,000 international units (IU) corresponding to 84.0 micrograms epoetin alfa. * Epoetin alfa HEXAL 20,000 IU/0.5 mL solution for injection in a pre-filled syringe Each mL of solution contains 40,000 IU of epoetin alfa* corresponding to 336.0 micrograms per mL A pre-filled syringe of 0.5 mL contains 20,000 international units (IU) corresponding to 168.0 micrograms epoetin alfa. * Epoetin alfa HEXAL 30,000 IU/0.75 mL solution for injection in a pre-filled syringe Each mL of solution contains 40,000 IU of epoetin alfa* corresponding to 336.0 micrograms per mL A pre-filled syringe of 0.75 mL contains 30,000 international units (IU) corresponding to 252.0 micrograms epoetin alfa. * Epoetin alfa HEXAL 40,000 IU/1 mL solution for injection in a pre-filled syringe Each mL of solution contains 40,000 IU of epoetin alfa* corresponding to 336.0 micrograms per mL A pre-filled syringe of 1 mL contains 40,000 international units (IU) corresponding to 336.0 micrograms epoetin alfa. * * Produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology For the full list of excipients, see section 6.1. This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”. 3. PHARMACEUTICAL FORM Solution for injection in a pre-filled syringe (injection) Clear, colourless solution 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Epoetin alfa HEXAL is indicated for the treatment of symptomatic anaemia associated with chronic renal failure (CRF): - in adults and children aged 1 to 18 years on haemodialysis and adult patients on peritoneal dialysis (see section 4.4). - in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients (see section 4.4). 4 Epoetin alfa HEXAL is indicated in adults receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma, and at risk of transfusion as assessed by the patient’s general status (e.g. cardiovascular status, pre-existing anaemia at the start of chemotherapy) for the treatment of anaemia and reduction of transfusion requirements. Epoetin alfa HEXAL is indicated in adults in a predonation programme to increase the yield of autologous blood. Treatment should only be given to patients with moderate anaemia (haemoglobin [Hb] concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency), if blood saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males). Epoetin alfa HEXAL is indicated for non-iron deficient adults prior to major elective orthopaedic surgery, having a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions. Use should be restricted to patients with moderate anaemia (e.g. haemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation programme available and with expected moderate blood loss (900 to 1,800 mL). Epoetin alfa HEXAL is indicated for the treatment of symptomatic anaemia (haemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes (MDS) who have low serum erythropoietin (< 200 mU/mL). 4.2 Posology and method of administration Treatment with Epoetin alfa HEXAL has to be initiated under the supervision of physicians experienced in the management of patients with the above indications. Posology All other causes of anaemia (iron, folate or vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be evaluated and treated prior to initiating therapy with epoetin alfa, and when deciding to increase the dose. In order to ensure optimum response to epoetin alfa, adequate iron stores should be assured and iron supplementation should be administered if necessary (see section 4.4). Treatment of symptomatic anaemia in adult chronic renal failure patients Anaemia symptoms and sequelae may vary with age, gender, and co-morbid medical conditions; a physician’s evaluation of the individual patient’s clinical course and condition is necessary. The recommended desired haemoglobin concentration range is between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). Epoetin alfa HEXAL should be administered in order to increase haemoglobin to not greater than 12 g/dL (7.5 mmol/L). A rise in haemoglobin of greater than 2 g/dL (1.25 mmol/L) over a four week period should be avoided. If it occurs, appropriate dose adjustment should be made as provided. Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin concentration range may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin concentration range of 10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L). A sustained haemoglobin level of greater than 12 g/dL (7.5 mmol/L) should be avoided. If the haemoglobin is rising by more than 2 g/dL (1.25 mmol/L) per month, or if the sustained haemoglobin exceeds 12 g/dL (7.5 mmol/L) reduce the Epoetin alfa HEXAL dose by 25%. If the haemoglobin exceeds 13 g/dL (8.1 mmol/L), discontinue therapy until it falls below 12 g/dL (7.5 mmol/L) and then reinstitute Epoetin alfa HEXAL therapy at a dose 25% below the previous dose. 5 Patients should be monitored closely to ensure that the lowest approved effective dose of Epoetin alfa HEXAL is used to provide adequate control of anaemia and of the symptoms of anaemia whilst maintaining a haemoglobin concentration below or at 12 g/dL (7.5 mmol/L). Caution should be exercised with escalation of Epoetin alfa HEXAL doses in patients with chronic renal failure. In patients with a poor haemoglobin response to Epoetin alfa HEXAL, alternative explanations for the poor response should be considered (see section 4.4 and 5.1). Treatment with Epoetin alfa HEXAL is divided into two stages – correction and maintenance phase. Adult haemodialysis patients In patients on haemodialysis where intravenous access is readily available, administration by the intravenous route is preferable. Correction phase The starting dose is 50 IU/kg, 3 times per week. If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desired haemoglobin concentration range between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L) is achieved (this should be done in steps of at least four weeks). Maintenance phase The recommended total weekly dose is between 75 IU/kg and 300 IU/kg. Appropriate adjustment of the dose should be made in order to maintain haemoglobin values within the desired concentration range between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). Patients with very low initial haemoglobin (< 6 g/dL or < 3.75 mmol/L) may require higher maintenance doses than patients whose initial anaemia is less severe (> 8 g/dL or > 5 mmol/L). Adult patients with renal insufficiency not yet undergoing dialysis Where intravenous access is not readily available Epoetin alfa HEXAL may be administered subcutaneously. Correction phase Starting dose of 50 IU/kg, 3 times per week, followed if necessary by a dosage increase with 25 IU/kg increments (3 times per week) until the desired goal is achieved (this should be done in steps of at least four weeks). Maintenance phase During the maintenance phase, Epoetin alfa HEXAL can be administered either 3 times per week, and in the case of subcutaneous administration, once weekly or once every 2 weeks. Appropriate adjustment of dose and dose intervals should be made in order to maintain haemoglobin values at the desired level: haemoglobin between 10 g/dL and 12 g/dL (6.2 to 7.5 mmol/L). Extending dose intervals may require an increase in dose. The maximum dosage should not exceed 150 IU/kg, 3 times per week, 240 IU/kg (up to a maximum of 20,000 IU) once weekly, or 480 IU/kg (up to a maximum of 40,000 IU) once every 2 weeks. Adult peritoneal dialysis patients Where intravenous access is not readily available Epoetin alfa HEXAL may be administered subcutaneously. 6 Correction phase The starting dose is 50 IU/kg, 2 times per week. Maintenance phase The recommended maintenance dose is between 25 IU/kg and 50 IU/kg, 2 times per week in 2 equal injections. Appropriate adjustment of the dose should be made in order to maintain haemoglobin values at the desired level between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). Treatment of adult patients with chemotherapy-induced anaemia Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary. Epoetin alfa HEXAL should be administered to patients with anaemia (e.g. haemoglobin concentration ≤ 10 g/dL (6.2 mmol/L)). The initial dose is 150 IU/kg subcutaneously, 3 times per week. Alternatively, Epoetin alfa HEXAL can be administered at an initial dose of 450 IU/kg subcutaneously once weekly. Appropriate adjustment of the dose should be made in order to maintain haemoglobin concentrations within the desired concentration range between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). Due to intra-patient variability, occasional individual haemoglobin concentrations for a patient above and below the desired haemoglobin concentration range may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the desired haemoglobin concentration range between 10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L). A sustained haemoglobin concentration of greater than 12 g/dL (7.5 mmol/L) should be avoided; guidance for appropriate dose adjustment for when haemoglobin concentrations exceed 12 g/dL (7.5 mmol/L) is described below. - If the haemoglobin concentration has increased by at least 1 g/dL (0.62 mmol/L) or the reticulocyte count has increased ≥ 40,000 cells/µL above baseline after 4 weeks of treatment, the dose should remain at 150 IU/kg 3 times per week or 450 IU/kg once weekly. - If the haemoglobin concentration increase is < 1 g/dL (< 0.62 mmol/L) and the reticulocyte count has increased < 40,000 cells/µL above baseline, increase the dose to 300 IU/kg 3 times per week. If after an additional 4 weeks of therapy at 300 IU/kg 3 times per week, the haemoglobin concentration has increased ≥ 1 g/dL (≥ 0.62 mmol/L) or the reticulocyte count has increased ≥ 40,000 cells/µL, the dose should remain at 300 IU/kg 3 times per week. - If the haemoglobin concentration has increased < 1 g/dL (< 0.62 mmol/L) and the reticulocyte count has increased < 40,000 cells/µL above baseline, response is unlikely and treatment should be discontinued. Dose adjustment to maintain haemoglobin concentrations between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L) If the haemoglobin concentration is increasing by more than 2 g/dL (1.25 mmol/L) per month, or if the haemoglobin concentration level exceeds 12 g/dL (7.5 mmol/L), reduce the Epoetin alfa HEXAL dose by about 25 to 50%. If the haemoglobin concentration level exceeds 13 g/dL (8.1 mmol/L), discontinue therapy until it falls below 12 g/dL (7.5 mmol/L) and then reinitiate Epoetin alfa HEXAL therapy at a dose 25% below the previous dose. 7 The recommended dosing regimen is described in the following diagram: 150 IU/kg 3x/week or 450 IU/kg once weekly for 4 weeks Reticulocyte count increase ≥ 40,000/µL Reticulocyte count increase < 40,000/µL or Hb increase ≥ 1 g/dL and Hb increase < 1 g/dL Target Hb 300 IU/kg (≤ 12 g/dL) 3x/week for 4 weeks Reticulocyte count increase ≥ 40,000/µL or Hb increase ≥ 1 g/dL Reticulocyte count increase < 40,000/µL and Hb increase < 1 g/dL Discontinue therapy Patients should be monitored closely to ensure that the lowest approved dose of erythropoiesis-stimulating agent (ESA) is used to provide adequate control of the symptoms of anaemia. Epoetin alfa therapy should continue until one month after the end of chemotherapy. Treatment of adult surgery patients in an autologous predonation programme Mildly anaemic patients (haematocrit of 33 to 39%) requiring predeposit of ≥ 4 units of blood should be treated with Epoetin alfa HEXAL 600 IU/kg intravenously, 2 times per week for 3 weeks prior to surgery. Epoetin alfa HEXAL should be administered after the completion of the blood donation procedure. Treatment of adult patients scheduled for major elective orthopaedic surgery The recommended dose is Epoetin alfa HEXAL 600 IU/kg, administered subcutaneously weekly for three weeks (days -21, -14 and -7) prior to surgery and on the day of surgery (day 0). In cases where there is a medical need to shorten the lead time before surgery to less than three weeks, Epoetin alfa HEXAL 300 IU/kg should be administered subcutaneously daily for 10 consecutive days prior to surgery, on the day of surgery and for four days immediately thereafter. 8 If the haemoglobin level reaches 15 g/dL (9.38 mmol/L), or higher, during the preoperative period, administration of Epoetin alfa HEXAL should be stopped and further dosages should not be administered. Treatment of adult patients with low- or intermediate-1-risk MDS Epoetin alfa HEXAL should be administered to patients with symptomatic anaemia (e.g. haemoglobin concentration ≤ 10 g/dL (6.2 mmol/L)). The recommended starting dose is Epoetin alfa HEXAL 450 IU/kg (maximum total dose is 40,000 IU) administered subcutaneously once every week, with not less than 5 days between doses. Appropriate dose adjustments should be made to maintain haemoglobin concentrations within the target range of 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). It is recommended that initial erythroid response be assessed 8 to 12 weeks following initiation of treatment. Dose increases and decreases should be done one dosing step at a time (see diagram below). A haemoglobin concentration of greater than 12 g/dL (7.5 mmol/L) should be avoided. Dose increase: Dose should not be increased over the maximum of 1050 IU/kg (total dose 80,000 IU) per week. If the patient loses response or haemoglobin concentration drops by ≥ 1 g/dL upon dose reduction the dose should be increased by one dosing step. A minimum of 4 weeks should elapse between dose increases. Dose hold and decrease: Epoetin alfa should be withheld when the haemoglobin concentration exceeds 12 g/dL (7.5 mmol/L). Once the haemoglobin level is < 11 g/dL the dose can be restarted on the same dosing step or one dosing step down based on physician judgement. Decreasing the dose by one dosing step should be considered if there is a rapid increase in haemoglobin (> 2 g/dL over 4 weeks). Anaemia symptoms and sequelae may vary with age, gender, and co-morbid medical conditions; a physician's evaluation of the individual patient's clinical course and condition is necessary. Paediatric population Treatment of symptomatic anaemia in chronic renal failure patients on haemodialysis Anaemia symptoms and sequelae may vary with age, gender, and co-morbid medical conditions; a physician’s evaluation of the individual patient’s clinical course and condition is necessary. In paediatric patients the recommended haemoglobin concentration range is between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L). Epoetin alfa HEXAL should be administered in order to increase haemoglobin to not greater than 11 g/dL (6.8 mmol/L). A rise in haemoglobin of greater than 2 g/dL (1.25 mmol/L) over a four week period should be avoided. If it occurs, appropriate dose adjustment should be made as provided. 9 Patients should be monitored closely to ensure that the lowest approved dose of Epoetin alfa HEXAL is used to provide adequate control of anaemia and of the symptoms of anaemia. Treatment with Epoetin alfa HEXAL is divided into two stages – correction and maintenance phase. In paediatric patients on haemodialysis where intravenous access is readily available, administration by the intravenous route is preferable. Correction phase The starting dose is 50 IU/kg intravenously, 3 times per week. If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desired haemoglobin concentration range of between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L) is achieved (this should be done in steps of at least four weeks). Maintenance phase Appropriate adjustment of the dose should be made in order to maintain haemoglobin levels within the desired concentration range between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L). Generally, children under 30 kg require higher maintenance doses than children over 30 kg and adults. Paediatric patients with very low initial haemoglobin (< 6.8 g/dL or < 4.25 mmol/L) may require higher maintenance doses than patients whose initial haemoglobin is higher (> 6.8 g/dL or > 4.25 mmol/L). Anaemia in chronic renal failure patients before initiation of dialysis or on peritoneal dialysis The safety and efficacy of epoetin alfa in chronic renal failure patients with anaemia before initiation of dialysis or on peritoneal dialysis have not been established. Currently available data for subcutaneous use of epoetin alfa in these populations are described in section 5.1 but no recommendation on posology can be made. Treatment of paediatric patients with chemotherapy-induced anaemia The safety and efficacy of epoetin alfa in paediatric patients receiving chemotherapy have not been established (see section 5.1). Treatment of paediatric surgery patients in an autologous predonation programme The safety and efficacy of epoetin alfa in paediatrics have not been established. No data are available. Treatment of paediatric patients scheduled for major elective orthopaedic surgery The safety and efficacy of epoetin alfa in paediatrics have not been established. No data are available. Method of administration Precautions to be taken before handling or administering the medicinal product. Before use, leave the Epoetin alfa HEXAL syringe to stand until it reaches room temperature. This usually takes between 15 and 30 minutes. As with any other injectable product, check that there are no particles in the solution or change in colour. Epoetin alfa HEXAL is a sterile but unpreserved product and is for single use only. Administer the amount required. Treatment of symptomatic anaemia in adult chronic renal failure patients In patients with chronic renal failure where intravenous access is routinely available (haemodialysis patients) administration of Epoetin alfa HEXAL by the intravenous route is preferable. 10 Where intravenous access is not readily available (patients not yet undergoing dialysis and peritoneal dialysis patients) Epoetin alfa HEXAL may be administered as a subcutaneous injection. Treatment of adult patients with chemotherapy-induced anaemia Epoetin alfa HEXAL should be administered as a subcutaneous injection. Treatment of adult surgery patients in an autologous predonation programme Epoetin alfa HEXAL should be administered by the intravenous route. Treatment of adult patients scheduled for major elective orthopaedic surgery Epoetin alfa HEXAL should be administered as a subcutaneous injection. Treatment of adult patients with low- or intermediate-1-risk MDS Epoetin alfa HEXAL should be administered as a subcutaneous injection. Treatment of symptomatic anaemia in paediatric chronic renal failure patients on haemodialysis In paediatric patients with chronic renal failure where intravenous access is routinely available (haemodialysis patients) administration of Epoetin alfa HEXAL by the intravenous route is preferable. Intravenous administration Administer over at least one to five minutes, depending on the total dose. In haemodialysed patients, a bolus injection may be given during the dialysis session through a suitable venous port in the dialysis line. Alternatively, the injection can be given at the end of the dialysis session via the fistula needle tubing, followed by 10 mL of isotonic saline to rinse the tubing and ensure satisfactory injection of the product into the circulation (see Posology, “Adult haemodialysis patients”). A slower administration is preferable in patients who react to the treatment with “flu-like” symptoms (see section 4.8). Do not administer Epoetin alfa HEXAL by intravenous infusion or in conjunction with other medicinal product solutions (please refer to section 6.6 for further information). Subcutaneous administration A maximum volume of 1 mL at one injection site should generally not be exceeded. In case of larger volumes, more than one site should be chosen for the injection. The injections should be given in the limbs or the anterior abdominal wall. In those situations in which the physician determines that a patient or caregiver can safely and effectively administer Epoetin alfa HEXAL subcutaneously themselves, instruction as to the proper dosage and administration should be provided. Graduation rings The syringe contains graduation rings to provide for the administration of a part of the dose (see section 6.6). However the product is for single use only. Only one dose of Epoetin alfa HEXAL from each syringe should be taken. “Instructions on how to inject Epoetin alfa HEXAL yourself” can be found at the end of the package leaflet. 4.3 Contraindications - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Patients who develop pure red cell aplasia (PRCA) following treatment with any erythropoietin should not receive Epoetin alfa HEXAL or any other erythropoietin (see section 4.4). 11 - Uncontrolled hypertension. - All contraindications associated with autologous blood predonation programmes should be respected in patients being supplemented with Epoetin alfa HEXAL. The use of Epoetin alfa HEXAL in patients scheduled for major elective orthopaedic surgery and not participating in an autologous blood predonation programme is contraindicated in patients with severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident. - Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis. 4.4 Special warnings and precautions for use General In all patients receiving epoetin alfa, blood pressure should be closely monitored and controlled as necessary. Epoetin alfa should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension. It may be necessary to add or increase anti-hypertensive treatment. If blood pressure cannot be controlled, epoetin alfa treatment should be discontinued. Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal (see section 4.8). Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity such as CNS infections and brain metastases. Epoetin alfa should be used with caution in patients with chronic liver failure. The safety of epoetin alfa has not been established in patients with hepatic dysfunction. An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see section 4.8). These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischaemic attacks) have been reported. The reported risk of these TVEs should be carefully weighed against the benefits to be derived from treatment with epoetin alfa particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs (e.g. deep venous thrombosis, pulmonary embolism, and cerebral vascular accident). In all patients, haemoglobin levels should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at haemoglobin levels above the concentration range for the indication of use. There may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with epoetin alfa. This regresses during the course of continued therapy. In addition, thrombocythaemia above the normal range has been reported. It is recommended that the platelet count is regularly monitored during the first 8 weeks of therapy. All other causes of anaemia (iron, folate or vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be evaluated and treated prior to initiating therapy with epoetin alfa, and when deciding to increase the dose. In 12 most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In order to ensure optimum response to epoetin alfa, adequate iron stores should be assured and iron supplementation should be administered if necessary (see section 4.2): - For chronic renal failure patients, iron supplementation (elemental iron 200 to 300 mg/day orally for adults and 100 to 200 mg/day orally for paediatrics) is recommended if serum ferritin levels are below 100 ng/mL. - For cancer patients, iron supplementation (elemental iron 200 to 300 mg/day orally) is recommended if transferrin saturation is below 20%. - For patients in an autologous predonation programme, iron supplementation (elemental iron 200 mg/day orally) should be administered several weeks prior to initiating the autologous predeposit in order to achieve high iron stores prior to starting epoetin alfa therapy, and throughout the course of epoetin alfa therapy. - For patients scheduled for major elective orthopaedic surgery, iron supplementation (elemental iron 200 mg/day orally) should be administered throughout the course of epoetin alfa therapy. If possible, iron supplementation should be initiated prior to starting epoetin alfa therapy to achieve adequate iron stores. Very rarely, development of or exacerbation of porphyria has been observed in epoetin alfa-treated patients. Epoetin alfa should be used with caution in patients with porphyria. Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment. More severe cases have been observed with long-acting epoetins. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Epoetin alfa HEXAL should be withdrawn immediately and an alternative treatment considered. If the patient has developed a severe cutaneous skin reaction such as SJS or TEN due to the use of Epoetin alfa HEXAL, treatment with Epoetin alfa HEXAL must not be restarted in this patient at any time. In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name and the batch number of the administered ESA should be clearly recorded (or stated) in the patient file. Patients should only be switched from one ESA to another under appropriate supervision. Pure Red Cell Aplasia (PRCA) Antibody-mediated PRCA has been reported after months to years of epoetin alfa treatment. Cases have also been reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. Epoetin alfa is not approved in the management of anaemia associated with hepatitis C. In patients developing sudden lack of efficacy defined by a decrease in haemoglobin (1 to 2 g/dL or 0.62 to 1.25 mmol/L per month) with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-response (e.g. iron, folate or vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be investigated. A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin alfa and perform anti-erythropoietin antibody testing. A bone marrow examination should also be considered for diagnosis of PRCA. 13 No other ESA therapy should be commenced because of the risk of cross-reaction. Treatment of symptomatic anaemia in adult and paediatric chronic renal failure patients Chronic renal failure patients being treated with epoetin alfa should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter. In chronic renal failure patients the rate of increase in haemoglobin should be approximately 1 g/dL (0.62 mmol/L) per month and should not exceed 2 g/dL (1.25 mmol/L) per month to minimise risks of an increase in hypertension. In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the haemoglobin concentration range as recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was observed when ESAs were administered to achieve a haemoglobin concentration level of greater than 12 g/dL (7.5 mmol/L). Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion. Caution should be exercised with escalation of Epoetin alfa HEXAL doses in patients with chronic renal failure since high cumulative epoetin doses may be associated with an increased risk of mortality, serious cardiovascular and cerebrovascular events. In patients with a poor haemoglobin response to epoetins, alternative explanations for the poor response should be considered (see section 4.2 and 5.1). Chronic renal failure patients treated with epoetin alfa by the subcutaneous route should be monitored regularly for loss of efficacy, defined as absent or decreased response to epoetin alfa treatment in patients who previously responded to such therapy. This is characterised by a sustained decrease in haemoglobin despite an increase in epoetin alfa dosage (see section 4.8). Some patients with more extended dosing intervals (greater than once weekly) of epoetin alfa may not maintain adequate haemoglobin levels (see section 5.1) and may require an increase in epoetin alfa dose. Haemoglobin levels should be monitored regularly. Shunt thromboses have occurred in haemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurysms, etc.). Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients. Hyperkalaemia has been observed in isolated cases though causality has not been established. Serum electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum potassium level is detected, then in addition to appropriate treatment of the hyperkalaemia, consideration should be given to ceasing epoetin alfa administration until the serum potassium level has been corrected. An increase in heparin dose during haemodialysis is frequently required during the course of therapy with epoetin alfa as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum. Based on information available to date, correction of anaemia with epoetin alfa in adult patients with renal insufficiency not yet undergoing dialysis does not accelerate the rate of progression of renal insufficiency. 14 Treatment of patients with chemotherapy-induced anaemia Cancer patients being treated with epoetin alfa should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter. Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumours. The role of ESAs on tumour progression or reduced progression-free survival cannot be excluded. In controlled clinical studies, use of epoetin alfa and other ESAs have been associated with decreased locoregional tumour control or decreased overall survival: - decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to achieve a haemoglobin concentration level of greater than 14 g/dL (8.7 mmol/L), - shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to achieve a haemoglobin concentration range of 12 to 14 g/dL (7.5 to 8.7 mmol/L), - increased risk of death when administered to achieve a haemoglobin concentration level of 12 g/dL (7.5 mmol/L) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population, - an observed 9% increase in risk for progress of disease (PD) or death in the epoetin alfa plus SOC group from a primary analysis and a 15% increased risk that cannot be statistically ruled out in patients with metastatic breast cancer receiving chemotherapy when administered to achieve a haemoglobin concentration range of 10 to 12 g/dL (6.2 to 7.5 mmol/L). In view of the above, in some clinical situations blood transfusion should be the preferred treatment for the management of anaemia in patients with cancer. The decision to administer recombinant erythropoietin treatment should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage; the degree of anaemia; life-expectancy; the environment in which the patient is being treated; and patient preference (see section 5.1). In cancer patients receiving chemotherapy, the 2 to 3 week delay between ESA administration and the appearance of erythropoietin-induced red cells should be taken into account when assessing if epoetin alfa therapy is appropriate (patient at risk of being transfused). Surgery patients in autologous predonation programmes All special warnings and special precautions associated with autologous predonation programmes, especially routine volume replacement, should be respected. Patients scheduled for major elective orthopaedic surgery Good blood management practices should always be used in the perisurgical setting. Patients scheduled for major elective orthopaedic surgery should receive adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those with underlying cardiovascular disease. In addition, special precaution should be taken in patients with predisposition for development of DVTs. Moreover, in patients with a baseline haemoglobin of 15 > 13 g/dL (> 8.1 mmol/L), the possibility that epoetin alfa treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, epoetin alfa should not be used in patients with baseline haemoglobin > 13 g/dL (> 8.1 mmol/L). Excipients This medicine contains less than 1 mmol sodium (23 mg) per pre-filled syringe, that is to say essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction No evidence exists that indicates that treatment with epoetin alfa alters the metabolism of other medicinal products. Medicinal products that decrease erythropoiesis may decrease the response to epoetin alfa. Since cyclosporin is bound by red blood cells (RBCs) there is potential for a medicinal product interaction. If epoetin alfa is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporin adjusted as the haematocrit rises. No evidence exists that indicates an interaction between epoetin alfa and granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) with regard to haematological differentiation or proliferation of tumour biopsy specimens in vitro. In female adult patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU/mL epoetin alfa with trastuzumab 6 mg/kg had no effect on the pharmacokinetics of trastuzumab. 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data from the use of epoetin alfa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Consequently, epoetin alfa should be used in pregnancy only if the potential benefit outweighs the potential risk to the foetus. The use of epoetin alfa is not recommended in pregnant surgical patients participating in an autologous blood predonation programme. Breast-feeding It is unknown whether exogenous epoetin alfa is excreted in human milk. Epoetin alfa should be used with caution in nursing women. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy with epoetin alfa taking into account the benefit of breast-feeding for the child and the benefit of epoetin alfa therapy for the woman. The use of epoetin alfa is not recommended in lactating surgical patients participating in an autologous blood predonation programme. Fertility There are no studies assessing the potential effect of epoetin alfa on male or female fertility. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Epoetin alfa HEXAL has no or negligible influence on the ability to drive and use machines. 16 4.8 Undesirable effects Summary of the safety profile The most frequent adverse drug reaction during treatment with epoetin alfa is a dose-dependent increase in blood pressure or aggravation of existing hypertension. Monitoring of the blood pressure should be performed, particularly at the start of therapy (see section 4.4). The most frequently occurring adverse drug reactions observed in clinical trials of epoetin alfa are diarrhoea, nausea, vomiting, pyrexia and headache. Influenza-like illness may occur especially at the start of treatment. Respiratory tract congestion, which includes events of upper respiratory tract congestion, nasal congestion and nasopharyngitis, have been reported in studies with extended interval dosing in adult patients with renal insufficiency not yet undergoing dialysis. An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see section 4.4). Tabulated list of adverse reactions Of a total 3,417 subjects in 25 randomised, double-blinded, placebo or standard of care controlled studies, the overall safety profile of epoetin alfa was evaluated in 2,094 anaemic subjects. Included were 228 epoetin alfa-treated CRF subjects in 4 chronic renal failure studies (2 studies in pre-dialysis [N = 131 exposed CRF subjects] and 2 in dialysis [N = 97 exposed CRF subjects]; 1,404 exposed cancer subjects in 16 studies of anaemia due to chemotherapy; 147 exposed subjects in 2 studies for autologous blood donation; 213 exposed subjects in 1 study in the perisurgical period, and 102 exposed subjects in 2 MDS studies. Adverse drug reactions reported by ≥ 1% of subjects treated with epoetin alfa in these trials are shown in the table below. Frequency estimate: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). MedDRA System Organ Classification (SOC) Adverse Reaction (Preferred Term Level) Frequency Blood and lymphatic system disorders Pure red cell aplasia3, Thrombocythaemia Rare Metabolism and nutrition disorders Hyperkalaemia 1 Uncommon Immune system disorders Hypersensitivity 3 Uncommon Anaphylactic reaction3 Rare Nervous system disorders Headache Common Convulsion Uncommon Vascular disorders Hypertension, Venous and arterial thromboses2 Common Hypertensive crisis3 Not known Respiratory, thoracic and mediastinal disorders Cough Common Respiratory tract congestion Uncommon Gastrointestinal disorders Diarrhoea, Nausea, Vomiting Very common Skin and subcutaneous tissue disorders Rash Common Urticaria3 Uncommon Angioneurotic oedema3 Not known Musculoskeletal and connective tissue disorders Arthralgia, Bone pain, Myalgia, Pain in extremity Common Congenital, familial and genetic disorders Porphyria acute 3 Rare General disorders and Pyrexia Very common 17 MedDRA System Organ Classification (SOC) Adverse Reaction (Preferred Term Level) Frequency administration site conditions Chills, Influenza like illness, Injection site reaction, Oedema peripheral Common Medicinal product ineffective3 Not known Investigations Anti-erythropoietin antibody positive Rare 1 Common in dialysis 2 Includes arterial and venous, fatal and non fatal events, such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascular accidents (including cerebral infarction and cerebral haemorrhage) transient ischaemic attacks, and shunt thrombosis (including dialysis equipment) and thrombosis within arteriovenous shunt aneurisms 3 Addressed in the subsection below and/or in section 4.4 Description of selected adverse reactions Hypersensitivity reactions, including cases of rash (including urticaria), anaphylactic reactions, and angioneurotic oedema have been reported (see section 4.4). Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal (see section 4.4). Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment (see section 4.4). Antibody-mediated pure red cell aplasia has been very rarely reported in < 1/10,000 cases per patient year after months to years of treatment with epoetin alfa (see section 4.4). More cases have been reported with subcutaneous (SC) route of administration, compared with the IV route. Adult patients with low- or intermediate-1-risk MDS In the randomised, double-blind, placebo-controlled, multicentre study 4 (4.7%) subjects experienced TVEs (sudden death, ischaemic stroke, embolism, and phlebitis). All TVEs occurred in the epoetin alfa group and in the first 24 weeks of the study. Three were confirmed TVE and in the remaining case (sudden death), the thromboembolic event was not confirmed. Two subjects had significant risk factors (atrial fibrillation, heart failure and thrombophlebitis). Paediatric population with chronic renal failure on haemodialysis The exposure of paediatric patients with chronic renal failure on haemodialysis in clinical trials and post-marketing experience is limited. No paediatric-specific adverse reactions not mentioned previously in the table above, or any that were not consistent with the underlying disease were reported in this population. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 18 4.9 Overdose The therapeutic margin of epoetin alfa is very wide. Overdosage of epoetin alfa may produce effects that are extensions of the pharmacological effects of the hormone. Phlebotomy may be performed if excessively high haemoglobin levels occur. Additional supportive care should be provided as necessary. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antianaemic preparations, erythropoietin, ATC code: B03XA01. Epoetin alfa HEXAL is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Mechanism of action Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response to hypoxia and is the key regulator of red blood cell (RBC) production. EPO is involved in all phases of erythroid development, and has its principal effect at the level of erythroid precursors. After EPO binds to its cell surface receptor, it activates signal transduction pathways that interfere with apoptosis and stimulates erythroid cell proliferation. Recombinant human EPO (epoetin alfa), expressed in Chinese hamster ovary cells, has a 165 amino acid sequence identical to that of human urinary EPO; the 2 are indistinguishable on the basis of functional assays. The apparent molecular weight of erythropoietin is 32,000 to 40,000 dalton. Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. Pharmacodynamic effects Healthy volunteers After single doses (20,000 to 160,000 IU subcutaneously) of epoetin alfa, a dose-dependent response was observed for the pharmacodynamic markers investigated including: reticulocytes, RBCs, and haemoglobin. A defined concentration-time profile with peak and return to baseline was observed for changes in percent reticulocytes. A less defined profile was observed for RBCs and haemoglobin. In general, all pharmacodynamic markers increased in a linear manner with dose reaching a maximum response at the highest dose levels. Further pharmacodynamic studies explored 40,000 IU once weekly versus 150 IU/kg 3 times per week. Despite differences in concentration-time profiles the pharmacodynamic response (as measured by changes in percent reticulocytes, haemoglobin, and total RBCs) was similar between these regimens. Additional studies compared the 40,000 IU once-weekly regimen of epoetin alfa with biweekly doses ranging from 80,000 to 120,000 IU subcutaneously. Overall, based on the results of these pharmacodynamic studies in healthy subjects, the 40,000 IU once-weekly dosing regimen seems to be more efficient in producing RBCs than the biweekly regimens despite an observed similarity in reticulocyte production in the once-weekly and biweekly regimens. Chronic renal failure Epoetin alfa has been shown to stimulate erythropoiesis in anaemic patients with CRF, including dialysis and pre-dialysis patients. The first evidence of a response to epoetin alfa is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, haemoglobin and haematocrit, usually within 2 to 6 weeks. The haemoglobin response varies between patients and may be impacted by iron stores and the presence of concurrent medical problems. 19 Chemotherapy-induced anaemia Epoetin alfa administered 3 times per week or once weekly has been shown to increase haemoglobin and decrease transfusion requirements after the first month of therapy in anaemic cancer patients receiving chemotherapy. In a study comparing the 150 IU/kg, 3 times per week and 40,000 IU, once-weekly dosing regimens in healthy subjects and in anaemic cancer subjects the time profiles of changes in percent reticulocytes, haemoglobin, and total red blood cells were similar between the two dosing regimens in both healthy and anaemic cancer subjects. The AUCs of the respective pharmacodynamic parameters were similar between the 150 IU/kg, 3 times per week and 40,000 IU, once-weekly dosing regimens in healthy subjects and also in anaemic cancer subjects. Adult surgery patients in an autologous predonation programme Epoetin alfa has been shown to stimulate red blood cell production in order to augment autologous blood collection, and to limit the decline in haemoglobin in adult patients scheduled for major elective surgery who are not expected to predeposit their complete perioperative blood needs. The greatest effects are observed in patients with low haemoglobin (≤ 13 g/dL). Treatment of adult patients scheduled for major elective orthopaedic surgery In patients scheduled for major elective orthopaedic surgery with a pretreatment haemoglobin of > 10 to ≤ 13 g/dL, epoetin alfa has been shown to decrease the risk of receiving allogeneic transfusions and hasten erythroid recovery (increased haemoglobin levels, haematocrit levels, and reticulocyte counts). Clinical efficacy and safety Chronic renal failure Epoetin alfa has been studied in clinical trials in adult anaemic CRF patients, including haemodialysis and pre-dialysis patients, to treat anaemia and maintain haematocrit within a target concentration range of 30 to 36%. In clinical trials at starting doses of 50 to 150 IU/kg, three times per week, approximately 95% of all patients responded with a clinically significant increase in haematocrit. After approximately two months of therapy, virtually all patients were transfusion-independent. Once the target haematocrit was achieved, the maintenance dose was individualised for each patient. In the three largest clinical trials conducted in adult patients on dialysis, the median maintenance dose necessary to maintain the haematocrit between 30 to 36% was approximately 75 IU/kg given 3 times per week. In a double-blind, placebo-controlled, multicentre, quality of life study in CRF patients on haemodialysis, clinically and statistically significant improvement was shown in the patients treated with epoetin alfa compared to the placebo group when measuring fatigue, physical symptoms, relationships and depression (Kidney Disease Questionnaire) after six months of therapy. Patients from the group treated with epoetin alfa were also enrolled in an open-label extension study which demonstrated improvements in their quality of life that were maintained for an additional 12 months. Adult patients with renal insufficiency not yet undergoing dialysis In clinical trials conducted in patients with CRF not on dialysis treated with epoetin alfa, the average duration of therapy was nearly five months. These patients responded to epoetin alfa therapy in a manner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and sustained increase in haematocrit when epoetin alfa was administered by either an intravenous or subcutaneous route. Similar rates of rise of haematocrit were noted when epoetin alfa was administered by either route. Moreover, epoetin alfa doses of 75 to 150 IU/kg per week have been shown to maintain haematocrits of 36 to 38% for up to six months. 20 In 2 studies with extended interval dosing of epoetin alfa (3 times per week, once weekly, once every 2 weeks, and once every 4 weeks) some patients with longer dosing intervals did not maintain adequate haemoglobin levels and reached protocol-defined haemoglobin withdrawal criteria (0% in once weekly, 3.7% in once-every-2-weeks, and 3.3% in the once-every-4-weeks groups). A randomised prospective trial evaluated 1,432 anaemic chronic renal failure patients who were not undergoing dialysis. Patients were assigned to epoetin alfa treatment targeting a maintenance haemoglobin level of 13.5 g/dL (higher than the recommended haemoglobin concentration level) or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke or hospitalisation for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher haemoglobin group compared to 97 (14%) among the 717 patients in the lower haemoglobin group (hazard ratio [HR] 1.3, 95% CI: 1.0, 1.7, p = 0.03). Pooled post-hoc analyses of clinical studies of ESAs have been performed in chronic renal failure patients (on dialysis, not on dialysis, in diabetic and non-diabetic patients). A tendency towards increased risk estimates for all-cause mortality, cardiovascular and cerebrovascular events associated with higher cumulative ESA doses independent of the diabetes or dialysis status was observed (see section 4.2 and section 4.4). Treatment of patients with chemotherapy-induced anaemia Epoetin alfa has been studied in clinical trials in adult anaemic cancer patients with lymphoid and solid tumors, and patients on various chemotherapy regimens, including platinum and non-platinum-containing regimens. In these trials, epoetin alfa administered 3 times per week and once weekly has been shown to increase haemoglobin and decrease transfusion requirements after the first month of therapy in anaemic cancer patients. In some studies, the double-blind phase was followed by an open-label phase during which all patients received epoetin alfa and a maintenance of effect was observed. Available evidence suggests patients with haematological malignancies and solid tumours respond equivalently to epoetin alfa therapy, and that patients with or without tumour infiltration of the bone marrow respond equivalently to epoetin alfa therapy. Comparable intensity of chemotherapy in the epoetin alfa and placebo groups in the chemotherapy trials was demonstrated by a similar area under the neutrophil time curve in patients treated with epoetin alfa and placebo-treated patients, as well as by a similar proportion of patients in groups treated with epoetin alfa and placebo-treated groups whose absolute neutrophil counts fell below 1,000 and 500 cells/µL. In a prospective, randomised, double-blind, placebo-controlled trial conducted in 375 anaemic patients with various non-myeloid malignancies receiving non-platinum chemotherapy, there was a significant reduction of anaemia-related sequelae (e.g. fatigue, decreased energy, and activity reduction), as measured by the following instruments and scales: Functional Assessment of Cancer Therapy-Anaemia (FACT-An) general scale, FACT-An fatigue scale, and Cancer Linear Analogue Scale (CLAS). Two other smaller, randomised, placebo-controlled trials failed to show a significant improvement in quality of life parameters on the EORTC-QLQ-C30 scale or CLAS, respectively. Survival and tumour progression have been examined in five large controlled studies involving a total of 2,833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. The studies either recruited patients who were being treated with chemotherapy (two studies) or used patient populations in which ESAs are not indicated: anaemia in patients with cancer not receiving chemotherapy, and head and neck cancer patients receiving radiotherapy. The desired haemoglobin concentration level in two studies was > 13 g/dL (8.1 mmol/L); in the remaining three studies it was 12 to 14 g/dL (7.5 to 8.7 mmol/L). In the open-label study there was no difference in overall survival between patients treated with recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazard ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have shown a consistent unexplained statistically significant excess mortality in patients who have anaemia associated with various common cancers who received recombinant human erythropoietin compared to controls. Overall survival outcome in the trials could not be satisfactorily explained by differences in the incidence of thrombosis and related complications between those given recombinant human erythropoietin and those in the control group. 21 A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-, radio-, chemoradio-, or no therapy) participating in 53 controlled clinical trials involving several epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in favour of controls (95% CI: 1.00, 1.12; 53 trials and 13,933 patients) and for the cancer patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and 10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section 4.4). A randomised, open-label, multicentre study was conducted in 2,098 anaemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non inferiority study designed to rule out a 15% risk increase in tumour progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. At the time of clinical data cutoff, the median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. Significantly fewer patients received RBC transfusions in the epoetin alfa plus SOC arm (5.8% versus 11.4%); however, significantly more patients had thrombotic vascular events in the epoetin alfa plus SOC arm (2.8% versus 1.4%). At the final analysis, 1653 deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07, 95% CI: 0.97, 1.18). The median time to progression (TTP) based on investigator-determined progressive disease (PD) was 7.5 months in the epoetin alfa plus SOC group and 7.5 months in the SOC group (HR 1.099, 95% CI: 0.998, 1.210). The median TTP based on IRC-determined PD was 8.0 months in the epoetin alfa plus SOC group and 8.3 months in the SOC group (HR 1.033, 95% CI: 0.924, 1.156). Autologous predonation programme The effect of epoetin alfa in facilitating autologous blood donation in patients with low haematocrits (≤ 39% and no underlying anaemia due to iron deficiency) scheduled for major orthopaedic surgery was evaluated in a double-blind, placebo-controlled study conducted in 204 patients, and a single-blind placebo controlled study in 55 patients. In the double-blind study, patients were treated with epoetin alfa 600 IU/kg or placebo intravenously once daily every 3 to 4 days over 3 weeks (total 6 doses). On average, patients treated with epoetin alfa were able to predeposit significantly more units of blood (4.5 units) than placebo-treated patients (3.0 units). In the single-blind study, patients were treated with epoetin alfa 300 IU/kg or 600 IU/kg or placebo intravenously once daily every 3 to 4 days over 3 weeks (total 6 doses). Patients treated with epoetin alfa were also able to predeposit significantly more units of blood (epoetin alfa 300 IU/kg = 4.4 units; epoetin alfa 600 IU/kg = 4.7 units) than placebo-treated patients (2.9 units). Epoetin alfa therapy reduced the risk of exposure to allogeneic blood by 50% compared to patients not receiving epoetin alfa. Major elective orthopaedic surgery The effect of epoetin alfa (300 IU/kg or 100 IU/kg) on the exposure to allogeneic blood transfusion has been evaluated in a placebo-controlled, double-blind clinical trial in non-iron deficient adult patients scheduled for major elective orthopaedic hip or knee surgery. Epoetin alfa was administered subcutaneously for 10 days prior to surgery, on the day of surgery, and for four days after surgery. Patients were stratified according to their baseline haemoglobin (≤ 10 g/dL, > 10 to ≤ 13 g/dL and > 13 g/dL). Epoetin alfa 300 IU/kg significantly reduced the risk of allogeneic transfusion in patients with a pretreatment haemoglobin of > 10 to ≤ 13 g/dL. Sixteen percent of epoetin alfa 300 IU/kg, 23% of epoetin alfa 100 IU/kg and 45% of placebo-treated patients required transfusion. 22 An open-label, parallel-group trial in non-iron deficient adult subjects with a pretreatment haemoglobin of ≥ 10 to ≤ 13 g/dL who were scheduled for major orthopaedic hip or knee surgery compared epoetin alfa 300 IU/kg subcutaneously daily for 10 days prior to surgery, on the day of surgery and for four days after surgery to epoetin alfa 600 IU/kg subcutaneously once weekly for 3 weeks prior to surgery and on the day of surgery. From pretreatment to presurgery, the mean increase in haemoglobin in the 600 IU/kg weekly group (1.44 g/dL) was twice than that observed in the 300 IU/kg daily group (0.73 g/dL). Mean haemoglobin levels were similar for the two treatment groups throughout the postsurgical period. The erythropoietic response observed in both treatment groups resulted in similar transfusion rates (16% in the 600 IU/kg weekly group and 20% in the 300 IU/kg daily group). Treatment of adult patients with low- or intermediate-1-risk MDS A randomised, double-blind, placebo-controlled, multicentre study evaluated the efficacy and safety of epoetin alfa in adult anaemic subjects with low- or intermediate-1-risk MDS. Subjects were stratified by serum erythropoetin (sEPO) level and prior transfusion status at screening. Key baseline characteristics for the < 200 mU/mL stratum are shown in the table below. Baseline Characteristics for Subjects with sEPO < 200 mU/mL at Screening Randomised Total (N)b Epoetin alfa 85a Placebo 45 Screening sEPO < 200 mU/mL (N) 71 39 Haemoglobin (g/L) N 71 39 Mean 92.1 (8.57) 92.1 (8.51) Median 94.0 96.0 Range (71, 109) (69, 105) 95% CI for mean (90.1, 94.1) (89.3, 94.9) Prior Transfusions N 71 39 Yes 31 (43.7%) 17 (43.6%) ≤ 2 RBC Units 16 (51.6%) 9 (52.9%) >2 and ≤4 RBC Units 14 (45.2%) 8 (47.1%) >4 RBC Units 1 (3.2%) 0 No 40 (56.3%) 22 (56.4%) a one subject did not have sEPO data b in the ≥ 200 mU/mL stratum there were 13 subjects in the epoetin alfa group and 6 subjects in the placebo group Erythroid response was defined according to International Working Group (IWG) 2006 criteria as a haemoglobin increase ≥ 1.5 g/dL from baseline or a reduction of RBC units transfused by an absolute number of at least 4 units every 8 weeks compared to the 8 weeks prior to baseline, and a response duration of at least 8 weeks. Erythroid response during the first 24 weeks of the study was demonstrated by 27/85 (31.8%) of the subjects in the epoetin alfa group compared to 2/45 (4.4%) of the subjects in the placebo group (p < 0.001). All of the responding subjects were in the stratum with sEPO < 200 mU/mL during screening. In that stratum, 20/40 (50%) subjects without prior transfusions demonstrated erythroid response during the first 24 weeks, compared with 7/31 (22.6%) subjects with prior transfusions (two subjects with prior transfusion reached primary endpoint based on reduction of RBC units transfused by an absolute number of at least 4 units every 8 weeks compared to the 8 weeks prior to baseline). 23 Median time from baseline to first transfusion was statistically significantly longer in the epoetin alfa group compared to placebo (49 vs. 37 days; p = 0.046). After 4 weeks of treatment the time to first transfusion was further increased in the epoetin alfa group (142 vs. 50 days, p = 0.007). The percentage of subjects who were transfused in the epoetin alfa group decreased from 51.8% in the 8 weeks prior to baseline to 24.7% between weeks 16 and 24, compared to the placebo group which had an increase in transfusion rate from 48.9% to 54.1% over the same time periods. Paediatric population Chronic renal failure Epoetin alfa was evaluated in an open-label, non-randomised, open dose-range, 52-week clinical study in paediatric CRF patients undergoing haemodialysis. The median age of patients enrolled in the study was 11.6 years (range 0.5 to 20.1 years). Epoetin alfa was administered at 75 IU/kg/week intravenously in 2 or 3 divided doses post-dialysis, titrated by 75 IU/kg/week at intervals of 4 weeks (up to a maximum of 300 IU/kg/week), to achieve a 1 g/dL/month increase in haemoglobin. The desired haemoglobin concentration range was 9.6 to 11.2 g/dL. Eighty-one percent of patients achieved the haemoglobin concentration level. The median time to target was 11 weeks and the median dose at target was 150 IU/kg/week. Of the patients who achieved the target, 90% did so on a 3 times-per-week dosing regimen. After 52 weeks, 57% of patients remained in the study, receiving a median dose of 200 IU/kg/week. Clinical data with subcutaneous administration in children are limited. In 5 small, open label, uncontrolled studies (number of patients ranged from 9-22, total N = 72), Epoetin alfa has been administered subcutaneously in children at starting doses of 100 IU/kg/week to 150 IU/kg/week with the possibility to increase up to 300 IU/kg/week. In these studies, most were predialysis patients (N = 44), 27 patients were on peritoneal dialysis and 2 were on haemodialysis with age ranging from 4 months to 17 years. Overall, these studies have methodological limitations but treatment was associated with positive trends towards higher haemoglobin levels. No unexpected adverse events were reported (see section 4.2). Chemotherapy-induced anaemia Epoetin alfa 600 IU/kg (administered intravenously or subcutaneously once weekly) has been evaluated in a randomised, double-blind, placebo-controlled, 16-week study and in a randomised, controlled, open-label, 20-week study in anaemic paediatric patients receiving myelosuppressive chemotherapy for the treatment of various childhood non-myeloid malignancies. In the 16-week study (n = 222), in the epoetin alfa-treated patients there was no statistically significant effect on patient-reported or parent-reported Paediatric Quality of Life Inventory or Cancer Module scores compared with placebo (primary efficacy endpoint). In addition, there was no statistical difference between the proportion of patients requiring pRBC transfusions between the Epoetin alfa group and placebo. In the 20-week study (n = 225), no significant difference was observed in the primary efficacy endpoint, i.e. the proportion of patients who required a RBC transfusion after Day 28 (62% of epoetin alfa patients versus 69% of standard therapy patients). 5.2 Pharmacokinetic properties Absorption Following subcutaneous injection, serum levels of epoetin alfa reach a peak between 12 and 18 hours post-dose. There was no accumulation after multiple dose administration of 600 IU/kg administered subcutaneously weekly. 24 The absolute bioavailability of subcutaneous injectable epoetin alfa is approximately 20% in healthy subjects. Distribution The mean volume of distribution was 49.3 mL/kg after intravenous doses of 50 and 100 IU/kg in healthy subjects. Following intravenous administration of epoetin alfa in subjects with chronic renal failure, the volume of distribution ranged from 57-107 mL/kg after single dosing (12 IU/kg) to 42– 64 mL/kg after multiple dosing (48–192 IU/kg), respectively. Thus, the volume of distribution is slightly greater than the plasma space. Elimination The half-life of epoetin alfa following multiple dose intravenous administration is approximately 4 hours in healthy subjects. The half-life for the subcutaneous route is estimated to be approximately 24 hours in healthy subjects. The mean CL/F for the 150 IU/kg 3 times-per-week and 40,000 IU once-weekly regimens in healthy subjects were 31.2 and 12.6 mL/h/kg, respectively. The mean CL/F for the 150 IU/kg, 3 times-per-week and 40,000 IU, once-weekly regimens in the anaemic cancer subjects were 45.8 and 11.3 mL/h/kg, respectively. In most anaemic subjects with cancer receiving cyclic chemotherapy, CL/F was lower after subcutaneous doses of 40,000 IU once weekly and 150 IU/kg, 3 times-per-week compared with the values for healthy subjects. Linearity/Non-linearity In healthy subjects, a dose-proportional increase in serum epoetin alfa concentrations was observed after intravenous administration of 150 and 300 IU/kg, 3 times per week. Administration of single doses of 300 to 2,400 IU/kg subcutaneous epoetin alfa resulted in a linear relationship between mean Cmax and dose and between mean AUC and dose. An inverse relationship between apparent clearance and dose was noted in healthy subjects. In studies to explore extending the dosing interval (40,000 IU once weekly and 80,000, 100,000, and 120,000 IU biweekly), a linear but non-dose-proportional relationship was observed between mean Cmax and dose, and between mean AUC and dose at steady state. Pharmacokinetic/pharmacodynamic relationships Epoetin alfa exhibits a dose-related effect on haematological parameters which is independent of route of administration. Paediatric population A half-life of approximately 6.2 to 8.7 hours has been reported in paediatric subjects with chronic renal failure following multiple dose intravenous administration of epoetin alfa. The pharmacokinetic profile of epoetin alfa in children and adolescents appears to be similar to that of adults. Pharmacokinetic data in neonates is limited. A study of 7 preterm very low birth weight neonates and 10 healthy adults given i.v. erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in healthy adults. Renal impairment In chronic renal failure patients, the half-life of intravenously administered epoetin alfa is slightly prolonged, approximately 5 hours, compared to healthy subjects. 5.3 Preclinical safety data In repeated dose toxicological studies in dogs and rats, but not in monkeys, epoetin alfa therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of 25 chronic renal failure in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of haemodialysis patients who were treated with epoetin alfa for 3 years compared to a matched control group of dialysis patients who had not been treated with epoetin alfa. Epoetin alfa does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. Long-term carcinogenicity studies have not been carried out. Conflicting reports in the literature, based on in vitro findings from human tumour samples, suggest erythropoietins may play a role as tumour proliferators. This is of uncertain significance in the clinical situation. In cell cultures of human bone marrow cells, epoetin alfa stimulates erythropoiesis specifically and does not affect leucopoiesis. Cytotoxic actions of epoetin alfa on bone marrow cells could not be detected. In animal studies, epoetin alfa has been shown to decrease foetal body weight, delay ossification and increase foetal mortality when given in weekly doses of approximately 20 times the recommended human weekly dose. These changes are interpreted as being secondary to decreased maternal body weight gain, and the significance to humans is unknown given therapeutic dose levels. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium dihydrogen phosphate dihydrate Disodium phosphate dihydrate Sodium chloride Glycine Polysorbate 80 Water for injections Hydrochloric acid (for pH-adjustment) Sodium hydroxide (for pH-adjustment) 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store and transport refrigerated (2°C to 8°C). This temperature range should be closely maintained until administration to the patient. For the purpose of ambulatory use, the medicinal product may be taken out of the refrigerator, without being replaced, for a maximum period of 3 days at a temperature not above 25°C. If the medicinal product has not been used at the end of this period, it should be disposed of. Do not freeze or shake. Store in the original package in order to protect from light. 26 6.5 Nature and contents of container Pre-filled syringes (glass type I), with or without a needle safety guard, with plunger stopper (Teflon-faced rubber) sealed in a blister. Epoetin alfa HEXAL 1,000 IU/0.5 mL solution for injection in a pre-filled syringe Each syringe contains 0.5 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 2,000 IU/1 mL solution for injection in a pre-filled syringe Each syringe contains 1 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 3,000 IU/0.3 mL solution for injection in a pre-filled syringe Each syringe contains 0.3 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 4,000 IU/0.4 mL solution for injection in a pre-filled syringe Each syringe contains 0.4 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 5,000 IU/0.5 mL solution for injection in a pre-filled syringe Each syringe contains 0.5 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 6,000 IU/0.6 mL solution for injection in a pre-filled syringe Each syringe contains 0.6 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 7,000 IU/0.7 mL solution for injection in a pre-filled syringe Each syringe contains 0.7 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 8,000 IU/0.8 mL solution for injection in a pre-filled syringe Each syringe contains 0.8 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 9,000 IU/0.9 mL solution for injection in a pre-filled syringe Each syringe contains 0.9 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 10,000 IU/1 mL solution for injection in a pre-filled syringe Each syringe contains 1 mL of solution for injection. Pack of 1 or 6 syringes. Epoetin alfa HEXAL 20,000 IU/0.5 mL solution for injection in a pre-filled syringe Each syringe contains 0.5 mL of solution for injection. Pack of 1, 4 or 6 syringes. Epoetin alfa HEXAL 30,000 IU/0.75 mL solution for injection in a pre-filled syringe Each syringe contains 0.75 mL of solution for injection. Pack of 1, 4 or 6 syringes. Epoetin alfa HEXAL 40,000 IU/1 mL solution for injection in a pre-filled syringe Each syringe contains 1 mL of solution for injection. Pack of 1, 4 or 6 syringes. 27 Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Epoetin alfa HEXAL should not be used and discarded - if the liquid is coloured or you can see particles floating in it, - if the seal is broken, - if you know, or think that it may have been accidentally frozen, or - if there has been a refrigerator failure. The pre-filled syringes are ready to use (see section 4.2). The pre-filled syringe should not be shaken. Syringes are embossed with graduation rings in order to enable partial use if required. Each graduation ring corresponds to a volume of 0.1 mL. The product is for single use only. Only take one dose of Epoetin alfa HEXAL from each syringe discarding unwanted solution before injection. Using the pre-filled syringe with a needle safety guard The needle safety guard covers the needle after injection to prevent needle stick injury. This does not affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has been given and the plunger cannot be depressed any further. While maintaining pressure on the plunger, remove the syringe from the patient. The needle safety guard will cover the needle when releasing the plunger. Using the pre-filled syringe without a needle safety guard Administer the dose as per standard protocol. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Hexal AG Industriestr. 25 D-83607 Holzkirchen Germany 8. MARKETING AUTHORISATION NUMBER(S) Epoetin alfa HEXAL 1,000 IU/0.5 mL solution for injection in a pre-filled syringe EU/1/07/411/001 EU/1/07/411/002 EU/1/07/411/027 EU/1/07/411/028 Epoetin alfa HEXAL 2,000 IU/1 mL solution for injection in a pre-filled syringe EU/1/07/411/003 EU/1/07/411/004 EU/1/07/411/029 EU/1/07/411/030 28 Epoetin alfa HEXAL 3,000 IU/0.3 mL solution for injection in a pre-filled syringe EU/1/07/411/005 EU/1/07/411/006 EU/1/07/411/031 EU/1/07/411/032 Epoetin alfa HEXAL 4,000 IU/0.4 mL solution for injection in a pre-filled syringe EU/1/07/411/007 EU/1/07/411/008 EU/1/07/411/033 EU/1/07/411/034 Epoetin alfa HEXAL 5,000 IU/0.5 mL solution for injection in a pre-filled syringe EU/1/07/411/009 EU/1/07/411/010 EU/1/07/411/035 EU/1/07/411/036 Epoetin alfa HEXAL 6,000 IU/0.6 mL solution for injection in a pre-filled syringe EU/1/07/411/011 EU/1/07/411/012 EU/1/07/411/037 EU/1/07/411/038 Epoetin alfa HEXAL 7,000 IU/0.7 mL solution for injection in a pre-filled syringe EU/1/07/411/017 EU/1/07/411/018 EU/1/07/411/039 EU/1/07/411/040 Epoetin alfa HEXAL 8,000 IU/0.8 mL solution for injection in a pre-filled syringe EU/1/07/411/013 EU/1/07/411/014 EU/1/07/411/041 EU/1/07/411/042 Epoetin alfa HEXAL 9,000 IU/0.9 mL solution for injection in a pre-filled syringe EU/1/07/411/019 EU/1/07/411/020 EU/1/07/411/043 EU/1/07/411/044 Epoetin alfa HEXAL 10,000 IU/1 mL solution for injection in a pre-filled syringe EU/1/07/411/015 EU/1/07/411/016 EU/1/07/411/045 EU/1/07/411/046 Epoetin alfa HEXAL 20,000 IU/0.5 mL solution for injection in a pre-filled syringe EU/1/07/411/021 EU/1/07/411/022 EU/1/07/411/047 EU/1/07/411/053 EU/1/07/411/048 29 Epoetin alfa HEXAL 30,000 IU/0.75 mL solution for injection in a pre-filled syringe EU/1/07/411/023 EU/1/07/411/024 EU/1/07/411/049 EU/1/07/411/054 EU/1/07/411/050 Epoetin alfa HEXAL 40,000 IU/1 mL solution for injection in a pre-filled syringe EU/1/07/411/025 EU/1/07/411/026 EU/1/07/411/051 EU/1/07/411/055 EU/1/07/411/052 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 28 August 2007 Date of latest renewal: 18 June 2012 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 30 ANNEX II A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 31 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Lek Pharmaceuticals d.d. Kolodvorska 27 SI-1234 Menges Slovenia Name and address of the manufacturer responsible for batch release Sandoz GmbH Biochemiestr. 10 A-6336 Langkampfen Austria B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 32 ANNEX III LABELLING AND PACKAGE LEAFLET 33 A. LABELLING 34 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 1,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.5 mL contains 1,000 international units (IU) corresponding to 8.4 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.5 mL 6 pre-filled syringes of 0.5 mL 1 pre-filled syringe of 0.5 mL with a needle safety guard 6 pre-filled syringes of 0.5 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 35 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/001 EU/1/07/411/002 EU/1/07/411/027 EU/1/07/411/028 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 1,000 IU/0.5 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 36 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 1,000 IU/0.5 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 37 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 2,000 IU/1 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 1 mL contains 2,000 international units (IU) corresponding to 16.8 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 1 mL 6 pre-filled syringes of 1 mL 1 pre-filled syringe of 1 mL with a needle safety guard 6 pre-filled syringes of 1 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 38 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/003 EU/1/07/411/004 EU/1/07/411/029 EU/1/07/411/030 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 2,000 IU/1 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 39 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 2,000 IU/1 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 40 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 3,000 IU/0.3 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.3 mL contains 3,000 international units (IU) corresponding to 25.2 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.3 mL 6 pre-filled syringes of 0.3 mL 1 pre-filled syringe of 0.3 mL with a needle safety guard 6 pre-filled syringes of 0.3 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 41 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/005 EU/1/07/411/006 EU/1/07/411/031 EU/1/07/411/032 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 3,000 IU/0.3 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 42 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 3,000 IU/0.3 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 43 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 4,000 IU/0.4 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.4 mL contains 4,000 international units (IU) corresponding to 33.6 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.4 mL 6 pre-filled syringes of 0.4 mL 1 pre-filled syringe of 0.4 mL with a needle safety guard 6 pre-filled syringes of 0.4 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 44 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/007 EU/1/07/411/008 EU/1/07/411/033 EU/1/07/411/034 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 4,000 IU/0.4 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 45 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 4,000 IU/0.4 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 46 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 5,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.5 mL contains 5,000 international units (IU) corresponding to 42.0 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.5 mL 6 pre-filled syringes of 0.5 mL 1 pre-filled syringe of 0.5 mL with a needle safety guard 6 pre-filled syringes of 0.5 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 47 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/009 EU/1/07/411/010 EU/1/07/411/035 EU/1/07/411/036 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 5,000 IU/0.5 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 48 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 5,000 IU/0.5 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 49 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 6,000 IU/0.6 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.6 mL contains 6,000 international units (IU) corresponding to 50.4 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.6 mL 6 pre-filled syringes of 0.6 mL 1 pre-filled syringe of 0.6 mL with a needle safety guard 6 pre-filled syringes of 0.6 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 50 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/011 EU/1/07/411/012 EU/1/07/411/037 EU/1/07/411/038 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 6,000 IU/0.6 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 51 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 6,000 IU/0.6 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 52 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 7,000 IU/0.7 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.7 mL contains 7,000 international units (IU) corresponding to 58.8 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.7 mL 6 pre-filled syringes of 0.7 mL 1 pre-filled syringe of 0.7 mL with a needle safety guard 6 pre-filled syringes of 0.7 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 53 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/017 EU/1/07/411/018 EU/1/07/411/039 EU/1/07/411/040 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 7,000 IU/0.7 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 54 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 7,000 IU/0.7 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 55 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 8,000 IU/0.8 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.8 mL contains 8,000 international units (IU) corresponding to 67.2 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.8 mL 6 pre-filled syringes of 0.8 mL 1 pre-filled syringe of 0.8 mL with a needle safety guard 6 pre-filled syringes of 0.8 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 56 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/013 EU/1/07/411/014 EU/1/07/411/041 EU/1/07/411/042 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 8,000 IU/0.8 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 57 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 8,000 IU/0.8 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 58 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 9,000 IU/0.9 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.9 mL contains 9,000 international units (IU) corresponding to 75.6 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.9 mL 6 pre-filled syringes of 0.9 mL 1 pre-filled syringe of 0.9 mL with a needle safety guard 6 pre-filled syringes of 0.9 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 59 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/019 EU/1/07/411/020 EU/1/07/411/043 EU/1/07/411/044 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 9,000 IU/0.9 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 60 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 9,000 IU/0.9 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 61 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 10,000 IU/1 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 1 mL contains 10,000 international units (IU) corresponding to 84.0 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 1 mL 6 pre-filled syringes of 1 mL 1 pre-filled syringe of 1 mL with a needle safety guard 6 pre-filled syringes of 1 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 62 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/015 EU/1/07/411/016 EU/1/07/411/045 EU/1/07/411/046 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 10,000 IU/1 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 63 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 10,000 IU/1 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 64 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 20,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.5 mL contains 20,000 international units (IU) corresponding to 168.0 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.5 mL 6 pre-filled syringes of 0.5 mL 1 pre-filled syringe of 0.5 mL with a needle safety guard 4 pre-filled syringes of 0.5 mL with a needle safety guard 6 pre-filled syringes of 0.5 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 65 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/021 EU/1/07/411/022 EU/1/07/411/047 EU/1/07/411/053 EU/1/07/411/048 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 20,000 IU/0.5 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 66 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 67 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 20,000 IU/0.5 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 68 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 30,000 IU/0.75 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 0.75 mL contains 30,000 international units (IU) corresponding to 252.0 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 0.75 mL 6 pre-filled syringes of 0.75 mL 1 pre-filled syringe of 0.75 mL with a needle safety guard 4 pre-filled syringes of 0.75 mL with a needle safety guard 6 pre-filled syringes of 0.75 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 69 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/023 EU/1/07/411/024 EU/1/07/411/049 EU/1/07/411/054 EU/1/07/411/050 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 30,000 IU/0.75 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 70 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 30,000 IU/0.75 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 71 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoetin alfa HEXAL 40,000 IU/1 mL solution for injection in a pre-filled syringe Epoetin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 pre-filled syringe of 1 mL contains 40,000 international units (IU) corresponding to 336.0 micrograms epoetin alfa. 3. LIST OF EXCIPIENTS Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection in a pre-filled syringe. 1 pre-filled syringe of 1 mL 6 pre-filled syringes of 1 mL 1 pre-filled syringe of 1 mL with a needle safety guard 4 pre-filled syringes of 1 mL with a needle safety guard 6 pre-filled syringes of 1 mL with a needle safety guard 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous and intravenous use. Read the package leaflet before use. Do not shake. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 72 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Hexal AG, Industriestr. 25, D-83607 Holzkirchen, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/07/411/025 EU/1/07/411/026 EU/1/07/411/051 EU/1/07/411/055 EU/1/07/411/052 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Epoetin alfa HEXAL 40,000 IU/1 mL 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 73 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 74 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL/SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoetin alfa HEXAL 40,000 IU/1 mL injection Epoetin alfa IV/SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 75 B. PACKAGE LEAFLET 76 Package leaflet: Information for the patient Epoetin alfa HEXAL 1,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 2,000 IU/1 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 3,000 IU/0.3 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 4,000 IU/0.4 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 5,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 6,000 IU/0.6 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 7,000 IU/0.7 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 8,000 IU/0.8 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 9,000 IU/0.9 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 10,000 IU/1 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 20,000 IU/0.5 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 30,000 IU/0.75 mL solution for injection in a pre-filled syringe Epoetin alfa HEXAL 40,000 IU/1 mL solution for injection in a pre-filled syringe Epoetin alfa Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Epoetin alfa HEXAL is and what it is used for 2. What you need to know before you use Epoetin alfa HEXAL 3. How to use Epoetin alfa HEXAL 4. Possible side effects 5. How to store Epoetin alfa HEXAL 6. Contents of the pack and other information 1. What Epoetin alfa HEXAL is and what it is used for Epoetin alfa HEXAL contains the active substance epoetin alfa, a protein that stimulates the bone marrow to produce more red blood cells which carry haemoglobin (a substance that transports oxygen). Epoetin alfa is a copy of the human protein erythropoietin (ee-rith-roe-po-eh-tin) and acts in the same way. Epoetin alfa HEXAL is used to treat symptomatic anaemia caused by kidney disease: • in children on haemodialysis 77 • in adults on haemodialysis or peritoneal dialysis • in severely anaemic adults not yet undergoing dialysis If you have kidney disease, you may be short of red blood cells if your kidney does not produce enough erythropoietin (necessary for red cell production). Epoetin alfa HEXAL is prescribed to stimulate your bone marrow to produce more red blood cells. Epoetin alfa HEXAL is used to treat anaemia in adults receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma (bone marrow cancer) who may have a need for a blood transfusion. Epoetin alfa HEXAL can reduce the need for a blood transfusion in these patients. Epoetin alfa HEXAL is used in moderately anaemic adults who donate some of their blood before surgery, so that it can be given back to them during or after the operation. Because Epoetin alfa HEXAL stimulates the production of red blood cells, doctors can take more blood from these people. Epoetin alfa HEXAL is used in moderately anaemic adults about to have major orthopaedic surgery (for example hip or knee replacement operations), to reduce the potential need for blood transfusions. Epoetin alfa HEXAL is used to treat anaemia in adults with a bone marrow disorder that causes a severe disruption in the creation of blood cells (myelodysplastic syndromes). Epoetin alfa HEXAL can reduce the need for a blood transfusion. 2. What you need to know before you use Epoetin alfa HEXAL Do not use Epoetin alfa HEXAL: • if you are allergic to epoetin alfa or any of the other ingredients of this medicine (listed in section 6). • if you have been diagnosed with Pure Red Cell Aplasia (the bone marrow cannot produce enough red blood cells) after previous treatment with any product that stimulates red blood cell production (including Epoetin alfa HEXAL). See section 4. • if you have high blood pressure not properly controlled with medicines. • to stimulate the production of your red blood cells (so that doctors can take more blood from you) if you cannot have transfusions with your own blood during or after surgery. • if you are due to have major elective orthopaedic surgery (such as hip or knee surgery), and you: • have severe heart disease • have severe disorders of the veins and arteries • have recently had a heart attack or stroke • can’t take medicines to thin the blood Epoetin alfa HEXAL may not be suitable for you. Please discuss with your doctor. While on Epoetin alfa HEXAL, some people need medicines to reduce the risk of blood clots. If you can’t take medicines that prevent blood clotting, you must not have Epoetin alfa HEXAL. Warnings and precautions: Talk to your doctor, pharmacist or nurse before using Epoetin alfa HEXAL. Epoetin alfa HEXAL and other products that stimulate red cell production may increase the risk of developing blood clots in all patients. This risk may be higher if you have other risk factors for developing blood clots (for example, if you have had a blood clot in the past or are overweight, have diabetes, have heart disease or you are off your feet for a long time because of 78 surgery or illness). Please tell your doctor about any of these things. Your doctor will help you to decide if Epoetin alfa HEXAL is suitable for you. It is important to tell your doctor if any of the following apply to you. You may still be able to use Epoetin alfa HEXAL, but discuss it with your doctor first. If you know you suffer, or have suffered, from: • high blood pressure; • epileptic seizures or fits; • liver disease; • anaemia from other causes; • porphyria (a rare blood disorder). If you are a cancer patient be aware that products that stimulate red blood cell production (like Epoetin alfa HEXAL) may act as a growth factor and therefore in theory may affect the progression of your cancer. Depending on your individual situation a blood transfusion may be preferable. Please discuss this with your doctor. If you are a patient with hepatitis C and you receive interferon and ribavirin, you should discuss this with your doctor because a combination of epoetin alfa with interferon and ribavirin has led to a loss of effect and development of a condition called pure red cell aplasia (PRCA), a severe form of anaemia, in rare cases. Epoetin alfa HEXAL is not approved in the management of anaemia associated with hepatitis C. If you are a patient with chronic renal failure, and particularly if you do not respond properly to Epoetin alfa HEXAL, your doctor will check your dose of Epoetin alfa HEXAL because repeatedly increasing your dose of Epoetin alfa HEXAL if you are not responding to treatment may increase the risk of having a problem of the heart or the blood vessels and could increase risk of myocardial infarction, stroke and death. If you are a cancer patient, be aware that use of Epoetin alfa HEXAL may be associated with shorter survival and a higher death rate in head and neck, and metastatic breast cancer patients who are receiving chemotherapy. Take special care with other products that stimulate red blood cell production: Epoetin alfa HEXAL is one of a group of products that stimulate the production of red blood cells like the human protein erythropoietin does. Your healthcare professional will always record the exact product you are using. If you are given a product in this group other than Epoetin alfa HEXAL during your treatment, speak to your doctor or pharmacist before using it. Take special care with Epoetin alfa HEXAL: Serious skin reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with epoetin treatment. SJS/TEN can appear initially as reddish target-like spots or circular patches often with central blisters on the trunk. Also, ulcers of mouth, throat, nose, genitals and eyes (red and swollen eyes) can occur. These serious skin rashes are often preceded by fever and/or flu-like symptoms. The rashes may progress to widespread peeling of the skin and life-threatening complications. If you develop a serious rash or another of these skin symptoms, stop taking Epoetin alfa HEXAL and contact your doctor or seek medical attention immediately. 79 Other medicines and Epoetin alfa HEXAL Tell your doctor if you are taking, have recently taken or might take any other medicines. If you are taking a medicine called cyclosporin (used e.g. after kidney transplants), your doctor may order blood tests to check the level of cyclosporin while you are taking Epoetin alfa HEXAL. Iron supplements and other blood stimulants may increase the effectiveness of Epoetin alfa HEXAL. Your doctor will decide if it is right for you to take them. If you visit a hospital, clinic or family doctor, tell them you are having Epoetin alfa HEXAL treatment. It may affect other treatments or test results. Pregnancy and breast-feeding It is important to tell your doctor if any of the following apply to you. You may still be able to use Epoetin alfa HEXAL, but discuss it with your doctor first: • if you are pregnant, or think you may be pregnant. • if you are breast-feeding. Epoetin alfa HEXAL contains sodium Epoetin alfa HEXAL contains less than 1 mmol sodium (23 mg) per dose that is to say essentially “sodium free”. 3. How to use Epoetin alfa HEXAL Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. Your doctor has carried out blood tests and decided you need Epoetin alfa HEXAL. Epoetin alfa HEXAL may be given by injection: • Either into a vein or a tube that goes into a vein (intravenously) • Or under the skin (subcutaneously). Your doctor will decide how Epoetin alfa HEXAL will be injected. Usually the injections will be given to you by a doctor, nurse or other health care professional. Some people, depending on why they need Epoetin alfa HEXAL treatment, may later learn how to inject themselves under the skin: see Instructions on how to inject Epoetin alfa HEXAL yourself at the end of the leaflet. Epoetin alfa HEXAL should not be used: • after the expiry date on the label and outer carton • if you know, or think that it may have been accidentally frozen, or • if there has been a refrigerator failure. The dose of Epoetin alfa HEXAL you receive is based on your body weight in kilograms. The cause of your anaemia is also a factor in your doctor deciding the correct dose. Your doctor will monitor your blood pressure regularly while you are using Epoetin alfa HEXAL. People with kidney disease 80 • Your doctor will maintain your haemoglobin level between 10 and 12 g/dL as a high haemoglobin level may increase the risk of blood clots and death. In children the haemoglobin level should be maintained between 9.5 and 11 g/dL. • The usual starting dose of Epoetin alfa HEXAL for adults and children is 50 International Units (IU) per kilogram (/kg) of body weight given three times a week. For patients on peritoneal dialysis Epoetin alfa HEXAL may be given twice a week. • For adults and children Epoetin alfa HEXAL is given as an injection either into a vein (intravenously) or a tube that goes into a vein. When this access (via a vein or tube) is not readily available, your doctor may decide that Epoetin alfa HEXAL should be injected under the skin (subcutaneously). This includes patients on dialysis and patients not yet on dialysis. • Your doctor will order regular blood tests to see how your anaemia is responding and may adjust the dose, usually no more frequently than every four weeks. A rise in haemoglobin of greater than 2 g/dL over a four week period should be avoided. • Once your anaemia has been corrected, your doctor will continue to check your blood regularly. Your Epoetin alfa HEXAL dose and frequency of administration may be further adjusted to maintain your response to treatment. Your doctor will use the lowest effective dose to control the symptoms of your anaemia. • If you do not respond adequately to Epoetin alfa HEXAL, your doctor will check your dose and will inform you if you need to change doses of Epoetin alfa HEXAL. • If you are on a more extended dosing interval (greater than once weekly) of Epoetin alfa HEXAL, you may not maintain adequate haemoglobin levels and you may require an increase in Epoetin alfa HEXAL dose or frequency of administration. • You may be given iron supplements before and during Epoetin alfa HEXAL treatment to make it more effective. • If you are having dialysis treatment when you begin treatment with Epoetin alfa HEXAL, your dialysis regime may need to be adjusted. Your doctor will decide this. Adults on chemotherapy • Your doctor may initiate treatment with Epoetin alfa HEXAL if your haemoglobin is 10 g/dL or less. • Your doctor will maintain your haemoglobin level between 10 and 12 g/dL as a high haemoglobin level may increase the risk of blood clots and death. • The starting dose is either 150 IU per kilogram body weight three times a week or 450 IU per kilogram body weight once a week. • Epoetin alfa HEXAL is given by injection under the skin. • Your doctor will order blood tests, and may adjust the dose, depending on how your anaemia responds to Epoetin alfa HEXAL treatment. • You may be given iron supplements before and during Epoetin alfa HEXAL treatment to make it more effective. • You will usually continue Epoetin alfa HEXAL treatment for one month after the end of chemotherapy. Adults donating their own blood • The usual dose is 600 IU per kilogram body weight twice a week. • Epoetin alfa HEXAL is given by injection into a vein immediately after you have donated blood for 3 weeks before your surgery. • You may be given iron supplements before and during Epoetin alfa HEXAL treatment to make it more effective. Adults scheduled for major orthopaedic surgery • The recommended dose is 600 IU per kilogram body weight once a week. • Epoetin alfa HEXAL is given by injection under the skin each week for three weeks before surgery and on the day of surgery. 81 • If there is a medical need to reduce the time before your operation, you will be given a daily dose of 300 IU/kg for up to ten days before surgery, on the day of surgery and for four days immediately afterwards. • If blood tests show your haemoglobin is too high before the operation, the treatment will be stopped. • You may be given iron supplements before and during Epoetin alfa HEXAL treatment to make it more effective. Adults with myelodysplastic syndrome • Your doctor may initiate treatment with Epoetin alfa HEXAL if your haemoglobin is 10 g/dL or less. The aim of treatment is to maintain your haemoglobin level between 10 and 12 g/dL as a higher haemoglobin level may increase the risk of blood clots and death. • Epoetin alfa HEXAL is given by injection under the skin. • The starting dose is 450 IU per kilogram bodyweight once a week. • Your doctor will order blood tests, and may adjust the dose, depending on how your anaemia responds to Epoetin alfa HEXAL treatment. Instructions on how to inject Epoetin alfa HEXAL yourself When treatment starts, Epoetin alfa HEXAL is usually injected by a medical professional or a nurse. Later, your doctor may suggest that you or your caregiver learn how to inject Epoetin alfa HEXAL under the skin (subcutaneously) yourself. • Do not attempt to inject yourself unless you have been trained to do so by your doctor or nurse. • Always use Epoetin alfa HEXAL exactly as instructed by your doctor or nurse. • Ensure that you only inject the amount of liquid as instructed by your doctor or nurse. • Only use Epoetin alfa HEXAL if it has been stored correctly – see section 5, How to store Epoetin alfa HEXAL. • Before use, leave the Epoetin alfa HEXAL syringe to stand until it reaches room temperature. This usually takes between 15 and 30 minutes. Use the syringe within 3 days of taking it out of the refrigerator. Only take one dose of Epoetin alfa HEXAL from each syringe. If Epoetin alfa HEXAL is injected under the skin (subcutaneously), the amount injected is not normally more than one millilitre (1 mL) in a single injection. Epoetin alfa HEXAL is given alone and not mixed with other liquids for injection. Do not shake Epoetin alfa HEXAL syringes. Prolonged vigorous shaking may damage the product. If the product has been shaken vigorously, don’t use it. Instructions on how to inject yourself with Epoetin alfa HEXAL can be found at the end of this leaflet. If you use more Epoetin alfa HEXAL than you should Tell your doctor or nurse immediately if you think too much Epoetin alfa HEXAL has been injected. Side effects from an overdose of Epoetin alfa HEXAL are unlikely. If you forget to use Epoetin alfa HEXAL Make the next injection as soon as you remember. If you are within a day of your next injection, forget the missed one and carry on with your normal schedule. Do not double up the injections to make up for a forgotten dose. 82 If you have any further questions on the use of this product, ask your doctor, nurse or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor or nurse immediately if you notice any of the effects in this list. Very common side effects These may affect more than 1 in 10 people. • Diarrhoea • Feeling sick in your stomach • Vomiting • Fever • Respiratory tract congestion, such as stuffy nose and sore throat, has been reported in patients with kidney disease not yet on dialysis. Common side effects These may affect up to 1 in 10 people. • Increased blood pressure. Headaches, particularly sudden, stabbing migraine-like headaches, feeling confused or having fits may be signs of a sudden increase in blood pressure. This requires urgent treatment. Raised blood pressure may require treatment with medicines (or adjustment to any medicines you already take for high blood pressure). • Blood clots (including deep vein thrombosis and embolism) that may require urgent treatment. You may have chest pain, breathlessness, and painful swelling and redness, usually in the leg as symptoms. • Cough. • Skin rashes, which may result from an allergic reaction. • Bone or muscle pain. • Flu-like symptoms, such as headache, aches and pains in the joints, feeling of weakness, chills, tiredness and dizziness. These may be more common at the start of treatment. If you have these symptoms during injection into the vein, a slower delivery of the injection may help to avoid them in the future. • Redness, burning and pain at the site of injection. • Swelling of the ankles, feet or fingers. • Arm or leg pain. Uncommon side effects These may affect up to 1 in 100 people. • High levels of blood potassium which can cause abnormal heart rhythm (this is a very common side effect in patients on dialysis). • Fits. • Nose or airway congestion. • Allergic reaction. • Hives. Rare side effects These may affect up to 1 in 1,000 people. • Symptoms of pure red cell aplasia (PRCA) 83 PRCA means the bone marrow does not make enough red blood cells. PRCA causes sudden and severe anaemia. The symptoms are: • unusual tiredness, • feeling dizzy, • breathlessness. PRCA has been very rarely reported mostly in patients with kidney disease after months to years of treatment with epoetin alfa and other products that stimulate red blood cell production. • An increase in levels of small blood cells (called platelets), which are normally involved in the formation of a blood clot may occur, particularly when starting treatment. Your doctor will check on this. • Severe allergic reaction that may include: • a swollen face, lips, mouth, tongue or throat, • difficulty swallowing or breathing, • itchy rash (hives). • Problem with the blood that may cause pain, dark coloured urine or increased sensitivity of the skin to sunlight (porphyria). If you are receiving haemodialysis: • Blood clots (thrombosis) may form in your dialysis shunt. This is more likely if you have low blood pressure or if your fistula has complications. • Blood clots may also form in your haemodialysis system. Your doctor may decide to increase your heparin dose during dialysis. Serious skin rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in association with epoetin treatment. These can appear as reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. Stop using Epoetin alfa HEXAL if you develop these symptoms and contact your doctor or seek medical attention immediately. See also section 2. Tell your doctor or nurse immediately if you are aware of any of these effects, or if you notice any other effects while you are receiving treatment with Epoetin alfa HEXAL. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Epoetin alfa HEXAL • Keep this medicine out of the sight and reach of children. • Do not use this medicine after the expiry date which is stated on the label and carton after EXP. • Store and transport refrigerated (2°C-8°C). 84 • You may take Epoetin alfa HEXAL out of the refrigerator and keep it at room temperature (up to 25°C) for no longer than 3 days. Once a syringe has been removed from the refrigerator and has reached room temperature (up to 25°C) it must either be used within 3 days or disposed of. • Do not freeze or shake. • Store in the original package in order to protect from light. Do not use this medicine if you notice that • it may have been accidentally frozen, or • if there has been a refrigerator failure, • the liquid is coloured or you can see particles floating in it, • the seal is broken. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Epoetin alfa HEXAL contains - The active substance is: epoetin alfa (for quantity see the table below). - The other ingredients are: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment), and water for injections. What Epoetin alfa HEXAL looks like and contents of the pack Epoetin alfa HEXAL is presented as a clear, colourless solution for injection in a pre-filled syringe. The syringes are sealed in a blister. Presentation Corresponding Presentations in Quantity/Volume for each Strength Amount of epoetin alfa Pre-filled syringes* 2,000 IU/mL: 1,000 IU/0.5 mL 2,000 IU/1 mL 10,000 IU/mL: 3,000 IU/0.3 mL 4,000 IU/0.4 mL 5,000 IU/0.5 mL 6,000 IU/0.6 mL 7,000 IU/0.7 mL 8,000 IU/0.8 mL 9,000 IU/0.9 mL 10,000 IU/1 mL 40,000 IU/mL: 20,000 IU/0.5 mL 30,000 IU/0.75 mL 40,000 IU/1 mL 8.4 micrograms 16.8 micrograms 25.2 micrograms 33.6 micrograms 42.0 micrograms 50.4 micrograms 58.8 micrograms 67.2 micrograms 75.6 micrograms 84.0 micrograms 168.0 micrograms 252.0 micrograms 336.0 micrograms *Pack size of 1, 4 or 6 pre-filled syringe(s) with or without a needle safety guard. Not all pack sizes may be marketed. 85 Marketing Authorisation Holder Hexal AG Industriestr. 25 D-83607 Holzkirchen Germany Manufacturer Sandoz GmbH Biochemiestr. 10 A-6336 Langkampfen Austria This leaflet was last revised in {MM/YYYY}. Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. ------------------------------------------------------------------------------------------------------------------ Instructions on how to inject yourself (for patients with symptomatic anaemia caused by kidney disease, for adult patients receiving chemotherapy, adult patients scheduled for orthopaedic surgery, or adult patients with myelodysplastic syndromes only) This section contains information on how to give yourself an injection of Epoetin alfa HEXAL. It is important that you do not try to give yourself the injection unless you have received special training from your doctor or nurse. Epoetin alfa HEXAL is provided with or without a needle safety guard and you will be shown how to use this by your doctor or nurse. If you are not sure about giving the injection or you have any questions, please ask your doctor or nurse for help. 1. Wash your hands. 2. Remove one syringe from the pack and remove the protective cap from the injection needle. Syringes are embossed with graduation rings in order to enable partial use if required. Each graduation ring corresponds to a volume of 0.1 mL. If partial use of a syringe is required, remove unwanted solution before injection. 3. Clean the skin at the injection site using an alcohol wipe. 4. Form a skin fold by pinching the skin between thumb and forefinger. 5. Insert the needle into the skin fold with a quick, firm action. Inject the Epoetin alfa HEXAL solution as you have been shown by your doctor. You should check with your doctor or pharmacist if you are not sure. Pre-filled syringe without needle safety guard 6. Always keeping your skin pinched, depress the plunger slowly and evenly. 7. After injecting the liquid, remove the needle and let go of your skin. Apply pressure over the injection site with a dry, sterile pad. 8. Discard any unused product or waste material. Only use each syringe for one injection. Pre-filled syringe with needle safety guard 6. Always keeping your skin pinched, depress the plunger slowly and evenly until the entire dose has been given and the plunger cannot be depressed any further. Do not release the pressure on the plunger! 86 7. After injecting the liquid, remove the needle while maintaining pressure on the plunger and then let go of your skin. Apply pressure over the injection site with a dry, sterile pad. 8. Let go of the plunger. The needle safety guard will rapidly move to cover the needle. 9. Discard any unused product or waste material. Only use each syringe for one injection. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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(bone marrow cancer) who may have a need for a blood transfusion. epoetin alfa hexal can reduce the need for a blood transfusion in these patients. epoetin alfa hexal is used in moderately anaemic adults who donate some of their blood before surgery, so that it can be given back to them during or after the operation. because epoetin alfa hexal stimulates the production of red blood cells, doctors can take more blood from these people. epoetin alfa hexal is used in moderately anaemic adults about to have major orthopaedic surgery (for example hip or knee replacement operations), to reduce the potential need for blood transfusions. epoetin alfa hexal is used to treat anaemia in adults with a bone marrow disorder that causes a severe disruption in the creation of blood cells (myelodysplastic syndromes). epoetin alfa hexal can reduce the need for a blood transfusion.', 'Entity_Recognition': [{'Text': 'epoetin alfa hexal', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 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{'Title': '2. what you need to know before you use epoetin alfa hexal', 'Section_Content': 'do not use epoetin alfa hexal: if you are allergic to epoetin alfa or any of the other ingredients of this medicine (listed in section 6). if you have been diagnosed with pure red cell aplasia (the bone marrow cannot produce enough red blood cells) after previous treatment with any product that stimulates red blood cell production (including epoetin alfa hexal). see section 4. if you have high blood pressure not properly controlled with medicines. to stimulate the production of your red blood cells (so that doctors can take more blood from you) if you cannot have transfusions with your own blood during or after surgery. if you are due to have major elective orthopaedic surgery (such as hip or knee surgery), and you: have severe heart disease have severe disorders of the veins and arteries have recently had a heart attack or stroke can\'t take medicines to thin the blood epoetin alfa hexal may not be suitable for you. please discuss with your doctor. while on epoetin alfa hexal, some people need medicines to reduce the risk of blood clots. if you can\'t take medicines that prevent blood clotting, you must not have epoetin alfa hexal. warnings and precautions: talk to your doctor, pharmacist or nurse before using epoetin alfa hexal. epoetin alfa hexal and other products that stimulate red cell production may increase the risk of developing blood clots in all patients. this risk may be higher if you have other risk factors for developing blood clots (for example, if you have had a blood clot in the past or are overweight, have diabetes, have heart disease or you are off your feet for a long time because of 78 surgery or illness). please tell your doctor about any of these things. your doctor will help you to decide if epoetin alfa hexal is suitable for you. it is important to tell your doctor if any of the following apply to you. you may still be able to use epoetin alfa hexal, but discuss it with your doctor first. if you know you suffer, or have suffered, from: high blood pressure; epileptic seizures or fits; liver disease; anaemia from other causes; porphyria (a rare blood disorder). if you are a cancer patient be aware that products that stimulate red blood cell production (like epoetin alfa hexal) may act as a growth factor and therefore in theory may affect the progression of your cancer. depending on your individual situation a blood transfusion may be preferable. please discuss this with your doctor. if you are a patient with hepatitis c and you receive interferon and ribavirin, you should discuss this with your doctor because a combination of epoetin alfa with interferon and ribavirin has led to a loss of effect and development of a condition called pure red cell aplasia (prca), a severe form of anaemia, in rare cases. epoetin alfa hexal is not approved in the management of anaemia associated with hepatitis c. if you are a patient with chronic renal failure, and particularly if you do not respond properly to epoetin alfa hexal, your doctor will check your dose of epoetin alfa hexal because repeatedly increasing your dose of epoetin alfa hexal if you are not responding to treatment may increase the risk of having a problem of the heart or the blood vessels and could increase risk of myocardial infarction, stroke and death. if you are a cancer patient, be aware that use of epoetin alfa hexal may be associated with shorter survival and a higher death rate in head and neck, and metastatic breast cancer patients who are receiving chemotherapy. take special care with other products that stimulate red blood cell production: epoetin alfa hexal is one of a group of products that stimulate the production of red blood cells like the human protein erythropoietin does. your healthcare professional will always record the exact product you are using. if you are given a product in this group other than epoetin alfa hexal during your treatment, speak to your doctor or pharmacist before using it. take special care with epoetin alfa hexal: serious skin reactions including stevens-johnson syndrome (sjs) and toxic epidermal necrolysis (ten) have been reported in association with epoetin treatment. sjs/ten can appear initially as reddish target-like spots or circular patches often with central blisters on the trunk. also, ulcers of mouth, throat, nose, genitals and eyes (red and swollen eyes) can occur. these serious skin rashes are often preceded by fever and/or flu-like symptoms. the rashes may progress to widespread peeling of the skin and life-threatening complications. if you develop a serious rash or another of these skin symptoms, stop taking epoetin alfa hexal and contact your doctor or seek medical attention immediately. other medicines and epoetin alfa hexal tell your doctor if you are taking, have recently taken or might take any other medicines. if you are taking a medicine called cyclosporin (used e.g. after kidney transplants), your doctor may order blood tests to check the level of cyclosporin while you are taking epoetin alfa hexal. iron supplements and other blood stimulants may increase the effectiveness of epoetin alfa hexal. your doctor will decide if it is right for you to take them. if you visit a hospital, clinic or family doctor, tell them you are having epoetin alfa hexal treatment. it may affect other treatments or test results. pregnancy and breast-feeding it is important to tell your doctor if any of the following apply to you. you may still be able to use epoetin alfa hexal, but discuss it with your doctor first: if you are pregnant, or think you may be pregnant. if you are breast-feeding. epoetin alfa hexal contains sodium epoetin alfa hexal contains less than 1 mmol sodium (23 mg) per dose that is to say essentially "sodium free".', 'Entity_Recognition': [{'Text': 'epoetin alfa hexal', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'epoetin alfa 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{'Title': '3. how to use epoetin alfa hexal', 'Section_Content': "always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. your doctor has carried out blood tests and decided you need epoetin alfa hexal. epoetin alfa hexal may be given by injection: either into a vein or a tube that goes into a vein (intravenously) or under the skin (subcutaneously). your doctor will decide how epoetin alfa hexal will be injected. usually the injections will be given to you by a doctor, nurse or other health care professional. some people, depending on why they need epoetin alfa hexal treatment, may later learn how to inject themselves under the skin: see instructions on how to inject epoetin alfa hexal yourself at the end of the leaflet. epoetin alfa hexal should not be used: after the expiry date on the label and outer carton if you know, or think that it may have been accidentally frozen, or if there has been a refrigerator failure. the dose of epoetin alfa hexal you receive is based on your body weight in kilograms. the cause of your anaemia is also a factor in your doctor deciding the correct dose. your doctor will monitor your blood pressure regularly while you are using epoetin alfa hexal. people with kidney disease 80 your doctor will maintain your haemoglobin level between 10 and 12 g/dl as a high haemoglobin level may increase the risk of blood clots and death. in children the haemoglobin level should be maintained between 9.5 and 11 g/dl. the usual starting dose of epoetin alfa hexal for adults and children is 50 international units (iu) per kilogram (/kg) of body weight given three times a week. for patients on peritoneal dialysis epoetin alfa hexal may be given twice a week. for adults and children epoetin alfa hexal is given as an injection either into a vein (intravenously) or a tube that goes into a vein. when this access (via a vein or tube) is not readily available, your doctor may decide that epoetin alfa hexal should be injected under the skin (subcutaneously). this includes patients on dialysis and patients not yet on dialysis. your doctor will order regular blood tests to see how your anaemia is responding and may adjust the dose, usually no more frequently than every four weeks. a rise in haemoglobin of greater than 2 g/dl over a four week period should be avoided. once your anaemia has been corrected, your doctor will continue to check your blood regularly. your epoetin alfa hexal dose and frequency of administration may be further adjusted to maintain your response to treatment. your doctor will use the lowest effective dose to control the symptoms of your anaemia. if you do not respond adequately to epoetin alfa hexal, your doctor will check your dose and will inform you if you need to change doses of epoetin alfa hexal. if you are on a more extended dosing interval (greater than once weekly) of epoetin alfa hexal, you may not maintain adequate haemoglobin levels and you may require an increase in epoetin alfa hexal dose or frequency of administration. you may be given iron supplements before and during epoetin alfa hexal treatment to make it more effective. if you are having dialysis treatment when you begin treatment with epoetin alfa hexal, your dialysis regime may need to be adjusted. your doctor will decide this. adults on chemotherapy your doctor may initiate treatment with epoetin alfa hexal if your haemoglobin is 10 g/dl or less. your doctor will maintain your haemoglobin level between 10 and 12 g/dl as a high haemoglobin level may increase the risk of blood clots and death. the starting dose is either 150 iu per kilogram body weight three times a week or 450 iu per kilogram body weight once a week. epoetin alfa hexal is given by injection under the skin. your doctor will order blood tests, and may adjust the dose, depending on how your anaemia responds to epoetin alfa hexal treatment. you may be given iron supplements before and during epoetin alfa hexal treatment to make it more effective. you will usually continue epoetin alfa hexal treatment for one month after the end of chemotherapy. adults donating their own blood the usual dose is 600 iu per kilogram body weight twice a week. epoetin alfa hexal is given by injection into a vein immediately after you have donated blood for 3 weeks before your surgery. you may be given iron supplements before and during epoetin alfa hexal treatment to make it more effective. adults scheduled for major orthopaedic surgery the recommended dose is 600 iu per kilogram body weight once a week. epoetin alfa hexal is given by injection under the skin each week for three weeks before surgery and on the day of surgery. if there is a medical need to reduce the time before your operation, you will be given a daily dose of 300 iu/kg for up to ten days before surgery, on the day of surgery and for four days immediately afterwards. if blood tests show your haemoglobin is too high before the operation, the treatment will be stopped. you may be given iron supplements before and during epoetin alfa hexal treatment to make it more effective. adults with myelodysplastic syndrome your doctor may initiate treatment with epoetin alfa hexal if your haemoglobin is 10 g/dl or less. the aim of treatment is to maintain your haemoglobin level between 10 and 12 g/dl as a higher haemoglobin level may increase the risk of blood clots and death. epoetin alfa hexal is given by injection under the skin. the starting dose is 450 iu per kilogram bodyweight once a week. your doctor will order blood tests, and may adjust the dose, depending on how your anaemia responds to epoetin alfa hexal treatment. instructions on how to inject epoetin alfa hexal yourself when treatment starts, epoetin alfa hexal is usually injected by a medical professional or a nurse. later, your doctor may suggest that you or your caregiver learn how to inject epoetin alfa hexal under the skin (subcutaneously) yourself. do not attempt to inject yourself unless you have been trained to do so by your doctor or nurse. always use epoetin alfa hexal exactly as instructed by your doctor or nurse. ensure that you only inject the amount of liquid as instructed by your doctor or nurse. only use epoetin alfa hexal if it has been stored correctly see section 5, how to store epoetin alfa hexal. before use, leave the epoetin alfa hexal syringe to stand until it reaches room temperature. this usually takes between 15 and 30 minutes. use the syringe within 3 days of taking it out of the refrigerator. only take one dose of epoetin alfa hexal from each syringe. if epoetin alfa hexal is injected under the skin (subcutaneously), the amount injected is not normally more than one millilitre (1 ml) in a single injection. epoetin alfa hexal is given alone and not mixed with other liquids for injection. do not shake epoetin alfa hexal syringes. prolonged vigorous shaking may damage the product. if the product has been shaken vigorously, don't use it. instructions on how to inject yourself with epoetin alfa hexal can be found at the end of this leaflet. if you use more epoetin alfa hexal than you should tell your doctor or nurse immediately if you think too much epoetin alfa hexal has been injected. side effects from an overdose of epoetin alfa hexal are unlikely. if you forget to use epoetin alfa hexal make the next injection as soon as you remember. if you are within a day of your next injection, forget the missed one and carry on with your normal schedule. do not double up the injections to make up for a forgotten dose. if you have any further questions on the use of this product, ask your doctor, nurse or pharmacist.", 'Entity_Recognition': [{'Text': 'epoetin alfa hexal', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Id': 31, 'BeginOffset': 134, 'EndOffset': 145, 'Score': 0.6213312149047852, 'Text': 'blood 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor or nurse immediately if you notice any of the effects in this list. very common side effects these may affect more than 1 in 10 people. diarrhoea feeling sick in your stomach vomiting fever respiratory tract congestion, such as stuffy nose and sore throat, has been reported in patients with kidney disease not yet on dialysis. common side effects these may affect up to 1 in 10 people. increased blood pressure. headaches, particularly sudden, stabbing migraine-like headaches, feeling confused or having fits may be signs of a sudden increase in blood pressure. this requires urgent treatment. raised blood pressure may require treatment with medicines (or adjustment to any medicines you already take for high blood pressure). blood clots (including deep vein thrombosis and embolism) that may require urgent treatment. you may have chest pain, breathlessness, and painful swelling and redness, usually in the leg as symptoms. cough. skin rashes, which may result from an allergic reaction. bone or muscle pain. flu-like symptoms, such as headache, aches and pains in the joints, feeling of weakness, chills, tiredness and dizziness. these may be more common at the start of treatment. if you have these symptoms during injection into the vein, a slower delivery of the injection may help to avoid them in the future. redness, burning and pain at the site of injection. swelling of the ankles, feet or fingers. arm or leg pain. uncommon side effects these may affect up to 1 in 100 people. high levels of blood potassium which can cause abnormal heart rhythm (this is a very common side effect in patients on dialysis). fits. nose or airway congestion. allergic reaction. hives. rare side effects these may affect up to 1 in 1,000 people. symptoms of pure red cell aplasia (prca) 83 prca means the bone marrow does not make enough red blood cells. prca causes sudden and severe anaemia. the symptoms are: unusual tiredness, feeling dizzy, breathlessness. prca has been very rarely reported mostly in patients with kidney disease after months to years of treatment with epoetin alfa and other products that stimulate red blood cell production. an increase in levels of small blood cells (called platelets), which are normally involved in the formation of a blood clot may occur, particularly when starting treatment. your doctor will check on this. severe allergic reaction that may include: a swollen face, lips, mouth, tongue or throat, difficulty swallowing or breathing, itchy rash (hives). problem with the blood that may cause pain, dark coloured urine or increased sensitivity of the skin to sunlight (porphyria). if you are receiving haemodialysis: blood clots (thrombosis) may form in your dialysis shunt. this is more likely if you have low blood pressure or if your fistula has complications. blood clots may also form in your haemodialysis system. your doctor may decide to increase your heparin dose during dialysis. serious skin rashes including stevens-johnson syndrome and toxic epidermal necrolysis have been reported in association with epoetin treatment. these can appear as reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. stop using epoetin alfa hexal if you develop these symptoms and contact your doctor or seek medical attention immediately. see also section 2. tell your doctor or nurse immediately if you are aware of any of these effects, or if you notice any other effects while you are receiving treatment with epoetin alfa hexal. if any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist. reporting of side effects if you get any side effects, talk 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'your fistula', 'Type': 'PROBLEM', 'BeginOffset': 2883, 'EndOffset': 2895}, {'Text': 'complications', 'Type': 'PROBLEM', 'BeginOffset': 2900, 'EndOffset': 2913}, {'Id': 117, 'BeginOffset': 2915, 'EndOffset': 2926, 'Score': 0.8617238998413086, 'Text': 'blood clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.409953236579895}, {'Name': 'DIAGNOSIS', 'Score': 0.5851503610610962}]}, {'Text': 'your haemodialysis system', 'Type': 'TREATMENT', 'BeginOffset': 2944, 'EndOffset': 2969}, {'Text': 'your heparin dose', 'Type': 'TREATMENT', 'BeginOffset': 3006, 'EndOffset': 3023}, {'Id': 134, 'BeginOffset': 3031, 'EndOffset': 3039, 'Score': 0.7790194153785706, 'Text': 'dialysis', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'serious skin rashes', 'Type': 'PROBLEM', 'BeginOffset': 3041, 'EndOffset': 3060}, {'Id': 119, 'BeginOffset': 3071, 'EndOffset': 3095, 'Score': 0.9918572902679443, 'Text': 'stevens-johnson syndrome', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9172623157501221}]}, {'Id': 120, 'BeginOffset': 3100, 'EndOffset': 3126, 'Score': 0.8382545113563538, 'Text': 'toxic epidermal necrolysis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.898911714553833}]}, {'Text': 'epoetin treatment', 'Type': 'TREATMENT', 'BeginOffset': 3166, 'EndOffset': 3183}, {'Id': 121, 'BeginOffset': 3213, 'EndOffset': 3232, 'Score': 0.41495561599731445, 'Text': 'target-like macules', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'circular patches', 'Type': 'PROBLEM', 'BeginOffset': 3236, 'EndOffset': 3252}, {'Text': 'central blisters on the trunk', 'Type': 'PROBLEM', 'BeginOffset': 3264, 'EndOffset': 3293}, {'Id': 123, 'BeginOffset': 3295, 'EndOffset': 3307, 'Score': 0.4542413055896759, 'Text': 'skin peeling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.734639048576355}]}, {'Text': 'ulcers of mouth, throat, nose, genitals and eyes', 'Type': 'PROBLEM', 'BeginOffset': 3309, 'EndOffset': 3357}, {'Id': 125, 'BeginOffset': 3381, 'EndOffset': 3386, 'Score': 0.9585452079772949, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7531166076660156}]}, {'Id': 126, 'BeginOffset': 3391, 'EndOffset': 3408, 'Score': 0.9401260018348694, 'Text': 'flu-like symptoms', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8643977046012878}]}, {'Text': 'epoetin alfa hexal', 'Type': 'TREATMENT', 'BeginOffset': 3421, 'EndOffset': 3439}, {'Text': 'these symptoms', 'Type': 'PROBLEM', 'BeginOffset': 3455, 'EndOffset': 3469}, {'Text': '2.', 'Type': 'NUMBER', 'BeginOffset': 3550, 'EndOffset': 3552}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 3692, 'EndOffset': 3701}, {'Text': 'epoetin alfa hexal', 'Type': 'TREATMENT', 'BeginOffset': 3707, 'EndOffset': 3725}, {'Id': 127, 'BeginOffset': 3741, 'EndOffset': 3753, 'Score': 0.8916184902191162, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6446642875671387}]}, {'Text': 'any side effects', 'Type': 'PROBLEM', 'BeginOffset': 3785, 'EndOffset': 3801}, {'Id': 129, 'BeginOffset': 3889, 'EndOffset': 3901, 'Score': 0.9042891263961792, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7325270175933838}]}, {'Id': 130, 'BeginOffset': 3917, 'EndOffset': 3929, 'Score': 0.913681149482727, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7611719965934753}]}, {'Id': 131, 'BeginOffset': 4000, 'EndOffset': 4012, 'Score': 0.9507562518119812, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6522246599197388}]}, {'Id': 138, 'BeginOffset': 4061, 'EndOffset': 4073, 'Score': 0.8156498670578003, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6592603325843811}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.4089646339416504, 'RelationshipScore': 0.5364780426025391, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 137, 'BeginOffset': 4127, 'EndOffset': 4135, 'Text': 'appendix', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 137, 'BeginOffset': 4127, 'EndOffset': 4135, 'Score': 0.4089646339416504, 'Text': 'appendix', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 139, 'BeginOffset': 4152, 'EndOffset': 4164, 'Score': 0.7559335827827454, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7085056900978088}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 4220, 'EndOffset': 4233}]}

{'Title': '5. how to store epoetin alfa hexal', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. store and transport refrigerated (2-8). you may take epoetin alfa hexal out of the refrigerator and keep it at room temperature (up to 25) for no longer than 3 days. once a syringe has been removed from the refrigerator and has reached room temperature (up to 25) it must either be used within 3 days or disposed of. do not freeze or shake. store in the original package in order to protect from light. do not use this medicine if you notice that it may have been accidentally frozen, or if there has been a refrigerator failure, the liquid is coloured or you can see particles floating in it, the seal is broken. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'epoetin alfa hexal', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 71, 'EndOffset': 84}, {'Text': 'epoetin alfa hexal', 'Type': 'TREATMENT', 'BeginOffset': 211, 'EndOffset': 229}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 293, 'EndOffset': 295}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 316, 'EndOffset': 317}, {'Text': 'a syringe', 'Type': 'TREATMENT', 'BeginOffset': 329, 'EndOffset': 338}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 418, 'EndOffset': 420}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 452, 'EndOffset': 453}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 572, 'EndOffset': 585}, {'Text': 'a refrigerator failure', 'Type': 'PROBLEM', 'BeginOffset': 664, 'EndOffset': 686}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what epoetin alfa hexal contains - the active substance is: epoetin alfa (for quantity see the table below). - the other ingredients are: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (for ph-adjustment), sodium hydroxide (for ph-adjustment), and water for injections. what epoetin alfa hexal looks like and contents of the pack epoetin alfa hexal is presented as a clear, colourless solution for injection in a pre-filled syringe. the syringes are sealed in a blister. presentation corresponding presentations in quantity/volume for each strength amount of epoetin alfa pre-filled syringes* 2,000 iu/ml: 1,000 iu/0.5 ml 2,000 iu/1 ml 10,000 iu/ml: 3,000 iu/0.3 ml 4,000 iu/0.4 ml 5,000 iu/0.5 ml 6,000 iu/0.6 ml 7,000 iu/0.7 ml 8,000 iu/0.8 ml 9,000 iu/0.9 ml 10,000 iu/1 ml 40,000 iu/ml: 20,000 iu/0.5 ml 30,000 iu/0.75 ml 40,000 iu/1 ml 8.4 micrograms 16.8 micrograms 25.2 micrograms 33.6 micrograms 42.0 micrograms 50.4 micrograms 58.8 micrograms 67.2 micrograms 75.6 micrograms 84.0 micrograms 168.0 micrograms 252.0 micrograms 336.0 micrograms *pack size of 1, 4 or 6 pre-filled syringe(s) with or without a needle safety guard. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'epoetin alfa hexal', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'epoetin alfa hexal', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 23}, {'Id': 1, 'BeginOffset': 60, 'EndOffset': 72, 'Score': 0.9957352876663208, 'Text': 'epoetin alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 138, 'EndOffset': 175, 'Score': 0.9954692125320435, 'Text': 'sodium dihydrogen phosphate dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 177, 'EndOffset': 205, 'Score': 0.9944619536399841, 'Text': 'disodium phosphate dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 207, 'EndOffset': 222, 'Score': 0.9997690320014954, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 224, 'EndOffset': 231, 'Score': 0.8522268533706665, 'Text': 'glycine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 233, 'EndOffset': 247, 'Score': 0.724995493888855, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 249, 'EndOffset': 266, 'Score': 0.9950941801071167, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ph-adjustment)', 'Type': 'TREATMENT', 'BeginOffset': 272, 'EndOffset': 286}, {'Id': 8, 'BeginOffset': 288, 'EndOffset': 304, 'Score': 0.9970610737800598, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ph-adjustment)', 'Type': 'TREATMENT', 'BeginOffset': 310, 'EndOffset': 324}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 340, 'EndOffset': 350}, {'Text': 'epoetin alfa hexal', 'Type': 'TREATMENT', 'BeginOffset': 357, 'EndOffset': 375}, {'Text': 'the pack epoetin alfa hexal', 'Type': 'TREATMENT', 'BeginOffset': 403, 'EndOffset': 430}, {'Text': 'a clear, colourless solution', 'Type': 'TREATMENT', 'BeginOffset': 447, 'EndOffset': 475}, {'Text': 'a pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 493, 'EndOffset': 513}, {'Text': 'the syringes', 'Type': 'TREATMENT', 'BeginOffset': 515, 'EndOffset': 527}, {'Text': 'a blister', 'Type': 'PROBLEM', 'BeginOffset': 542, 'EndOffset': 551}, {'Text': 'volume for each strength amount', 'Type': 'TREATMENT', 'BeginOffset': 606, 'EndOffset': 637}, {'Text': 'epoetin alfa pre-filled syringes', 'Type': 'TREATMENT', 'BeginOffset': 641, 'EndOffset': 673}, {'Text': '2,000', 'Type': 'NUMBER', 'BeginOffset': 675, 'EndOffset': 680}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 688, 'EndOffset': 693}, {'Text': '2,000', 'Type': 'NUMBER', 'BeginOffset': 704, 'EndOffset': 709}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 713, 'EndOffset': 714}, {'Text': '10,000', 'Type': 'NUMBER', 'BeginOffset': 718, 'EndOffset': 724}, {'Text': '3,000', 'Type': 'NUMBER', 'BeginOffset': 732, 'EndOffset': 737}, {'Text': '4,000', 'Type': 'NUMBER', 'BeginOffset': 748, 'EndOffset': 753}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 759, 'EndOffset': 760}, {'Text': '5,000', 'Type': 'NUMBER', 'BeginOffset': 764, 'EndOffset': 769}, {'Text': '6,000', 'Type': 'NUMBER', 'BeginOffset': 780, 'EndOffset': 785}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 791, 'EndOffset': 792}, {'Text': '7,000', 'Type': 'NUMBER', 'BeginOffset': 796, 'EndOffset': 801}, {'Text': '8,000', 'Type': 'NUMBER', 'BeginOffset': 812, 'EndOffset': 817}, {'Text': '9,000', 'Type': 'NUMBER', 'BeginOffset': 828, 'EndOffset': 833}, {'Text': 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D151F97A5AD8B5F9FF3AF280F2883C51

https://www.ema.europa.eu/documents/product-information/farydak-epar-product-information_en.pdf

Farydak

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Farydak 10 mg hard capsules Farydak 15 mg hard capsules Farydak 20 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Farydak 10 mg hard capsules Each hard capsule contains panobinostat lactate anhydrous equivalent to 10 mg panobinostat. Farydak 15 mg hard capsules Each hard capsule contains panobinostat lactate anhydrous equivalent to 15 mg panobinostat. Farydak 20 mg hard capsules Each hard capsule contains panobinostat lactate anhydrous equivalent to 20 mg panobinostat. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule (capsule). Farydak 10 mg hard capsules Light green opaque hard gelatin capsule (15.6–16.2 mm) containing white to almost white powder, with radial marking “LBH 10 mg” in black ink on cap and two radial bands in black ink on body. Farydak 15 mg hard capsules Orange opaque hard gelatin capsule (19.1–19.7 mm) containing white to almost white powder, with radial marking “LBH 15 mg” in black ink on cap and two radial bands in black ink on body. Farydak 20 mg hard capsules Red opaque hard gelatin capsule (19.1–19.7 mm) containing white to almost white powder, with radial marking “LBH 20 mg” in black ink on cap and two radial bands in black ink on body. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Farydak, in combination with bortezomib and dexamethasone, is indicated for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent. 4.2 Posology and method of administration Treatment with Farydak should be initiated by a physician experienced in the use of anti-cancer 3 therapies. Posology The recommended starting dose of panobinostat is 20 mg, taken orally once a day, on days 1, 3, 5, 8, 10 and 12 of a 21-day cycle. Patients should be treated initially for eight cycles. It is recommended that patients with clinical benefit continue the treatment for eight additional cycles. The total duration of treatment is up to 16 cycles (48 weeks). Panobinostat is administered in combination with bortezomib and dexamethasone, as shown in Tables 1 and 2. The bortezomib and dexamethasone prescribing information should be consulted prior to the start of the combination treatment to assess whether a dose reduction is required. The recommended dose of bortezomib is 1.3 mg/m2 given as an injection. The recommended dose of dexamethasone is 20 mg taken orally on a full stomach. Table 1 Recommended dosing schedule of panobinostat in combination with bortezomib and dexamethasone (cycles 1-8) Cycles 1-8 (3-week cycles) Week 1 Days Week 2 Days Week 3 Farydak 1 3 5 8 10 12 Rest period Bortezomib 1 4 8 11 Rest period Dexamethasone 1 2 4 5 8 9 11 12 Rest period Table 2 Recommended dosing schedule of panobinostat in combination with bortezomib and dexamethasone (cycles 9-16) Cycles 9-16 (3-week cycles) Week 1 Days Week 2 Days Week 3 Farydak 1 3 5 8 10 12 Rest period Bortezomib 1 8 Rest period Dexamethasone 1 2 8 9 Rest period Monitoring recommendations Blood cell counts A complete blood cell count must be performed before initiating treatment with panobinostat. The baseline platelet count should be ≥100 x 109/l and the baseline absolute neutrophil count (ANC) ≥1.0 x 109/l. Complete blood counts should be frequently monitored during treatment (in particular before each injection of bortezomib, i.e. on days 1, 4, 8 and 11 of cycles 1 to 8 and on days 1 and 8 of cycles 9 to 16), especially for thrombocytopenia (see section 4.4). Prior to initiating any cycle of therapy with panobinostat in combination with bortezomib and dexamethasone, platelet count should be at least ≥100 x 109/l (see section 4.4). Additional blood counts should be considered during the “rest period” – e.g. on days 15 and/or 18, especially in patients ≥65 years and patients with a baseline platelet count below 150 x 109/l. ECG Panobinostat may increase the QTc interval (see section 4.4). Therefore an ECG should be recorded prior to the start of therapy and repeated periodically before each treatment cycle. QTcF should be <480 msec prior to initiation of treatment with panobinostat (see below section on dose adjustments and section 4.4). Blood electrolytes Blood electrolytes, especially potassium, magnesium and phosphorus, should be measured at baseline and monitored periodically as clinically indicated, especially in patients with diarrhoea. Abnormal values should be corrected as clinically indicated (see section 4.4). 4 Liver function tests Liver function should be monitored prior to treatment and regularly during treatment as clinically indicated, especially in patients with hepatic impairment (see section 4.4). Thyroid function tests Mild hypothyroidism was reported in patients treated with panobinostat + bortezomib + dexamethasone in Study D2308; some patients required treatment (see section 4.4). Thyroid and pituitary function should be monitored by measuring hormone levels (e.g. free T4 and TSH) as clinically indicated. Dose adjustments Modification of the treatment dose and/or schedule may be required based on individual tolerability. Clinical judgement on how to continue the treatment should be exercised when a patient experiences an adverse drug reaction. If a dose reduction is required, the dose of panobinostat should be reduced by decrements of 5 mg (i.e. from 20 mg to 15 mg or from 15 mg to 10 mg). The dose should not be reduced below 10 mg and the same treatment schedule (3-week treatment cycle) should be kept. Thrombocytopenia Platelet counts should be monitored prior to each dose of bortezomib (i.e. on days 1, 4, 8 and 11 of cycles 1-8, see Table 1, and on days 1 and 8 of cycles 9-16, see Table 2). If patients experience thrombocytopenia, panobinostat may need to be temporarily withheld and the subsequent dose may need to be reduced (see Table 3). In patients with platelet count <50 x 109/l (complicated by bleeding) or <25 x 109/l, Farydak therapy should be withheld and resumed at a reduced dose upon recovery to platelet count ≥50 x 109/l. Platelet counts should be monitored at least twice a week until ≥50 x 109/l. Platelet transfusions may be required, if clinically indicated (see section 4.4). Discontinuation of treatment may be considered if thrombocytopenia does not improve despite the treatment modifications described below and/or the patient requires repeated platelet transfusions. Additionally, dose adjustment of bortezomib may be considered (see bortezomib SmPC and Table 3). Table 3 Recommended dose modifications for thrombocytopenia Thrombocytopenia grade on day of treatment Modification of panobinostat starting dose Panobinostat dose on recovery to grade 2 thrombocytopenia (≥50 x 109/l) Modification of bortezomib starting dose Bortezomib dose on recovery to grade 2 thrombocytopenia (≥50 x 109/l) 1 dose omitted More than 1 dose omitted Grade 3 Platelets <50 x 109/l with bleeding Omit dose Resume at reduced dose Omit dose Resume at same dose Resume at reduced dose Grade 4 Platelets <25 x 109/l Omit dose Resume at reduced dose Omit dose Resume at same dose Resume at reduced dose Gastrointestinal toxicity Gastrointestinal toxicity is very common in patients treated with panobinostat. Patients who experience diarrhoea and nausea or vomiting may require temporary dose discontinuation or dose 5 reduction as outlined in Table 4. Table 4 Recommended dose modifications for gastrointestinal toxicity Adverse drug reaction Grade on day of treatment Modification of panobinostat starting dose Panobinostat dose on recovery to ≤ grade 1 Modification of bortezomib starting dose Bortezomib dose on recovery to ≤ grade 1 Diarrhoea Grade 2 despite anti-diarrhoeal medicinal product Omit dose Resume at the same dose Omit dose Resume at reduced dose or change to once weekly Grade 3 despite anti-diarrhoeal medicinal product Omit dose Resume at reduced dose Omit dose Resume at reduced dose or with the same dose but with a once-weekly schedule Grade 4 despite anti-diarrhoeal medicinal product Permanently discontinue Permanently discontinue At the first sign of abdominal cramping, loose stools or onset of diarrhoea, it is recommended that the patient be treated with an anti-diarrhoeal medicinal product (e.g. loperamide). In the event of grade 3 nausea or grade 3 or 4 vomiting despite administration of an anti-emetic, panobinostat should be temporarily discontinued and resumed at a reduced dose on recovery to grade 1. Prophylactic anti-emetics should be administered at the discretion of the physician and in accordance with local medical practice (see section 4.4). Neutropenia Neutropenia may require temporary or permanent dose reduction. Instructions for dose interruptions and reductions for panobinostat are outlined in Table 5. Table 5 Recommended dose modifications for neutropenia Neutropenia grade on day of treatment Modification of panobinostat starting dose Panobinostat dose on recovery to grade 2 neutropenia (<1.5-1.0 x 109/l) Modification of bortezomib starting dose Bortezomib dose on recovery to grade 2 neutropenia (<1.5-1.0 x 109/l) Grade 3 neutropenia (<1.0-0.5 x 109/l) Omit dose Resume at same dose Omit dose Resume at same dose Grade 4 neutropenia (<0.5 x 109/l) or febrile neutropenia (<1.0 x 109/l and fever ≥38.5°C) Omit dose Resume at reduced dose Omit dose Resume at same dose In the event of grade 3 or 4 neutropenia, physicians should consider the use of growth factors (e.g. G-CSF) according to local guidelines. Discontinuation of treatment may be considered if neutropenia does not improve despite the dose modifications and/or despite the addition of granulocyte colony stimulating factor therapy according to local medical practice and treatment guidelines, and/or in the 6 event of severe secondary infections. QTc prolongation In the event of long QT interval prior to initiation of panobinostat (QTcF ≥480 msec at baseline), the start of treatment should be delayed until pre-dose average QTcF has returned to <480 msec. In addition any abnormal serum potassium, magnesium or phosphorus values should be corrected prior to initiation of Farydak therapy (see section 4.4). In the event of QT prolongation during treatment: • The dose should be omitted, if QTcF is ≥480 msec or above 60 msec from baseline. • If QT prolongation is resolved within 7 days, resume treatment at prior dose for initial occurrence or at reduced dose if QT prolongation is recurrent. • If QT prolongation is unresolved within 7 days, treatment should be discontinued. • If any QTcF value is above 500 msec, Farydak therapy should be permanently discontinued. Other adverse drug reactions For patients experiencing severe adverse drug reactions other than thrombocytopenia, gastrointestinal toxicity, neutropenia or QTc prolongation, the recommendation is the following: • CTC grade 2 toxicity recurrence or CTC grades 3 and 4 - omit the dose until recovery to CTC grade ≤1 and resume treatment at a reduced dose. • CTC grade 3 or 4 toxicity recurrence - a further dose reduction may be considered once the adverse reaction has resolved to CTC grade <1. Special populations Patients with renal impairment Plasma exposure of panobinostat is not altered in cancer patients with mild to severe renal impairment. Therefore, starting dose adjustments are not necessary. Panobinostat has not been studied in patients with end-stage renal disease (ESRD) or patients on dialysis (see section 5.2). Patients with hepatic impairment A clinical study in cancer patients with impaired hepatic function showed that plasma exposure of panobinostat increased by 43% (1.4-fold) and 105% (2-fold) in patients with mild and moderate hepatic impairment, respectively. Patients with mild hepatic impairment should be started on panobinostat at a reduced dose of 15 mg during the first treatment cycle. A dose escalation from 15 mg to 20 mg may be considered based on patient tolerability. Patients with moderate hepatic impairment should be started on panobinostat at a reduced dose of 10 mg during the first treatment cycle. A dose escalation from 10 mg to 15 mg may be considered based on patient tolerability. Frequency of monitoring of these patients should be increased during treatment with panobinostat, particularly during the dose escalation phase. Panobinostat should not be administered in patients with severe hepatic impairment due to lack of experience and safety data in this population. Adjustment of bortezomib dose should also be considered (see bortezomib SmPC and Table 6). 7 Table 6 Recommended starting dose modification for patients with hepatic impairment Grade of hepatic impairment* Bilirubin level SGOT (AST) levels Modification of panobinostat starting dose Modification of bortezomib starting dose Mild ≤1.0 x ULN >ULN Reduce panobinostat dose to 15 mg in the first treatment cycle. Consider dose escalation up to 20 mg in subsequent cycles based on patient tolerability. None >1.0 x ULN and ≤1.5 x ULN Any Moderate >1.5 x ULN and ≤3.0 x ULN Any Reduce panobinostat dose to 10 mg in the first treatment cycle. Consider dose escalation up to 15 mg in subsequent cycles based on patient tolerability. Reduce bortezomib dose to 0.7 mg/m2 in the first treatment cycle. Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability. SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase ULN = upper limit of the normal range * Based on NCI-CTEP classification Elderly population Patients over 65 years of age had a higher frequency of selected adverse reactions and of discontinuation of treatment because of adverse reactions. It is recommended to monitor patients over 65 years of age more frequently, especially for thrombocytopenia and gastrointestinal toxicity (see sections 4.4 and 4.8). For patients >75 years of age, depending on the patient’s general condition and concomitant diseases, an adjustment of the starting doses or schedule of the components of the combination regimen may be considered. Panobinostat may be started at a dose of 15 mg, and if tolerated in the first cycle escalated to 20 mg in the second cycle. Bortezomib may be started at 1.3 mg/m2 once weekly on days 1 and 8, and dexamethasone at 20 mg on days 1 and 8. Paediatric population There is no relevant use of panobinostat in paediatric patients below the age of 18 years in the indication multiple myeloma (see section 5.2). Strong CYP3A4 inhibitors In patients who take concomitant medicinal products which are strong CYP3A and/or Pgp inhibitors, including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone, the dose of panobinostat should be reduced to 10 mg (see section 4.5). If continuous treatment with a strong CYP3A4 inhibitor is required, a dose escalation from 10 mg to 15 mg panobinostat may be considered based on patient tolerability. In patients with hepatic impairment receiving concomitant medicinal products which are strong CYP3A4 inhibitors, treatment with panobinostat should be avoided due to lack of experience and safety data in this patient population. Strong CYP3A inhibitors should not be started in patients who have already received a reduced dose 8 of panobinostat due to adverse reactions. If this is unavoidable, patients should be closely monitored and further dose reduction or discontinuation may be considered as clinically indicated (see section 4.5). Method of administration Farydak should be administered orally once daily on scheduled days only, at the same time each day. The capsules should be swallowed whole with water, with or without food (see section 5.2), and they should not be opened, crushed or chewed. If a dose is missed, it can be taken up to 12 hours after the specified dose time. If vomiting occurs the patient should not take an additional dose, but should take the next usual prescribed dose. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Breast-feeding (see section 4.6). 4.4 Special warnings and precautions for use Panobinostat is used in combination treatment, therefore the prescribing information of bortezomib and dexamethasone should be consulted prior to initiation of treatment with panobinostat. Decrease in blood cell count Haematological adverse drug reactions, including severe thrombocytopenia, neutropenia and anaemia (CTC grade 3 to 4) were reported in patients treated with panobinostat. Therefore a complete blood count must be performed before initiating therapy with panobinostat, with frequent monitoring during treatment (in particular before each injection of bortezomib as per bortezomib SmPC). The platelet count should be ≥100 x 109/l and the absolute neutrophil count ≥1.0 x 109/l prior to initiation of treatment. Platelet count should be ≥100 x 109/l prior to initiating any cycle of treatment (see section 4.2). In the phase III study, thrombocytopenia typically recovered to baseline by the start of the next 21-day cycle (see Figure 1). The median time to onset for grade 3 and 4 thrombocytopenia was one month and the median time to recovery was 12 days. 9 Figure 1 Median platelet counts over time (Study D2308, Safety set, cycles 1-8) PAN=panobinostat BTZ= bortezomib Dex = dexamethasone In patients with CTC grade 3 thrombocytopenia (platelet count <50 x 109/l with bleeding) panobinostat may need to be temporarily withheld and/or the subsequent dose may need to be reduced. Platelet transfusions may be required as clinically indicated (see sections 4.2 and 4.8). Haemorrhage Haemorrhage has been reported in patients during treatment with panobinostat. CTC grade 3 or 4 haemorrhage was reported in 4.2% of patients, including cases of gastrointestinal and pulmonary haemorrhage with fatal outcomes. Therefore, physicians and patients should be aware of the increased risk of thrombocytopenia and the potential for haemorrhage, especially in patients with coagulation disorders or in those who are receiving chronic anti-coagulation therapy. Infection Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections including hepatitis B virus and herpes simplex, have been reported in patients taking panobinostat. Some of these infections (e.g. pneumonia) have been severe (e.g. leading to sepsis, or respiratory or multi-organ failure) and have had fatal outcomes (see section 4.8). Of note, whereas grade 3 and grade 4 neutropenia were observed in 28% and 7% of patients, respectively, febrile neutropenia was observed in 1% of patients (see section 4.8). Physicians and patients should be aware of the increased risk of infection with panobinostat. Farydak treatment should not be initiated in patients with active infections. Pre-existing infections should be treated prior to initiation of the therapy. Patients should be monitored for signs and symptoms of infections during treatment with panobinostat; if a diagnosis of infection is made, appropriate anti-infective treatment should be instituted promptly and interruption or discontinuation of Farydak considered. If a diagnosis of invasive systemic fungal infection is made, panobinostat should be discontinued and appropriate anti-fungal therapy instituted. (BL) 1:4 1:8 1:11 2:1 2:4 2:8 2:11 3:1 3:4 3:8 3:11 4:1 4:4 4:8 4:11 5:1 5:4 5:8 5:11 6:1 6:4 6:8 6:11 7:1 7:4 7:8 7:11 8:1 8:4 8:8 8:11 100 200 300 400 500 0 PAN+BTZ+Dex PBO+BTZ+Dex PAN+BTZ+Dex n= 381 370 367 363 351 342 335 320 323 310 298 283 285 265 268 250 253 232 238 225 230 206 206 199 205 183 188 175 185 159 170 155 PBO+BTZ+Dex n= 377 364 368 365 357 349 340 339 335 325 313 302 308 292 292 279 275 255 259 241 251 234 242 203 233 209 217 204 211 192 194 188 Cycle:Day Pl at el et s 10 x 1 09 /l 10 Gastrointestinal disorders Severe nausea, diarrhoea, constipation and vomiting, sometimes requiring the use of anti-emetic and anti-diarrhoeal medicinal products, have been reported in patients treated with Farydak (see section 4.8). Fluid and electrolyte blood levels, especially potassium, magnesium and phosphate, should be monitored periodically during therapy and corrected as clinically indicated to prevent potential dehydration and electrolyte disturbances (see section 4.2). Prophylactic anti-emetics (e.g. prochlorperazine) may be considered at the discretion of the physician and in accordance with local medical practice. Anti-emetic medicinal products with a known risk of QT prolongation such as dolasetron, granisetron, ondansetron and tropisetron should be used with caution (see section 4.5). At the first sign of abdominal cramping, loose stools or onset of diarrhoea, it is recommended that the patient be treated with anti-diarrhoeal medicinal product (e.g. loperamide) or any additional treatment in accordance with local treatment guidelines. Replacement intravenous fluids and electrolytes may be used as appropriate. Medicinal products with laxative properties should be used with caution because of the potential for exacerbation of diarrhoea. Patients should be advised to contact their physician to discuss the use of any laxative product. Electrocardiographic changes Panobinostat may prolong cardiac ventricular repolarisation (QT interval). No episodes of QTcF prolongation >500 msec were reported with the dose of 20 mg Farydak in the phase III clinical study, in combination with bortezomib and dexamethasone. Pooled clinical data from over 500 patients treated with panobinostat alone in multiple indications and at different dose levels have shown that the incidence of CTC grade 3 QTc prolongation (QTcF >500 msec) was approximately 1% overall and 5% or more at a dose of 60 mg or higher; no episodes of torsades de pointes were observed. Additional analysis suggests that the risk of QTc prolongation does not increase over time (see section 4.2). QTcF should be <480 msec prior to initiation of treatment with Farydak. Appropriate monitoring of electrolytes (e.g. potassium, magnesium and phosphorus) and ECG should be performed at baseline and periodically during treatment, particularly in patients with severe gastrointestinal adverse drug reaction (see section 4.2). Farydak should be used with caution in patients who already have or who are at significant risk of developing QTc prolongation. This includes patients: • with long QT syndrome. • with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia. Concomitant administration of medicinal products that are known to cause QTc prolongation should be used with caution (see section 4.5). In case of concomitant use of agents that may increase panobinostat plasma concentrations, such as strong CYP3A4 inhibitors, dose adjustment is required (see sections 4.5 and 4.2). Hepatotoxicity Hepatic dysfunction, primarily mild transient elevations in aminotransferases and total bilirubin, has been reported in patients during treatment with panobinostat. 11 Liver function should be monitored prior to treatment and regularly during treatment. If results of liver function tests show abnormalities according to the NCI-CTEP classification, dose adjustments for patients with mild and moderate hepatic impairment are recommended and the patient should be followed until values return to normal or pre-treatment levels. Panobinostat should not be administered in patients with severe hepatic impairment due to lack of experience and safety data in this population. Adjustment of bortezomib dose should also be considered (see bortezomib SmPC and Table 6). Elderly population It is recommended to monitor patients over 65 years of age more frequently, especially for thrombocytopenia and gastrointestinal toxicity (see section 4.8 and section 4.2). For patients >75 years of age, depending on the patient’s general condition and concomitant diseases, an adjustment of the starting doses or schedule of the components of the combination regimen may be considered (see section 4.2). Strong CYP3A4 inducers Strong inducers may reduce the efficacy of panobinostat, therefore the concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum), should be avoided (see section 4.5). Women of childbearing potential Women of childbearing potential taking panobinostat in combination with bortezomib and dexamethasone must use highly effective contraception for three months after stopping treatment (see sections 4.5 and 4.6 and bortezomib and dexamethasone SmPC). Women using hormonal contraceptives should additionally use a barrier method of contraception. Hypothyroidism Hypothyroidism events were reported in 8 of 381 patients treated with panobinostat + bortezomib + dexamethasone in Study D2308, of whom 2 required treatment. Thyroid and pituitary function should be monitored by measuring hormone levels (e.g. free T4 and TSH) as clinically indicated (see section 4.2). 4.5 Interaction with other medicinal products and other forms of interaction Farydak metabolism is through both non-CYP and CYP mediated routes. Approximately 40% of panobinostat is metabolised through CYP3A4. Metabolism via CYP2D6 and 2C19 was minor. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of panobinostat. Panobinostat is a P-gp substrate. Agents that may increase panobinostat plasma concentrations Co-administration of a single 20 mg panobinostat dose with ketoconazole, a strong CYP3A inhibitor, increased the Cmax and AUC of panobinostat by 1.6- and 1.8-fold, respectively, compared to when panobinostat was given alone. In patients who take concomitant medicinal products which are strong CYP3A and/or Pgp inhibitors, including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone, the dose of panobinostat should be reduced (see section 4.2). Patients should be instructed to avoid star fruit, grapefruit, grapefruit juice, pomegranates and pomegranate juice, as these are known to inhibit cytochrome P450 3A enzymes and may increase the bioavailability of panobinostat. 12 Agents that are predicted to decrease panobinostat concentrations The panobinostat fraction metabolised through CYP3A4 is approximately 40%. In clinical studies in multiple myeloma, the exposure of panobinostat was decreased by approximately 20% by the concomitant use of dexamethasone, which is a dose-dependent mild/moderate CYP3A4 inducer. Strong inducers are expected to have greater effects, and may reduce the efficacy of panobinostat, therefore the concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum), should be avoided. Agents whose plasma concentrations may be increased by panobinostat Panobinostat increased the Cmax and the AUC of dextromethorphan (a substrate of CYP2D6) by 1.8- and 1.6-fold, respectively, and it cannot be excluded that the effect may be larger on a more sensitive CYP2D6 substrate. Avoid panobinostat use in patients who are taking CYP2D6 substrates with a narrow therapeutic index (including, but not limited to, pimozide). When Farydak is co-administered with sensitive CYP2D6 substrates (e.g. atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine and pimozide), dose titrate individual CYP2D6 substrates based on tolerability and frequently monitor patients for adverse reactions. Agents whose plasma exposure can be decreased by panobinostat Hormonal contraceptives It is currently unknown whether panobinostat may reduce the effectiveness of hormonal contraceptives. In addition, when panobinostat is administered together with dexamethasone, which is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy of contraceptives needs to be considered. Women using hormonal contraceptives should additionally use a barrier method of contraception. No data is available that can be used to exclude the risk that panobinostat could be a weak inducer of the enzyme CYP3A4 in the gastrointestinal tract. This could potentially lead to slightly decreased exposure to sensitive CYP3A4 substrates. Anticipated pharmacodynamic interactions Prolongation of QT interval Based on preclinical and clinical data, panobinostat has the potential to prolong the QT interval. Concomitant use of anti-arrhythmic medicinal products (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine and sotalol) and other substances that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, methadone, moxifloxacin, bepridil and pimozide) is not recommended. Anti-emetic medicinal products with a known risk of QT prolongation such as dolasetron, granisetron, ondansetron and tropisetron should be used with caution (see section 4.4). 4.6 Fertility, pregnancy and lactation Women of child-bearing potential/Contraception in males and females Based on findings in animals, the likelihood of panobinostat increasing the risk of both foetal death and developmental skeletal abnormalities when administered to pregnant women is predicted to be high. Women of child-bearing potential should have a pregnancy test prior to the initiation of treatment with Farydak and must use a highly effective method of contraception during treatment and for three months after the last dose of Farydak. Women using hormonal contraceptives should additionally use a barrier method of contraception. 13 Due to its cytostatic/cytotoxic mode of action, panobinostat can influence the quality of sperm formed during treatment. Sexually active men taking Farydak and their female partners should use a highly effective method of contraception during the man’s treatment and for six months after his last dose of Farydak. When panobinostat is administered together with dexamethasone, which is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy of hormonal contraceptives needs to be considered. In addition, it is currently unknown whether panobinostat may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should additionally use a barrier method of contraception. Pregnancy There are no clinical studies on the use of Farydak in pregnant patients. Studies in animals have shown reproductive and embryo-foetal toxicity (see section 5.3). Given panobinostat’s cytostatic/cytotoxic mode of action, the potential risk to the foetus is high. Farydak should only be used during pregnancy if the expected benefits outweigh the potential risks to the foetus. If it is used during pregnancy or if the patient becomes pregnant while using it, the patient must be informed of the potential risk to the foetus. Breast-feeding It is unknown whether panobinostat is excreted in human milk. Given its cytostatic/cytotoxic mode of action, breast-feeding is contraindicated during Farydak treatment (see section 4.3). Fertility Based on non-clinical findings, male fertility may be compromised by treatment with Farydak (see section 5.3). 4.7 Effects on ability to drive and use machines Farydak has a minor influence on the ability to drive and use machines. Dizziness may occur following administration of Farydak (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The safety data of panobinostat have been assessed from a total of 451 patients with multiple myeloma treated with panobinostat in combination with bortezomib and dexamethasone and from a total of 278 patients treated with panobinostat as a single agent. The safety data reported below are based on the phase III clinical study (Panorama 1) in 381 patients with multiple myeloma treated with 20 mg panobinostat once a day three times per week, on a 2 weeks on and 1 week off dosing regimen in combination with bortezomib and dexamethasone. The median duration of exposure in the study was 5.0 months. 15.7% of patients were exposed to study treatment for ≥48 weeks. The most common non-haematological adverse reactions were diarrhoea, fatigue, nausea and vomiting. Treatment-emergent haematological toxicities included thrombocytopenia, anaemia, neutropenia and lymphopenia. QTcF >480 and <500 msec was recorded in 1.3% of patients and change from baseline of >60 msec was observed in 0.8% of patients. No patient had an absolute QTcF >500 msec. 14 Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation and sinus tachycardia) were reported in 17.6% of panobinostat + bortezomib + dexamethasone-treated patients versus 9.8% of placebo + bortezomib + dexamethasone-treated patients and syncope events were reported in 6.0% versus 2.4%, respectively. Discontinuation due to adverse events, regardless of causality, was observed in 36.2% of patients. The most common adverse events (AEs) leading to treatment discontinuation were diarrhoea (4.5%), asthenia and fatigue (2.9% each) and pneumonia (1.3%). On-treatment deaths not due to the study indication (multiple myeloma) were reported in 6.8% of panobinostat + bortezomib + dexamethasone-treated patients versus 3.2% of placebo + bortezomib + dexamethasone-treated patients. Tabulated list of adverse drug reactions from clinical studies Adverse drug reactions from the phase III study (Panorama 1) are shown in Table 7. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from available data). Table 7 includes adverse drug reactions that occur due to the addition of panobinostat to the bortezomib and dexamethasone combination. The frequency category reflects the combination of all the medicinal products i.e. panobinostat + bortezomib + dexamethasone. For adverse drug reactions that are related to bortezomib or dexamethasone treatment, please refer to the relevant SmPC. Table 7 Panobinostat adverse drug reactions observed in multiple myeloma patients in the phase III study System Organ Class Frequency Adverse reaction Infections and infestations Very common Upper respiratory tract infection, pneumonia Common Septic shock, urinary tract infection, viral infection, oral herpes, Clostridium difficile colitis, otitis media, cellulitis, sepsis, gastroenteritis, lower respiratory tract infection, candidiasis Uncommon Pneumonia fungal, hepatitis B, aspergillosis Blood and lymphatic system disorders a Very common Pancytopenia, thrombocytopenia, anaemia, leukopenia, neutropenia, lymphopenia Endocrine disorders Common Hypothyroidism Metabolism and nutrition disorders Very common Decreased appetite, hypophosphataemia a, hyponatraemia a, hypokalaemia a Common Hyperglycaemia, dehydration, hypoalbuminaemia, fluid retention, hyperuricaemia, hypocalcaemia, hypomagnesaemia Psychiatric disorders Very common Insomnia Nervous system disorders Very common Dizziness, headache Common Haemorrhage intracranial, syncope, tremor, dysgeusia Eye disorders Common Conjunctival haemorrhage 15 Cardiac disorders Common Bradycardia, atrial fibrillation, sinus tachycardia, tachycardia, palpitation Uncommon Myocardial infarction Vascular disorders Very common Hypotension Common Hypertension, haematoma, orthostatic hypotension Uncommon Shock haemorrhagic Respiratory, thoracic and mediastinal disorders Very common Cough, dyspnoea Common Respiratory failure, rales, wheezing, epistaxis Uncommon Pulmonary haemorrhage, haemoptysis Gastrointestinal disorders Very common Diarrhoea, nausea, vomiting, abdominal pain, dyspepsia Common Gastrointestinal haemorrhage, haematochezia, gastritis, cheilitis, abdominal distension, dry mouth, flatulence Uncommon Colitis, haematemesis, gastrointestinal pain Hepatobiliary disorders Common Hepatic function abnormal, hyperbilirubinaemia a Skin and subcutaneous disorders Common Skin lesions, rash, erythema Uncommon Petechiae Musculoskeletal and connective tissue disorders Common Joint swelling Renal and urinary disorders Common Renal failure, haematuria, urinary incontinence General disorders and administration site conditions Very common Fatigue, oedema peripheral, pyrexia, asthenia Common Chills, malaise Investigations Very common Weight decreased Common Blood urea increased, glomerular filtration rate decreased, blood alkaline phosphatase increased, electrocardiogram QT prolonged, blood creatinine increased a, SGPT alanine transaminase (ALT) increased a, SGOT aspartate transaminase (AST) increased a a Frequency is based on laboratory values Description of selected adverse drug reactions Gastrointestinal Gastrointestinal toxicity, primarily diarrhoea, nausea and vomiting, is among the most frequently reported adverse reactions. However, treatment discontinuation due to these reactions was reported in a relatively small proportion of patients, with diarrhoea at 4.5% and nausea and vomiting at 0.5% each. Patients should be advised to contact their physician if severe gastrointestinal toxicity occurs and dose adjustment or discontinuation may be required (see section 4.4). Thrombocytopenia Due to the nature of multiple myeloma and the known haematotoxicity for panobinostat and its combination agent bortezomib, thrombocytopenia, often severe, has been frequently observed. CTC grade 3 or 4 thrombocytopenia occurred in 256 patients, with a median onset time of one month. However, thrombocytopenia is reversible (median time to recovery of 12 days) and can usually be managed by dose adjustment and interruption with or without platelet transfusion (see section 4.4). 33.3% patients in the panobinostat + bortezomib + dexamethasone arm and 10.3% patients in the placebo + bortezomib + dexamethasone arm received platelet transfusions during treatment. Thrombocytopenia rarely leads to treatment discontinuation (1.6% of patients). Most patients with thrombocytopenia did not experience haemorrhage. 20.7% of patients experienced haemorrhage, most 16 frequently epistaxis (4.7%), haematoma (2.6%), and conjunctival haemorrhage (2.1%). CTC grade 3 or 4 haemorrhage was reported in 4.2% of patients, mostly commonly involving gastrointestinal haemorrhage. Five patients (1.3%) died of events associated with haemorrhage. Amongst the patients who died of haemorrhage, one patient had thrombocytopenia grade 4, three patients had thrombocytopenia grade 3 and 1 patient had thrombocytopenia grade 1. Neutropenia Neutropenia was frequently reported on the basis of laboratory findings determined during the study (all grades: 75%). Most newly occurring severe neutropenia was grade 3 (28%), with considerably fewer cases of grade 4 (6.6%). While many patients developed neutropenia, febrile neutropenia only occurred in a fraction of treated patients (1.0%, both for CTC all grades and for grades 3 and 4). Patients with neutropenia are prone to infection, mostly upper respiratory tract infection or pneumonia. Only 0.3% of the patients were discontinued from the treatment due to neutropenia. Fatigue and asthenia Fatigue and asthenia were reported in 41.2% and 22.0% of patients, respectively. CTC grade 3 fatigue was reported in 15.7% of the patients, and grade 4 in 1.3%. Grade 3 asthenia was observed in 9.4% of the patients, with no patients experiencing asthenia at CTC grade 4. The treatment was discontinued in 2.9% of patients due to fatigue and asthenia. Infections Relapsed or refractory multiple myeloma patients are at risk of infections. Potential contributing factors may include prior history of chemotherapy, stem cell transplant, the nature of the disease and neutropenia or lymphopenia associated with Farydak treatment. The most frequently reported infections include upper respiratory tract infection, pneumonia and nasopharyngitis. Fatalities involving either pneumonia or sepsis were reported. Treatment discontinuation due to infections was reported in 5% of patients. QT prolongation and ECG abnormalities QTc prolongation was observed and was mostly mild in degree: QTcF interval >450 msec and ≤480 msec was reported in 10.8% of patients, with maximum increase from baseline >30 msec and ≤60 msec in 14.5% of patients. QTcF >500 msec was not reported in any patient. ECG (electrocardiogram) abnormalities have been reported in patients treated with panobinostat + bortezomib + dexamethasone, mainly involving ST-T depression (21.7%) and T wave changes (39.6%). Regardless of events chronology, syncope was reported in 9% of patients with ST-T depression and 7.2% of patients with T wave change and 4.9% of patients with neither of these ECG abnormalities. Likewise ischaemic heart disease (including myocardial infarction and ischaemia) were reported in 4.5% of patients with ST-T depression and 4.8% of patients with T wave change and 2.7% of patients with neither of these ECG abnormalities. Special populations Elderly population The incidence of deaths not related to study indication was 8.8% in patients ≥65 years of age compared to 5.4% in patients <65 years of age. Adverse reactions leading to permanent discontinuation occurred in 30%, 44% and 47% of patients aged <65 years, 65-75 years and ≥75 years, respectively. Grade 3-4 events more frequently observed in patients included the following (percentages presented for patients <65 years, 65-75 years and ≥75 years of age, respectively): thrombocytopenia (60%, 74%, and 91%), anaemia (16%, 17% and 29%), diarrhoea (21%, 27% and 47%), and fatigue (18%, 28% and 47%). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 17 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Limited experience with overdose has been reported during clinical studies. Adverse reactions observed were consistent with the safety profile, with events primarily involving haematological and gastrointestinal disorders such as thrombocytopenia, pancytopenia, diarrhoea, nausea, vomiting and anorexia. Cardiac monitoring and assessment of electrolytes and platelet counts should be undertaken and supportive care given as necessary in the event of overdose. It is not known whether panobinostat is dialysable. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX42 Mechanism of action Farydak is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations. HDACs catalyse the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat. Panobinostat shows more cytotoxicity towards tumour cells compared to normal cells. Pharmacodynamic effects Treatment of tumour cells with panobinostat resulted in a dose-dependent increase in acetylation of histones H3 and H4 both in vitro and in xenograft animal pre-clinical models, demonstrating target inhibition. In addition, increased expression of the tumour suppressor gene p21CDKNIA (cyclin dependent kinase inhibitor 1/p21) gene, a key mediator of G1 arrest and differentiation, was triggered with panobinostat exposure. Clinical efficacy and safety Clinical efficacy in patients with relapsed and relapsed and refractory multiple myeloma (Study D2308 – Panorama 1) The efficacy and safety of panobinostat in combination with bortezomib and dexamethasone were evaluated in a randomised, double-blind, placebo-controlled, multicentre phase III study in patients with relapsed or relapsed and refractory multiple myeloma who had received 1-3 prior lines of therapies. Patients received panobinostat (20 mg taken orally once a day, three times per week, on a 2 weeks on and 1 week off dosing regimen), in combination with bortezomib (1.3 mg/m2 injected intravenously) and dexamethasone (20 mg). Treatment was administered for a maximum of 16 cycles (see Tables 1 and 2). A total of 768 patients were randomised in a 1:1 ratio to either the panobinostat + bortezomib + dexamethasone (n=387) or the placebo + bortezomib + dexamethasone (n=381) arm, stratified by prior use of bortezomib [Yes (n=336 (43.8%)), No (n=432 (56.3%))] and number of prior lines of anti-myeloma therapy [1 prior line (n=352 (45.8%)), 2 to 3 prior lines (n=416 (54.2%))]. Demographics and baseline disease characteristics were balanced and comparable between the study http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 18 arms. The median age was 63 years, range 28-84; 42.1% of patients were older than 65 years. A total of 53.0% of patients were male. Caucasians comprised 65.0% of the study population, Asians 30.2% and blacks 2.9%. ECOG performance status was 0-1 in 93% of patients. The median number of prior therapies was 1.0. More than half (57.2%) of the patients had undergone prior stem cell transplantation and 62.8% of the patients were relapsed after previous anti-neoplastic therapies (e.g. melphalan 79.6%, dexamethasone 81.1%, thalidomide 51.2%, cyclophosphamide 45.3%, bortezomib 43.0%, combined bortezomib and dexamethasone 37.8%, lenalidomide 20.4%). More than one third (35.8%) of the patients were relapsed and refractory to prior treatment. The median duration of follow-up was 28.75 months in the panobinostat + bortezomib + dexamethasone arm and 29.04 months in the placebo + bortezomib + dexamethasone arm. The primary endpoint was progression free survival (PFS) as per modified European Bone Marrow Transplant Group (mEBMT) criteria and as assessed by the investigator. In the overall patient population PFS based on the full analysis set (FAS) was statistically significantly different between the treatment arms (stratified Log-rank test p<0.0001, with an estimated 37% risk reduction in the panobinostat + bortezomib + dexamethasone arm compared to the placebo + bortezomib + dexamethasone arm (Hazard ratio: 0.63 (95% CI: 0.52, 0.76)). The median PFS (95% CI) was 12.0 months (10.3, 12.9) and 8.1 months (7.6, 9.2), respectively. Overall survival (OS) was the key secondary endpoint. OS was not statistically significantly different between the two treatment groups. The median OS was 40.3 months in the panobinostat + bortezomib + dexamethasone arm and 35.8 months in the placebo + bortezomib + dexamethasone arm (Hazard ratio: 0.94 (95% CI: 0.78, 1.14)). Out of the pre-specified subgroup of patients with prior treatment with bortezomib and an immunomodulatory agent (N=193), 76% of patients had received at least two prior regimens. In this subset of patients (N=147), the median duration of treatment was 4.5 months in the panobinostat + bortezomib + dexamethasone arm and 4.8 months in the placebo + bortezomib + dexamethasone arm. The median PFS (95% CI) was 12.5 months (7.26, 14.03) in the panobinostat + bortezomib + dexamethasone arm and 4.7 months (3.71, 6.05) in the placebo + bortezomib + and dexamethasone arm [HR: 0.47 (0.31, 0.72)]. These patients had a median of 3 prior therapies. Efficacy results are summarised in Table 8 and the Kaplan-Meier curves for PFS are provided in Figure 2. Table 8 Progression-free survival in patients who received at least two prior regimens including bortezomib and an immunomodulating agent Farydak bortezomib and dexamethasone N=73 Placebo bortezomib and dexamethasone N=74 Progression-free survival Median, months [95% CI] 12.5 [7.26, 14.03] 4.7 [3.71, 6.05] Hazard ratio [95% CI]1 0.47 (0.31, 0.72) 1 Hazard ratio obtained from stratified Cox model 19 Figure 2 Kaplan-Meier plot of progression-free survival in patients with multiple myeloma who received at least two prior regimens including bortezomib and an immunomodulatory agent PAN= panobinostat PBO= placebo BTZ= bortezomib Dex = dexamethasone In the subgroup of patients who had received at least two prior regimens including bortezomib and an immunomodulatory agent (n=147), the overall response rate using modified EBMT criteria was 59% in the panobinostat + bortezomib + dexamethasone arm and 39% in the placebo + bortezomib + dexamethasone arm. Response rates are summarised in Table 9. Table 9 Response rates in patients with multiple myeloma who received at least two prior regimens including bortezomib and an immunomodulatory agent Farydak bortezomib and dexamethasone N=73 Placebo bortezomib and dexamethasone N=74 Overall response 43 (59%) 29 (39%) [95% CI] (46.8, 70.3) (28, 51.2) Complete response 6 (8%) 0 Near complete response 10 (14%) 6 (8%) Partial response 27 (37%) 23 (31%) Clinical efficacy in patients with bortezomib-refractory multiple myeloma (Study DUS71 – Panorama 2) Study DUS71 was a two-stage, single-arm, open-label multicentre phase II study of oral panobinostat (20 mg) in combination with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) in 55 patients with relapsed and refractory multiple myeloma, who were bortezomib-refractory and had received at least two prior lines of therapy. Patients had to be exposed to an IMiD (lenalidomide or thalidomide). Refractoriness to bortezomib was defined as disease progression on or within 60 days of the last bortezomib-containing line of therapy. The primary endpoint of the study was to assess overall response rate (ORR) after 8 cycles of therapy 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 PAN+BTZ+Dex PBO+BTZ+Dex 6 36 23 8 32 11 10 25 9 12 20 5 14 15 4 16 10 2 18 6 2 20 4 2 22 3 2 24 2 2 26 2 0 28 1 0 30 0 0 0 73 74 2 57 54 4 42 37 0 20 40 60 80 100 P ro gr es si on -fr ee s ur vi va l P ro ba bi lit y (% ) Number of patients at risk Time (months) Time (months) Hazard Ratio= 0.47 95% CI [0.31; 0.72] Logrank p-value=0.0003 Kaplan Meier medians PAN+BTZ+Dex: 12.48 months PBO+BTZ+Dex: 4.70 months Censoring Times PAN+BTZ+Dex (n/N=44/73) PBO+BTZ+Dex (n/N=54/74) 20 as per mEBMT criteria. Patients were heavily pre-treated and had received multiple prior regimens (median: 4; range: 2-11). All 55 patients were previously treated with bortezomib and at least one IMiD (lenalidomide: 98.2%, thalidomide: 69.1%). The majority of patients had received prior transplant (63.6%). The median duration of exposure to study treatment was 4.6 months (range: 0.1-24.1 months). Patients achieved an ORR (≥PR (partial response)) of 34.5% and 52.7% (≥MR (minimal response)). The median time to response was 1.4 months and the median duration of response was 6.0 months. The median OS was 17.5 months. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Farydak in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Panobinostat is rapidly and almost completely absorbed with Tmax reached within 2 hours of oral administration in patients with advanced cancer. The absolute oral bioavailability of panobinostat was approximately 21%. After oral administration, panobinostat pharmacokinetics appear to be linear in the dose range 10-30 mg, but AUC increases less than proportionally with dose at higher doses. Overall panobinostat exposure and inter-patient variability remained unchanged with or without food, whereas Cmax was reduced by <45% and Tmax prolonged by 1 to 2.5 hours with food (i.e. both normal and high-fat breakfasts). Since food did not alter overall bioavailability (AUC), panobinostat can be administered regardless of food in cancer patients. Distribution Panobinostat is moderately (approximately 90%) bound to human plasma proteins. Its fraction in the erythrocyte is 0.60 in vitro, independent of the concentration. The volume of distribution of panobinostat at steady state (Vss) is approximately 1,000 litres based on final parameter estimates in the population pharmacokinetic analysis. Biotransformation Panobinostat is extensively metabolised, and a large fraction of the dose is metabolised before reaching the systemic circulation. Pertinent metabolic pathways involved in the biotransformation of panobinostat are reduction, hydrolysis, oxidation and glucuronidation processes. Oxidative metabolism of panobinostat played a less prominent role, with approximately 40% of the dose eliminated by this pathway. Cytochrome P450 3A4 (CYP3A4) is the main oxidation enzyme, with potential minor involvement of CYP2D6 and 2C19. Panobinostat represented 6 to 9% of the drug-related exposure in plasma. The parent substance is deemed to be responsible for the overall pharmacological activity of panobinostat. Elimination After a single oral dose of [14C] panobinostat in patients, 29 to 51% of administered radioactivity is excreted in the urine and 44 to 77% in the faeces. Unchanged panobinostat accounted for <2.5% of the dose in urine and <3.5% of the dose in faeces. The remainders are metabolites. Apparent panobinostat renal clearance (CLR/F) was found to range from 2.4 to 5.5 l/h. Panobinostat has a terminal elimination half-life of approximately 37 hours based on final parameters estimate in the population PK analysis. 21 Special populations Paediatric population Panobinostat was not evaluated in multiple myeloma patients under 18 years of age. Elderly population In the phase III clinical study 162 out of 387 patients were aged 65 years or over. Plasma exposure of panobinostat in patients aged 65 years or younger was similar to those older than 65 years in the pooling of single-agent panobinostat studies between the dose range of 10 mg and 80 mg. Patients with hepatic impairment The effect of hepatic impairment on the pharmacokinetics of panobinostat was evaluated in a phase I study, in 24 patients with solid tumours and with varying degrees of hepatic impairment. Mild and moderate hepatic impairment as per NCI-CTEP classification increased panobinostat plasma exposure by 43% and 105%, respectively. No pharmacokinetic data are available for patients with severe hepatic impairment. Patients with renal impairment The effect of renal impairment on the pharmacokinetics of panobinostat was assessed in a phase I study in 37 patients with advanced solid tumours with varying degrees of renal function. Mild, moderate and severe renal impairment based on baseline urinary creatinine clearance did not increase the panobinostat plasma exposure in mild, moderate and severe groups. 5.3 Preclinical safety data Repeated dose toxicity studies The primary target organs of toxicity following administration of panobinostat in rats and dogs were identified as the erythropoietic, myelopoietic and lymphatic systems. The thyroid changes including hormones in dogs (decrease triodothyronine (T3)) and rats (decrease in triodothyronine (T3), tetraiodothyronine (T4) (males) and thyroid stimulating hormone (TSH)) were observed at exposures corresponding to 0.07-2.2 of the human AUC observed clinically. Carcinogenesis and mutagenesis Carcinogenicity studies have not been performed with panobinostat. Panobinostat has demonstrated mutagenic potential in the Ames assay, endo reduplication effects in human peripheral blood lymphocytes in vitro. Additionally, in vivo DNA damage was observed in a COMET study in mouse lymphoma L5178Y cells and a dose-dependent molecular mechanisms study in murine bone marrow cells. The in vitro and in vivo findings are attributed to the pharmacological mode of action. Reproduction toxicity An increase in early resorptions was observed in female rats (doses ≥30 mg/kg). Prostatic atrophy accompanied by reduced secretory granules, testicular degeneration, oligospermia and increased epididymal debris were observed in dogs at exposures corresponding to 0.41-0.69 of the human clinical AUC and not fully reversible after a 4 week recovery period. Based on animal data, the likelihood of panobinostat increasing the risk of foetal death and developmental skeletal abnormalities is predicted to be high. Embryo foetal lethality and increases in skeletal anomalies (extra sternabrae, extra ribs, increases in minor skeletal variations, delayed ossification and variations of the sternabrae) were seen above exposures corresponding to 0.25 of the human clinical AUC. 22 The effects of panobinostat on labour and post-natal growth and maturation were not evaluated in animal studies. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule content Magnesium stearate Mannitol Microcrystalline cellulose Pregelatinised starch (maize) Capsule shell Farydak 10 mg hard capsules Gelatin Titanium dioxide (E171) Brilliant blue FCF (E133) Iron oxide, yellow (E172) Farydak 15 mg hard capsules Gelatin Titanium dioxide (E171) Iron oxide, yellow (E172) Iron oxide, red (E172) Farydak 20 mg hard capsules Gelatin Titanium dioxide (E171) Iron oxide, red (E172) Printing ink Iron oxide, black (E172) Propylene glycol (E1520) Shellac glaze 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage Do not store above 30°C. Store in the original package in order to protect from moisture. 6.5 Nature and contents of container PVC/PCTFE/Alu blister containing 6 capsules. 23 Packs containing 6, 12 or 24 capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Secura Bio Limited 32 Molesworth Street Dublin 2 Ireland 8. MARKETING AUTHORISATION NUMBER(S) Farydak 10 mg hard capsules EU/1/15/1023/001-003 Farydak 15 mg hard capsules EU/1/15/1023/004-006 Farydak 20 mg hard capsules EU/1/15/1023/007-009 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 28 August 2015 Date of latest renewal: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/ 24 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 25 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Novartis Pharma GmbH Roonstrasse 25 90429 Nuremberg Germany B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures Prior to launch of Farydak in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority. The educational programme is aimed to address the risk of medication error. 26 The MAH shall ensure that in each Member State where Farydak is marketed, all patients/carers who are expected to use Farydak have access to/are provided with the following educational package: • Patient information pack The patient information pack should contain: o Patient information leaflet o A patient compliance card • The patient compliance card shall contain instructions on the following key messages: o How to become familiar with the compliance card: this section provides a general overview of the compliance card and its purpose. o How to use the compliance card: this section provides a general overview on how to use the compliance card. o How to take medication according to the prescription: this section provides guidance on how to fill in the compliance card. o Recommendation to bring compliance card to each visit: this section reminds the patient to bring the compliance card to the HCP at each visit. o A table describing the treatment regimen for each day of the cycle with space for the patient to note what medication they took. 27 ANNEX III LABELLING AND PACKAGE LEAFLET 28 A. LABELLING 29 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Farydak 10 mg hard capsules panobinostat 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains panobinostat lactate anhydrous equivalent to 10 mg panobinostat. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 6 capsules 12 capsules 24 capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic: handle with caution. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. Store in the original package in order to protect from moisture. 30 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Secura Bio Limited 32 Molesworth Street Dublin 2 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1023/001 6 capsules EU/1/15/1023/002 12 capsules EU/1/15/1023/003 24 capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Farydak 10 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 31 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Farydak 10 mg capsules panobinostat 2. NAME OF THE MARKETING AUTHORISATION HOLDER Secura Bio Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Week 1 Week 2 Week 3 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21 32 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Farydak 15 mg hard capsules panobinostat 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains panobinostat lactate anhydrous equivalent to 15 mg panobinostat. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 6 capsules 12 capsules 24 capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic: handle with caution. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. Store in the original package in order to protect from moisture. 33 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Secura Bio Limited 32 Molesworth Street Dublin 2 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1023/004 6 capsules EU/1/15/1023/005 12 capsules EU/1/15/1023/006 24 capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Farydak 15 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 34 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Farydak 15 mg capsules panobinostat 2. NAME OF THE MARKETING AUTHORISATION HOLDER Secura Bio Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Week 1 Week 2 Week 3 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21 35 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Farydak 20 mg hard capsules panobinostat 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains panobinostat lactate anhydrous equivalent to 20 mg panobinostat. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 6 capsules 12 capsules 24 capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic: handle with caution. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. Store in the original package in order to protect from moisture. 36 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Secura Bio Limited 32 Molesworth Street Dublin 2 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1023/007 6 capsules EU/1/15/1023/008 12 capsules EU/1/15/1023/009 24 capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Farydak 20 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 37 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Farydak 20 mg capsules panobinostat 2. NAME OF THE MARKETING AUTHORISATION HOLDER Secura Bio Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Week 1 Week 2 Week 3 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21 38 B. PACKAGE LEAFLET 39 Package leaflet: Information for the patient Farydak 10 mg hard capsules Farydak 15 mg hard capsules Farydak 20 mg hard capsules panobinostat Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Farydak is and what it is used for 2. What you need to know before you take Farydak 3. How to take Farydak 4. Possible side effects 5. How to store Farydak 6. Contents of the pack and other information 1. What Farydak is and what it is used for What Farydak is Farydak is an anti-cancer medicine that contains the active substance panobinostat, which belongs to a group of medicines called pan-deacetylase inhibitors. What Farydak is used for Farydak is used to treat adult patients with a rare type of blood cancer called multiple myeloma. Multiple myeloma is a disorder of plasma cells (a type of blood cell) that grow out of control in the bone marrow. Farydak blocks the growth of cancerous plasma cells and reduces the number of cancer cells. Farydak is always used together with two other medicines: bortezomib and dexamethasone. If you have any questions about how Farydak works or why you have been given it, ask your doctor or pharmacist. 2. What you need to know before you take Farydak Do not take Farydak: - if you are allergic to panobinostat or any of the other ingredients of this medicine (listed in section 6). - if you are breast-feeding Warnings and precautions Follow all your doctor’s instructions carefully. 40 Talk to your doctor or pharmacist before taking Farydak: - if you have liver problems or have ever had liver disease. - if you have heart or heartbeat problems, such as irregular heartbeat or a condition called long QT syndrome. - if you have a bacterial, viral or fungal infection. - if you have gastrointestinal problems such as diarrhoea, nausea or vomiting. - if you have blood clotting problems (coagulation disorder). Tell your doctor or pharmacist straight away during treatment with Farydak: - if you notice any signs of a gastrointestinal problem. - if you notice any signs of a liver problem. - if you notice any signs of an infection. - if you notice any signs of a heart problem. The list of associated symptoms is provided in section 4, Possible side effects. Your doctor may need to change your dose, temporarily stop or completely stop your treatment with Farydak in case you experience side effects. Monitoring during your treatment with Farydak You will have regular blood tests during treatment with Farydak. These are to: - check how well your liver is working (by measuring your blood levels of bilirubin and transaminase, which are substances made by the liver). - check the amounts of certain cells of your blood (white blood cells, red blood cells, platelets). - check the amount of electrolytes (such as potassium, magnesium, phosphate) in your body. - check how well your thyroid and pituitary gland are working (by measuring your blood levels of thyroid hormones). Your heart rate will also be checked using a machine that measures the electrical activity of the heart (called an ECG). Children and adolescents Farydak is not to be used in children or adolescents under 18 years of age. Other medicines and Farydak Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription, such as vitamins or herbal supplements, because they might interact with Farydak. In particular tell your doctor or pharmacist if you are taking any of the following medicines: - medicines used to treat infections, including fungal infections (such as ketoconazole, itraconazole, voriconazole or posaconazole) and some bacterial infections (such as antibiotics like clarithromycin or telithromycin). Medicines used to treat tuberculosis, such as rifabutin or rifampicin. - medicines used to stop seizures or fits (anti-epileptics such as carbamazepine, pherphenazine, phenobarbital or phenytoin). - medicines used to treat HIV, such as ritonavir or saquinavir. - medicines used to treat depression, such as nefazodone. - St. John’s wort, a herbal medicine used to treat depression. - medicines to prevent blood clotting called anti-coagulants, such as warfarin or heparin. - medicines used to treat cough, such as dextromethorphan. - medicines used to treat irregular heartbeat, such as amiodarone, disopyramide, procainamide, quinidine, propafenone or sotalol. - medicines that may have an unwanted effect on the heart (called QT prolongation), such as chloroquine, halofantrine, methadone, moxifloxacin, bepridil or pimozide. - medicines used to treat hypertension, such as metoprolol or nebivolol. - medicines used to treat severe mental health problems, such as risperidone. - medicines used to treat breast cancer, such as tamoxifen. 41 - medicines used to treat nausea and vomiting such as dolasetron, granisetron, ondansetron or tropisetron; these may also have an unwanted effect on the heart (QT prolongation). - atomoxetine, a medicine used to treat attention deficit hyperactivity disorder. These medicines should be used with care or may need to be avoided during your treatment with Farydak. If you are taking any of these medicines, your doctor might prescribe a different medicine for you during your treatment with Farydak. Ask your doctor or pharmacist if you are not sure whether your medicine is one of the medicines listed above. During Farydak treatment, you should also tell your doctor or your pharmacist if you are prescribed another medicine that you have not already been taking. Farydak with food and drink You should not eat star fruit, pomegranate or grapefruit or drink pomegranate or grapefruit juice during your treatment with Farydak, as they may increase the amount of the medicine that passes into your blood. Pregnancy and breast-feeding Due to the potential risk of death or malformation to the foetus, Farydak should not be taken during: - Pregnancy Farydak should not be taken during pregnancy, unless the potential benefit to the mother is greater than the potential risk to the baby. If you are pregnant, think you might be pregnant or plan to become pregnant, ask your doctor for advice. Your doctor will discuss with you the possible risks of taking Farydak during pregnancy. - Breast-feeding You must not take Farydak if you are breast-feeding. Contraception for women and men Due to the potential risk of death or malformation to the foetus, you should use the following methods of contraception while taking Farydak: - For women taking Farydak If you are a sexually active woman, you should have a pregnancy test before starting Farydak treatment and you must use a highly effective method of contraception during treatment with Farydak. You must also use this for three months after you have stopped taking Farydak. Your doctor will discuss with you which is the best method for you to use. If you use a hormonal contraceptive you must also use a barrier method of contraception (such as condom or diaphragm) in addition. - For men taking Farydak If you are a sexually active man, you should use condoms during treatment with Farydak. You should also do this for six months after you have stopped taking Farydak. If your partner is able to become pregnant she should also use a highly effective method of contraception during your treatment and for six months after. Tell your doctor straight away if your partner becomes pregnant while you are taking Farydak or during the six months following your treatment with Farydak. Driving and using machines Farydak may have a minor influence on the ability to drive and use machines. If you feel dizzy while taking this medicine, do not drive a vehicle or use any tools or machines. 3. How to take Farydak Always take this medicine exactly as your doctor has told you. Check with your doctor or your 42 pharmacist if you are not sure. How much to take - Farydak is taken over 21 days (2 weeks on and 1 week off) – this is called a treatment cycle. - You do not take the medicine every day. - Based on the recommendation of your doctor, the dose of Farydak is either 20 mg or 15 mg or 10 mg, to be taken once a day on days 1, 3, 5, 8, 10 and 12 of the 21-day cycle. - Do not take Farydak in Week 3. - After Week 3 you start a new cycle again as shown in Tables 1 and 2 below. Please refer to Table 1 for cycles 1 to 8 and Table 2 for cycles 9-16. Table 1 Recommended schedule for taking Farydak in combination with bortezomib and dexamethasone (cycles 1-8) Cycles 1-8 (3-week cycles) Week 1 Days Week 2 Days Week 3 Farydak 1 3 5 8 10 12 Rest period Bortezomib 1 4 8 11 Rest period Dexamethasone 1 2 4 5 8 9 11 12 Rest period Table 2 Recommended schedule for taking Farydak in combination with bortezomib and dexamethasone (cycles 9-16). Cycles 9-16 (3-week cycles) Week 1 Days Week 2 Days Week 3 Farydak 1 3 5 8 10 12 Rest period Bortezomib 1 8 Rest period Dexamethasone 1 2 8 9 Rest period Your doctor will tell you exactly how many capsules of Farydak you need to take. Do not change the dose without talking to your doctor. Take Farydak once a day at the same time each day only on the scheduled days. Taking this medicine - Swallow the capsules whole with a glass of water. - The medicine can be taken with or without food. - Do not chew or crush the capsules. If you vomit after you swallow the Farydak capsules, do not take any more capsules until your next scheduled dose. 43 How to use the Farydak blister One Farydak blister = 3 weeks = 1 cycle The days of the cycle are numbered on the blister. Take Farydak on days 1, 3 and 5 and on days 8, 10 and 12. Push the Farydak capsule through the pocket on days 1, 3 and 5 of week 1 and days 8, 10 and 12 of week 2. On days when you do not have to take Farydak, including the rest period in week 3, scratch the relevant empty cavities with your finger nail to help you keep track of your medicine schedule. How long to take Farydak Keep taking Farydak for as long as your doctor tells you. This is a long-term treatment with 16 cycles (48 weeks). Your doctor will monitor your condition to see if the treatment is working. If you have questions about how long to take Farydak, talk to your doctor or pharmacist. If you take more Farydak than you should If you accidentally take more capsules than you should, or if someone else accidentally takes your medicine, talk to a doctor or go to a hospital straight away. Take the pack and this leaflet with you. You may need medical treatment. If you forget to take Farydak - If it is less than 12 hours since you should have taken the medicine, take the missed dose as soon as you remember. Then continue taking the medicine as normal. - If it is more than 12 hours since you should have taken the medicine, skip the missed dose. Then continue taking the medicine as normal. Do not take a double dose to make up for a forgotten dose. Never take a missed dose of Farydak on one of the “off” days when no Farydak dose is planned. Tell your doctor about all the doses that you have missed during any 21-day cycle of treatment. 44 If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some side effects could be serious STOP taking Farydak and seek medical help immediately if you experience any of the following: • difficulty in breathing or swallowing, swelling of the face, lips, tongue or throat, severe itching of the skin, with a red rash or raised bumps (potential signs of an allergic reaction) • severe headache, feeling weak or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (potential signs of nervous system problems such as bleeding or swelling in the skull or brain) • fast breathing, feeling dizzy • sudden and crushing chest pain, feeling tired, irregular heartbeat (potential signs of a heart attack) • coughing up blood, oozing of bloody fluid from the nose (signs of bleeding in the lungs) • vomiting blood, black or bloody stools, passage of fresh blood through the anus, usually in or with stools (signs of gastrointestinal bleeding) • difficulty in breathing with blueness around the mouth, which could lead to loss of consciousness (sign of serious lung problems) • fever, chest pain, increased heart rate, decreased blood pressure, shortness of breath or rapid breathing (signs of blood poisoning, which is also known as sepsis) • chest pain or discomfort, changes in heartbeat (faster or slower), palpitations, light-headedness, fainting, dizziness, blue discolouration of your lips, shortness of breath, swelling of lower limbs or skin (signs of heart problems) Tell a doctor or a pharmacist straight away if you notice any of these side effects: • stomach or abdominal pain, nausea, diarrhoea, vomiting, black or bloody stools, constipation, heartburn, swelling or bloating of the abdomen (signs of a gastrointestinal problem) • new or worsening symptoms such as cough with or without mucus, fever, difficult or painful breathing, wheezing, pain in chest when breathing, shortness of breath or, difficulty breathing, pain or burning feeling when passing urine, exaggerated sense of needing to pass urine, blood in urine (signs of an infection in the lungs or urinary tract) • fever, sore throat, or mouth ulcers due to infections (signs of a low level of white blood cells) • sudden bleeding or bruising underneath the skin (signs of low level of blood platelets) • diarrhoea, abdominal pain, fever (signs of an inflamed colon) • light-headedness, particularly when standing up (a sign of low blood pressure) • feeling thirsty, low urine output, weight loss, dry flushed skin, irritability (signs of dehydration) • swollen ankles (a sign of a low level of albumin in the blood which is known as hypoalbuminaemia) • feeling tired, itching, yellowing of the skin and whites of the eyes, nausea or vomiting, loss of appetite, pain on the right side of your stomach, dark or brown urine, bleeding or bruising more easily than normal (signs of a liver problem) • severely decreased urine output, swelling of the legs (signs of a kidney problem) • muscle weakness, muscle spasms, unusual heartbeat (signs of changes in the level of potassium in the blood) Other possible side effects If any of the side effects below becomes severe, tell your doctor, or your pharmacist. Very common (may affect more than 1 in 10 people) • feeling tired (fatigue), pale skin. These could be signs of a low level of red blood cells. • decreased appetite or weight loss • difficulty falling or staying asleep (insomnia) • headache 45 • feeling dizzy, tired or weak • vomiting, nausea, upset stomach, indigestion • swelling of the legs or arms • reduced blood level of phosphate or sodium Common (may affect up to 1 in 10 people) • rash of small fluid-filled blisters, appearing on reddened skin, mouth or gums (signs of a potentially severe viral infection) • inflamed ear, nose bleed or bleeding in the white of the eye, bruising, inflamed skin caused by infection (rash, red skin, which is also known as erythema) • abdominal pain, diarrhoea, swelling or bloating of the abdomen (signs of inflamed stomach lining) • oral thrush (yeast infection of the mouth) • feeling thirsty, high urine output, increased appetite with weight loss (signs of a high level of sugar in the blood) • fast weight gain, swelling of hands, ankles, feet or face (signs of water retention) • reduced level of calcium in the blood, sometimes leading to cramps • uncontrolled shaking of the body • palpitations • clicking, rattling or crackling noise made by the lungs when breathing • cracked, chapped lips • dry mouth or changes to your sense of taste • flatulence • joint pain or inflammation • blood in urine (a sign of a kidney problem) • being unable to control the flow of urine because of loss of or weak bladder control • chills • weight gain, feeling tired, hair loss, muscle weakness, feeling cold (signs of an underactive thyroid gland, which is known as hypothyroidism) • generally feeling unwell • increased blood level of uric acid • reduced blood level of magnesium • increased blood level of the waste product creatinine • increased blood levels of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP). Uncommon (may affect up to 1 in 100 people) • red or purple, flat pinhead spots under the skin Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Farydak - Keep this medicine out of the sight and reach of children. - Do not take this medicine after the expiry date, which is stated on the carton and blister foil. - Do not store above 30°C. - Store in the original package in order to protect from moisture. - Do not take this medicine if you notice any damage to the packaging or if there are any signs of tampering. - Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 46 6. Contents of the pack and other information What Farydak contains - The active substance of Farydak is panobinostat. - Each Farydak 10 mg hard capsule contains panobinostat lactate anhydrous equivalent to 10 mg panobinostat. The other ingredients are: magnesium stearate, mannitol, microcrystalline cellulose, pregelatinised starch, gelatin, titanium dioxide (E171), brilliant blue FCF (E133), yellow iron oxide (E172), black iron oxide (E172), propylene glycol (E1520), shellac glaze. - Each Farydak 15 mg hard capsule contains panobinostat lactate anhydrous equivalent to 15 mg panobinostat. The other ingredients are: magnesium stearate, mannitol, microcrystalline cellulose, pregelatinised starch, gelatin, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172), black iron oxide (E172), propylene glycol (E1520), shellac glaze. - Each Farydak 20 mg hard capsule contains panobinostat lactate anhydrous equivalent to 20 mg panobinostat. The other ingredients are: magnesium stearate, mannitol, microcrystalline cellulose, pregelatinised starch, gelatin, titanium dioxide (E171), red iron oxide (E172), black iron oxide (E172), propylene glycol (E1520), shellac glaze. What Farydak looks like and contents of the pack Farydak 10 mg hard capsules are light green opaque capsules (15.6–16.2 mm) containing white to almost white powder, with radial marking “LBH 10 mg” in black ink on the cap and two radial bands in black ink on the body, provided in blisters. Farydak 15 mg hard capsules are orange opaque capsules (19.1–19.7 mm) containing white to almost white powder, with radial marking “LBH 15 mg” in black ink on the cap and two radial bands in black ink on the body, provided in blisters. Farydak 20 mg hard capsules are red opaque capsules (19.1–19.7 mm) containing white to almost white powder, with radial marking “LBH 20 mg” in black ink on the cap and two radial bands in black ink on the body, provided in blisters. The following pack sizes are available: blister packs containing 6, 12 or 24 capsules. Not all pack sizes may be marketed. Marketing Authorisation Holder Secura Bio Limited 32 Molesworth Street Dublin 2 Ireland Manufacturer Novartis Pharma GmbH Roonstrasse 25 90429 Nuremberg Germany This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu http://www.ema.europa.eu/ 47 Annex IV Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s) 48 Scientific conclusions Taking into account the PRAC Assessment Report on the PSUR(s) for panobinostat, the scientific conclusions of CHMP are as follows: In view of available data from the literature regarding DNA damage in an in vivo dose-dependent molecular mechanisms study in murine bone marrow cells, the PRAC concluded that the existing wording in section 5.3 of the Summary of Product Characteristics of products containing panobinostat should be amended to include this information. The CHMP agrees with the scientific conclusions made by the PRAC. Grounds for the variation to the terms of the marketing authorisation(s) On the basis of the scientific conclusions for panobinostat the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing panobinostat is unchanged subject to the proposed changes to the product information. The CHMP recommends that the terms of the marketing authorisation(s) should be varied. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT LABELLING AND PACKAGE LEAFLET A. LABELLING B. PACKAGE LEAFLET Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)

{'Title': '1. what farydak is and what it is used for', 'Section_Content': 'what farydak is farydak is an anti-cancer medicine that contains the active substance panobinostat, which belongs to a group of medicines called pan-deacetylase inhibitors. what farydak is used for farydak is used to treat adult patients with a rare type of blood cancer called multiple myeloma. multiple myeloma is a disorder of plasma cells (a type of blood cell) that grow out of control in the bone marrow. farydak blocks the growth of cancerous plasma cells and reduces the number of cancer cells. farydak is always used together with two other medicines: bortezomib and dexamethasone. if you have any questions about how farydak works or why you have been given it, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'farydak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'an anti-cancer medicine', 'Type': 'TREATMENT', 'BeginOffset': 27, 'EndOffset': 50}, {'Text': 'the active substance panobinostat', 'Type': 'TREATMENT', 'BeginOffset': 65, 'EndOffset': 98}, {'Text': 'a group of medicines', 'Type': 'TREATMENT', 'BeginOffset': 117, 'EndOffset': 137}, {'Id': 2, 'BeginOffset': 145, 'EndOffset': 171, 'Score': 0.6399014592170715, 'Text': 'pan-deacetylase inhibitors', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 198, 'EndOffset': 205, 'Score': 0.2903680205345154, 'Text': 'farydak', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 258, 'EndOffset': 270, 'Score': 0.899931013584137, 'Text': 'blood cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9799537658691406}]}, {'Id': 7, 'BeginOffset': 278, 'EndOffset': 294, 'Score': 0.6935424208641052, 'Text': 'multiple myeloma', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9765695929527283}]}, {'Id': 8, 'BeginOffset': 296, 'EndOffset': 312, 'Score': 0.6864137053489685, 'Text': 'multiple myeloma', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9598801732063293}]}, {'Text': 'a disorder of plasma cells', 'Type': 'PROBLEM', 'BeginOffset': 316, 'EndOffset': 342}, {'Text': 'blood cell', 'Type': 'TEST', 'BeginOffset': 354, 'EndOffset': 364}, {'Text': 'control in the bone marrow', 'Type': 'PROBLEM', 'BeginOffset': 383, 'EndOffset': 409}, {'Text': 'cancerous plasma cells', 'Type': 'PROBLEM', 'BeginOffset': 440, 'EndOffset': 462}, {'Text': 'cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 489, 'EndOffset': 501}, {'Id': 4, 'BeginOffset': 561, 'EndOffset': 571, 'Score': 0.9986376166343689, 'Text': 'bortezomib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 576, 'EndOffset': 589, 'Score': 0.9997696280479431, 'Text': 'dexamethasone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}]}

{'Title': '2. what you need to know before you take farydak', 'Section_Content': "do not take farydak: - if you are allergic to panobinostat or any of the other ingredients of this medicine (listed in section 6). - if you are breast-feeding warnings and precautions follow all your doctor's instructions carefully. talk to your doctor or pharmacist before taking farydak: - if you have liver problems or have ever had liver disease. - if you have heart or heartbeat problems, such as irregular heartbeat or a condition called long qt syndrome. - if you have a bacterial, viral or fungal infection. - if you have gastrointestinal problems such as diarrhoea, nausea or vomiting. - if you have blood clotting problems (coagulation disorder). tell your doctor or pharmacist straight away during treatment with farydak: - if you notice any signs of a gastrointestinal problem. - if you notice any signs of a liver problem. - if you notice any signs of an infection. - if you notice any signs of a heart problem. the list of associated symptoms is provided in section 4, possible side effects. your doctor may need to change your dose, temporarily stop or completely stop your treatment with farydak in case you experience side effects. monitoring during your treatment with farydak you will have regular blood tests during treatment with farydak. these are to: - check how well your liver is working (by measuring your blood levels of bilirubin and transaminase, which are substances made by the liver). - check the amounts of certain cells of your blood (white blood cells, red blood cells, platelets). - check the amount of electrolytes (such as potassium, magnesium, phosphate) in your body. - check how well your thyroid and pituitary gland are working (by measuring your blood levels of thyroid hormones). your heart rate will also be checked using a machine that measures the electrical activity of the heart (called an ecg). children and adolescents farydak is not to be used in children or adolescents under 18 years of age. other medicines and farydak tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription, such as vitamins or herbal supplements, because they might interact with farydak. in particular tell your doctor or pharmacist if you are taking any of the following medicines: - medicines used to treat infections, including fungal infections (such as ketoconazole, itraconazole, voriconazole or posaconazole) and some bacterial infections (such as antibiotics like clarithromycin or telithromycin). medicines used to treat tuberculosis, such as rifabutin or rifampicin. - medicines used to stop seizures or fits (anti-epileptics such as carbamazepine, pherphenazine, phenobarbital or phenytoin). - medicines used to treat hiv, such as ritonavir or saquinavir. - medicines used to treat depression, such as nefazodone. - st. john's wort, a herbal medicine used to treat depression. - medicines to prevent blood clotting called anti-coagulants, such as warfarin or heparin. - medicines used to treat cough, such as dextromethorphan. - medicines used to treat irregular heartbeat, such as amiodarone, disopyramide, procainamide, quinidine, propafenone or sotalol. - medicines that may have an unwanted effect on the heart (called qt prolongation), such as chloroquine, halofantrine, methadone, moxifloxacin, bepridil or pimozide. - medicines used to treat hypertension, such as metoprolol or nebivolol. - medicines used to treat severe mental health problems, such as risperidone. - medicines used to treat breast cancer, such as tamoxifen. - medicines used to treat nausea and vomiting such as dolasetron, granisetron, ondansetron or tropisetron; these may also have an unwanted effect on the heart (qt prolongation). - atomoxetine, a medicine used to treat attention deficit hyperactivity disorder. these medicines should be used with care or may need to be avoided during your treatment with farydak. if you are taking any of these medicines, your doctor might prescribe a different medicine for you during your treatment with farydak. ask your doctor or pharmacist if you are not sure whether your medicine is one of the medicines listed above. during farydak treatment, you should also tell your doctor or your pharmacist if you are prescribed another medicine that you have not already been taking. farydak with food and drink you should not eat star fruit, pomegranate or grapefruit or drink pomegranate or grapefruit juice during your treatment with farydak, as they may increase the amount of the medicine that passes into your blood. pregnancy and breast-feeding due to the potential risk of death or malformation to the foetus, farydak should not be taken during: - pregnancy farydak should not be taken during pregnancy, unless the potential benefit to the mother is greater than the potential risk to the baby. if you are pregnant, think you might be 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treatment with farydak. you should also do this for six months after you have stopped taking farydak. if your partner is able to become pregnant she should also use a highly effective method of contraception during your treatment and for six months after. tell your doctor straight away if your partner becomes pregnant while you are taking farydak or during the six months following your treatment with farydak. driving and using machines farydak may have a minor influence on the ability to drive and use machines. if you feel dizzy while taking this medicine, do not drive a vehicle or use any tools or machines.", 'Entity_Recognition': [{'Text': 'farydak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 14, 'BeginOffset': 12, 'EndOffset': 19, 'Score': 0.45205986499786377, 'Text': 'farydak', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 34, 'EndOffset': 42}, {'Id': 15, 'BeginOffset': 46, 'EndOffset': 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{'Title': '3. how to take farydak', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or your 42 pharmacist if you are not sure. how much to take - farydak is taken over 21 days (2 weeks on and 1 week off) this is called a treatment cycle. - you do not take the medicine every day. - based on the recommendation of your doctor, the dose of farydak is either 20 mg or 15 mg or 10 mg, to be taken once a day on days 1, 3, 5, 8, 10 and 12 of the 21-day cycle. - do not take farydak in week 3. - after week 3 you start a new cycle again as shown in tables 1 and 2 below. please refer to table 1 for cycles 1 to 8 and table 2 for cycles 9-16. table 1 recommended schedule for taking farydak in combination with bortezomib and dexamethasone (cycles 1-8) cycles 1-8 (3-week cycles) week 1 days week 2 days week 3 farydak 1 3 5 8 10 12 rest period bortezomib 1 4 8 11 rest period dexamethasone 1 2 4 5 8 9 11 12 rest period table 2 recommended schedule for taking farydak in combination with bortezomib and dexamethasone (cycles 9-16). cycles 9-16 (3-week cycles) week 1 days week 2 days week 3 farydak 1 3 5 8 10 12 rest period bortezomib 1 8 rest period dexamethasone 1 2 8 9 rest period your doctor will tell you exactly how many capsules of farydak you need to take. do not change the dose without talking to your doctor. take farydak once a day at the same time each day only on the scheduled days. taking this medicine - swallow the capsules whole with a glass of water. - the medicine can be taken with or without food. - do not chew or crush the capsules. if you vomit after you swallow the farydak capsules, do not take any more capsules until your next scheduled dose. how to use the farydak blister one farydak blister = 3 weeks = 1 cycle the days of the cycle are numbered on the blister. take farydak on days 1, 3 and 5 and on days 8, 10 and 12. push the farydak capsule through the pocket on days 1, 3 and 5 of week 1 and days 8, 10 and 12 of week 2. on days when you do not have to take farydak, including the rest period in week 3, scratch the relevant empty cavities with your finger nail to help you keep track of your medicine schedule. how long to take farydak keep taking farydak for as long as your doctor tells you. this is a long-term treatment with 16 cycles (48 weeks). your doctor will monitor your condition to see if the treatment is working. if you have questions about how long to take farydak, talk to your doctor or pharmacist. if you take more farydak than you should if you accidentally take more capsules than you should, or if someone else accidentally takes your medicine, talk to a doctor or go to a hospital straight away. take the pack and this leaflet with you. you may need medical treatment. if you forget to take farydak - if it is less than 12 hours since you should have taken the medicine, take the missed dose as soon as you remember. then continue taking the medicine as normal. - if it is more than 12 hours since you should have taken the medicine, skip the missed dose. then continue taking the medicine as normal. do not take a double dose to make up for a forgotten dose. never take a missed dose of farydak on one of the "off" days when no farydak dose is planned. tell your doctor about all the doses that you have missed during any 21-day cycle of treatment. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'farydak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': '42', 'Type': 'NUMBER', 'BeginOffset': 94, 'EndOffset': 96}, {'Id': 0, 'BeginOffset': 148, 'EndOffset': 155, 'Score': 0.6063218116760254, 'Text': 'farydak', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'DURATION', 'Score': 0.467528373003006, 'RelationshipScore': 0.9959327578544617, 'RelationshipType': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects could be serious stop taking farydak and seek medical help immediately if you experience any of the following: difficulty in breathing or swallowing, swelling of the face, lips, tongue or throat, severe itching of the skin, with a red rash or raised bumps (potential signs of an allergic reaction) severe headache, feeling weak or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (potential signs of nervous system problems such as bleeding or swelling in the skull or brain) fast breathing, feeling dizzy sudden and crushing chest pain, feeling tired, irregular heartbeat (potential signs of a heart attack) coughing up blood, oozing of bloody fluid from the nose (signs of bleeding in the lungs) vomiting blood, black or bloody stools, passage of fresh blood through the anus, usually in or with stools (signs of gastrointestinal bleeding) difficulty in breathing with blueness around the mouth, which could lead to loss of consciousness (sign of serious lung problems) fever, chest pain, increased heart rate, decreased blood pressure, shortness of breath or rapid breathing (signs of blood poisoning, which is also known as sepsis) chest pain or discomfort, changes in heartbeat (faster or slower), palpitations, light-headedness, fainting, dizziness, blue discolouration of your lips, shortness of breath, swelling of lower limbs or skin (signs of heart problems) tell a doctor or a pharmacist straight away if you notice any of these side effects: stomach or abdominal pain, nausea, diarrhoea, vomiting, black or bloody stools, constipation, heartburn, swelling or bloating of the abdomen (signs of a gastrointestinal problem) new or worsening symptoms such as cough with or without mucus, fever, difficult or painful breathing, wheezing, pain in chest when breathing, shortness of breath or, difficulty breathing, pain or burning feeling when passing urine, exaggerated sense of needing to pass urine, blood in urine (signs of an infection in the lungs or urinary tract) fever, sore throat, or mouth ulcers due to infections (signs of a low level of white blood cells) sudden bleeding or bruising underneath the skin (signs of low level of blood platelets) diarrhoea, abdominal pain, fever (signs of an inflamed colon) light-headedness, particularly when standing up (a sign of low blood pressure) feeling thirsty, low urine output, weight loss, dry flushed skin, irritability (signs of dehydration) swollen ankles (a sign of a low level of albumin in the blood which is known as hypoalbuminaemia) feeling tired, itching, yellowing of the skin and whites of the eyes, nausea or vomiting, loss of appetite, pain on the right side of your stomach, dark or brown urine, bleeding or bruising more easily than normal (signs of a liver problem) severely decreased urine output, swelling of the legs (signs of a kidney problem) muscle weakness, muscle spasms, unusual heartbeat (signs of changes in the level of potassium in the blood) other possible side effects if any of the side effects below becomes severe, tell your doctor, or your pharmacist. very common (may affect more than 1 in 10 people) feeling tired (fatigue), pale skin. these could be signs of a low level of red blood cells. decreased appetite or weight loss difficulty falling or staying asleep (insomnia) headache 45 feeling dizzy, tired or weak vomiting, nausea, upset stomach, indigestion swelling of the legs or arms reduced blood level of phosphate or sodium common (may affect up to 1 in 10 people) rash of small fluid-filled blisters, appearing on reddened skin, mouth or gums (signs of a potentially severe viral infection) inflamed ear, nose bleed or bleeding in the white of the eye, bruising, inflamed skin caused by infection (rash, red skin, which is also known as erythema) abdominal pain, diarrhoea, swelling or bloating of the abdomen (signs of inflamed stomach lining) oral thrush (yeast infection of the mouth) feeling thirsty, high urine output, increased appetite with weight loss (signs of a high level of sugar in the blood) fast weight gain, swelling of hands, ankles, feet or face (signs of water retention) reduced level of calcium in the blood, sometimes leading to cramps uncontrolled shaking of the body palpitations clicking, rattling or crackling noise made by the lungs when breathing cracked, chapped lips dry mouth or changes to your sense of taste flatulence joint pain or inflammation blood in urine (a sign of a kidney problem) being unable to control the flow of urine because of loss of or weak bladder control chills weight gain, feeling tired, hair loss, muscle weakness, feeling cold (signs of an underactive thyroid gland, which is known as hypothyroidism) generally feeling unwell increased blood level of uric acid reduced blood level of magnesium increased blood level of the waste product creatinine increased blood levels of the liver enzymes alanine aminotransferase (alt), aspartate aminotransferase (ast) or alkaline phosphatase (alp). uncommon (may affect up to 1 in 100 people) red or purple, flat pinhead spots under the skin reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'farydak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 32, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9655634760856628, 'Text': 'side effects', 'Category': 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{'Title': '5. how to store farydak', 'Section_Content': '- keep this medicine out of the sight and reach of children. - do not take this medicine after the expiry date, which is stated on the carton and blister foil. - do not store above 30. - store in the original package in order to protect from moisture. - do not take this medicine if you notice any damage to the packaging or if there are any signs of tampering. - do not throw away any medicines via wastewater. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'farydak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 75, 'EndOffset': 88}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 181, 'EndOffset': 184}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 266, 'EndOffset': 279}, {'Id': 0, 'BeginOffset': 298, 'EndOffset': 304, 'Score': 0.33850982785224915, 'Text': 'damage', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'the packaging', 'Type': 'TREATMENT', 'BeginOffset': 308, 'EndOffset': 321}, {'Text': 'tampering', 'Type': 'PROBLEM', 'BeginOffset': 351, 'EndOffset': 360}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 479, 'EndOffset': 493}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what farydak contains - the active substance of farydak is panobinostat. - each farydak 10 mg hard capsule contains panobinostat lactate anhydrous equivalent to 10 mg panobinostat. the other ingredients are: magnesium stearate, mannitol, microcrystalline cellulose, pregelatinised starch, gelatin, titanium dioxide (e171), brilliant blue fcf (e133), yellow iron oxide (e172), black iron oxide (e172), propylene glycol (e1520), shellac glaze. - each farydak 15 mg hard capsule contains panobinostat lactate anhydrous equivalent to 15 mg panobinostat. the other ingredients are: magnesium stearate, mannitol, microcrystalline cellulose, pregelatinised starch, gelatin, titanium dioxide (e171), yellow iron oxide (e172), red iron oxide (e172), black iron oxide (e172), propylene glycol (e1520), shellac glaze. - each farydak 20 mg hard capsule contains panobinostat lactate anhydrous equivalent to 20 mg panobinostat. the other ingredients are: magnesium stearate, mannitol, microcrystalline cellulose, pregelatinised starch, gelatin, titanium dioxide (e171), red iron oxide (e172), black iron oxide (e172), propylene glycol (e1520), shellac glaze. what farydak looks like and contents of the pack farydak 10 mg hard capsules are light green opaque capsules (15.616.2 mm) containing white to almost white powder, with radial marking "lbh 10 mg" in black ink on the cap and two radial bands in black ink on the body, provided in blisters. farydak 15 mg hard capsules are orange opaque capsules (19.119.7 mm) containing white to almost white powder, with radial marking "lbh 15 mg" in black ink on the cap and two radial bands in black ink on the body, provided in blisters. farydak 20 mg hard capsules are red opaque capsules (19.119.7 mm) containing white to almost white powder, with radial marking "lbh 20 mg" in black ink on the cap and two radial bands in black ink on the body, provided in blisters. the following pack sizes are available: blister packs containing 6, 12 or 24 capsules. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'farydak', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 48, 'EndOffset': 55, 'Score': 0.7094067335128784, 'Text': 'farydak', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 59, 'EndOffset': 71, 'Score': 0.9564206004142761, 'Text': 'panobinostat', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.902173638343811, 'RelationshipScore': 0.9992827773094177, 'RelationshipType': 'FORM', 'Id': 8, 'BeginOffset': 99, 'EndOffset': 106, 'Text': 'capsule', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each farydak', 'Type': 'TREATMENT', 'BeginOffset': 75, 'EndOffset': 87}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 88, 'EndOffset': 90}, {'Text': 'panobinostat lactate anhydrous', 'Type': 'TREATMENT', 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936476B9D52F5CDC9529480E5B920534

https://www.ema.europa.eu/documents/product-information/aripiprazole-mylan-pharma-epar-product-information_en.pdf

Aripiprazole Mylan Pharma

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 5 mg tablets Aripiprazole Mylan Pharma 10 mg tablets Aripiprazole Mylan Pharma 15 mg tablets Aripiprazole Mylan Pharma 30 mg tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Aripiprazole Mylan Pharma 5 mg tablets Each tablet contains 5 mg of aripiprazole. Excipient with known effect 28 mg of maltose per tablet Aripiprazole Mylan Pharma 10 mg tablets Each tablet contains 10 mg of aripiprazole. Excipient with known effect 56 mg of maltose per tablet Aripiprazole Mylan Pharma 15 mg tablets Each tablet contains 15 mg of aripiprazole. Excipient with known effect 84 mg of maltose per tablet Aripiprazole Mylan Pharma 30 mg tablets Each tablet contains 30 mg of aripiprazole. Excipient with known effect 168 mg of maltose per tablet For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablet Aripiprazole Mylan Pharma 5 mg tablets Blue round and biconvex tablets of 6.1 mm in diameter, engraved with “5” on one side Aripiprazole Mylan Pharma 10 mg tablets Pink, round and biconvex tablets of 8.1 mm in diameter, engraved with “10” on one side 3 Aripiprazole Mylan Pharma 15 mg tablets Yellow, round and biconvex tablets of 10.1 mm in diameter, engraved with “15” on one side Aripiprazole Mylan Pharma 30 mg tablets Pink, oval and biconvex tablets of 17.1 mm in length, 8.1 mm in width, engraved with “30” on one side 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aripiprazole Mylan Pharma is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and older. Aripiprazole Mylan Pharma is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1). Aripiprazole Mylan Pharma is indicated for the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older (see section 5.1). 4.2 Posology and method of administration Posology Adults Schizophrenia: the recommended starting dose for aripiprazole is 10 mg/day or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole is effective in a dose range of 10 mg/day to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg. Manic episodes in Bipolar I Disorder: the recommended starting dose for aripiprazole is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see section 5.1). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg. Recurrence prevention of manic episodes in Bipolar I Disorder: for preventing recurrence of manic episodes in patients, who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status. Paediatric population Schizophrenia in adolescents aged 15 years and older: the recommended dose for aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section 5.1). Aripiprazole is effective in a dose range of 10 mg/day to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose. 4 Aripiprazole is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy (see sections 4.8 and 5.1). Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain (see section 4.8). Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring (see sections 4.4, 4.8 and 5.1). Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, aripiprazole is not recommended for use in patients below 13 years of age (see sections 4.8 and 5.1). Irritability associated with autistic disorder: the safety and efficacy of aripiprazole in children and adolescents aged below 18 years have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Tics associated with Tourette’s disorder: the safety and efficacy of aripiprazole in children and adolescents 6 to 18 years of age have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Special populations Elderly The safety and efficacy of aripiprazole in the treatment of schizophrenia or manic episodes in Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant (see section 4.4). Hepatic impairment Νο dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section 5.2). Renal impairment Νο dosage adjustment is required in patients with renal impairment. Gender No dosage adjustment is required for female patients as compared to male patients (see section 5.2). Smoking status According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers (see section 4.5). Dose adjustments due to interactions When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5). When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see section 4.5). 5 Method of administration Aripiprazole Mylan Pharma is for oral use. Orodispersible tablets or oral solution may be used as an alternative to Aripiprazole Mylan Pharma tablets for patients who have difficulty swallowing Aripiprazole Mylan Pharma tablets (see section 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period. Suicidality The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic treatment. Cardiovascular disorders Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken. QT prolongation In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation (see section 4.8). Tardive dyskinesia In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered (see section 4.8). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. Other extrapyramidal symptoms In paediatric clinical trials of aripiprazole akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered. Neuroleptic Malignant Syndrome (NMS) 6 NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued. Seizure In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures (see section 4.8). Elderly patients with dementia-related psychosis Increased mortality In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56 to 99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in aripiprazole- treated patients was 3.5 % compared to 1.7 % in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature (see section 4.8). Cerebrovascular adverse reactions In the same trials, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78 to 88 years). Overall, 1.3 % of aripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6 % of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole (see section 4.8). Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis. Hyperglycaemia and diabetes mellitus Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotic, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8). Hypersensitivity Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). Weight gain 7 Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain in adults (see section 5.1). In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section 4.8). Dysphagia Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia. Pathological gambling and other impulse control disorders Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole (see section 4.8). Patients with attention deficit hyperactivity disorder (ADHD) comorbidity Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered. Falls Aripiprazole may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls. Caution should be taken when treating patients at higher risk and a lower starting dose should be considered (e.g. elderly or debilitated patients; see section 4.2). Excipients Aripiprazole Mylan Pharma tablets contain maltose. Patients with rare glucose-galactose malabsorption should not take this medicine. Aripiprazole Mylan Pharma tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’. 4.5 Interaction with other medicinal products and other forms of interaction Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products. Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8). 8 If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. Potential for other medicinal products to affect aripiprazole A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant. Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers. Quinidine and other CYP2D6 inhibitors In a clinical trial in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Aripiprazole dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of aripiprazole with quinidine occurs. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied. Ketoconazole and other CYP3A4 inhibitors In a clinical trial in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro- aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers. When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconazole with aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors, may be expected to have similar effects and similar dose reductions should therefore be applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be increased to the level prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly with aripiprazole, modest increases in plasma aripiprazole concentrations may be expected. Carbamazepine and other CYP3A4 inducers Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC for aripiprazole were 68 % and 73 % lower, respectively, compared to when aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively, than those following treatment with aripiprazole alone. Aripiprazole dose should be doubled when concomitant administration of aripiprazole occurs with carbamazepine. Concomitant administration of aripiprazole and other inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of strong CYP3A4 inducers, the dosage of aripiprazole should be reduced to the recommended dose. Valproate and lithium When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations and therefore no dose adjustment is necessary when either valproate or lithium is administered with aripiprazole. Potential for aripiprazole to affect other medicinal products In clinical studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). Additionally, 9 aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, aripiprazole is unlikely to cause clinically important medicinal product interactions mediated by these enzymes. When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations. Serotonin syndrome Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as selective serotonin reuptake inhibitor/selective serotonin noradrenalin reuptake inhibitor (SSRI/SNRI), or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8). 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole. Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus. Newborn infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborn infants should be monitored carefully (see section 4.8). Breast-feeding Aripiprazole/metabolites are excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from aripiprazole therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Aripiprazole did not impair fertility based on data from reproductive toxicity studies. 4.7 Effects on ability to drive and use machines Aripiprazole has minor to moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions in placebo-controlled trials were akathisia and nausea each occurring in more than 3 % of patients treated with oral aripiprazole. Tabulated list of adverse reactions 10 The incidences of the Adverse Drug Reactions (ADRs) associated with aripiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials and/or post- marketing use. All ADRs are listed by system organ class and frequency; very common (≥ 1 /10), common (≥ 1/100 to< 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as "not known”. Common Uncommon Not known Blood and lymphatic system disorders Leukopenia Neutropenia Thrombocytopenia Immune system disorders Allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus allergic, or urticaria) Endocrine disorders Hyperprolactinaemia Diabetic hyperosmolar coma Diabetic ketoacidosis Metabolism and nutrition disorders Diabetes mellitus Hyperglycaemia Hyponatremia Anorexia Psychiatric disorders Insomnia Anxiety Restlessness Depression, Hypersexuality Suicide attempt, suicidal ideation and completed suicide (see section 4.4) Pathological gambling Impulse-control disorders Binge eating Compulsive shopping Poriomania Aggression Agitation Nervousness Nervous system disorders Akathisia Extrapyramidal disorder Tremor Headache Sedation Somnolence Dizziness Tardive dyskinesia Dystonia Neuroleptic Malignant Syndrome Grand mal convulsion Serotonin syndrome Speech disorder Eye disorders Vision blurred Diplopia Photophobia Oculogyric crisis 11 Cardiac disorders Tachycardia Sudden death unexplained Torsades de pointes Ventricular arrhythmias Cardiac arrest Bradycardia Vascular disorders Orthostatic hypotension Venous thromboembolism (including pulmonary embolism and deep vein thrombosis) Hypertension Syncope Respiratory, thoracic and mediastinal disorders Hiccups Aspiration pneumonia Laryngospasm Oropharyngeal spasm Gastrointestinal disorders Constipation Dyspepsia Nausea Salivary hypersecretion Vomiting Pancreatitis Dysphagia Diarrhoea Abdominal discomfort Stomach discomfort Hepatobiliary disorders Hepatic failure Hepatitis Jaundice Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Hyperhidrosis Musculoskeletal and connective tissue disorders Rhabdomyolysis Myalgia Stiffness Renal and urinary disorders Urinary incontinence Urinary retention Pregnancy, puerperium and perinatal conditions Drug withdrawal syndrome neonatal (see section 4.6) Reproductive system and breast disorders Priapism General disorders and administration site conditions Fatigue Temperature regulation disorder (e.g. hypothermia, pyrexia) Chest pain Peripheral oedema 12 Investigations Weight decreased Weight gain Alanine Aminotransferase increased Aspartate Aminotransferase increased Gamma-glutamyltransferase increased Alkaline phosphatase increased QT prolonged Blood glucose increased Glycosylated haemoglobin increased Blood glucose fluctuation Creatine phosphokinase increased Description of selected adverse reactions Adults Extrapyramidal symptoms (EPS) Schizophrenia: in a long-term 52-week controlled trial, aripiprazole- treated patients had an overall-lower incidence (25.8 %) of EPS including Parkinsonism, akathisia, dystonia and dyskinesia compared with those treated with haloperidol (57.3 %). In a long-term 26-week placebo-controlled trial, the incidence of EPS was 19 % for aripiprazole-treated patients and 13.1 % for placebo-treated patients. In another long-term 26-week controlled trial, the incidence of EPS was 14.8 % for aripiprazole-treated patients and 15.1 % for olanzapine-treated patients. Manic episodes in Bipolar I Disorder: in a 12-week controlled trial, the incidence of EPS was 23.5 % for aripiprazole-treated patients and 53.3 % for haloperidol-treated patients. In another 12-week trial, the incidence of EPS was 26.6 % for patients treated with aripiprazole and 17.6 % for those treated with lithium. In the long-term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2 % for aripiprazole-treated patients and 15.7 % for placebo-treated patients. Akathisia In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1 % with aripiprazole and 3.2 % with placebo. In schizophrenia patients the incidence of akathisia was 6.2 % with aripiprazole and 3.0 % with placebo. Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups. Prolactin In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (section 5.1). Laboratory parameters Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5 % of aripiprazole treated patients as compared to 2.0 % of patients who received placebo. Paediatric population 13 Schizophrenia in adolescents aged 15 years and older In a short-term placebo-controlled clinical trial involving 302 adolescents (13 to 17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults except for the following reactions that were reported more frequently in adolescents receiving aripiprazole than in adults receiving aripiprazole (and more frequently than placebo): Somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite, and orthostatic hypotension were reported commonly (≥ 1/100, < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. The safety profile of a long-term, double-blind, placebo-controlled trial was also similar except for the following reactions that were reported more frequently than paediatric patients taking placebo: weight decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (≥ 1/100, < 1/10). In the pooled adolescent schizophrenia population (13 to 17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) was 29.5 % and 48.3 %, respectively. In the adolescent (13 to 17 years) schizophrenia population with aripiprazole exposure of 5 mg to 30 mg up to 72 months, incidence of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) was 25.6 % and 45.0 %, respectively. In two long-term trials with adolescent (13 to 17 years) schizophrenia and bipolar patients treated with aripiprazole, incidence of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) was 37.0 % and 59.4 %, respectively. Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older The frequency and type of adverse reactions in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (≥ 1/10) somnolence (23.0 %), extrapyramidal disorder (18.4 %), akathisia (16.0 %), and fatigue (11.8 %); and commonly (≥ 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia. The following adverse reactions had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1 %; 30 mg, 28.8 %; placebo, 1.7 %); and akathisia (incidences were 10 mg, 12.1 %; 30 mg, 20.3 %; placebo, 1.7 %). Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively. In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia. In the paediatric bipolar population (10 to 17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) was 28.0 % and 53.3 %, respectively. Pathological gambling and other impulse control disorders Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating can occur in patients treated with aripiprazole (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Signs and symptoms http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 14 In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities. The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms. Management of overdose Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore, cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers. Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax by about 41 % and AUC by about 51 %, suggesting that charcoal may be effective in the treatment of overdose. Haemodialysis Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12 Mechanism of action It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism of serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole. Aripiprazole doses ranging from 0.5 mg to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography. Clinical efficacy and safety Adults Schizophrenia 15 In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. Aripiprazole is effective in maintaining the clinical improvement during continuation therapy in adult patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (aripiprazole 77 % and haloperidol 73 %). The overall completion rate was significantly higher for patients on aripiprazole (43 %) than for haloperidol (30 %). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Åsberg Depression Rating Scale (MADRS) showed a significant improvement over haloperidol. In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34 % in aripiprazole group and 57 % in placebo. Weight gain In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain. In a 26-week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 adult patients and where the primary endpoint was weight gain, significantly less patients had at least 7 % weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of~80.5 kg) on aripiprazole (n = 18, or 13 % of evaluable patients), compared to olanzapine (n = 45, or 33 % of evaluable patients). Lipid parameters In a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, High Density Lipoprotein (HDL) and Low Density Lipoproten (LDL). Prolactin Prolactin levels were evaluated in all trials of all doses of aripiprazole (n = 28,242). The incidence of hyperprolactinaemia or increased serum prolactin in patients treated with aripiprazole (0.3 %) was similar to that of placebo (0.2 %). For patients receiving aripiprazole, the median time to onset was 42 days and median duration was 34 days. The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazole was 0.4 %, compared with 0.02 % for patients treated with placebo. For patients receiving aripiprazole, the median time to onset was 30 days and median duration was 194 days. Manic episodes in Bipolar I Disorder In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction of manic symptoms over 3 weeks. These trials included patients with or without psychotic features and with or without a rapid-cycling course. In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo. In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12. Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium or haloperidol at week 12. In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as 16 adjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy. In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomisation, aripiprazole demonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence into depression. In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I Disorder who achieved sustained remission (Youn Mania Rating Scale [YMRS] and MADRS with total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated superiority over placebo with a 46 % decreased risk (hazard ratio of 0.54) in preventing bipolar recurrence and a 65 % decreased risk (hazard ratio of 0.35) in preventing recurrence into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure in Clinical Global Impression Bipolar version(CGI-BP) Severity of Illness (SOI; mania) scores. In this trial, patients were assigned by investigators with either open-label lithium or valproate monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer. Stabilized patients were then randomised to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16 % in aripiprazole + lithium and 18 % in aripiprazole + valproate compared to 45 % in placebo + lithium and 19 % in placebo + valproate. Paediatric population Schizophrenia in adolescents In a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13 to 17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74 % of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial. In a 60- to 89-week, randomised, double-blind, placebo-controlled trial in adolescent subjects (n = 146; ages 13 to 17 years) with schizophrenia, there was a statistically significant difference in the rate of relapse of psychotic symptoms between the aripiprazole (19.39 %) and placebo (37.50 %) groups. The point estimate of the hazard ratio (HR) was 0.461 (95 % confidence interval, 0.242 to 0.879) in the full population. In sub-group analyses the point estimate of the HR was 0.495 for subjects 13 to 14 years of age compared to 0.454 for subjects 15 to 17 years of age. However, the estimation of the HR for the younger (13 to 14 years) group was not precise, reflecting the smaller number of subjects in that group (aripiprazole, n = 29; placebo, n = 12), and the confidence interval for this estimation (ranging from 0.151 to 1.628) did not allow conclusions to be drawn on the presence of a treatment effect. In contrast the 95 % confidence interval for the HR in the older subgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242 to 0.879 and hence a treatment effect could be concluded in the older patients. Manic episodes in Bipolar I Disorder in children and adolescents Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children and adolescents (10 to 17 years), who met DSM-IV criteria (Diagnostic and Statistical Manual of Mental Disorders) for Bipolar I Disorder with manic or mixed episodes with or without psychotic features and had a YMRS score ≥ 20 at baseline. Among the patients included in the primary efficacy analysis, 139 patients had a current co-morbid diagnosis of ADHD. 17 Aripiprazole was superior to placebo in change from baseline at week 4 and at week 12 on the Y-MRS total score. In a post-hoc analysis, the improvement over placebo was more pronounced in the patients with associated co-morbidity of ADHD compared to the group without ADHD, where there was no difference from placebo. Recurrence prevention was not established. The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidal disorder (28.3 %), somnolence (27.3 %), headache (23.2 %), and nausea (14.1 %). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with placebo. Irritability associated with autistic disorder in paediatric patients (see section 4.2) Aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2 mg/day to 15 mg/day) and one fixed-dose (5 mg/day, 10 mg/day, or 15 mg/day)] and in one 52-week open-label trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly increments to the target dose. Over 75% of patients were less than 13 years of age. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the Aberrant Behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In the pooled trials, the incidence of low serum prolactin levels in females (<3 ng/mL) and males (<2 ng/mL) in aripiprazole-treated patients was 27/46 (58.7%) and 258/298 (86.6%), respectively. In the placebo- controlled trials, the mean weight gain was 0.4 kg for placebo and 1.6 kg for aripiprazole. Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial. After a 13 to 26 week stabilisation on aripiprazole (2 mg/day to 15 mg/day) patients with a stable response were either maintained on aripiprazole or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo; the hazard ratio for relapse within 16 weeks (aripiprazole/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26 weeks) on aripiprazole was 3.2 kg, and a further mean increase of 2.2 kg for aripiprazole as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17% of patients, with tremor accounting for 6.5%. Tics associated with Tourette’s disorder in paediatric patients (see section 4.2) The efficacy of aripiprazole was studied in paediatric subjects with Tourette’s disorder (aripiprazole: n = 99, placebo: n = 44) in a randomised, double-blind, placebo-controlled, 8 week study using a fixed dose weight-based treatment group design over the dose range of 5 mg/day to 20 mg/day and a starting dose of 2 mg. Patients were 7 to 17 years of age and presented an average score of 30 on Total Tic Score on the Yale Global Tic Severity Scale (TTS-YGTSS) at baseline. Aripiprazole showed an improvement on TTS-YGTSS change from baseline to week 8 of 13.35, for the low dose group (5 mg or 10 mg) and 16.94 for the high dose group (10 mg or 20 mg) as compared with an improvement of 7.09 in the placebo group. The efficacy of aripiprazole in paediatric subjects with Tourette’s syndrome (aripiprazole: n = 32, placebo: n = 29) was also evaluated over a flexible dose range of 2 mg/day to 20 mg/day and a starting dose of 2 mg, in a 10 week, randomised, double blind, placebo-controlled study conducted in South- Korea. Patients were 6 to 18 years and presented an average score of 29 on TTS-YGTSS at baseline. Aripiprazole group showed an improvement of 14.97 on TTS-YGTSS change from baseline to week 10 as compared with an improvement of 9.62 in the placebo group. In both of these short-term trials, the clinical relevance of the efficacy findings has not been established, considering the magnitude of treatment effect compared to the large placebo effect and the unclear effects regarding psycho-social functioning. No long-term data are available with regard to the efficacy and the safety of aripiprazole in this fluctuating disorder. 18 The European Medicines Agency has deferred the obligation to submit the results of studies with aripiprazole in one or more subsets of the paediatric population in the treatment of schizophrenia and in the treatment of bipolar affective disorder (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3 to 5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87 %. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole. Distribution Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99 % bound to serum proteins, binding primarily to albumin. Biotransformation Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. Elimination The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6. The total body clearance of aripiprazole is 0.7 mL/min/kg, which is primarily hepatic. Following a single oral dose of [14C]-labelled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60 % in the faeces. Less than 1 % of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces. Paediatric population The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of age were similar to those in adults after correcting for the differences in body weights. Pharmacokinetics in special patient groups Elderly There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients. Gender There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients. 19 Smoking Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from smoking on the pharmacokinetics of aripiprazole. Race Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole. Renal impairment The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects. Hepatic impairment A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 mg/kg/day to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC at the maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose. An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 mg/kg/day to 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m2). However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6 % of the bile concentrations found in the monkeys in the 39-week study and are well below (6 %) their limits of in vitro solubility. In repeat-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse reactions on development. Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non- genotoxic. Aripiprazole did not impair fertility in reproductive toxicity studies. Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients 20 Tablet core Crystalline Maltose Microcrystalline cellulose Pregelatinised starch Croscarmellose Sodium Magnesium stearate Tablet coat Aripiprazole Mylan Pharma 5 mg tablets Indigo carmine (E132) Aripiprazole Mylan Pharma 10 mg tablets Iron Oxide Red (E172) Aripiprazole Mylan Pharma 15 mg tablets Iron Oxide Yellow (E172) Aripiprazole Mylan Pharma 30 mg tablets Iron Oxide Red (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container PA/Alu/PVC- Aluminium foil perforated blisters (alu-alu blister) in cartons of 14, 28, 56 and 98 tablets and 28 x 1 tablets (unit dose). Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Mylan S.A.S, 117, Allée des Parcs, 69800 Saint-Priest, France 8. MARKETING AUTHORISATION NUMBER(S) 21 Aripiprazole Mylan Pharma 5 mg tablets EU/1/15/1005/001 EU/1/15/1005/002 EU/1/15/1005/003 EU/1/15/1005/013 EU/1/15/1005/014 Aripiprazole Mylan Pharma 10 mg tablets EU/1/15/1005/004 EU/1/15/1005/005 EU/1/15/1005/006 EU/1/15/1005/015 EU/1/15/1005/016 Aripiprazole Mylan Pharma 15 mg tablets EU/1/15/1005/007 EU/1/15/1005/008 EU/1/15/1005/009 EU/1/15/1005/017 EU/1/15/1005/018 Aripiprazole Mylan Pharma 30 mg tablets EU/1/15/1005/010 EU/1/15/1005/011 EU/1/15/1005/012 EU/1/15/1005/019 EU/1/15/1005/020 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 30 June 2015 Date of latest renewal: 25 February 2020 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 22 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 23 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Pharmathen S.A. 6, Dervenakion Pallini 15351 Attiki, Greece or Pharmathen International S.A Industrial Park Sapes, Rodopi Prefecture, Block No 5, Rodopi 69300, Greece The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 24 ANNEX III LABELLING AND PACKAGE LEAFLET 25 A. LABELLING 26 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 5 mg tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE Each tablet contains 5 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains maltose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet 14 tablets 28 tablets 56 tablets 98 tablets 28 x 1 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 27 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S, 117, Allée des Parcs, 69800 Saint-Priest, France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1005/001 EU/1/15/1005/002 EU/1/15/1005/003 EU/1/15/1005/013 EU/1/15/1005/014 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Mylan Pharma 5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 28 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 5 mg tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 29 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 10 mg tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE Each tablet contains 10 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains maltose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet 14 tablets 28 tablets 56 tablets 98 tablets 28 x 1 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 30 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTSOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IFAPPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S, 117, Allée des Parcs, 69800 Saint-Priest, France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1005/004 EU/1/15/1005/005 EU/1/15/1005/006 EU/1/15/1005/015 EU/1/15/1005/016 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Mylan Pharma 10 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 31 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 10 mg tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 32 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 15 mg tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE Each tablet contains 15 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains maltose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet 14 tablets 28 tablets 56 tablets 98 tablets 28 x 1 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 33 Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S, 117, Allée des Parcs, 69800 Saint-Priest, France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1005/007 EU/1/15/1005/008 EU/1/15/1005/009 EU/1/15/1005/017 EU/1/15/1005/018 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Mylan Pharma 15 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 34 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 15 mg tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 35 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 30 mg tablets aripiprazole 2. STATEMENT OF ACTIVE SUBSTANCE Each tablet contains 30 mg of aripiprazole. 3. LIST OF EXCIPIENTS Contains maltose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablet 14 tablets 28 tablets 56 tablets 98 tablets 28 x 1 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 36 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S, 117, Allée des Parcs, 69800 Saint-Priest, France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1005/010 EU/1/15/1005/011 EU/1/15/1005/012 EU/1/15/1005/019 EU/1/15/1005/020 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Aripiprazole Mylan Pharma 30 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 37 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Aripiprazole Mylan Pharma 30 mg tablets aripiprazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 38 B. PACKAGE LEAFLET 39 Package leaflet: Information for the user Aripiprazole Mylan Pharma 5 mg tablets Aripiprazole Mylan Pharma 10 mg tablets Aripiprazole Mylan Pharma 15 mg tablets Aripiprazole Mylan Pharma 30 mg tablets aripiprazole Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or pharmacist. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Aripiprazole Mylan Pharma is and what it is used for 2. What you need to know before you take Aripiprazole Mylan Pharma 3. How to take Aripiprazole Mylan Pharma 4. Possible side effects 5. How to store Aripiprazole Mylan Pharma 6. Contents of the pack and other information 1. What Aripiprazole Mylan Pharma is and what it is used for Aripiprazole Mylan Pharma contains the active substance aripiprazole and belong to a group of medicines called antipsychotics. It is used to treat adults and adolescents aged 15 years and older who suffer from a disease characterised by symptoms such as hearing, seeing or sensing things which are not there, suspiciousness, mistaken beliefs, incoherent speech and behaviour and emotional flatness. People with this condition may also feel depressed, guilty, anxious or tense. Aripiprazole Mylan Pharma is used to treat adults and adolescents aged 13 years and older who suffer from a condition with symptoms such as feeling "high", having excessive amounts of energy, needing much less sleep than usual, talking very quickly with racing ideas and sometimes severe irritability. In adults it also prevents this condition from returning in patients who have responded to the treatment with Aripiprazole Mylan Pharma. 2. What you need to know before you take Aripiprazole Mylan Pharma Do not take Aripiprazole Mylan Pharma • if you are allergic to aripiprazole or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor before taking Aripiprazole Mylan Pharma Suicidal thoughts and behaviours have been reported during aripiprazole treatment. Tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. Before treatment with Aripiprazole Mylan Pharma tell your doctor if you suffer from • high blood sugar (characterised by symptoms such as excessive thirst, passing of large amounts of urine, increase in appetite and feeling weak) or family history of diabetes 40 • fits (seizures) since your doctor may want to monitor you more closely • involuntary, irregular muscle movements, especially in the face • cardiovascular diseases (diseases of the heart and circulation), family history of cardiovascular disease, stroke or "mini" stroke, abnormal blood pressure • blood clots, or family history of blood clots, as antipsychotics have been associated with formation of blood clots • past experience with excessive gambling If you notice you are gaining weight, develop unusual movements, experience somnolence that interferes with normal daily activities, any difficulty in swallowing or allergic symptoms, please tell your doctor. If you are an elderly patient suffering from dementia (loss of memory and other mental abilities), you or your carer/relative should tell your doctor if you have ever had a stroke or "mini" stroke. Tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. Suicidal thoughts and behaviours have been reported during aripiprazole treatment. Tell your doctor immediately if you suffer from muscle stiffness or inflexibility with high fever, sweating, altered mental status, or very rapid or irregular heart beat. Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or preoccupation with an increase in sexual thoughts or feelings. Your doctor may need to adjust or stop your dose. Aripiprazole may cause sleepiness, fall in blood pressure when standing up, dizziness and changes in your ability to move and balance, which may lead to falls. Caution should be taken, particularly if you are an elderly patient or have some debility. Children and adolescents Do not use this medicine in children and adolescents under 13 years of age. It is not known if it is safe and effective in these patients. Other medicines and Aripiprazole Mylan Pharma Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. Blood pressure-lowering medicines: Aripiprazole Mylan Pharma may increase the effect of medicines used to lower the blood pressure. Be sure to tell your doctor if you take a medicine to keep your blood pressure under control. Taking Aripiprazole Mylan Pharma with some medicines may mean the doctor will need to change your dose of Aripiprazole Mylan Pharma or the other medicines. It is especially important to mention the following to your doctor: • medicines to correct heart rhythm (such as quinidine, amiodarone, flecainide) • antidepressants or herbal remedy used to treat depression and anxiety (such as fluoxetine, paroxetine, venlafaxine, St. John's Wort) • antifungal medicines (such as ketoconazole, itraconazole) • certain medicines to treat HIV infection (such as efavirenz, nevirapine, and protease inhibitors e.g. indinavir, ritonavir) • anticonvulsants used to treat epilepsy (such as carbamazepine, phenytoin, phenobarbital) • certain antibiotics used to treat tuberculosis (rifabutin, rifampicin) 41 These medicines may increase the risk of side effects or reduce the effect of Aripiprazole Mylan Pharma; if you get any unusual symptom taking any of these medicines together with Aripiprazole Mylan Pharma you should see your doctor. Medicines that increase the level of serotonin are typically used in conditions including depression, generalised anxiety disorder, obsessive-compulsive disorder (OCD) and social phobia as well as migraine and pain: • triptans, tramadol and tryptophan used for conditions including depression, generalised anxiety disorder, obsessive compulsive disorder (OCD) and social phobia as well as migraine and pain • selective-serotonin-reuptake-inhibitors (SSRIs) (such as paroxetine and fluoxetine) used for depression, OCD, panic and anxiety • other anti-depressants (such as venlafaxine and tryptophan) used in major depression • tricyclic’s (such as clomipramine and amitriptyline) used for depressive illness • St John’s Wort (Hypericum perforatum) used as a herbal remedy for mild depression • pain killers (such as tramadol and pethidine) used for pain relief • triptans (such as sumatriptan and zolmitripitan) used for treating migraine These medicines may increase the risk of side effects; if you get any unusual symptom taking any of these medicines together with Aripiprazole Mylan Pharma, you should see your doctor. Aripiprazole Mylan Pharma with food, drink and alcohol This medicine can be taken regardless of meals. Alcohol should be avoided. Pregnancy, breast-feeding and fertility If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. The following symptoms may occur in newborn babies, of mothers that have used Aripiprazole Mylan Pharma tablets in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms you may need to contact your doctor. If you are taking, Aripiprazole Mylan Pharma your doctor will discuss with you whether you should breast-feed considering the benefit to you of your therapy and the benefit to your baby of breast-feeding. You should not do both. Talk to your doctor about the best way to feed your baby if you are taking this medicine. Driving and using machines Dizziness and vision problems may occur during treatment with this medicine (see section 4). This should be considered in cases where full alertness is required, e.g. when driving a car or handling machines. Aripiprazole Mylan Pharma contains maltose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Sodium content This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’. 3. How to take Aripiprazole Mylan Pharma Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. http://en.wikipedia.org/wiki/Major_depressive_disorder http://en.wikipedia.org/wiki/Generalized_anxiety_disorder http://en.wikipedia.org/wiki/Social_anxiety_disorder 42 The recommended dose for adults is 15 mg once a day. However, your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. Use in children and adolescents This medicinal product may be started at a low dose with the oral solution (liquid) form. The dose may be gradually increased to the recommended dose for adolescents of 10 mg once a day. However, your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. If you have the impression that the effect of Aripiprazole Mylan Pharma is too strong or too weak, talk to your doctor or pharmacist. Try to take Aripiprazole Mylan Pharma at the same time each day. It does not matter whether you take it with or without food. Always take the tablet with water and swallow it whole. Even if you feel better, do not alter or discontinue the daily dose of Aripiprazole Mylan Pharma without first consulting your doctor. If you take more Aripiprazole Mylan Pharma than you should If you realise you have taken more Aripiprazole Mylan Pharma than your doctor has recommended (or if someone else has taken some of your Aripiprazole Mylan Pharma), contact your doctor right away. If you cannot reach your doctor, go to the nearest hospital and take the pack with you. Patients who have taken too much aripiprazole have experienced the following symptoms: • rapid heartbeat, agitation/aggressiveness, problems with speech. • unusual movements (especially of the face or tongue) and reduced level of consciousness. Other symptoms may include: • acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, • muscle stiffness, and drowsiness or sleepiness, slower breathing, choking, high or low blood pressure, abnormal rhythms of the heart. Contact your doctor or hospital immediately if you experience any of the above. If you forget to take your Aripiprazole Mylan Pharma If you miss a dose, take the missed dose as soon as you remember but do not take two doses in one day. If you stop taking Aripiprazole Mylan Pharma Do not stop your treatment just because you feel better. It is important that you carry on taking Aripiprazole Mylan Pharma for as long as your doctor has told you to. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Common side effects (may affect up to 1 in 10 people): • diabetes mellitus, • difficulty sleeping, • feeling anxious, • feeling restless and unable to keep still, difficulty sitting still, • uncontrollable twitching, jerking or writhing movements, restless legs, • trembling, • headache, 43 • tiredness, • sleepiness, • light-headedness, • shaking and blurred vision, • decreased number of or difficulty making bowel movements, • indigestion, • feeling sick, • more saliva in mouth than normal, • vomiting, • feeling tired. Uncommon side effects (may affect up to 1 in 100 people): • increased blood levels of the hormone prolactin, • too much sugar in the blood, • depression, • altered or increased sexual interest; • uncontrollable movements of mouth, tongue and limbs (tardive dyskinesia), • muscle disorder causing twisting movements (dystonia), • double vision, • eye sensitivity to light, • fast heartbeat, • a fall in blood pressure on standing up which causes dizziness, light-headedness or fainting, • hiccups. The following side effects have been reported since the marketing of oral aripiprazole but the frequency for them to occur is not known: • low levels of white blood cells, • low levels of blood platelets, • allergic reaction (e.g. swelling in the mouth, tongue, face and throat, itching, hives), • onset or worsening of diabetes, ketoacidosis (ketones in the blood and urine) or coma, • high blood sugar, • not enough sodium in the blood, • loss of appetite (anorexia), • weight loss, • weight gain, • thoughts of suicide, suicide attempt and suicide, • feeling aggressive, • agitation, • nervousness, • combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness and sudden changes in blood pressure and heart rate, fainting (neuroleptic malignant syndrome), • seizure, • serotonin syndrome (a reaction which may cause feelings of great happiness, drowsiness, clumsiness, restlessness, feeling of being drunk, fever, sweating or rigid muscles), • speech disorder, • fixation of the eyeballs in one position, • sudden unexplained death, • life-threatening irregular heartbeat, • heart attack, • slower heartbeat, • blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek medical advice immediately), 44 • high blood pressure, • fainting, • accidental inhalation of food with risk of pneumonia (lung infection), • spasm of the muscles around the voice box, • inflammation of the pancreas, • difficulty swallowing, • diarrhoea, • abdominal discomfort, • stomach discomfort, • liver failure, • inflammation of the liver, • yellowing of the skin and white part of eyes, • reports of abnormal liver test values, • skin rash, • skin sensitivity to light, • baldness, • excessive sweating, • abnormal muscle breakdown which can lead to kidney problems, • muscle pain, • stiffness, • involuntary loss of urine (incontinence), • difficulty in passing urine, • withdrawal symptoms in newborn babies in case of exposure during pregnancy, • prolonged and/or painful erection, • difficulty controlling core body temperature or overheating, • chest pain, • swelling of hands, ankles or feet, • in blood tests: increased or fluctuating blood sugar, increased glycosylated haemoglobin. • Inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include: - strong impulse to gamble excessively despite serious personal or family consequences - altered or increased sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive - uncontrollable excessive shopping - binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger) - a tendency to wander away. Tell your doctor if you experience any of these behaviours; he/she will discuss ways of managing or reducing the symptoms. In elderly patients with dementia, more fatal cases have been reported while taking aripiprazole. In addition, cases of stroke or "mini" stroke have been reported. Additional side effects in children and adolescents Adolescents aged 13 years and older experienced side effects that were similar in frequency and type to those in adults except that sleepiness, uncontrollable twitching or jerking movements, restlessness, and tiredness were very common (greater than 1 in 10 patients) and upper abdominal pain, dry mouth, increased heart rate, weight gain, increased appetite, muscle twitching, uncontrolled movements of the limbs, and feeling dizzy, especially when getting up from a lying or sitting position, were common (greater than 1 in 100 patients). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system 45 listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Aripiprazole Mylan Pharma Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister and on the carton after EXP. The expiry date refers to the last day of that month. Store in the original package in order to protect from moisture. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Aripiprazole Mylan Pharma contains • The active substance is aripiprazole. Each tablet of 5, 10, 15, 30 mg containing 5, 10, 15, 30 mg of aripiprazole respectively. • The other ingredients for 5 mg are crystalline maltose, microcrystalline cellulose, pregelatinised starch, croscarmellose sodium, indigo carmine (E132) and magnesium stearate. • The other ingredients for 10, 30 mg are crystalline maltose, microcrystalline cellulose, pregelatinised starch, croscarmellose sodium, iron oxide red (E172) and magnesium stearate. • The other ingredients for 15 mg are crystalline maltose, microcrystalline cellulose, pregelatinised starch, croscarmellose sodium, iron oxide yellow (E172) and magnesium stearate. What Aripiprazole Mylan Pharma look like and contents of the pack Aripiprazole Mylan Pharma 5 mg tablets are blue, round and biconvex of 6.1 mm in diameter, engraved with ‘5’ on one side. Aripiprazole Mylan Pharma 10 mg tablets are pink, round and biconvex of 8.1 mm in diameter, engraved with ‘10’ on one side. Aripiprazole Mylan Pharma 15 mg tablets are yellow, round and biconvex of 10.1 mm in diameter, engraved with ‘15’ on one side. Aripiprazole Mylan Pharma 30 mg tablets are pink, oval and biconvex of 17.1mm in length, 8.1 mm in width, engraved with ‘30’ on one side. They are supplied in PA/Alu/PVC-Aluminium foil perforated blisters packed in cardboard box containing 14, 28, 56 or 98 tablets and 28 x 1 tablets (unit dose). Not all pack sizes may be marketed. Marketing Authorisation Holder Mylan S.A.S, 117, Allée des Parcs, 69800 Saint-Priest, France Manufacturer Pharmathen International S.A., Industrial Park Sapes, Rodopi Prefecture, Block No 5, Rodopi 69300, Greece or Pharmathen S.A., 6, Dervenakion, Pallini 15351, Attiki, Greece For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 46 België/Belgique/Belgien Mylan bvba/sprl Tél/Tel: + 32 (0)2 658 61 00 Lietuva BGP Products UAB Tel: +370 5 205 1288 България Майлан ЕООД Тел: +359 2 44 55 400 Luxembourg/Luxemburg Mylan bvba/sprl Tel: + 32 (0)2 658 61 00 (Belgique/Belgien) Česká republika Mylan Healthcare CZ s.r.o. Tel: +420 222 004 400 Magyarország Mylan EPD Kft Tel: + 36 1 465 2100 Danmark Mylan Denmark ApS Tel: +45 28 11 69 32 Malta V.J. Salomone Pharma Ltd Tel: + 356 21 22 01 74 Deutschland Mylan Healthcare GmbH Tel: +49 (0) 800 0700 800 Nederland Mylan BV Tel: +31 (0)20 426 3300 Eesti BGP Products Switzerland GmbH Eesti filiaal Tel: + 372 6363 052 Norge Mylan Healthcare Norge AS Tel: + 47 66 75 33 00 Ελλάδα Generics Pharma Hellas ΕΠΕ Τηλ: +30 210 993 6410 Österreich Arcana Arzneimittel GmbH Tel: +43 1 416 2418 España Mylan Pharmaceuticals, S.L Tel: + 34 900 102 712 Polska Mylan Healthcare Sp. z.o.o. Tel: + 48 22 546 64 00 France Mylan S.A.S Tel: +33 4 37 25 75 00 Portugal Mylan, Lda. Tel: + 351 21 412 72 56 Hrvatska Mylan Hrvatska d.o.o. Tel: +385 1 23 50 599 România BGP Products SRL Tel: +40 372 579 000 Ireland Mylan Ireland Limited Tel: +353 (0) 87 1694982 Slovenija Mylan Healthcare d.o.o Tel: + 386 1 23 63 180 Ísland Icepharma hf Tel: +354 540 8000 Slovenská republika Mylan s.r.o. Tel: +421 2 32 199 100 Italia Mylan Italia S.r.l Tel: + 39 02 612 46921 Suomi/Finland Mylan Finland OY Puh/Tel: +358 20 720 9555 Κύπρος Varnavas Hadjipanayis Ltd Τηλ: +357 2220 7700 Sverige Mylan AB Tel: + 46 855 522 750 47 Latvija Mylan Healthcare SIA Tel: +371 676 055 80 United Kingdom Generics [UK] Ltd Tel: +44 1707 853000 This leaflet was last revised in MM/YYYY. Other sources of information Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take aripiprazole mylan pharma', 'Section_Content': 'do not take aripiprazole mylan pharma if you are allergic to aripiprazole or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor before taking aripiprazole mylan pharma suicidal thoughts and behaviours have been reported during aripiprazole treatment. tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. before treatment with aripiprazole mylan pharma tell your doctor if you suffer from high blood sugar (characterised by symptoms such as excessive thirst, passing of large amounts of urine, increase in appetite and feeling weak) or family history of diabetes 40 fits (seizures) since your doctor may want to monitor you more closely involuntary, irregular muscle movements, especially in the face cardiovascular diseases (diseases of the heart and circulation), family history of cardiovascular disease, stroke or "mini" stroke, abnormal blood pressure blood clots, or family history of blood clots, as antipsychotics have been associated with formation of blood clots past experience with excessive gambling if you notice you are gaining weight, develop unusual movements, experience somnolence that interferes with normal daily activities, any difficulty in swallowing or allergic symptoms, please tell your doctor. if you are an elderly patient suffering from dementia (loss of memory and other mental abilities), you or your carer/relative should tell your doctor if you have ever had a stroke or "mini" stroke. tell your doctor immediately if you are having any thoughts or feelings about hurting yourself. suicidal thoughts and behaviours have been reported during aripiprazole treatment. tell your doctor immediately if you suffer from muscle stiffness or inflexibility with high fever, sweating, altered mental status, or very rapid or irregular heart beat. tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. these are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or preoccupation with an increase in sexual thoughts or feelings. your doctor may need to adjust or stop your dose. aripiprazole may cause sleepiness, fall in blood pressure when standing up, dizziness and changes in your ability to move and balance, which may lead to falls. caution should be taken, particularly if you are an elderly patient or have some debility. children and adolescents do not use this medicine in children and adolescents under 13 years of age. it is not known if it is safe and effective in these patients. other medicines and aripiprazole mylan pharma tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. blood pressure-lowering medicines: aripiprazole mylan pharma may increase the effect of medicines used to lower the blood pressure. be sure to tell your doctor if you take a medicine to keep your blood pressure under control. taking aripiprazole mylan pharma with some medicines may mean the doctor will need to change your dose of aripiprazole mylan pharma or the other medicines. it is especially important to mention the following to your doctor: medicines to correct heart rhythm (such as quinidine, amiodarone, flecainide) antidepressants or herbal remedy used to treat depression and anxiety (such as fluoxetine, paroxetine, venlafaxine, st. john\'s wort) antifungal medicines (such as ketoconazole, itraconazole) certain medicines to treat hiv infection (such as efavirenz, nevirapine, and protease inhibitors e.g. indinavir, ritonavir) anticonvulsants used to treat epilepsy (such as carbamazepine, phenytoin, phenobarbital) certain antibiotics used to treat tuberculosis (rifabutin, rifampicin) 41 these medicines may increase the risk of side effects or reduce the effect of aripiprazole mylan pharma; if you get any unusual symptom taking any of these medicines together with aripiprazole mylan pharma you should see your doctor. medicines that increase the level of serotonin are typically used in conditions including depression, generalised anxiety disorder, obsessive-compulsive disorder (ocd) and social phobia as well as migraine and pain: triptans, tramadol and tryptophan used for conditions including depression, generalised anxiety disorder, obsessive compulsive disorder (ocd) and social phobia as well as migraine and pain selective-serotonin-reuptake-inhibitors (ssris) (such as paroxetine and fluoxetine) used for depression, ocd, panic and anxiety other anti-depressants (such as venlafaxine and tryptophan) used in major depression tricyclic\'s (such as clomipramine and amitriptyline) used for depressive illness st john\'s wort (hypericum perforatum) used as a herbal remedy for mild depression pain killers (such as tramadol and pethidine) used for pain relief triptans (such as sumatriptan and zolmitripitan) used for treating migraine these medicines may increase the risk of side effects; if you get any unusual symptom taking any of these medicines together with aripiprazole mylan pharma, you should see your doctor. aripiprazole mylan pharma with food, drink and alcohol this medicine can be taken regardless of meals. alcohol should be avoided. pregnancy, breast-feeding and fertility if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. the following symptoms may occur in newborn babies, of mothers that have used aripiprazole mylan pharma tablets in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. if your baby develops any of these symptoms you may need to contact your doctor. if you are taking, aripiprazole mylan pharma your doctor will discuss with you whether you should breast-feed considering the benefit to you of your therapy and the benefit to your baby of breast-feeding. you should not do both. talk to your doctor about the best way to feed your baby if you are taking this medicine. driving and using machines dizziness and vision problems may occur during treatment with this medicine (see section 4). this should be considered in cases where full alertness is required, e.g. when driving a car or handling machines. aripiprazole mylan pharma contains maltose if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. sodium content this medicine contains less than 1 mmol sodium (23 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{'Title': '3. how to take aripiprazole mylan pharma', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose for adults is 15 mg once a day. however, your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. use in children and adolescents this medicinal product may be started at a low dose with the oral solution (liquid) form. the dose may be gradually increased to the recommended dose for adolescents of 10 mg once a day. however, your doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. if you have the impression that the effect of aripiprazole mylan pharma is too strong or too weak, talk to your doctor or pharmacist. try to take aripiprazole mylan pharma at the same time each day. it does not matter whether you take it with or without food. always take the tablet with water and swallow it whole. even if you feel better, do not alter or discontinue the daily dose of aripiprazole mylan pharma without first consulting your doctor. if you take more aripiprazole mylan pharma than you should if you realise you have taken more aripiprazole mylan pharma than your doctor has recommended (or if someone else has taken some of your aripiprazole mylan pharma), contact your doctor right away. if you cannot reach your doctor, go to the nearest hospital and take the pack with you. patients who have taken too much aripiprazole have experienced the following symptoms: rapid heartbeat, agitation/aggressiveness, problems with speech. unusual movements (especially of the face or tongue) and reduced level of consciousness. other symptoms may include: acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, muscle stiffness, and drowsiness or sleepiness, slower breathing, choking, high or low blood pressure, abnormal rhythms of the heart. contact your doctor or hospital immediately if you experience any of the above. if you forget to take your aripiprazole mylan pharma if you miss a dose, take the missed dose as soon as you remember but do not take two doses in one day. if you stop taking aripiprazole mylan pharma do not stop your treatment just because you feel better. it is important that you carry on taking aripiprazole mylan pharma for as long as your doctor has told you to. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'aripiprazole mylan pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': '15', 'Type': 'NUMBER', 'BeginOffset': 170, 'EndOffset': 172}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 262, 'EndOffset': 264}, {'Text': 'this medicinal product', 'Type': 'TREATMENT', 'BeginOffset': 312, 'EndOffset': 334}, {'Text': 'the oral solution (liquid)', 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. common side effects (may affect up to 1 in 10 people): diabetes mellitus, difficulty sleeping, feeling anxious, feeling restless and unable to keep still, difficulty sitting still, uncontrollable twitching, jerking or writhing movements, restless legs, trembling, headache, 43 tiredness, sleepiness, light-headedness, shaking and blurred vision, decreased number of or difficulty making bowel movements, indigestion, feeling sick, more saliva in mouth than normal, vomiting, feeling tired. uncommon side effects (may affect up to 1 in 100 people): increased blood levels of the hormone prolactin, too much sugar in the blood, depression, altered or increased sexual interest; uncontrollable movements of mouth, tongue and limbs (tardive dyskinesia), muscle disorder causing twisting movements (dystonia), double vision, eye sensitivity to light, fast heartbeat, a fall in blood pressure on standing up which causes dizziness, light-headedness or fainting, hiccups. the following side effects have been reported since the marketing of oral aripiprazole but the frequency for them to occur is not known: low levels of white blood cells, low levels of blood platelets, allergic reaction (e.g. swelling in the mouth, tongue, face and throat, itching, hives), onset or worsening of diabetes, ketoacidosis (ketones in the blood and urine) or coma, high blood sugar, not enough sodium in the blood, loss of appetite (anorexia), weight loss, weight gain, thoughts of suicide, suicide attempt and suicide, feeling aggressive, agitation, nervousness, combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness and sudden changes in blood pressure and heart rate, fainting (neuroleptic malignant syndrome), seizure, serotonin syndrome (a reaction which may cause feelings of great happiness, drowsiness, clumsiness, restlessness, feeling of being drunk, fever, sweating or rigid muscles), speech disorder, fixation of the eyeballs in one position, sudden unexplained death, life-threatening irregular heartbeat, heart attack, slower heartbeat, blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek medical advice immediately), 44 high blood pressure, fainting, accidental inhalation of food with risk of pneumonia (lung infection), spasm of the muscles around the voice box, inflammation of the pancreas, difficulty swallowing, diarrhoea, abdominal discomfort, stomach discomfort, liver failure, inflammation of the liver, yellowing of the skin and white part of eyes, reports of abnormal liver test values, skin rash, skin sensitivity to light, baldness, excessive sweating, abnormal muscle breakdown which can lead to kidney problems, muscle pain, stiffness, involuntary loss of urine (incontinence), difficulty in passing urine, withdrawal symptoms in newborn babies in case of exposure during pregnancy, prolonged and/or painful erection, difficulty controlling core body temperature or overheating, chest pain, swelling of hands, ankles or feet, in blood tests: increased or fluctuating blood sugar, increased glycosylated haemoglobin. inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include: - strong impulse to gamble excessively despite serious personal or family consequences - altered or increased sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive - uncontrollable excessive shopping - binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger) - a tendency to wander away. tell your doctor if you experience any of these behaviours; he/she will discuss ways of managing or reducing the symptoms. in elderly patients with dementia, more fatal cases have been reported while taking aripiprazole. in addition, cases of stroke or "mini" stroke have been reported. additional side effects in children and adolescents adolescents aged 13 years and older experienced side effects that were similar in frequency and type to those in adults except that sleepiness, uncontrollable twitching or jerking movements, restlessness, and tiredness were very common (greater than 1 in 10 patients) and upper abdominal pain, dry mouth, increased heart rate, weight gain, increased appetite, muscle twitching, uncontrolled movements of the limbs, and feeling dizzy, especially when getting up from a lying or sitting position, were common (greater than 1 in 100 patients). reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side 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{'Title': '5. how to store aripiprazole mylan pharma', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what aripiprazole mylan pharma contains the active substance is aripiprazole. each tablet of 5, 10, 15, 30 mg containing 5, 10, 15, 30 mg of aripiprazole respectively. the other ingredients for 5 mg are crystalline maltose, microcrystalline cellulose, pregelatinised starch, croscarmellose sodium, indigo carmine (e132) and magnesium stearate. the other ingredients for 10, 30 mg are crystalline maltose, microcrystalline cellulose, pregelatinised starch, croscarmellose sodium, iron oxide red (e172) and magnesium stearate. the other ingredients for 15 mg are crystalline maltose, microcrystalline cellulose, pregelatinised starch, croscarmellose sodium, iron oxide yellow (e172) and magnesium stearate. what aripiprazole mylan pharma look like and contents of the pack aripiprazole mylan pharma 5 mg tablets are blue, round and biconvex of 6.1 mm in diameter, engraved with '5' on one side. aripiprazole mylan pharma 10 mg tablets are pink, round and biconvex of 8.1 mm in diameter, engraved with '10' on one side. aripiprazole mylan pharma 15 mg tablets are yellow, round and biconvex of 10.1 mm in diameter, engraved with '15' on one side. aripiprazole mylan pharma 30 mg tablets are pink, oval and biconvex of 17.1mm in length, 8.1 mm in width, engraved with '30' on one side. they are supplied in pa/alu/pvc-aluminium foil perforated blisters packed in cardboard box containing 14, 28, 56 or 98 tablets and 28 x 1 tablets (unit dose). not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'aripiprazole mylan pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'aripiprazole mylan pharma', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 30}, {'Id': 2, 'BeginOffset': 64, 'EndOffset': 76, 'Score': 0.9989659786224365, 'Text': 'aripiprazole', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.7034569978713989, 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75BE3B140AA61F85E17ECDEEC52C5598

https://www.ema.europa.eu/documents/product-information/episalvan-epar-product-information_en.pdf

Episalvan

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Episalvan gel 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1g gel contains: 100 mg extract (as dry extract, refined) from birch bark from Betula pendula Roth, Betula pubescens Ehrh. as well as hybrids of both species (equivalent to 0.5-1.0 g birch bark), corresponding to 72-88 mg betulin. Extraction solvent: n-Heptane For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Gel. Colourless to slightly yellowish, opalescent. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of partial thickness wounds in adults. See section 4.4 and 5.1 with respect to type of wounds studied. 4.2 Posology and method of administration Posology The gel should be applied to the wound surface at a thickness of approximately 1 mm and covered by sterile wound dressing. The gel should be re-applied at each wound dressing change, until the wound is healed, for up to 4 weeks. See section 4.4 with respect to wound size and duration of treatment. Special populations Renal or hepatic impairment No formal studies have been conducted with Episalvan in patients with renal or hepatic impairment. No dose adjustment or special considerations are anticipated for patients with renal or hepatic impairment, see section 5.2. Elderly No dose adjustment is required. 3 Paediatric population The safety and efficacy of Episalvan in children and adolescents under 18 years have not yet been established. No data are available. Method of administration For cutaneous application. Fresh wounds should achieve haemostasis prior to application of Episalvan. If necessary, wounds (accidental wounds) should be cleaned according to standard procedure, using e.g. wound antiseptic solution, prior to application of Episalvan. Episalvan is for single use only. Once opened, the product should be used immediately and be discarded after use. 4.3 Contraindications Hypersensitivity to the active substance or to the excipient listed in section 6.1. 4.4 Special warnings and precautions for use Wound infection Episalvan gel is sterile. However, wound infection is an important and serious complication that can occur during wound healing. In the case of infection, it is recommended to discontinue treatment with Episalvan. Additional standard treatment may be required (see section 4.5). Wound size The mean wound size treated with Episalvan in clinical studies in split-thickness skin graft donor site wounds was 40.7 cm² (range 8-300 cm²). In the Grade 2a burn wound study, the mean wound size treated with Episalvan was 108 cm² (range 23-395 cm²). Duration of use There is no information available on clinical use of Episalvan for more than 4 weeks. Partial thickness burn wounds Repeated critical assessment of burn depth and healing progression is needed. Wounds that are assessed as unable to heal within an acceptable time frame may need surgical measures (e.g., split-thickness skin grafting) to reduce the risk of hypertrophic scarring. Other wound types There is no clinical experience from use of Episalvan for the treatment of chronic wounds, e.g. diabetic foot ulcers, venous leg ulcers or wounds in patients with epidermolysis bullosa. Birch pollen allergy Episalvan is safe to use for people who are allergic to birch pollen, as these allergens are not present in Episalvan. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Since the systemic exposure of Episalvan following cutaneous application is negligible no interaction with systemic treatments is expected. Interactions with topical products have not been investigated in clinical trials. Other topical products should not be concomitantly used together with Episalvan but rather sequentially or alternatively depending on the clinical need. 4 4.6 Fertility, pregnancy and lactation Pregnancy No studies in pregnant women have been conducted. No effects during pregnancy are anticipated, since systemic exposure to Episalvan is negligible. Episalvan can be used during pregnancy. Breast-feeding No data are available to evaluate whether Episalvan is excreted into human milk. No effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to Episalvan is negligible. Episalvan can be used during breast-feeding, unless the chest area is subject to treatment. Fertility Fertility studies have not been conducted. No effects on human fertility are anticipated, since the systemic exposure is negligible. 4.7 Effects on ability to drive and use machines Episalvan has no influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most frequently observed adverse reactions were wound complication (in 2.9% of patients), pain of skin (2.5%) and pruritus (1.3%). Adverse reactions were administration site reactions only. Wound complication adverse reactions such as wound infection and wound necrosis are complications of healing of partial thickness skin wounds and can be serious. See also section 4.4. Tabulated list of adverse reactions In the following table, adverse reactions are listed by MedDRA system organ class and preferred term. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Table 1: Adverse reactions reported in clinical trials System organ class Common Uncommon Infections and infestations Wound infection Immune system disorders Hypersensitivity Skin and subcutaneous tissue disorders Pain of skin Dermatitis Pruritus Rash pruritic Purpura General disorders and administration site conditions Pain Injury, poisoning and procedural complications Wound complication* * Wound complication comprises different kinds of local complications such as post-procedural complications, wound necrosis, wound secretion, impaired healing, or inflammation of wound. 5 In addition, there is one case report of contact dermatitis reported from a literature in a patient after prolonged use of a topical birch bark extract containing cosmetic product. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Overdosing with Episalvan is unlikely: in patients in which wound sizes >300 cm2 were repeatedly treated with Episalvan, no betulin plasma levels could be detected. No data have been generated to study the effect of accidental ingestion of Episalvan. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Preparation for treatment of wounds and ulcers; ATC code: D03AX13 . Mechanism of action and pharmacodynamic effects The active substance accelerated re-epithelialization in an in vitro wound scratch assay using human primary keratinocytes at the dosage of 1 μg/ml, and in a porcine ex vivo wound healing model at the dosage of 10 µg/ml. The precise mechanism of action of the active substance in wound healing in humans is not known. Clinical efficacy and safety Three Phase III studies were conducted to assess the efficacy and safety of Episalvan in the treatment of partial thickness wounds of the skin: two studies which investigated split-thickness skin graft donor site wounds, which included a total of 219 patients (ITT: N=217), and one further study in 61 patients with Grade 2a burn wounds (ITT: N=57). Patients with deeper burn wounds (Grade 2b) were not included. The 219 patients with split-thickness skin graft donor site wounds had a mean age of 53 years; their donor site mean wound size was 81.5 cm2. In the burn wound study with 61 patients, the mean study wound area was 216 cm2; the total burn injury of these patients was larger and affected 5.8% of the total body surface area. The Phase III studies were blindly evaluated, prospective, intra-individually controlled, randomised, multicentre trials. The target wound area of each patient was divided into two treatment areas of approximately the same size; the treatment allocation to the two halves of the wound (distal vs. proximal) was determined by randomization (in the burn trial, two similar wounds could be used). Episalvan plus wound dressing was applied to half of the wound area, and the same kind of non-adhesive wound dressing alone was applied to the other half as the control in the split-thickness skin graft donor site studies. In the Grade 2a burn wound study an octenidine containing antiseptic wound gel and fatty gauze dressing were used as control. Application was at each wound dressing change every third to fourth day until full wound closure up to 28 days for the split- thickness skin graft trials, and every other day up to 21 days for the Grade 2a burn trial. Photographs of the wound were taken at each visit for the blinded evaluation. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 6 The primary endpoint for the two split-thickness skin graft trials was the intra-individual difference in time to wound closure (at least 95% epithelialisation) based on blinded photo evaluations. Median time to wound healing was 14 days. Wound halves treated with Episalvan healed faster than the wound halves treated with standard of care (mean 1.1 days according to primary endpoints, p<0.0001, two-sided paired t-test). Table 2: Overview of Efficacy Results: Intra-patient difference in time to wound closure Mean intra-patient difference in time to wound closure (95% epithelialisation) Split-thickness skin graft donor site wound studies (pooled) Grade 2a burn wound study N = 217 N=57 Observer-blinded photo assessment (blinded read), mean expert evaluation primary blinded read / very conservative calculation (primary endpoint for STSG studies) -1.1 days (CI: -1.5, -0.7) faster wound closure with Episalvan, p<0.0001a -1.0 days (CI: -1.4, -0.6) faster wound closure with Episalvan, p<0.0001a Intention-to-treat (ITT) data set. ‘Primary’ vs. ‘secondary’ blinded read: In the primary blinded read evaluation a rigorous quality check was implemented to assure blinding of the observers. In consequence a substantial number of photographs were excluded and not presented in the primary blinded read because of apparent gel residues. The secondary blinded read was conducted with all photographs presented to the blinded observers. ’Very conservative calculation’ means that the first observation of wound closure was taken as time of wound closure. Difference in time to wound closure was set to 0 for photo series rated as ‘not evaluable’. If wound closure was not observed in a wound half photo series, it was calculated to have occurred one day after the last photograph in the series. ‘Less conservative calculation’ differs from the ‘very conservative calculation’ in one aspect: If wound closure was not observed in a wound half photo series, it was calculated to have occurred not one day, but approximately 3 days later (the mean time interval between wound dressing changes in the studies). CI: 95% confidence interval; MTWDC: mean time to wound dressing change; N: number of patients in the analysis set; STSG Split-thickness skin graft The primary endpoint for the Grade 2a burn wound trial was the percentage of patients with earlier healing (at least 95% epithelialisation) based on blinded photo evaluations. Median time to wound healing was 7.3 days. Of the patients with a between-treatment difference in wound healing (N=35), the percentage of patients who showed earlier healing (primary endpoint) of their Episalvan treated wound half (85.7% [95% CI: 69.7%, 95.2%]) was higher than those who showed earlier healing of their standard of care control treated wound half (14.3% [95% CI: 4.8%, 30.3%]) (p < 0.0001, binomial test). In follow-up visits at 3 months and 12 months after the day of surgery or of burn injury the treated wound halves were found to be equal in the majority of patients with regard to pigmentation, redness, texture and hair growth of the regenerated epidermis. For a subset of patients blinded photo-evaluation indicated better results for Episalvan treated wound halves compared to standard of care in pigmentation, redness and texture of the former wound areas. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Episalvan in one or more subsets of the paediatric population for the treatment of skin injuries. See section 4.2 for information on paediatric use. 7 5.2 Pharmacokinetic properties Absorption Episalvan gel is administered topically to skin wounds and shows poor absorbtion. Based on data from three clinical studies with a total of 280 patients, application of Episalvan gel to open wounds did not lead to betulin plasma levels higher than natural background-levels originating e.g. from nutritional sources. Since no biologically relevant levels of betulin were found in patients, no further studies related to distribution, biotransformation and elimination were performed. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, local tolerance, and phototoxicity. Repeated dose toxicity and local tolerance have been studied for up to 4 weeks. Toxicity studies of longer duration than 4 weeks have not been performed. The active substance was not genotoxic in in vitro assays. Carcinogenicity and reproductive and developmental toxicity studies have not been performed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sunflower oil, refined. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. For single use only. Once opened, the product should be used immediately and be discarded after use. 6.4 Special precautions for storage Store below 30°C. 6.5 Nature and contents of container White collapsible aluminium tube, interior lacquered with epoxy phenolic coating, and with a sealing compound in the fold. The tubes are closed with a tamper-evident aluminium membrane and fitted with a white polypropylene screw cap. The single-use tube is packed in a cardboard box. Pack size: 1 single-use tube containing 23.4 g gel. 6.6 Special precautions for disposal and other handling No special requirements. 8 7. MARKETING AUTHORISATION HOLDER Amryt GmbH Streiflingsweg 11 75223 Niefern-Öschelbronn Germany tel +49 (0) 7233 9749 - 0 fax +49 (0) 7233 9749 – 210 Email: info.de@amrytpharma.com 8. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1069/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 14 January 2016 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 9 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 10 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Amryt GmbH Streiflingsweg 11 75223 Niefern-Öschelbronn GERMANY B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 11 ANNEX III LABELLING AND PACKAGE LEAFLET 12 A. LABELLING 13 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING OUTER CARTON and TUBE 1. NAME OF THE MEDICINAL PRODUCT Episalvan gel Birch bark extract 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1g gel contains: 100 mg birch bark extract (as dry extract, refined) from Betula pendula/Betula pubescens, corresponding to 72-88 mg betulin. 3. LIST OF EXCIPIENTS Excipient: Sunflower oil. 4. PHARMACEUTICAL FORM AND CONTENTS Gel. 23.4 g 5. METHOD AND ROUTE(S) OF ADMINISTRATION Cutaneous use. Read the package leaflet before use. For single-use only. Discard after use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 14 9. SPECIAL STORAGE CONDITIONS Store below 30°C. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Amryt GmbH Streiflingsweg 11 75223 Niefern-Öschelbronn Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1069/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Episalvan gel (carton only) 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA < PC: {number} SN: {number} NN: {number}> 15 B. PACKAGE LEAFLET 16 Package leaflet: Information for the patient Episalvan gel Birch bark extract This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Episalvan is and what it is used for 2. What you need to know before you use Episalvan 3. How to use Episalvan 4. Possible side effects 5. How to store Episalvan 6. Contents of the pack and other information 1. What Episalvan is and what it is used for Episalvan gel is a herbal medicinal product which contains dry extract from birch bark. It is used in adults for the treatment of skin wounds, resulting for example from grade 2a burn wounds or from surgical skin graft transplantation. There is no experience of the use of Episalvan for the treatment of chronic wounds, e.g. diabetic foot ulcers or venous leg ulcers. 2. What you need to know before you use Episalvan Do not use Episalvan - if you are allergic to birch bark or any of the other ingredients of this medicine (listed in section 6). Episalvan does not contain birch pollen, so it may be used by people with birch pollen allergy. Warnings and precautions Talk to your doctor or nurse before using Episalvan. If you have an infection in the wound additional treatment may be required. Wound infection is a serious complication that can occur during the healing process. Possible signs of a wound infection are that the wound begins to drain yellow or greenish fluid (pus), or that the skin around the wound becomes red, warm, swollen, or increasingly painful. Children and adolescents There is insufficient experience of the use of Episalvan in children and adolescents under 18 years of age, therefore it should not be used in these patients. 17 Other medicines and Episalvan Tell your doctor or nurse if you are using, have recently used or might use any other medicines. No studies have been performed to establish whether Episalvan will interact with other medicines. However, since the amount of Episalvan absorbed into the body is extremely low it is not expected that Episalvan will interact with other medicines. No data are available on possible interaction between Episalvan and other medicines applied to the skin. Do not apply other products to the skin wound area at the same time of applying Episalvan. Pregnancy, breast-feeding and fertility No studies have been done on the effects of Episalvan on pregnant women, but since the absorption of this medicine into the body is extremely low, the risk to the unborn baby is negligible. Episalvan can be used during pregnancy. It is not known whether Episalvan passes into human breast milk, but since the absorption of this medicine into the body is minimal, the risk to the baby is negligible. Episalvan can be used during breast-feeding, unless the chest area is being treated. The effect of Episalvan on fertility has not been studied, but since the absorption of this medicine into the body is extremely low, it is not expected to have an effect on your fertility. Driving and using machines Your ability to drive and use machines will not be affected by this medicine. 3. How to use Episalvan Always use this medicine exactly as your doctor or nurse has told you. Check with your doctor or nurse if you are not sure. Method of administration • If necessary, wounds should be cleansed using a suitable antiseptic solution prior to application of Episalvan • Episalvan should be applied to the wound surface at a thickness of approximately 1 mm and covered by a sterile wound dressing. • Re-apply the gel each time the dressing is changed, until the wound is healed. • Once the single-use tube has been opened, use the gel immediately and discard the tube, even if there’s some left. Duration of use Episalvan should be used until the wound is healed or up to 4 weeks. Your doctor or nurse will tell you for how long you should use the gel. There is no experience from long-term use of Episalvan for more than 4 weeks. If you use more Episalvan than you should Episalvan is applied to the skin and the absorption into the body is minimal. This makes overdose very unlikely, even if applied to large skin areas and for a long period of time. If you forget to use Episalvan Do not use a double dose to make up for a forgotten dose. Apply Episalvan at the next planned change of the wound dressing, continuing with your normal routine. 18 If you stop using Episalvan Episalvan should be used as advised by your doctor or nurse. Do not stop using it without consulting your doctor or nurse. If your wound shows no signs of improvement over time, talk to your doctor or nurse. If you have any further questions on the use of this medicine, ask your doctor or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The most frequently reported side effects are: Common side effects (may affect up to 1 in 10 people): - painful skin - itching - complications in the wound healing process Other side effects include: Uncommon side effects (may affect up to 1 in 100 people): - wound infection - allergic reaction (hypersensitivity) - skin irritation (dermatitis) - itchy rash - purple coloured rash - pain Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Episalvan Keep this medicine out of the sight and reach of children. Store below 30°C. Do not use this medicine after the expiry date which is stated on the carton and tube after ‘EXP’. The expiry date refers to the last day of that month. This product is for single use only and once opened, the product should be used immediately. Discard the tube after first use. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Episalvan contains The active substance is a dry extract from birch bark. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 19 1 g gel contains: 100 mg extract (as dry extract, refined) from birch bark from Betula pendula, Betula pubescens as well as hybrids of both species (equivalent to 0.5-1.0 g birch bark), corresponding to 72-88 mg betulin. Extraction solvent: n-heptane. The other ingredient is refined sunflower oil. What Episalvan looks like and contents of the pack Episalvan is a colourless to slightly yellowish, opalescent gel. Episalvan gel is packed in white collapsible aluminium tubes. The tubes are closed with a tamper-evident aluminium membrane and fitted with a white polypropylene screw cap. The single-use tube is packed in a cardboard box. Pack size:1 tube of 23.4 g gel. Marketing Authorisation Holder and Manufacturer Amryt GmbH Streiflingsweg 11 75223 Niefern-Öschelbronn Germany tel +49 (0) 7233 9749 - 0 fax+49 (0) 7233 9749 – 210 Email: info.de@amrytpharma.com This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you use episalvan', 'Section_Content': 'do not use episalvan - if you are allergic to birch bark or any of the other ingredients of this medicine (listed in section 6). episalvan does not contain birch pollen, so it may be used by people with birch pollen allergy. warnings and precautions talk to your doctor or nurse before using episalvan. if you have an infection in the wound additional treatment may be required. wound infection is a serious complication that can occur during the healing process. possible signs of a wound infection are that the wound begins to drain yellow or greenish fluid (pus), or that the skin around the wound becomes red, warm, swollen, or increasingly painful. children and adolescents there is insufficient experience of the use of episalvan in children and adolescents under 18 years of age, therefore it should not be used in these patients. other medicines and episalvan tell your doctor or nurse if you are using, have recently used or might use any other medicines. no studies have been performed to establish whether episalvan will interact with other medicines. however, since the amount of episalvan absorbed into the body is extremely low it is not expected that episalvan will interact with other medicines. no data are available on possible interaction between episalvan and other medicines applied to the skin. do not apply other products to the skin wound area at the same time of applying episalvan. pregnancy, breast-feeding and fertility no studies have been done on the effects of episalvan on pregnant women, but since the absorption of this medicine into the body is extremely low, the risk to the unborn baby is negligible. episalvan can be used during pregnancy. it is not known whether episalvan passes into human breast milk, but since the absorption of this medicine into the body is minimal, the risk to the baby is negligible. episalvan can be used during breast-feeding, unless the chest area is 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[]}, {'Id': 20, 'BeginOffset': 1847, 'EndOffset': 1856, 'Score': 0.9173964262008667, 'Text': 'episalvan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'breast-feeding', 'Type': 'TREATMENT', 'BeginOffset': 1876, 'EndOffset': 1890}, {'Id': 6, 'BeginOffset': 1903, 'EndOffset': 1913, 'Score': 0.5930151343345642, 'Text': 'chest area', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 21, 'BeginOffset': 1946, 'EndOffset': 1955, 'Score': 0.9167733192443848, 'Text': 'episalvan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2019, 'EndOffset': 2032}, {'Id': 7, 'BeginOffset': 2042, 'EndOffset': 2046, 'Score': 0.6903289556503296, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your fertility', 'Type': 'PROBLEM', 'BeginOffset': 2105, 'EndOffset': 2119}, {'Text': 'machines', 'Type': 'TREATMENT', 'BeginOffset': 2178, 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{'Title': '3. how to use episalvan', 'Section_Content': "always use this medicine exactly as your doctor or nurse has told you. check with your doctor or nurse if you are not sure. method of administration if necessary, wounds should be cleansed using a suitable antiseptic solution prior to application of episalvan episalvan should be applied to the wound surface at a thickness of approximately 1 mm and covered by a sterile wound dressing. re-apply the gel each time the dressing is changed, until the wound is healed. once the single-use tube has been opened, use the gel immediately and discard the tube, even if there's some left. duration of use episalvan should be used until the wound is healed or up to 4 weeks. your doctor or nurse will tell you for how long you should use the gel. there is no experience from long-term use of episalvan for more than 4 weeks. if you use more episalvan than you should episalvan is applied to the skin and the absorption into the body is minimal. this makes overdose very unlikely, even if applied to large skin areas and for a long period of time. if you forget to use episalvan do not use a double dose to make up for a forgotten dose. apply episalvan at the next planned change of the wound dressing, continuing with your normal routine. if you stop using episalvan episalvan should be used as advised by your doctor or nurse. do not stop using it without consulting your doctor or nurse. if your wound shows no signs of improvement over time, talk to your doctor or nurse. if you have any further questions on the use of this medicine, ask your doctor or nurse.", 'Entity_Recognition': [{'Text': 'episalvan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Text': 'method of administration', 'Type': 'TREATMENT', 'BeginOffset': 124, 'EndOffset': 148}, {'Id': 11, 'BeginOffset': 163, 'EndOffset': 169, 'Score': 0.7210688591003418, 'Text': 'wounds', 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the most frequently reported side effects are: common side effects (may affect up to 1 in 10 people): - painful skin - itching - complications in the wound healing process other side effects include: uncommon side effects (may affect up to 1 in 100 people): - wound infection - allergic reaction (hypersensitivity) - skin irritation (dermatitis) - itchy rash - purple coloured rash - pain reporting of side effects if you get any side effects, talk to your doctor or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'episalvan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 3, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9670836329460144, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7197489142417908}]}, {'Id': 4, 'BeginOffset': 121, 'EndOffset': 133, 'Score': 0.9533642530441284, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7761372923851013}]}, {'Text': 'common side effects', 'Type': 'PROBLEM', 'BeginOffset': 139, 'EndOffset': 158}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 177, 'EndOffset': 178}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 182, 'EndOffset': 184}, {'Id': 7, 'BeginOffset': 204, 'EndOffset': 218, 'Score': 0.5161846876144409, 'Text': 'skin - 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{'Title': '5. how to store episalvan', 'Section_Content': "keep this medicine out of the sight and reach of children. store below 30. do not use this medicine after the expiry date which is stated on the carton and tube after 'exp'. the expiry date refers to the last day of that month. this product is for single use only and once opened, the product should be used immediately. discard the tube after first use. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.", 'Entity_Recognition': [{'Text': 'episalvan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 71, 'EndOffset': 74}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 86, 'EndOffset': 99}, {'Text': 'the tube', 'Type': 'TREATMENT', 'BeginOffset': 329, 'EndOffset': 337}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what episalvan contains the active substance is a dry extract from birch bark. 1 g gel contains: 100 mg extract (as dry extract, refined) from birch bark from betula pendula, betula pubescens as well as hybrids of both species (equivalent to 0.5-1.0 g birch bark), corresponding to 72-88 mg betulin. extraction solvent: n-heptane. the other ingredient is refined sunflower oil. what episalvan looks like and contents of the pack episalvan is a colourless to slightly yellowish, opalescent gel. episalvan gel is packed in white collapsible aluminium tubes. the tubes are closed with a tamper-evident aluminium membrane and fitted with a white polypropylene screw cap. the single-use tube is packed in a cardboard box. pack size:1 tube of 23.4 g gel.', 'Entity_Recognition': [{'Text': 'episalvan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 2, 'BeginOffset': 5, 'EndOffset': 14, 'Score': 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3AC9F22A3B04A8DC8C0550DA9CE0C0D0

https://www.ema.europa.eu/documents/product-information/comirnaty-epar-product-information_en.pdf

Comirnaty

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Comirnaty concentrate for dispersion for injection COVID-19 mRNA Vaccine (nucleoside modified) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION This is a multidose vial and must be diluted before use. One vial (0.45 mL) contains 6 doses of 0.3 mL after dilution, see sections 4.2 and 6.6. 1 dose (0.3 mL) contains 30 micrograms of COVID-19 mRNA Vaccine (embedded in lipid nanoparticles). Single-stranded, 5’-capped messenger RNA (mRNA) produced using a cell-free in vitro transcription from the corresponding DNA templates, encoding the viral spike (S) protein of SARS-CoV-2. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for dispersion for injection (sterile concentrate). The vaccine is a white to off-white frozen dispersion (pH: 6.9 - 7.9). 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Comirnaty is indicated for active immunisation to prevent COVID-19 caused by SARS-CoV-2 virus, in individuals 16 years of age and older. The use of this vaccine should be in accordance with official recommendations. 4.2 Posology and method of administration Posology Individuals 16 years of age and older Comirnaty is administered intramuscularly after dilution as a course of 2 doses (0.3 mL each) at least 21 days apart (see sections 4.4 and 5.1). There are no data available on the interchangeability of Comirnaty with other COVID-19 vaccines to complete the vaccination course. Individuals who have received 1 dose of Comirnaty should receive a second dose of Comirnaty to complete the vaccination course. Paediatric population The safety and efficacy of Comirnaty in children and adolescents aged less than 16 years of age have not yet been established. Limited data are available. 2 Elderly population No dosage adjustment is required in elderly individuals ≥ 65 years of age. Method of administration Comirnaty should be administered intramuscularly after dilution (see section 6.6). After dilution, vials of Comirnaty contain six doses of 0.3 mL of vaccine. In order to extract six doses from a single vial, low dead-volume syringes and/or needles should be used. The low dead-volume syringe and needle combination should have a dead volume of no more than 35 microlitres. If standard syringes and needles are used, there may not be sufficient volume to extract a sixth dose from a single vial. Irrespective of the type of syringe and needle: • Each dose must contain 0.3 mL of vaccine. • If the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume. • Do not pool excess vaccine from multiple vials. The preferred site is the deltoid muscle of the upper arm. Do not inject the vaccine intravascularly, subcutaneously or intradermally. The vaccine should not be mixed in the same syringe with any other vaccines or medicinal products. For precautions to be taken before administering the vaccine, see section 4.4. For instructions regarding thawing, handling and disposal of the vaccine, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. General recommendations Hypersensitivity and anaphylaxis Events of anaphylaxis have been reported. Appropriate medical treatment and supervision should always be readily available in case of an anaphylactic reaction following the administration of the vaccine. Close observation for at least 15 minutes is recommended following vaccination. A second dose of the vaccine should not be given to those who have experienced anaphylaxis to the first dose of Comirnaty. Anxiety-related reactions Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress‐related reactions may occur in association with vaccination as a psychogenic response to the needle injection. It is important that precautions are in place to avoid injury from fainting. 3 Concurrent illness Vaccination should be postponed in individuals suffering from acute severe febrile illness or acute infection. The presence of a minor infection and/or low-grade fever should not delay vaccination. Thrombocytopenia and coagulation disorders As with other intramuscular injections, the vaccine should be given with caution in individuals receiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such as haemophilia) because bleeding or bruising may occur following an intramuscular administration in these individuals. Immunocompromised individuals The efficacy, safety and immunogenicity of the vaccine has not been assessed in immunocompromised individuals, including those receiving immunosuppressant therapy. The efficacy of Comirnaty may be lower in immunosuppressed individuals. Duration of protection The duration of protection afforded by the vaccine is unknown as it is still being determined by ongoing clinical trials. Limitations of vaccine effectiveness As with any vaccine, vaccination with Comirnaty may not protect all vaccine recipients. Individuals may not be fully protected until 7 days after their second dose of vaccine. Excipients This vaccine contains less than 1 mmol potassium (39 mg) per dose, that is to say essentially ‘potassium-free’. This vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Concomitant administration of Comirnaty with other vaccines has not been studied. 4.6 Fertility, pregnancy and lactation Pregnancy There is limited experience with use of Comirnaty in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or post-natal development (see section 5.3). Administration of Comirnaty in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and foetus. Breast-feeding It is unknown whether Comirnaty is excreted in human milk. Fertility Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). 4 4.7 Effects on ability to drive and use machines Comirnaty has no or negligible influence on the ability to drive and use machines. However, some of the effects mentioned under section 4.8 may temporarily affect the ability to drive or use machines. 4.8 Undesirable effects Summary of safety profile The safety of Comirnaty was evaluated in participants 16 years of age and older in 2 clinical studies that included 21,744 participants that have received at least one dose of Comirnaty. In Study 2, a total of 21,720 participants 16 years of age or older received at least 1 dose of Comirnaty and a total of 21,728 participants 16 years of age or older received placebo (including 138 and 145 adolescents 16 and 17 years of age in the vaccine and placebo groups, respectively). A total of 20,519 participants 16 years of age or older received 2 doses of Comirnaty. At the time of the analysis of Study 2, a total of 19,067 (9,531 Comirnaty and 9,536 placebo) participants 16 years of age or older were evaluated for safety for at least 2 months after the second dose of Comirnaty. This included a total of 10,727 (5,350 Comirnaty and 5,377 placebo) participants 16 to 55 years of age and a total of 8,340 (4,181 Comirnaty and 4,159 placebo) participants 56 years and older. The most frequent adverse reactions in participants 16 years of age and older were injection site pain (> 80%), fatigue (> 60%), headache (> 50%), myalgia and chills (> 30%), arthralgia (> 20%), pyrexia and injection site swelling (> 10%) and were usually mild or moderate in intensity and resolved within a few days after vaccination. A slightly lower frequency of reactogenicity events was associated with greater age. Tabulated list of adverse reactions from clinical studies Adverse reactions observed during clinical studies are listed below according to the following frequency categories: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000), Not known (cannot be estimated from the available data). Table 1: Adverse reactions from Comirnaty clinical trials System Organ Class Very common (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) Rare (≥ 1/10,000 to < 1/1,000) Not known (cannot be estimated from the available data) Blood and lymphatic system disorders Lymphadenopathy Immune system disorders Anaphylaxis; hypersensitivity Psychiatric disorders Insomnia 5 System Organ Class Very common (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) Rare (≥ 1/10,000 to < 1/1,000) Not known (cannot be estimated from the available data) Nervous system disorders Headache Acute peripheral facial paralysis† Gastrointestinal disorders Nausea Musculoskeletal and connective tissue disorders Arthralgia; myalgia Pain in extremity General disorders and administration site conditions Injection site pain; fatigue; chills; pyrexia*; injection site swelling Injection site redness Malaise; injection site pruritus * A higher frequency of pyrexia was observed after the 2nd dose. † Throughout the safety follow-up period to date, acute peripheral facial paralysis (or palsy) was reported by four participants in the COVID-19 mRNA Vaccine group. Onset was Day 37 after Dose 1 (participant did not receive Dose 2) and Days 3, 9, and 48 after Dose 2. No cases of acute peripheral facial paralysis (or palsy) were reported in the placebo group. The safety profile in 545 subjects receiving Comirnaty, that were seropositive for SARS-CoV-2 at baseline, was similar to that seen in the general population. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V and include batch/Lot number if available. 4.9 Overdose Overdose data is available from 52 study participants included in the clinical trial that due to an error in dilution received 58 micrograms of Comirnaty. The vaccine recipients did not report an increase in reactogenicity or adverse reactions. In the event of overdose, monitoring of vital functions and possible symptomatic treatment is recommended. 6 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: vaccines, other viral vaccines, ATC code: J07BX03 Mechanism of action The nucleoside-modified messenger RNA in Comirnaty is formulated in lipid nanoparticles, which enable delivery of the non replicating RNA into host cells to direct transient expression of the SARS-CoV-2 S antigen. The mRNA codes for membrane-anchored, full-length S with two point mutations within the central helix. Mutation of these two amino acids to proline locks S in an antigenically preferred prefusion conformation. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike (S) antigen, which may contribute to protection against COVID-19. Efficacy Study 2 is a multicentre, multinational, Phase 1/2/3 randomised, placebo-controlled, observer-blind dose-finding, vaccine candidate selection and efficacy study in participants 12 years of age and older. Randomisation was stratified by age: 12 through 15 years of age, 16 through 55 years of age, or 56 years of age and older, with a minimum of 40% of participants in the ≥ 56-year stratum. The study excluded participants who were immunocompromised and those who had previous clinical or microbiological diagnosis of COVID-19. Participants with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 6 weeks before enrolment, were included as were participants with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV). At the time of the analysis of Study 2, information presented is based on participants 16 years and older. Efficacy in participants 16 years of age and older In the Phase 2/3 portion, approximately 44,000 participants were randomised equally and were to receive 2 doses of COVID-19 mRNA Vaccine or placebo separated by 21 days. The efficacy analyses included participants that received their second vaccination within 19 to 42 days after their first vaccination. Participants are planned to be followed for up to 24 months after Dose 2, for assessments of safety and efficacy against COVID-19. In the clinical study, participants were required to observe a minimum interval of 14 days before and after administration of an influenza vaccine in order to receive either placebo or COVID-19 mRNA Vaccine. In the clinical study, participants were required to observe a minimum interval of 60 days before or after receipt of blood/plasma products or immunoglobulins within through conclusion of the study in order to receive either placebo or COVID-19 mRNA Vaccine. The population for the analysis of the primary efficacy endpoint included, 36,621 participants 12 years of age and older (18,242 in the COVID-19 mRNA Vaccine group and 18,379 in the placebo group) who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose. In addition, 134 participants were between the ages of 16 to 17 years of age (66 in the COVID-19 mRNA Vaccine group and 68 in the placebo group) and 1616 participants 75 years of age and older (804 in the COVID-19 mRNA Vaccine group and 812 in the placebo group). Efficacy against COVID-19 At the time of the primary efficacy analysis, participants had been followed for symptomatic COVID-19 for in total 2,214 person-years for the COVID-19 mRNA Vaccine and in total 2,222 person-years in the placebo group. There were no meaningful clinical differences in overall vaccine efficacy in participants who were at risk of severe COVID-19 including those with 1 or more comorbidities that increase the risk of severe 7 COVID-19 (e.g. asthma, body mass index (BMI) ≥ 30 kg/m2, chronic pulmonary disease, diabetes mellitus, hypertension). The vaccine efficacy information is presented in Table 2. Table 2: Vaccine efficacy – First COVID-19 occurrence from 7 days after Dose 2, by age subgroup – participants without evidence of infection prior to 7 days after Dose 2 – evaluable efficacy (7 days) population First COVID-19 occurrence from 7 days after Dose 2 in participants without evidence of prior SARS-CoV-2 infection* Subgroup COVID-19 mRNA Vaccine Na = 18,198 Cases n1b Surveillance timec (n2d) Placebo Na = 18,325 Cases n1b Surveillance timec (n2d) Vaccine efficacy % (95% CI)f All subjectse 8 2.214 (17,411) 162 2.222 (17,511) 95.0 (90.0, 97.9) 16 to 64 years 7 1.706 (13,549) 143 1.710 (13,618) 95.1 (89.6, 98.1) 65 years and older 1 0.508 (3848) 19 0.511 (3880) 94.7 (66.7, 99.9) 65 to 74 years 1 0.406 (3074) 14 0.406 (3095) 92.9 (53.1, 99.8) 75 years and older 0 0.102 (774) 5 0.106 (785) 100.0 (-13.1, 100.0) Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 [*Case definition: (at least 1 of) fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhoea or vomiting.] * Participants who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by nucleic acid amplification tests (NAAT) [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis. a. N = number of participants in the specified group. b. n1 = Number of participants meeting the endpoint definition. c. Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period. d. n2 = Number of subjects at risk for the endpoint. e. No confirmed cases were identified in participants 12 to 15 years of age. f. Confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time. CI not adjusted for multiplicity. In the second primary analysis, compared to placebo, efficacy of COVID-19 mRNA Vaccine in participants from first COVID-19 occurrence from 7 days after Dose 2 compared to participants with or without evidence of prior infection with SARS-CoV-2 was 94.6% (95% credible interval of 89.9% to 97.3%) in participants 16 years of age and older. Additionally, subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across genders, ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19. 8 Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Comirnaty in the paediatric population in prevention of COVID-19 (see section 4.2 for information on paediatric use). This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary. 5.2 Pharmacokinetic properties Not applicable. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dose toxicity and reproductive and developmental toxicity. General toxicity Rats intramuscularly administered Comirnaty (receiving 3 full human doses once weekly, generating relatively higher levels in rats due to body weight differences) demonstrated some injection site oedema and erythema and increases in white blood cells (including basophils and eosinophils) consistent with an inflammatory response as well as vacuolation of portal hepatocytes without evidence of liver injury. All effects were reversible. Genotoxicity/Carcinogenicity Neither genotoxicity nor carcinogenicity studies were performed. The components of the vaccine (lipids and mRNA) are not expected to have genotoxic potential. Reproductive toxicity Reproductive and developmental toxicity were investigated in rats in a combined fertility and developmental toxicity study where female rats were intramuscularly administered Comirnaty prior to mating and during gestation (receiving 4 full human doses that generate relatively higher levels in rat due to body weight differences, spanning between pre-mating day 21 and gestational day 20). SARS-CoV-2 neutralizing antibody responses were present in maternal animals from prior to mating to the end of the study on postnatal day 21 as well as in foetuses and offspring. There were no vaccine-related effects on female fertility, pregnancy, or embryo-foetal or offspring development. No Comirnaty data are available on vaccine placental transfer or excretion in milk. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315) 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159) 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) Cholesterol Potassium chloride Potassium dihydrogen phosphate Sodium chloride 9 Disodium phosphate dihydrate Sucrose Water for injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial 6 months at -90 °C to -60 °C. Once removed from the freezer, the unopened vaccine can be stored for up to 5 days at 2 °C to 8 °C, and up to 2 hours at temperatures up to 30 °C, prior to use. Once thawed, the vaccine should not be re-frozen. Closed-lid vial trays containing 195 vials removed from frozen storage (< -60 °C) may be at room temperature (< 25 °C) for up to 5 minutes for transfer between ultra-low-temperature environments. After vial trays are returned to frozen storage following room temperature exposure, they must remain in frozen storage for at least 2 hours before they can be removed again. Diluted medicinal product Chemical and physical in-use stability has been demonstrated for 6 hours at 2 ºC to 30 ºC after dilution in sodium chloride 9 mg/mL (0.9%) solution for injection. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. 6.4 Special precautions for storage Store in a freezer at -90 °C to -60 °C. Store in the original package in order to protect from light. During storage, minimise exposure to room light, and avoid exposure to direct sunlight and ultraviolet light. Thawed vials can be handled in room light conditions. When you are ready to thaw or use the vaccine • Open-lid vial trays, or vial trays containing less than 195 vials removed from frozen storage (< -60 °C) may be at room temperature (< 25 °C) for up to 3 minutes to remove vials or for transfer between ultra-low-temperature environments. • Once a vial is removed from the vial tray, it should be thawed for use. • After vial trays are returned to frozen storage following room temperature exposure, they must remain in frozen storage for at least 2 hours before they can be removed again. For storage conditions after thawing and dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 2 mL clear multidose vial (type I glass) with a stopper (synthetic bromobutyl rubber) and a flip-off plastic cap with aluminium seal. Each vial contains 6 doses, see section 6.6. Pack size: 195 vials 10 6.6 Special precautions for disposal and other handling Handling instructions Comirnaty should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared dispersion. THAWING PRIOR TO DILUTION • The multidose vial is stored frozen and must be thawed prior to dilution. Frozen vials should be transferred to an environment of 2 °C to 8 °C to thaw; a 195 vial pack may take 3 hours to thaw. Alternatively, frozen vials may also be thawed for 30 minutes at temperatures up to 30 °C for immediate use. • Allow the thawed vial to come to room temperature and gently invert it 10 times prior to dilution. Do not shake. • Prior to dilution, the thawed dispersion may contain white to off-white opaque amorphous particles. DILUTION • The thawed vaccine must be diluted in its original vial with 1.8 mL sodium chloride 9 mg/mL (0.9%) solution for injection, using a 21 gauge or narrower needle and aseptic techniques. No more than 2 hours at room temperature (up to 30 °C) 1.8 mL of 0.9% sodium chloride injection 11 • Equalise vial pressure before removing the needle from the vial stopper by withdrawing 1.8 mL air into the empty diluent syringe. • Gently invert the diluted dispersion 10 times. Do not shake. • The diluted vaccine should present as an off-white dispersion with no particulates visible. Discard the diluted vaccine if particulates or discolouration are present. Pull back plunger to 1.8 mL to remove air from vial Gently x 10 12 • The diluted vials should be marked with the appropriate date and time. • Do not freeze or shake the diluted dispersion. If refrigerated, allow the diluted dispersion to come to room temperature prior to use. PREPARATION OF INDIVIDUAL 0.3 mL DOSES OF COMIRNATY • After dilution, the vial contains 2.25 mL from which 6 doses of 0.3 mL can be extracted. • Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab. • Withdraw 0.3 mL of Comirnaty. Low dead-volume syringes and/or needles should be used in order to extract 6 doses from a single vial. The low dead-volume syringe and needle combination should have a dead volume of no more than 35 microlitres. If standard syringes and needles are used, there may not be sufficient volume to extract a sixth dose from a single vial. • Each dose must contain 0.3 mL of vaccine. • If the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume. • Discard any unused vaccine within 6 hours after dilution. Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Record appropriate date and time. Use within 6 hours after dilution 0.3 mL diluted vaccine 13 7. MARKETING AUTHORISATION HOLDER BioNTech Manufacturing GmbH An der Goldgrube 12 55131 Mainz Germany Phone: +49 6131 90840 Fax: +49 6131 9084390 info@biontech.de 8. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1528 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 21 December 2020 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 14 http://www.ema.europa.eu/ ANNEX II A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION 15 A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers of the biological active substance(s) BioNTech Manufacturing GmbH An der Goldgrube 12 55131 Mainz Germany Rentschler Biopharma SE Erwin-Rentschler-Strasse 21 88471 Laupheim Germany Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC 1 Burtt Road Andover, MA 01810 USA Name and address of the manufacturers responsible for batch release BioNTech Manufacturing GmbH Kupferbergterrasse 17 - 19 55116 Mainz Germany Pfizer Manufacturing Belgium NV Rijksweg 12 2870 Puurs Belgium The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. In view of the declared Public Health Emergency of International Concern and in order to ensure early supply this medicinal product is subject to a time-limited exemption allowing reliance on batch control testing conducted in the registered site(s) that are located in a third country. This exemption ceases to be valid on 31 August 2021. Implementation of EU based batch control arrangements, including the necessary variations to the terms of the marketing authorisation, has to be completed by 31 August 2021 at the latest, in line with the agreed plan for this transfer of testing. Progress reports have to be submitted on 31 March 2021 and included in the annual renewal application. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. • Official batch release In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be undertaken by a state laboratory or a laboratory designated for that purpose. 16 C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION This being a conditional marketing authorisation and pursuant to Article 14-a of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: Description Due date In order to complete the characterisation of the active substance and finished product, the MAH should provide additional data. July 2021. Interim reports: 31 March 2021 In order to ensure consistent product quality, the MAH should provide additional information to enhance the control strategy, including the active substance and finished product specifications. July 2021. Interim reports: March 2021 In order to confirm the consistency of the finished product manufacturing process, the MAH should provide additional validation data. March 2021 In order to confirm the purity profile and ensure comprehensive quality control and batch-to-batch consistency throughout the lifecycle of the finished product, the MAH should provide additional information about the synthetic process and control strategy for the excipient ALC-0315. July 2021. Interim reports: January 2021, April 2021 In order to confirm the purity profile and ensure comprehensive quality control and batch-to-batch consistency throughout the lifecycle of the finished product, the MAH should provide additional information about the synthetic process and control strategy for the excipient ALC-0159. July 2021. Interim reports: January 2021, April 2021 17 Description Due date In order to confirm the efficacy and safety of Comirnaty, the MAH should submit the final Clinical Study Report for the randomized, placebo-controlled, observer-blind study C4591001. December 2023 18 ANNEX III LABELLING AND PACKAGE LEAFLET 19 A. LABELLING 20 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON BOX LABEL 1. NAME OF THE MEDICINAL PRODUCT COMIRNATY concentrate for dispersion for injection COVID-19 mRNA Vaccine (nucleoside modified) 2. STATEMENT OF ACTIVE SUBSTANCE(S) After dilution each vial contains 6 doses of 0.3 mL. 3. LIST OF EXCIPIENTS Excipients: ALC-0315, ALC-0159, DSPC, cholesterol, potassium chloride, potassium dihydrogen phosphate, sodium chloride, disodium phosphate dihydrate, sucrose, water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for dispersion for injection 195 multidose vials 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intramuscular use after dilution. Read the package leaflet before use. Scan QR code for more information. Dilute before use: Dilute each vial with 1.8 mL sodium chloride 9 mg/mL (0.9%) solution for injection. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 21 9. SPECIAL STORAGE CONDITIONS Storage: Prior to dilution, store at -90 °C to -60 °C in the original package in order to protect from light. After dilution, store the vaccine at 2 °C to 30 °C and use within 6 hours. Discard any unused vaccine. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER BioNTech Manufacturing GmbH An der Goldgrube 12 55131 Mainz, Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1528 13. BATCH NUMBER LOT 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 22 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION COMIRNATY sterile concentrate COVID-19 mRNA Vaccine IM 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER LOT 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6 doses after dilution 6. OTHER Discard date/time: 23 B. PACKAGE LEAFLET 24 Package leaflet: Information for the user Comirnaty concentrate for dispersion for injection COVID-19 mRNA Vaccine (nucleoside modified) This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you receive this vaccine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, pharmacist or nurse. • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Comirnaty is and what it is used for 2. What you need to know before you receive Comirnaty 3. How Comirnaty is given 4. Possible side effects 5. How to store Comirnaty 6. Contents of the pack and other information 1. What Comirnaty is and what it is used for Comirnaty is a vaccine used for preventing COVID-19 caused by SARS-CoV-2 virus. Comirnaty is given to adults and adolescents from 16 years of age and older. The vaccine causes the immune system (the body’s natural defences) to produce antibodies and blood cells that work against the virus, so giving protection against COVID-19. As Comirnaty does not contain the virus to produce immunity, it cannot give you COVID-19. 2. What you need to know before you receive Comirnaty Comirnaty should not be given • if you are allergic to the active substance or any of the other ingredients of this medicine (listed in section 6) Warnings and precautions Talk to your doctor, pharmacist or nurse before you are given the vaccine if: • you have ever had a severe allergic reaction or breathing problems after any other vaccine injection or after you were given Comirnaty in the past. • you have ever fainted following any needle injection. • you have a severe illness or infection with high fever. However, you can have your vaccination if you have a mild fever or upper airway infection like a cold. • you have a bleeding problem, you bruise easily or you use a medicine to prevent blood-clots. • you have a weakened immune system, because of a disease such as HIV infection or a medicine such as corticosteroid that affects your immune system As with any vaccine, the 2-dose vaccination course of Comirnaty may not fully protect all those who receive it and it is not known how long you will be protected. 25 Children and adolescents Comirnaty is not recommended for children aged under 16 years. Other medicines and Comirnaty Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines or have recently received any other vaccine. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before you receive this vaccine. Driving and using machines Some of the effects of vaccination mentioned in section 4 (Possible side effects) may temporarily affect your ability to drive or use machines. Wait until these effects have worn off before you drive or use machines. Comirnaty contains potassium and sodium This vaccine contains less than 1 mmol potassium (39 mg) per dose, that is to say essentially ‘potassium-free’. This vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. 3. How Comirnaty is given Comirnaty is given after dilution as an injection of 0.3 mL into a muscle of your upper arm. You will receive 2 injections, given at least 21 days apart. After the first dose of Comirnaty, you should receive a second dose of the same vaccine after 21 days to complete the vaccination course. If you have any further questions on the use of Comirnaty, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all vaccines, Comirnaty can cause side effects, although not everybody gets them. Very common side effects: may affect more than 1 in 10 people • injection site: pain, swelling • tiredness • headache • muscle pain • joint pain • chills, fever Common side effects: may affect up to 1 in 10 people • injection site redness • nausea 26 Uncommon side effects: may affect up to 1 in 100 people • enlarged lymph nodes • feeling unwell • pain in limb • insomnia • injection site itching Rare side effects: may affect up to 1 in 1,000 people • temporary one sided facial drooping Not known (cannot be estimated from the available data) • severe allergic reaction Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V and include batch/Lot number if available. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Comirnaty Keep this medicine out of the sight and reach of children. The following information about storage, expiry and use and handling is intended for healthcare professionals. Do not use this medicine after the expiry date which is stated on the carton and label after EXP. The expiry date refers to the last day of that month. Store in freezer at -90 °C to -60 °C. Store in the original package in order to protect from light. After thawing, the vaccine should be diluted and used immediately. However, in-use stability data have demonstrated that once removed from freezer, the undiluted vaccine can be stored for up to 5 days at 2 °C to 8 °C, or up to 2 hours at temperatures up to 30 °C, prior to use. After dilution, store the vaccine at 2 °C to 30 °C and use within 6 hours. Discard any unused vaccine. Once removed from the freezer and diluted, the vials should be marked with the new discard date and time. Once thawed, the vaccine cannot be re-frozen. Do not use this vaccine if you notice particulates in the dilution or discolouration. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 27 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 6. Contents of the pack and other information What Comirnaty contains • The active substance is COVID-19 mRNA Vaccine. After dilution, the vial contains 6 doses of 0.3 mL with 30 micrograms mRNA each. • The other ingredients are: − ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315) − 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159) − 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) − cholesterol − potassium chloride − potassium dihydrogen phosphate − sodium chloride − disodium phosphate dihydrate − sucrose − water for injections What Comirnaty looks like and contents of the pack The vaccine is a white to off-white dispersion (pH: 6.9 - 7.9) provided in a multidose vial of 6 doses in a 2 mL clear vial (type I glass), with a rubber stopper and a flip-off plastic cap with aluminium seal. Pack size: 195 vials Marketing Authorisation Holder BioNTech Manufacturing GmbH An der Goldgrube 12 55131 Mainz Germany Phone: +49 6131 90840 Fax: +49 6131 9084390 info@biontech.de Manufacturers BioNTech Manufacturing GmbH Kupferbergterrasse 17 - 19 55116 Mainz Germany Pfizer Manufacturing Belgium NV Rijksweg 12 2870 Puurs Belgium For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Luxembourg/Luxemburg Pfizer S.A./N.V. Tél/Tel: +32 (0)2 554 62 11 Lietuva Pfizer Luxembourg SARL filialas Lietuvoje Tel. +370 52 51 4000 България Пфайзер Люксембург САРЛ, Клон България Teл: +359 2 970 4333 Magyarország Pfizer Kft Tel: +36 1 488 3700 28 Česká republika Pfizer, spol. s r.o. Tel: +420 283 004 111 Malta Vivian Corporation Ltd. Tel: +35621 344610 Danmark Pfizer ApS Tlf: +45 44 201 100 Norge Pfizer AS Tlf: +47 67 526 100 Deutschland BioNTech Manufacturing GmbH Tel: +49 6131 90840 Nederland Pfizer BV Tel: +31 (0)10 406 43 01 Eesti Pfizer Luxembourg SARL Eesti filiaal Tel: +372 666 7500 Österreich Pfizer Corporation Austria Ges.m.b.H Tel: +43 (0)1 521 15-0 Ελλάδα Pfizer Ελλάς A.E. Τηλ.: +30 210 6785 800 Polska Pfizer Polska Sp. z o.o. Tel.: +48 22 335 61 00 España Pfizer, S.L. Télf:+34914909900 Portugal Pfizer Biofarmacêutica, Sociedade Unipessoal Lda Tel: +351 21 423 5500 France Pfizer Tél +33 1 58 07 34 40 România Pfizer Romania S.R.L Tel: +40 (0) 21 207 28 00 Hrvatska Pfizer Croatia d.o.o. Tel: +385 1 3908 777 Slovenija Pfizer Luxembourg SARL Pfizer, podružnica za svetovanje s področja farmacevtske dejavnosti, Ljubljana Tel.: +386 (0) 1 52 11 400 Ireland Pfizer Healthcare Ireland Tel: 1800 633 363 (toll free) +44 (0)1304 616161 Slovenská republika Pfizer Luxembourg SARL, organizačná zložka Tel: +421 2 3355 5500 Ísland Icepharma hf Simi: +354 540 8000 Suomi/Finland Pfizer Oy Puh/Tel: +358 (0)9 430 040 Italia Pfizer S.r.l. Tel: +39 06 33 18 21 Sverige Pfizer AB Tel: +46 (0)8 550 520 00 Κύπρος Pfizer Ελλάς Α.Ε. (Cyprus Branch) Tηλ: +357 22 817690 United Kingdom (Northern Ireland) Pfizer Limited Tel: +44 (0) 1304 616161 Latvija Pfizer Luxembourg SARL filiāle Latvijā Tel.: +371 670 35 775 29 This leaflet was last revised in {MM/YYYY} This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine. The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary. Scan the code with a mobile device to get the package leaflet in different languages. URL: www.comirnatyglobal.com Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. This package leaflet is available in all EU/EEA languages on the European Medicines Agency website. ------------------------------------------------------------------------------------------------------------------------ The following information is intended for healthcare professionals only: Administer Comirnaty intramuscularly after dilution as a course of 2 doses (0.3 mL each) at least 21 days apart. Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Handling instructions Comirnaty should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared dispersion. THAWING PRIOR TO DILUTION • The multidose vial is stored frozen and must be thawed prior to dilution. Frozen vials should be transferred to an environment of 2 °C to 8 °C to thaw; a 195 vial pack may take 3 hours to thaw. Alternatively, frozen vials may also be thawed for 30 minutes at temperatures up to 30 °C for immediate use. • Allow the thawed vial to come to room temperature and gently invert it 10 times prior to dilution. Do not shake. • Prior to dilution, the thawed dispersion may contain white to off-white opaque amorphous particles. No more than 2 hours at room temperature (up to 30 °C) 30 http://www.comirnatyglobal.com/ DILUTION • The thawed vaccine must be diluted in its original vial with 1.8 mL sodium chloride 9 mg/mL (0.9%) solution for injection, using a 21 gauge or narrower needle and aseptic techniques. • Equalise vial pressure before removing the needle from the vial stopper by withdrawing 1.8 mL air into the empty diluent syringe. 1.8 mL of 0.9% sodium chloride injection Pull back plunger to 1.8 mL to remove air from vial 31 • Gently invert the diluted dispersion 10 times. Do not shake. • The diluted vaccine should present as an off-white dispersion with no particulates visible. Discard the diluted vaccine if particulates or discolouration are present. • The diluted vials should be marked with the appropriate date and time. • Do not freeze or shake the diluted dispersion. If refrigerated, allow the diluted dispersion to come to room temperature prior to use. Gently x 10 Record appropriate date and time. Use within 6 hours after dilution 32 PREPARATION OF INDIVIDUAL 0.3 mL DOSES OF COMIRNATY • After dilution, the vial contains 2.25 mL from which 6 doses of 0.3 mL can be extracted. • Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab. • Withdraw 0.3 mL of Comirnaty. Low dead-volume syringes and/or needles should be used in order to extract 6 doses from a single vial. The low dead-volume syringe and needle combination should have a dead volume of no more than 35 microlitres. If standard syringes and needles are used, there may not be sufficient volume to extract a sixth dose from a single vial. • Each dose must contain 0.3 mL of vaccine. • If the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume. • Discard any unused vaccine within 6 hours after dilution. Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 0.3 mL diluted vaccine 33 SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how comirnaty is given', 'Section_Content': 'comirnaty is given after dilution as an injection of 0.3 ml into a muscle of your upper arm. you will receive 2 injections, given at least 21 days apart. after the first dose of comirnaty, you should receive a second dose of the same vaccine after 21 days to complete the vaccination course. if you have any further questions on the use of comirnaty, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'comirnaty', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 6, 'BeginOffset': 40, 'EndOffset': 49, 'Score': 0.43031203746795654, 'Text': 'injection', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Text': '0.3', 'Type': 'NUMBER', 'BeginOffset': 53, 'EndOffset': 56}, {'Id': 0, 'BeginOffset': 67, 'EndOffset': 73, 'Score': 0.6958130598068237, 'Text': 'muscle', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 2, 'BeginOffset': 88, 'EndOffset': 91, 'Score': 0.9613873958587646, 'Text': 'arm', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '2 injections', 'Type': 'TREATMENT', 'BeginOffset': 110, 'EndOffset': 122}, {'Text': '21', 'Type': 'NUMBER', 'BeginOffset': 139, 'EndOffset': 141}, {'Text': 'the same vaccine', 'Type': 'TREATMENT', 'BeginOffset': 225, 'EndOffset': 241}, {'Id': 10, 'BeginOffset': 242, 'EndOffset': 255, 'Score': 0.8897777795791626, 'Text': 'after 21 days', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.6497992873191833, 'RelationshipScore': 0.627871036529541, 'RelationshipType': 'OVERLAP', 'Id': 9, 'BeginOffset': 272, 'EndOffset': 283, 'Text': 'vaccination', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': '21', 'Type': 'NUMBER', 'BeginOffset': 248, 'EndOffset': 250}, {'Text': 'the vaccination course', 'Type': 'TREATMENT', 'BeginOffset': 268, 'EndOffset': 290}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all vaccines, comirnaty can cause side effects, although not everybody gets them. very common side effects: may affect more than 1 in 10 people injection site: pain, swelling tiredness headache muscle pain joint pain chills, fever common side effects: may affect up to 1 in 10 people injection site redness nausea 26 uncommon side effects: may affect up to 1 in 100 people enlarged lymph nodes feeling unwell pain in limb insomnia injection site itching rare side effects: may affect up to 1 in 1,000 people temporary one sided facial drooping not known (cannot be estimated from the available data) severe allergic reaction reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v and include batch/lot number if available. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'comirnaty', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all vaccines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 17}, {'Id': 5, 'BeginOffset': 39, 'EndOffset': 51, 'Score': 0.966289758682251, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6903327107429504}]}, {'Id': 6, 'BeginOffset': 99, 'EndOffset': 111, 'Score': 0.8990243077278137, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8150768280029297}]}, {'Id': 7, 'BeginOffset': 117, 'EndOffset': 123, 'Score': 0.29682573676109314, 'Text': 'affect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 134, 'EndOffset': 135}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 139, 'EndOffset': 141}, {'Id': 8, 'BeginOffset': 165, 'EndOffset': 169, 'Score': 0.9944135546684265, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8791685700416565}]}, {'Text': 'swelling tiredness', 'Type': 'PROBLEM', 'BeginOffset': 171, 'EndOffset': 189}, {'Id': 11, 'BeginOffset': 190, 'EndOffset': 198, 'Score': 0.9962496161460876, 'Text': 'headache', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9776116609573364}]}, {'Id': 12, 'BeginOffset': 199, 'EndOffset': 210, 'Score': 0.7986720204353333, 'Text': 'muscle pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9716535806655884}]}, {'Id': 13, 'BeginOffset': 211, 'EndOffset': 221, 'Score': 0.7843196988105774, 'Text': 'joint pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.963301956653595}]}, {'Id': 14, 'BeginOffset': 222, 'EndOffset': 228, 'Score': 0.9981817007064819, 'Text': 'chills', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9837102890014648}]}, {'Text': 'fever common side effects', 'Type': 'PROBLEM', 'BeginOffset': 230, 'EndOffset': 255}, {'Id': 17, 'BeginOffset': 261, 'EndOffset': 267, 'Score': 0.22846530377864838, 'Text': 'affect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 274, 'EndOffset': 275}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 279, 'EndOffset': 281}, {'Text': 'redness nausea', 'Type': 'PROBLEM', 'BeginOffset': 304, 'EndOffset': 318}, {'Text': '26', 'Type': 'NUMBER', 'BeginOffset': 319, 'EndOffset': 321}, {'Text': 'uncommon side effects', 'Type': 'PROBLEM', 'BeginOffset': 322, 'EndOffset': 343}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 362, 'EndOffset': 363}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 367, 'EndOffset': 370}, {'Id': 21, 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{'Title': '5. how to store comirnaty', 'Section_Content': 'keep this medicine out of the sight and reach of children. the following information about storage, expiry and use and handling is intended for healthcare professionals. do not use this medicine after the expiry date which is stated on the carton and label after exp. the expiry date refers to the last day of that month. store in freezer at -90 to -60 . store in the original package in order to protect from light. after thawing, the vaccine should be diluted and used immediately. however, in-use stability data have demonstrated that once removed from freezer, the undiluted vaccine can be stored for up to 5 days at 2 to 8 , or up to 2 hours at temperatures up to 30 , prior to use. after dilution, store the vaccine at 2 to 30 and use within 6 hours. discard any unused vaccine. once removed from the freezer and diluted, the vials should be marked with the new discard date and time. once thawed, the vaccine cannot be re-frozen. do not use this vaccine if you notice particulates in the dilution or discolouration. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'comirnaty', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 181, 'EndOffset': 194}, {'Text': '-90', 'Type': 'NUMBER', 'BeginOffset': 342, 'EndOffset': 345}, {'Text': '-60', 'Type': 'NUMBER', 'BeginOffset': 349, 'EndOffset': 352}, {'Text': 'the vaccine', 'Type': 'TREATMENT', 'BeginOffset': 432, 'EndOffset': 443}, {'Id': 7, 'BeginOffset': 471, 'EndOffset': 482, 'Score': 0.999997615814209, 'Text': 'immediately', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.4428710639476776, 'RelationshipScore': 0.6168684959411621, 'RelationshipType': 'OVERLAP', 'Id': 0, 'BeginOffset': 436, 'EndOffset': 443, 'Text': 'vaccine', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'the undiluted vaccine', 'Type': 'TREATMENT', 'BeginOffset': 565, 'EndOffset': 586}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 611, 'EndOffset': 612}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 621, 'EndOffset': 622}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 626, 'EndOffset': 627}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 639, 'EndOffset': 640}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 669, 'EndOffset': 671}, {'Text': 'dilution', 'Type': 'TREATMENT', 'BeginOffset': 694, 'EndOffset': 702}, {'Text': 'the vaccine', 'Type': 'TREATMENT', 'BeginOffset': 710, 'EndOffset': 721}, {'Id': 10, 'BeginOffset': 725, 'EndOffset': 726, 'Score': 0.6032617688179016, 'Text': '2', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.5172812342643738, 'RelationshipScore': 0.9220974445343018, 'RelationshipType': 'OVERLAP', 'Id': 2, 'BeginOffset': 714, 'EndOffset': 721, 'Text': 'vaccine', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 730, 'EndOffset': 732}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 748, 'EndOffset': 749}, {'Text': 'any unused vaccine', 'Type': 'TREATMENT', 'BeginOffset': 765, 'EndOffset': 783}, {'Text': 'the vials', 'Type': 'TREATMENT', 'BeginOffset': 828, 'EndOffset': 837}, {'Text': 'the vaccine', 'Type': 'TREATMENT', 'BeginOffset': 904, 'EndOffset': 915}, {'Text': 'this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 948, 'EndOffset': 960}, {'Text': 'discolouration', 'Type': 'PROBLEM', 'BeginOffset': 1007, 'EndOffset': 1021}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what comirnaty contains the active substance is covid-19 mrna vaccine. after dilution, the vial contains 6 doses of 0.3 ml with 30 micrograms mrna each. the other ingredients are: − ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (alc-0315) − 2-[(polyethylene glycol)-2000]-n,n-ditetradecylacetamide (alc-0159) − 1,2-distearoyl-sn-glycero-3-phosphocholine (dspc) − cholesterol − potassium chloride − potassium dihydrogen phosphate − sodium chloride − disodium phosphate dihydrate − sucrose − water for injections what comirnaty looks like and contents of the pack the vaccine is a white to off-white dispersion (ph: 6.9 - 7.9) provided in a multidose vial of 6 doses in a 2 ml clear vial (type i glass), with a rubber stopper and a flip-off plastic cap with aluminium seal. pack size: 195 vials', 'Entity_Recognition': [{'Text': 'comirnaty', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, 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D6C195BCFFB90ECB7E0A4CC0B9EA813E

https://www.ema.europa.eu/documents/product-information/rivastigmine-teva-epar-product-information_en.pdf

Rivastigmine Teva

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 Me dic ina l p rod uc t n o l on ge r a uth ori se d 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 1.5 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule White cap imprinted with “R” & white body imprinted with “1.5” 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s disease. 4.2 Posology and method of administration Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient. Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole. Initial dose: 1.5 mg twice a day. Dose titration The starting dose is 1.5 mg twice a day. If the dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level. If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued. 2 Me dic ina l p rod uc t n o l on ge r a uth ori se d Maintenance dose The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present. Individual response to rivastigmine cannot be predicted. However a greater treatment effect was seen in Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson’s disease patients with visual hallucinations (see section 5.1). Treatment effect has not been studied in placebo-controlled trials beyond 6 months. Re-initiation of therapy: If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above. Renal and hepatic impairment: No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment, However, due to increased exposure in these populations dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.4 and 5.2). Patients with severe hepatic impairment have not been studied (see section 4.4). Children: Rivastigmine is not recommended for use in children. 4.3 Contraindications The use of this medicinal product is contraindicated in patients with - hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation, 4.4 Special warnings and precautions for use The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting). Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8). Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occur particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse reactions occur more commonly in women. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with serious outcomes. 3 Me dic ina l p rod uc t n o l on ge r a uth ori se d Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored. In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine. Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8). Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions. Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases. The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended. Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7 % on rivastigmine vs 0 % on placebo). Clinical monitoring is recommended for these adverse reactions. Special Populations Patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.2 and 5.2). Patients with severe hepatic impairment have not been studied. However, Rivastigmine Teva may be used in this patient population and close monitoring is necessary. Patients with body weight below 50 kg may experience more adverse reactions and may be more likely to discontinue due to adverse reactions. 4.5 Interaction with other medicinal products and other forms of interaction As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed. In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine. According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances. 4 Me dic ina l p rod uc t n o l on ge r a uth ori se d 4.6 Fertility, pregnancy and lactation For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary. In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed 4.7 Effects on ability to drive and use machines Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician. 4.8 Undesirable effects The most commonly reported adverse reactions are gastrointestinal, including nausea (38 %) and vomiting (23 %), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss. The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine. Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Table 1 Infections and infestations Very rare Urinary infection Metabolism and nutrition disorders Very common Anorexia Not known Dehydration Psychiatric disorders Common Agitation Common Confusion Common Anxiety Uncommon Insomnia Uncommon Depression Very rare Hallucinations Not known Aggression, restlessness 5 Me dic ina l p rod uc t n o l on ge r a uth ori se d Nervous system disorders Very common Dizziness Common Headache Common Somnolence Common Tremor Uncommon Syncope Rare Seizures Very rare Extrapyramidal symptoms (including worsening of Parkinson's disease) Cardiac disorders Rare Angina pectoris Very rare Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia) Not known Sick sinus syndrome Vascular Disorders Very rare Hypertension Gastrointestinal disorders Very common Nausea Very common Vomiting Very common Diarrhoea Common Abdominal pain and dyspepsia Rare Gastric and duodenal ulcers Very rare Gastrointestinal haemorrhage Very rare Pancreatitis Not known Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4). Hepatobiliary disorders Uncommon Elevated liver function tests Not known Hepatitis Skin and subcutaneous tissue disorders Common Hyperhydrosis Rare Rash Not known Pruritus General disorders and administration site conditions Common Fatigue and asthenia Common Malaise Uncommon Fall 6 Me dic ina l p rod uc t n o l on ge r a uth ori se d Investigations Common Weight loss Table 2 shows the adverse reactions reported in patients with dementia associated with Parkison’s disease treated with rivastigmine. Table 2 Metabolism and nutrition disorders Common Anorexia Common Dehydration Psychiatric disorders Common Insomnia Common Anxiety Common Restlessness Not known Aggression Nervous system disorders Very common Tremor Common Dizziness Common Somnolence Common Headache Common Worsening of Parkinson’s disease Common Bradykinesia Common Dyskinesia Uncommon Dystonia Cardiac disorders Common Bradycardia Uncommon Atrial fibrillation Uncommon Atrioventricular block Not known Sick sinus syndrome Gastrointestinal disorders Very common Nausea Very common Vomiting Common Diarrhoea Common Abdominal pain and dyspepsia Common Salivary hypersecretion Hepatobiliary disorders Not known Hepatitis 7 Me dic ina l p rod uc t n o l on ge r a uth ori se d Skin and subcutaneous tissue disorders Common Hyperhydrosis Musculoskeletal and connective tissue disorders Common Muscle rigidity General disorders and administration site conditions Common Fatigue and asthenia Common Gait abnormality Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms. Table 3 Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson's disease Rivastigmine n (%) Placebo n (%) Total patients studied 362 (100) 179 (100) Total patients with pre-defined AE(s) 99 (27.3) 28 (15.6) Tremor 37 (10.2) 7 (3.9) Fall 21 (5.8) 11 (6.1) Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) Salivary hypersecretion 5 (1.4) 0 Dyskinesia 5 (1.4) 1 (0.6) Parkinsonism 8 (2.2) 1 (0.6) Hypokinesia 1 (0.3) 0 Movement disorder 1 (0.3) 0 Bradykinesia 9 (2.5) 3 (1.7) Dystonia 3 (0.8) 1 (0.6) Gait abnormality 5 (1.4) 0 Muscle rigidity 1 (0.3) 0 Balance disorder 3 (0.8) 2 (1.1) Musculoskeletal stiffness 3 (0.8) 0 Rigors 1 (0.3) 0 Motor dysfunction 1 (0.3) 0 4.9 Overdose Symptoms 8 Me dic ina l p rod uc t n o l on ge r a uth ori se d Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours. Treatment As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary. In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03 Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease. Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40 % within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE. Clinical studies in Alzheimer's dementia The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.). The patients studied had an MMSE (Mini-Mental State Examination) score of 10 – 24. The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10 % improvement on the PDS. 9 Me dic ina l p rod uc t n o l on ge r a uth ori se d In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid. Table 4 Patients with Clinically Significant Response (%) Intent to Treat Last Observation Carried Forward Response Measure Rivastigmine 6–12 mg N=473 Placebo N=472 Rivastigmine 6–12 mg N=379 Placebo N=444 ADAS-Cog: improvement of at least 4 points 21*** 12 25*** 12 CIBIC-Plus: improvement 29*** 18 32*** 19 PDS: improvement of at least 10% 26*** 17 30*** 18 At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS 10* 6 12** 6 *p<0.05, **p<0.01, ***p<0.001 Clinical studies in dementia associated with Parkinson's disease The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10 – 24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study- Clinician's Global Impression of Change). Table 5 Dementia associated with Parkinson's Disease ADAS-Cog Rivastigmine ADAS-Cog Placebo ADCS-CGIC Rivastigmine ADCS-CGIC Placebo ITT + RDO population (n=329) (n=161) (n=329) (n=165) Mean baseline ± SD 23.8±10.2 24.3±10.5 n/a n/a Mean change at 24 weeks ± SD 2.1±8.2 -0.7±7.5 3.8±1.4 4.3±1.5 Adjusted treatment difference 2.881 n/a p-value versus placebo <0.0011 0.0072 ITT - LOCF population (n=287) (n=154) (n=289) (n=158) Mean baseline ± SD 24.0±10.3 24.5±10.6 n/a n/a Mean change at 24 weeks ± SD 2.5±8.4 -0.8±7.5 3.7±1.4 4.3±1.5 Adjusted treatment 3.541 n/a 10 Me dic ina l p rod uc t n o l on ge r a uth ori se d difference p-value versus placebo <0.0011 <0.0012 1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement. 2 Mean data shown for convenience, categorical analysis performed using van Elteren test ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6). Table 6 Dementia associated with Parkinson's Disease ADAS-Cog Rivastigmine ADAS-Cog Placebo ADAS-Cog Rivastigmine ADAS-Cog Placebo Patients with visual hallucinations Patients without visual hallucinations ITT + RDO population (n=107) (n=60) (n=220) (n=101) Mean baseline ± SD 25.4±9.9 27.4±10.4 23.1±10.4 22.5±10.1 Mean change at 24 weeks ± SD 1.0±9.2 -2.1±8.3 2.6±7.6 0.1±6.9 Adjusted treatment difference 4.271 2.091 p-value versus placebo 0.0021 0.0151 Patients with moderate dementia (MMSE 10-17) Patients with mild dementia (MMSE 18-24) ITT + RDO population (n=87) (n=44) (n=237) (n=115) Mean baseline ± SD 32.6±10.4 33.7±10.3 20.6±7.9 20.7±7.9 Mean change at 24 weeks ± SD 2.6±9.4 -1.8±7.2 1.9±7.7 -0.2±7.5 Adjusted treatment difference 4.731 2.141 p-value versus placebo 0.0021 0.0101 1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement. ITT: Intent-To-Treat; RDO: Retrieved Drop Outs 5.2 Pharmacokinetic properties Absorption Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36 % ± 13 %. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30 %. Distribution Protein binding of rivastigmine is approximately 40 %. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8 – 2.7 l/kg. 11 Me dic ina l p rod uc t n o l on ge r a uth ori se d Metabolism Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10 %). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose. Excretion Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90 %) within 24 hours. Less than 1 % of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease. Elderly subjects While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age. Subjects with hepatic impairment The Cmax of rivastigmine was approximately 60 % higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects. Subjects with renal impairment Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal impairment. 5.3 Preclinical safety data Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used. Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 104 times the maximum clinical exposure. The in vivo micronucleus test was negative. No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals. In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule contents Microcrystalline cellulose Hypromellose Colloidal silicon dioxide 12 Me dic ina l p rod uc t n o l on ge r a uth ori se d Magnesium stearate Capsule shell Titanium dioxide (E171) Gelatin Ink used for imprinting - Black S-1-17822/S-1-17823: Shellac glaze-45% Iron oxide black Ammonium hydroxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container - HDPE tablet container with a polypropylene cap and induction seal: 250 capsules - 28, 56 or 112 capsules in transparent PVC/Alu push through blisters - 50 x 1 capsules in PVC/Alu push through perforated unit dose blisters Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/001 EU/1/09/513/002 EU/1/09/513/003 EU/1/09/513/004 EU/1/09/513/005 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17/04/2009 10. DATE OF REVISION OF THE TEXT 13 Me dic ina l p rod uc t n o l on ge r a uth ori se d Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu 14 Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 3 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3 mg For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule Flesh colour cap imprinted with “R” & flesh color body imprinted with “3” 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s disease. 4.2 Posology and method of administration Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient. Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole. Initial dose 1.5 mg twice a day. Dose titration The starting dose is 1.5 mg twice a day. If the dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level. If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued. Maintenance dose The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for 15 Me dic ina l p rod uc t n o l on ge r a uth ori se d patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present. Individual response to rivastigmine cannot be predicted. However a greater treatment effect was seen in Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson’s disease patients with visual hallucinations (see section 5.1). Treatment effect has not been studied in placebo-controlled trials beyond 6 months. Re-initiation of therapy If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above. Renal and hepatic impairment No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. However, due to increased exposure in these populations dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.4 and 5.2). Patients with severe hepatic impairment have not been studied (see section 4.4) Children Rivastigmine is not recommended for use in children. 4.3 Contraindications The use of this medicinal product is contraindicated in patients with - hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation, 4.4 Special warnings and precautions for use The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting). Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8). Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occur particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse reactions occur more commonly in women. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with serious outcomes. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored. In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with 16 Me dic ina l p rod uc t n o l on ge r a uth ori se d oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine. Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8). Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions. Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases. The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended. Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7 % on rivastigmine vs 0 % on placebo). Clinical monitoring is recommended for these adverse reactions. Special Populations Patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.2 and 5.2). Patients with severe hepatic impairment have not been studied. However, Rivastigmine Teva may be used in this patient population and close monitoring is necessary. Patients with body weight below 50 kg may experience more adverse reactions and may be more likely to discontinue due to adverse reactions. 4.5 Interaction with other medicinal products and other forms of interaction As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recomemended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed. In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine. According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances. 4.6 Fertility, pregnancy and lactation For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary. 17 Me dic ina l p rod uc t n o l on ge r a uth ori se d In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed 4.7 Effects on ability to drive and use machines Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician. 4.8 Undesirable effects The most commonly reported adverse reactions are gastrointestinal, including nausea (38 %) and vomiting (23 %), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss. The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine. Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Table 1 * Infections and infestations Very rare Urinary infection Metabolism and nutrition disorders Very common Anorexia Not known Dehydration Psychiatric disorders Common Agitation Common Confusion Common Anxiety Uncommon Insomnia Uncommon Depression Very rare Hallucinations Not known Aggression, restlessness Nervous system disorders Very common Dizziness Common Headache Common Somnolence 18 Me dic ina l p rod uc t n o l on ge r a uth ori se d Common Tremor Uncommon Syncope Rare Seizures Very rare Extrapyramidal symptoms (including worsening of Parkinson's disease) Cardiac disorders Rare Angina pectoris Very rare Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia) Not known Sick sinus syndrome Vascular Disorders Very rare Hypertension Gastrointestinal disorders Very common Nausea Very common Vomiting Very common Diarrhoea Common Abdominal pain and dyspepsia Rare Gastric and duodenal ulcers Very rare Gastrointestinal haemorrhage Very rare Pancreatitis Not known Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4). Hepatobiliary disorders Uncommon Elevated liver function tests Not known Hepatitis Skin and subcutaneous tissue disorders Common Hyperhydrosis Rare Rash Not known Pruritus General disorders and administration site conditions Common Fatigue and asthenia Common Malaise Uncommon Fall Investigations Common Weight loss Table 2 shows the adverse reactions reported in patients with dementia associated with Parkison’s disease treated with rivastigmine. 19 Me dic ina l p rod uc t n o l on ge r a uth ori se d Table 2 Metabolism and nutrition disorders Common Anorexia Common Dehydration Psychiatric disorders Common Insomnia Common Anxiety Common Restlessness Not known Aggression Nervous system disorders Very common Tremor Common Dizziness Common Somnolence Common Headache Common Worsening of Parkinson’s disease Common Bradykinesia Common Dyskinesia Uncommon Dystonia Cardiac disorders Common Bradycardia Uncommon Atrial fibrillation Uncommon Atrioventricular block Not known Sick sinus syndrome Gastrointestinal disorders Very common Nausea Very common Vomiting Common Diarrhoea Common Abdominal pain and dyspepsia Common Salivary hypersecretion Hepatobililary disorders Not known Heptatitis Skin and subcutaneous tissue disorders Common Hyperhydrosis Musculoskeletal and connective tissue disorders 20 Me dic ina l p rod uc t n o l on ge r a uth ori se d Common Muscle rigidity General disorders and administration site conditions Common Fatigue and asthenia Common Gait abnormality Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms. Table 3 Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson's disease Rivastigmine n (%) Placebo n (%) Total patients studied 362 (100) 179 (100) Total patients with pre-defined AE(s) 99 (27.3) 28 (15.6) Tremor 37 (10.2) 7 (3.9) Fall 21 (5.8) 11 (6.1) Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) Salivary hypersecretion 5 (1.4) 0 Dyskinesia 5 (1.4) 1 (0.6) Parkinsonism 8 (2.2) 1 (0.6) Hypokinesia 1 (0.3) 0 Movement disorder 1 (0.3) 0 Bradykinesia 9 (2.5) 3 (1.7) Dystonia 3 (0.8) 1 (0.6) Gait abnormality 5 (1.4) 0 Muscle rigidity 1 (0.3) 0 Balance disorder 3 (0.8) 2 (1.1) Musculoskeletal stiffness 3 (0.8) 0 Rigors 1 (0.3) 0 Motor dysfunction 1 (0.3) 0 4.9 Overdose Symptoms Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours. 21 Me dic ina l p rod uc t n o l on ge r a uth ori se d Treatment As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary. In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03 Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease. Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40 % within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE. Clinical studies in Alzheimer's dementia The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.). The patients studied had an MMSE (Mini-Mental State Examination) score of 10 – 24. The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10 % improvement on the PDS. In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid. 22 Me dic ina l p rod uc t n o l on ge r a uth ori se d Table 4 Patients with Clinically Significant Response (%) Intent to Treat Last Observation Carried Forward Response Measure Rivastigmine 6–12 mg N=473 Placebo N=472 Rivastigmine 6–12 mg N=379 Placebo N=444 ADAS-Cog: improvement of at least 4 points 21*** 12 25*** 12 CIBIC-Plus: improvement 29*** 18 32*** 19 PDS: improvement of at least 10% 26*** 17 30*** 18 At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS 10* 6 12** 6 *p<0.05, **p<0.01, ***p<0.001 Clinical studies in dementia associated with Parkinson's disease The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10 – 24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study- Clinician's Global Impression of Change). Table 5 Dementia associated with Parkinson's Disease ADAS-Cog Rivastigmine ADAS-Cog Placebo ADCS-CGIC Rivastigmine ADCS-CGIC Placebo ITT + RDO population (n=329) (n=161) (n=329) (n=165) Mean baseline ± SD 23.8±10.2 24.3±10.5 n/a n/a Mean change at 24 weeks ± SD 2.1±8.2 -0.7±7.5 3.8±1.4 4.3±1.5 Adjusted treatment difference 2.881 n/a p-value versus placebo <0.0011 0.0072 ITT - LOCF population (n=287) (n=154) (n=289) (n=158) Mean baseline ± SD 24.0±10.3 24.5±10.6 n/a n/a Mean change at 24 weeks ± SD 2.5±8.4 -0.8±7.5 3.7±1.4 4.3±1.5 Adjusted treatment difference 3.541 n/a p-value versus placebo <0.0011 <0.0012 1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement. 2 Mean data shown for convenience, categorical analysis performed using van Elteren test ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward 23 Me dic ina l p rod uc t n o l on ge r a uth ori se d Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6). Table 6 Dementia associated with Parkinson's Disease ADAS-Cog Rivastigmine ADAS-Cog Placebo ADAS-Cog Rivastigmine ADAS-Cog Placebo Patients with visual hallucinations Patients without visual hallucinations ITT + RDO population (n=107) (n=60) (n=220) (n=101) Mean baseline ± SD 25.4±9.9 27.4±10.4 23.1±10.4 22.5±10.1 Mean change at 24 weeks ± SD 1.0±9.2 -2.1±8.3 2.6±7.6 0.1±6.9 Adjusted treatment difference 4.271 2.091 p-value versus placebo 0.0021 0.0151 Patients with moderate dementia (MMSE 10-17) Patients with mild dementia (MMSE 18-24) ITT + RDO population (n=87) (n=44) (n=237) (n=115) Mean baseline ± SD 32.6±10.4 33.7±10.3 20.6±7.9 20.7±7.9 Mean change at 24 weeks ± SD 2.6±9.4 -1.8±7.2 1.9±7.7 -0.2±7.5 Adjusted treatment difference 4.731 2.141 p-value versus placebo 0.0021 0.0101 1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement. ITT: Intent-To-Treat; RDO: Retrieved Drop Outs 5.2 Pharmacokinetic properties Absorption: Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36 %±13 %. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30 %. Distribution: Protein binding of rivastigmine is approximately 40 %. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8 – 2.7 l/kg. Metabolism: Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10 %). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose. 24 Me dic ina l p rod uc t n o l on ge r a uth ori se d Excretion: Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90 %) within 24 hours. Less than 1 % of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease. Elderly subjects: While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age. Subjects with hepatic impairment: The Cmax of rivastigmine was approximately 60 % higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects. Subjects with renal impairment: Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal impairment. 5.3 Preclinical safety data Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used. Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 104 times the maximum clinical exposure. The in vivo micronucleus test was negative. No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals. In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule contents Microcrystalline cellulose Hypromellose Colloidal silicon dioxide Magnesium stearate Capsule shell Red iron oxide (E 172) Yellow iron oxide (E 172) Titanium dioxide (E 171) Gelatin 25 Me dic ina l p rod uc t n o l on ge r a uth ori se d Ink used for imprinting - Black S-1-17822/S-1-17823 Shellac glaze-45% Iron oxide black Ammonium hydroxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions 6.5 Nature and contents of container - HDPE tablet container with a polypropylene cap and induction seal: 250 capsules - 28, 56 or 112 capsules in transparent PVC/Alu push through blisters - 50 x 1 capsules in PVC/Alu push through perforated unit dose blisters Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/006 EU/1/09/513/007 EU/1/09/513/008 EU/1/09/513/009 EU/1/09/513/010 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17/04/2009 10. DATE OF REVISION OF THE TEXT Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu 26 Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 27 Me dic ina l p rod uc t n o l on ge r a uth ori se d 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 4.5 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule Orange colour cap imprinted with “R” & orange color body imprinted with “4.5” 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s disease. 4.2 Posology and method of administration Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient. Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole. Initial dose: 1.5 mg twice a day. Dose titration: The starting dose is 1.5 mg twice a day. If the dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level. If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued. Maintenance dose: The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day. 28 Me dic ina l p rod uc t n o l on ge r a uth ori se d Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present. Individual response to rivastigmine cannot be predicted. However a greater treatment effect was seen in Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson’s disease patients with visual hallucinations (see section 5.1). Treatment effect has not been studied in placebo-controlled trials beyond 6 months. Re-initiation of therapy: If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above. Renal and hepatic impairment: No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. However, due to increased exposure in these populations dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.4 and 5.2). Patients with severe hepatic impairment have not been studied (see section 4.4). Children: Rivastigmine is not recommended for use in children. 4.3 Contraindications The use of this medicinal product is contraindicated in patients with - hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation, 4.4 Special warnings and precautions for use The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting). Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8). Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occur particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse reactions occur more commonly in women. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with serious outcomes. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored. 29 Me dic ina l p rod uc t n o l on ge r a uth ori se d In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine. Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8). Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions. Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases. The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore the use in these patient populations is not recommended. Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7 % on rivastigmine vs 0 % on placebo). Clinical monitoring is recommended for these adverse reactions. Special Populations Patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.2 and 5.2). Patients with severe hepatic impairment have not been studied. However, Rivastigmine Teva may be used in this patient population and close monitoring is necessary. Patients with body weight below 50 kg may experience more adverse reactions and may be more likely to discontinue due to adverse reactions. 4.5 Interaction with other medicinal products and other forms of interaction As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed. In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine. According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances. 4.6 Fertility, pregnancy and lactation 30 Me dic ina l p rod uc t n o l on ge r a uth ori se d For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary. In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed 4.7 Effects on ability to drive and use machines Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machinges. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician. 4.8 Undesirable effects The most commonly reported adverse reactions are gastrointestinal, including nausea (38 %) and vomiting (23 %), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss. The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine. Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data) Table 1 Infections and infestations Very rare Urinary infection Metabolism and nutrition disorders Very common Anorexia Not known Dehydration Psychiatric disorders Common Agitation Common Confusion Common Anxiety Uncommon Insomnia Uncommon Depression Very rare Hallucinations Not known Aggression, restlessness Nervous system disorders Very common Dizziness 31 Me dic ina l p rod uc t n o l on ge r a uth ori se d Common Headache Common Somnolence Common Tremor Uncommon Syncope Rare Seizures Very rare Extrapyramidal symptoms (including worsening of Parkinson's disease) Cardiac disorders Rare Angina pectoris Very rare Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia) Not known Sick-sinus syndrome Vascular Disorders Very rare Hypertension Gastrointestinal disorders Very common Nausea Very common Vomiting Very common Diarrhoea Common Abdominal pain and dyspepsia Rare Gastric and duodenal ulcers Very rare Gastrointestinal haemorrhage Very rare Pancreatitis Not known Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4). Hepato-biliary disorders Uncommon Elevated liver function tests Not known Hepatitis Skin and subcutaneous tissue disorders Common Hyperhydrosis Rare Rash Not known Pruritus General disorders and administration site conditions Common Fatigue and asthenia Common Malaise Uncommon Fall Investigations Common Weight loss 32 Me dic ina l p rod uc t n o l on ge r a uth ori se d Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson’s disease treated with rivastigmine. Table 2 Metabolism and nutrition disorders Common Anorexia Common Dehydration Psychiatric disorders Common Insomnia Common Anxiety Common Restlessness Not known Aggression Nervous system disorders Very common Tremor Common Dizziness Common Somnolence Common Headache Common Worsening of Parkinson’s disease Common Bradykinesia Common Dyskinesia Uncommon Dystonia Cardiac disorders Common Bradycardia Uncommon Atrial fibrillation Uncommon Atrioventricular block Not known Sick sinus syndrome Gastrointestinal disorders Very common Nausea Very common Vomiting Common Diarrhoea Common Abdominal pain and dyspepsia Common Salivary hypersecretion Hepatobiliary disorders Not known Hepatitis Skin and subcutaneous tissue disorders 33 Me dic ina l p rod uc t n o l on ge r a uth ori se d Common Hyperhydrosis Musculoskeletal and connective tissue disorders Common Muscle rigidity General disorders and administration site conditions Common Fatigue and asthenia Common Gait abnormality Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms. Table 3 Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson's disease Rivastigmine n (%) Placebo n (%) Total patients studied 362 (100) 179 (100) Total patients with pre-defined AE(s) 99 (27.3) 28 (15.6) Tremor 37 (10.2) 7 (3.9) Fall 21 (5.8) 11 (6.1) Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) Salivary hypersecretion 5 (1.4) 0 Dyskinesia 5 (1.4) 1 (0.6) Parkinsonism 8 (2.2) 1 (0.6) Hypokinesia 1 (0.3) 0 Movement disorder 1 (0.3) 0 Bradykinesia 9 (2.5) 3 (1.7) Dystonia 3 (0.8) 1 (0.6) Gait abnormality 5 (1.4) 0 Muscle rigidity 1 (0.3) 0 Balance disorder 3 (0.8) 2 (1.1) Musculoskeletal stiffness 3 (0.8) 0 Rigors 1 (0.3) 0 Motor dysfunction 1 (0.3) 0 4.9 Overdose Symptoms Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have 34 Me dic ina l p rod uc t n o l on ge r a uth ori se d occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours. Treatment As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary. In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03 Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease. Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40 % within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE. Clinical studies in Alzheimer's dementia The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.). The patients studied had an MMSE (Mini-Mental State Examination) score of 10 – 24. The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10 % improvement on the PDS. 35 Me dic ina l p rod uc t n o l on ge r a uth ori se d In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6 – 12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid. Table 4 Patients with Clinically Significant Response (%) Intent to Treat Last Observation Carried Forward Response Measure Rivastigmine 6–12 mg N=473 Placebo N=472 Rivastigmine 6–12 mg N=379 Placebo N=444 ADAS-Cog: improvement of at least 4 points 21*** 12 25*** 12 CIBIC-Plus: improvement 29*** 18 32*** 19 PDS: improvement of at least 10% 26*** 17 30*** 18 At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS 10* 6 12** 6 *p<0.05, **p<0.01, ***p<0.001 Clinical studies in dementia associated with Parkinson's disease The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10 – 24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study- Clinician's Global Impression of Change). Table 5 Dementia associated with Parkinson's Disease ADAS-Cog Rivastigmine ADAS-Cog Placebo ADCS-CGIC Rivastigmine ADCS-CGIC Placebo ITT + RDO population (n=329) (n=161) (n=329) (n=165) Mean baseline ± SD 23.8±10.2 24.3±10.5 n/a n/a Mean change at 24 weeks ± SD 2.1±8.2 -0.7±7.5 3.8±1.4 4.3±1.5 Adjusted treatment difference 2.881 n/a p-value versus placebo <0.0011 0.0072 ITT - LOCF population (n=287) (n=154) (n=289) (n=158) Mean baseline ± SD 24.0±10.3 24.5±10.6 n/a n/a Mean change at 24 weeks ± SD 2.5±8.4 -0.8±7.5 3.7±1.4 4.3±1.5 Adjusted treatment difference 3.541 n/a 36 Me dic ina l p rod uc t n o l on ge r a uth ori se d p-value versus placebo <0.0011 <0.0012 1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement. 2 Mean data shown for convenience, categorical analysis performed using van Elteren test ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6). Table 6 Dementia associated with Parkinson's Disease ADAS-Cog Rivastigmine ADAS-Cog Placebo ADAS-Cog Rivastigmine ADAS-Cog Placebo Patients with visual hallucinations Patients without visual hallucinations ITT + RDO population (n=107) (n=60) (n=220) (n=101) Mean baseline ± SD 25.4±9.9 27.4±10.4 23.1±10.4 22.5±10.1 Mean change at 24 weeks ± SD 1.0±9.2 -2.1±8.3 2.6±7.6 0.1±6.9 Adjusted treatment difference 4.271 2.091 p-value versus placebo 0.0021 0.0151 Patients with moderate dementia (MMSE 10-17) Patients with mild dementia (MMSE 18-24) ITT + RDO population (n=87) (n=44) (n=237) (n=115) Mean baseline ± SD 32.6±10.4 33.7±10.3 20.6±7.9 20.7±7.9 Mean change at 24 weeks ± SD 2.6±9.4 -1.8±7.2 1.9±7.7 -0.2±7.5 Adjusted treatment difference 4.731 2.141 p-value versus placebo 0.0021 0.0101 1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement. ITT: Intent-To-Treat; RDO: Retrieved Drop Outs 5.2 Pharmacokinetic properties Absorption Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine's interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36 %±13 %. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30 %. Distribution Protein binding of rivastigmine is approximately 40 %. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8 – 2.7 l/kg. Metabolism 37 Me dic ina l p rod uc t n o l on ge r a uth ori se d Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10 %). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose. Excretion Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90 %) within 24 hours. Less than 1 % of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease. Elderly subjects While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age. Subjects with hepatic impairment The Cmax of rivastigmine was approximately 60 % higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects. Subjects with renal impairment Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal impairment. 5.3 Preclinical safety data Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used. Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 104 times the maximum clinical exposure. The in vivo micronucleus test was negative. No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals. In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule contents Microcrystalline cellulose Hypromellose Colloidal silicon dioxide Magnesium stearate 38 Me dic ina l p rod uc t n o l on ge r a uth ori se d Capsule shell Red iron oxide (E172) Yellow iron oxide (E 172) Titanium dioxide (E171) Gelatin Ink used for imprinting - Black S-1-17822/S-1-17823 Shellac glaze-45% Iron oxide black Ammonium hydroxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage instructions. 6.5 Nature and contents of container - HDPE tablet container with a polypropylene cap and induction seal: 250 capsules - 28, 56 or 112 capsules in transparent PVC/Alu push through blisters - 50 x 1 capsules in PVC/Alu push through perforated unit dose blisters Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/011 EU/1/09/513/012 EU/1/09/513/013 EU/1/09/513/014 EU/1/09/513/015 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17/04/2009 39 Me dic ina l p rod uc t n o l on ge r a uth ori se d 10. DATE OF REVISION OF THE TEXT Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu 40 Me dic ina l p rod uc t n o l on ge r a uth ori se d 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 6 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 6 mg For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule Orange cap imprinted with “R” & flesh color body imprinted with “6” 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s disease. 4.2 Posology and method of administration Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient. Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole. Initial dose: 1.5 mg twice a day. Dose titration: The starting dose is 1.5 mg twice a day. If the dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued. Maintenance dose: The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day. 41 Me dic ina l p rod uc t n o l on ge r a uth ori se d Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present. Individual response to rivastigmine cannot be predicted. However a greater treatment effect was seen in Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in Parkison’s disease patients with visual hallucinations (see section 5.1). Treatment effect has not been studied in placebo-controlled trials beyond 6 months. Re-initiation of therapy: If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above. Renal and hepatic impairment: No dose adjustment is necessary for patientS with mild to moderate renal or hepatic impairment. However, due to increased exposure in these populations dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.4 and 5.2). Patients with severe hepatic impairment have not been studied (see section 4.4). Children: Rivastigmine is not recommended for use in children. 4.3 Contraindications The use of this medicinal product is contraindicated in patients with - hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation. 4.4 Special warnings and precautions for use The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting). Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8). Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occur particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse reactions occur more commonly in women. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with serious outcomes. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored. 42 Me dic ina l p rod uc t n o l on ge r a uth ori se d In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine. Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8). Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions. Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases. The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended. Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7 % on rivastigmine vs 0 % on placebo). Clinical monitoring is recommended for these adverse reactions. Special Populations Patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.2 and 5.2). Patients with severe hepatic impairment have not been studied. However, Rivastigmine Teva may be used in this patient population and close monitoring is necessary. Patients with body weight below 50 kg may experience more adverse reactions and may be more likely to discontinue due to adverse reactions. 4.5 Interaction with other medicinal products and other forms of interaction As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed. In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine. According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances. 4.6 Fertility, pregnancy and lactation 43 Me dic ina l p rod uc t n o l on ge r a uth ori se d For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary. In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed 4.7 Effects on ability to drive and use machines Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician. 4.8 Undesirable effects The most commonly reported adverse reactions are gastrointestinal, including nausea (38 %) and vomiting (23 %), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss. The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine. Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Table 1 Infections and infestations Very rare Urinary infection Metabolism and nutrition disorders Very common Anorexia Not known Dehydration Psychiatric disorders Common Agitation Common Confusion Common Anxiety Uncommon Insomnia Uncommon Depression Very rare Hallucinations Not known Aggression, restlessness Nervous system disorders Very common Dizziness 44 Me dic ina l p rod uc t n o l on ge r a uth ori se d Common Headache Common Somnolence Common Tremor Uncommon Syncope Rare Seizures Very rare Extrapyramidal symptoms (including worsening of Parkinson's disease) Cardiac disorders Rare Angina pectoris Very rare Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia) Not known Sick sinus syndrome Vascular Disorders Very rare Hypertension Gastrointestinal disorders Very common Nausea Very common Vomiting Very common Diarrhoea Common Abdominal pain and dyspepsia Rare Gastric and duodenal ulcers Very rare Gastrointestinal haemorrhage Very rare Pancreatitis Not known Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4). Hepatobiliary disorders Uncommon Elevated liver function tests Not known Hepatitis Skin and subcutaneous tissue disorders Common Hyperhydrosis Rare Rash Not known Pruritus General disorders and administration site conditions Common Fatigue and asthenia Common Malaise Uncommon Fall Investigations Common Weight loss 45 Me dic ina l p rod uc t n o l on ge r a uth ori se d Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson’s disease treated with rivastigmine. Table 2 Metabolism and nutrition disorders Common Anorexia Common Dehydration Psychiatric disorders Common Insomnia Common Anxiety Common Restlessness Not known Aggression Nervous system disorders Very common Tremor Common Dizziness Common Somnolence Common Headache Common Worsening of Parkinson’s disease Common Bradykinesia Common Dyskinesia Uncommon Dystonia Cardiac disorders Common Bradycardia Uncommon Atrial fibrillation Uncommon Atrioventricular block Not known Sick sinus syndrome Gastrointestinal disorders Very common Nausea Very common Vomiting Common Diarrhoea Common Abdominal pain and dyspesia Common Salivary hypersecretion Hepatobiliary disorders Not known Hepatitis Skin and subcutaneous tissue disorders Common Hyperhydrosis 46 Me dic ina l p rod uc t n o l on ge r a uth ori se d Musculoskeletal and connective tissue disorders Common Muscle rigidity General disorders and administration site conditions Common Fatigue and asthenia Common Gait abnormality Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms. Table 3 Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson's disease Rivastigmine n (%) Placebo n (%) Total patients studied 362 (100) 179 (100) Total patients with pre-defined AE(s) 99 (27.3) 28 (15.6) Tremor 37 (10.2) 7 (3.9) Fall 21 (5.8) 11 (6.1) Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) Salivary hypersecretion 5 (1.4) 0 Dyskinesia 5 (1.4) 1 (0.6) Parkinsonism 8 (2.2) 1 (0.6) Hypokinesia 1 (0.3) 0 Movement disorder 1 (0.3) 0 Bradykinesia 9 (2.5) 3 (1.7) Dystonia 3 (0.8) 1 (0.6) Gait abnormality 5 (1.4) 0 Muscle rigidity 1 (0.3) 0 Balance disorder 3 (0.8) 2 (1.1) Musculoskeletal stiffness 3 (0.8) 0 Rigors 1 (0.3) 0 Motor dysfunction 1 (0.3) 0 4.9 Overdose Symptoms Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may 47 Me dic ina l p rod uc t n o l on ge r a uth ori se d also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours. Treatment As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary. In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: anticholinesterases, ATC code: N06D A03 Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease. Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40 % within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE. Clinical studies in Alzheimer's dementia The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.). The patients studied had an MMSE (Mini-Mental State Examination) score of 10 – 24. The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10 % improvement on the PDS. In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6 – 12 48 Me dic ina l p rod uc t n o l on ge r a uth ori se d mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid. Table 4 Patients with Clinically Significant Response (%) Intent to Treat Last Observation Carried Forward Response Measure Rivastigmine 6–12 mg N=473 Placebo N=472 Rivastigmine 6–12 mg N=379 Placebo N=444 ADAS-Cog: improvement of at least 4 points 21*** 12 25*** 12 CIBIC-Plus: improvement 29*** 18 32*** 19 PDS: improvement of at least 10% 26*** 17 30*** 18 At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS 10* 6 12** 6 *p<0.05, **p<0.01, ***p<0.001 Clinical studies in dementia associated with Parkinson's disease The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10 – 24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study- Clinician's Global Impression of Change). Table 5 Dementia associated with Parkinson's Disease ADAS-Cog Rivastigmine ADAS-Cog Placebo ADCS-CGIC Rivastigmine ADCS-CGIC Placebo ITT + RDO population (n=329) (n=161) (n=329) (n=165) Mean baseline ± SD 23.8±10.2 24.3±10.5 n/a n/a Mean change at 24 weeks ± SD 2.1±8.2 -0.7±7.5 3.8±1.4 4.3±1.5 Adjusted treatment difference 2.881 n/a p-value versus placebo <0.0011 0.0072 ITT - LOCF population (n=287) (n=154) (n=289) (n=158) Mean baseline ± SD 24.0±10.3 24.5±10.6 n/a n/a Mean change at 24 weeks ± SD 2.5±8.4 -0.8±7.5 3.7±1.4 4.3±1.5 Adjusted treatment difference 3.541 n/a p-value versus placebo <0.0011 <0.0012 1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement. 49 Me dic ina l p rod uc t n o l on ge r a uth ori se d 2 Mean data shown for convenience, categorical analysis performed using van Elteren test ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6). Table 6 Dementia associated with Parkinson's Disease ADAS-Cog Rivastigmine ADAS-Cog Placebo ADAS-Cog Rivastigmine ADAS-Cog Placebo Patients with visual hallucinations Patients without visual hallucinations ITT + RDO population (n=107) (n=60) (n=220) (n=101) Mean baseline ± SD 25.4±9.9 27.4±10.4 23.1±10.4 22.5±10.1 Mean change at 24 weeks ± SD 1.0±9.2 -2.1±8.3 2.6±7.6 0.1±6.9 Adjusted treatment difference 4.271 2.091 p-value versus placebo 0.0021 0.0151 Patients with moderate dementia (MMSE 10-17) Patients with mild dementia (MMSE 18-24) ITT + RDO population (n=87) (n=44) (n=237) (n=115) Mean baseline ± SD 32.6±10.4 33.7±10.3 20.6±7.9 20.7±7.9 Mean change at 24 weeks ± SD 2.6±9.4 -1.8±7.2 1.9±7.7 -0.2±7.5 Adjusted treatment difference 4.731 2.141 p-value versus placebo 0.0021 0.0101 1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement. ITT: Intent-To-Treat; RDO: Retrieved Drop Outs 5.2 Pharmacokinetic properties Absorption: Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36 % ± 13 %. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30 %. Distribution: Protein binding of rivastigmine is approximately 40 %. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8 – 2.7 l/kg. Metabolism: Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10 %). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine 50 Me dic ina l p rod uc t n o l on ge r a uth ori se d metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose. Excretion: Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90 %) within 24 hours. Less than 1 % of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease. Elderly subjects: While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age. Subjects with hepatic impairment: The Cmax of rivastigmine was approximately 60 % higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects. Subjects with renal impairment: Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal impairment. 5.3 Preclinical safety data Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used. Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 104 times the maximum clinical exposure. The in vivo micronucleus test was negative. No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals. In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule contents Microcrystalline cellulose Hypromellose Colloidal silicon dioxide Magnesium stearate Capsule shell Red iron oxide (E172) Yellow iron oxide (E172) 51 Me dic ina l p rod uc t n o l on ge r a uth ori se d Titanium dioxide (E171) Gelatin Ink used for imprinting - Black S-1-17822/S-1-17823 Shellac glaze-45% Iron oxide black Ammonium hydroxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage instructions. 6.5 Nature and contents of container - HDPE tablet container with a polypropylene cap and induction seal: 250 capsules - 28, 56 or 112 capsules in transparent PVC/Alu push through blisters - 50 x 1 capsules in PVC/Alu push through perforated unit dose blisters Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/016 EU/1/09/513/017 EU/1/09/513/018 EU/1/09/513/019 EU/1/09/513/020 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17/04/2009 10. DATE OF REVISION OF THE TEXT Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu 52 Me dic ina l p rod uc t n o l on ge r a uth ori se d ANNEX II A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION 53 Me dic ina l p rod uc t n o l on ge r a uth ori se d A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Teva Pharmaceutical Works Private Limited Company . Pallagi út 13 4042 Debrecen Hungary TEVA Pharmaceutical Works Private Limited Company H-2100 Gödöllő, Táncsics Mihály út 82 Hungary TEVA UK Ltd Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG United Kingdom Pharmachemie B.V. Swensweg 5, 2031 GA Haarlem The Netherlands TEVA Santé, Rue Bellocier, 89100, Sens, France Teva Czech Industries s.r.o. Ostravska 29, c.p. 305 747 70 Opava-Komarov Czech Republic The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OF THE MARKETING AUTHORISATION • CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, Section 4.2 ). • CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Not applicable 54 Me dic ina l p rod uc t n o l on ge r a uth ori se d • OTHER CONDITIONS Pharmacovigilance system The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and whilst the product is on the market. PSURs The PSUR submission schedule for Rivastigmine TEVA hard capsules should follow PSURs submission schedule for the reference medicinal product. 55 Me dic ina l p rod uc t n o l on ge r a uth ori se d ANNEX III LABELLING AND PACKAGE LEAFLET 56 Me dic ina l p rod uc t n o l on ge r a uth ori se d A. LABELLING 57 Me dic ina l p rod uc t n o l on ge r a uth ori se d PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton – Rivastigmine Teva 1.5 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 1.5 mg hard capsules Rivastigmine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Blisters 28 hard capsules 50 x 1 hard capsules 56 hard capsules 112 hard capsules Bottles 250 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. To be swallowed whole without crushing or opening Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 58 Me dic ina l p rod uc t n o l on ge r a uth ori se d 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/001 EU/1/09/513/002 EU/1/09/513/003 EU/1/09/513/004 EU/1/09/513/005 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Rivastigmine Teva 1.5 mg 59 Me dic ina l p rod uc t n o l on ge r a uth ori se d MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister – Rivastigmine Teva 1.5 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 1.5 mg hard capsules Rivastigmine 2. NAME OF THE MARKETING AUTHORISATION HOLDER Teva Pharma B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER BN 5. OTHER 60 Me dic ina l p rod uc t n o l on ge r a uth ori se d PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Tablet container - Self-adhesive, paper label – Rivastigmine Teva 1.5 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 1.5 mg hard capsules Rivastigmine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 250 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. To be swallowed whole without crushing or opening Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 61 Me dic ina l p rod uc t n o l on ge r a uth ori se d Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/001 EU/1/09/513/002 EU/1/09/513/003 EU/1/09/513/004 EU/1/09/513/005 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 62 Me dic ina l p rod uc t n o l on ge r a uth ori se d PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton – Rivastigmine Teva 3 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 3 mg hard capsules Rivastigmine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3 mg 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Blisters 28 hard capsules 50 x 1 hard capsules 56 hard capsules 112 hard capsules Bottles 250 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. To be swallowed whole without crushing or opening Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 63 Me dic ina l p rod uc t n o l on ge r a uth ori se d 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/006 EU/1/09/513/007 EU/1/09/513/008 EU/1/09/513/009 EU/1/09/513/010 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Rivastigmine Teva 3 mg 64 Me dic ina l p rod uc t n o l on ge r a uth ori se d MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister – Rivastigmine Teva 3 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 3 mg hard capsules Rivastigmine 2. NAME OF THE MARKETING AUTHORISATION HOLDER Teva Pharma B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER BN 5. OTHER Not applicable 65 Me dic ina l p rod uc t n o l on ge r a uth ori se d PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Tablet container - Self-adhesive, paper label – Rivastigmine Teva 3 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 3 mg hard capsules Rivastigmine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3 mg 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 250 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. To be swallowed whole without crushing or opening Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 66 Me dic ina l p rod uc t n o l on ge r a uth ori se d Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/006 EU/1/09/513/007 EU/1/09/513/008 EU/1/09/513/009 EU/1/09/513/010 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 67 Me dic ina l p rod uc t n o l on ge r a uth ori se d PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton – Rivastigmine Teva 4.5 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 4.5 mg hard capsules Rivastigmine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Blisters 28 hard capsules 50 x 1 hard capsules 56 hard capsules 112 hard capsules Bottles 250 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. To be swallowed whole without crushing or opening Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 68 Me dic ina l p rod uc t n o l on ge r a uth ori se d 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/011 EU/1/09/513/012 EU/1/09/513/013 EU/1/09/513/014 EU/1/09/513/015 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Rivastigmine Teva 4.5 mg 69 Me dic ina l p rod uc t n o l on ge r a uth ori se d MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister – Rivastigmine Teva 4.5 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 4.5 mg hard capsules Rivastigmine 2. NAME OF THE MARKETING AUTHORISATION HOLDER Teva Pharma B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER BN 5. OTHER 70 Me dic ina l p rod uc t n o l on ge r a uth ori se d PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Tablet Container - Self-adhesive, paper label – Rivastigmine Teva 4.5 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 4.5 mg hard capsules Rivastigmine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 250 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. To be swallowed whole without crushing or opening Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 71 Me dic ina l p rod uc t n o l on ge r a uth ori se d Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/011 EU/1/09/513/012 EU/1/09/513/013 EU/1/09/513/014 EU/1/09/513/015 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 72 Me dic ina l p rod uc t n o l on ge r a uth ori se d PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton – Rivastigmine Teva 6 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 6 mg hard capsules Rivastigmine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 6 mg 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Blisters 28 hard capsules 50 x 1 hard capsules 56 hard capsules 112 hard capsules Bottles 250 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. To be swallowed whole without crushing or opening Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 73 Me dic ina l p rod uc t n o l on ge r a uth ori se d 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/016 EU/1/09/513/017 EU/1/09/513/018 EU/1/09/513/019 EU/1/09/513/020 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Rivastigmine Teva 6 mg 74 Me dic ina l p rod uc t n o l on ge r a uth ori se d MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister – Rivastigmine Teva 6 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 6 mg hard capsules Rivastigmine 2. NAME OF THE MARKETING AUTHORISATION HOLDER Teva Pharma B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER BN 5. OTHER 75 Me dic ina l p rod uc t n o l on ge r a uth ori se d PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING Tablet container - Self-adhesive, paper label – Rivastigmine Teva 6 mg hard capsules 1. NAME OF THE MEDICINAL PRODUCT Rivastigmine Teva 6 mg hard capsules Rivastigmine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 6 mg 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 250 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. To be swallowed whole without crushing or opening Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 76 Me dic ina l p rod uc t n o l on ge r a uth ori se d Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/513/016 EU/1/09/513/017 EU/1/09/513/018 EU/1/09/513/019 EU/1/09/513/020 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 77 Me dic ina l p rod uc t n o l on ge r a uth ori se d B. PACKAGE LEAFLET 78 Me dic ina l p rod uc t n o l on ge r a uth ori se d PACKAGE LEAFLET: INFORMATION FOR THE USER Rivastigmine Teva 1.5 mg hard capsules Rivastigmine Teva 3 mg hard capsules Rivastigmine Teva 4.5 mg hard capsules Rivastigmine Teva 6 mg hard capsules Rivastigmine Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Rivastigmine Teva is and what it is used for 2. Before you take Rivastigmine Teva 3. How to take Rivastigmine Teva 4. Possible side effects 5. How to store Rivastigmine Teva 6. Further information 1. WHAT RIVASTIGMINE TEVA IS AND WHAT IT IS USED FOR The active substance of Rivastigmine Teva is rivastigmine Rivastigmine belongs to a class of substances called cholinesterase inhibitors. Rivastigmine Teva is used for the treatment of memory disorders in patients with Alzheimer’s disease. It is also used for the treatment of dementia in patients with Parkinson’s disease. 2. BEFORE YOU TAKE RIVASTIGMINE TEVA Do NOT take Rivastigmine Teva - If you are allergic (hypersensitive) to rivastigmine (the active substance in Rivastigmine Teva) or to any of the other ingredients of Rivastigmine Teva listed in section 6 of this leaflet - If this applies to you, tell your doctor and do not take Rivastigmine Teva. Take special care with Rivastigmine Teva - if you have, or have ever had, irregular heartbeat. - if you have, or have ever had, an active stomach ulcer. - if you have, or have ever had, difficulties in passing urine. - if you have, or have ever had, seizures. - if you have, or have ever had, asthma or severe respiratory disease. - if you have, or have ever had, impaired kidney function. - if you have, or have ever had, impaired liver function. - if you suffer from trembling. - if you have a low body weight. 79 Me dic ina l p rod uc t n o l on ge r a uth ori se d - If you have gastrointestinal reactions such as feeling sick (nausea) and being sick (vomiting) and diarrhoea. You may become dehydrated (losing too much fluid) if vomiting or diarhoea are prolonged. If any of these apply to you, your doctor may need to monitor you more closely while you are on this medicine. If you have not taken Rivastigmine Teva for several days, do not take the next dose until you have talked to your doctor. The use of Rivastigmine Teva in children and adolescents (age below 18 years) is not recommended. Taking other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Rivastigmine Teva should not be given at the same time as other medicines with similar effects to Rivastigmine Teva. Rivastigmine Teva might interfere with anticholinergic medicines (medicines used to relieve stomach cramps or spasms, to treat Parkinson’s disease or to prevent travel sickness). If you have to undergo surgery whilst taking Rivastigmine Teva, tell your doctor before you are given any anaesthetics, because Rivastigmine Teva may exaggerate the effects of some muscle relaxants during anaesthesia. Pregnancy and breast-feeding Tell your doctor if you become pregnant during treatment. It is preferable to avoid the use of Rivastigmine Teva during pregnancy, unless clearly necessary. You should not breast-feed during treatment with Rivastigmine Teva. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely.. Rivastigmine Teva may cause dizziness and somnolence, mainly at the start of treatment or when increasing the dose.If you feel dizzy or sleepy do not drive, use machines or perform any tasks that require your attention. 3. HOW TO TAKE RIVASTIGMINE TEVA Always take Rivastigmine Teva exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. How to start treatment Your doctor will tell you what dose of Rivastigmine Teva to take. • Treatment usually starts with a low dose. • Your doctor will slowly increase your dose depending on how you respond to the treatment. • The highest dose that should be taken is 6.0 mg twice a day. Your doctor will regularly check if the medicine is working for you. Your doctor will also monitor your weight whilst you are taking this medicine. If you have not taken Rivastigmine Teva for several days, do not take the next dose until you have talked to your doctor. 80 Me dic ina l p rod uc t n o l on ge r a uth ori se d Taking this medicine • Tell your caregiver that you are taking Rivastigmine Teva. • To benefit from your medicine, take it every day. • Take Rivastigmine Teva twice a day, in the morning and evening, with food. • Swallow the capsules whole with a drink. • Do not open or crush the capsules. If you take more Rivastigmine Teva than you should If you accidentally take more Rivastigmine Teva than you should, inform your doctor. You may require medical attention. Some people who have accidentally taken too much Rivastigmine Teva have experienced feeling sick (nausea), being sick (vomiting), diarrhoea, high blood pressure and hallucinations. Slow heart beat and fainting may also occur. If you forget to take Rivastigmine Teva If you find you have forgotten to take your dose of Rivastigmine Teva, wait and take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose. 4. POSSIBLE SIDE EFFECTS Like all medicines, Rivastigmine Teva can cause side effects, although not everybody gets them. You may have side effects more often when you start your medicine or when your dose is increased. Usually, the side effects slowly go away as your body gets used to the medicine. The frequencies are defined as: Very common (affects more than 1 patient in 10) Common (affects 1 to 10 patients in 100) Uncommon (affects 1 to 10 patients in 1,000) Rare (affects 1 to 10 patients in 10, 000) Very rare (affects less than 1 patient in 10,000) Not known (frequency cannot be estimated from the available data) Very common • Feeling dizzy • Loss of appetite • Stomach problems such as feeling sick (nausea) or being sick (vomiting), diarrhoea Common • Anxiety • Sweating • Headache • Heartburn • Weight loss • Stomach pain • Feeling agitated • Feeling tired or weak • Generally feeling unwell • Trembling or feeling confused Uncommon • Depression • Difficulty in sleeping • Fainting or accidentally falling • Changes in how your liver is working 81 Me dic ina l p rod uc t n o l on ge r a uth ori se d Rare • Chest pain • Rash, itching Fits (seizures) • Ulcers in your stomach or intestine Very rare • High blood pressure • Urinary tract infection • Seeing things that are not there (hallucinations) • Problems with your heartbeat such as fast or slow heartbeat • Bleeding in the gut - shows as blood in stools or when being sick • Inflammation of the pancreas – the signs include serious upper stomach pain, often with feeling sick (nausea) or being sick (vomiting) • The signs of Parkinson’s disease get worse or getting similar signs – such as stiff muscles, difficulty in carrying out movements Not known • Being violently sick (vomiting) that can cause tearing of the tube that connects your mouth with your stomach (oesophagus). • Dehydration (losing too much fluid) • Liver disorders (yellow skin, yellowing of the whites of eyes, abnormal darkening of the urine or unexplained nausea, vomiting, tiredness and loss of appetite) • Aggression , feeling restless • Uneven heartbeat Patients with dementia and Parkinson’s disease These patients have some side effects more often. They also have some additional side effects: Very common • Trembling Common • Anxiety • Feeling restless, • Slow heartbeat • Difficulty in sleeping • Too much saliva and dehydration • Unusually slow movements or movements you cannot control • The signs of Parkinson’s disease get worse or getting similar signs – such as stiff muscles, difficulty in carrying out movements Uncommon • Uneven heartbeat and poor control of movements Other side effects seen with Rivastigmine transdermal patches and which may occur with hard capsules: Common • Fever • Severe confusion If you get any of these side effects, contact your doctor as you may need medical assistance. If any of these side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 82 Me dic ina l p rod uc t n o l on ge r a uth ori se d 5. HOW TO STORE RIVASTIGMINE TEVA Keep out of the reach and sight of children. Do not use Rivastigmine Teva after the expiry date that is stated on the carton. The expiry date refers to the last day of that month. This medicinal product does not require any special storage conditions Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Rivastigmine Teva contains The active substance is rivastigmine Rivastigmine Teva 1.5 mg hard capsules contains 1.5 mg rivastigmine as rivastigmine hydrogen tartrate Rivastigmine Teva 3 mg hard capsules contains 3 mg rivastigmine as rivastigmine hydrogen tartrate Rivastigmine Teva 4.5 mg hard capsules contains 4.5 mg rivastigmine as rivastigmine hydrogen tartrate Rivastigmine Teva 6 mg hard capsules contains 6 mg rivastigmine as rivastigmine hydrogen tartrate The other ingredients are: Capsule contents - microcrystalline cellulose, hypromellose, colloidal silicon dioxide, magnesium stearate. Capsule shell – titanium dioxide (E171), gelatin and ink used for imprinting Black S-1-17822/S-1- 17823 (shellac glaze-45% in ethanol containing iron oxide black, N-butyl alcohol, isopropyl alcohol, propylene alcohol and ammonium hydroxide). In addition, Rivastigmine Teva 3 mg, 4.5 mg and 6 mg hard capsules contain red iron oxide (E172) and yellow iron oxide (E 172). What Rivastigmine Teva looks like and contents of the pack Hard capsule - Rivastigmine Teva 1.5 mg hard capsules: White cap imprinted with “R” & white body imprinted with “1.5” - Rivastigmine Teva 3 mg hard capsules: Flesh colour cap imprinted with “R” & flesh colour body imprinted with “3” - Rivastigmine Teva 4.5 mg hard capsules: Orange colour cap imprinted with “R” & orange colour body imprinted with “4.5” - Rivastigmine Teva 6 mg hard capsules: Orange cap imprinted with “R” & flesh colour body imprinted with “6” Rivastigmine Teva hard capsules are available in blister packs of 28, 56 and 112 capsules, perforated blisters containing 50 x 1 capsules, and bottles containing 250 capsules. Marketing Authorisation Holder Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands Manufacturer 83 Me dic ina l p rod uc t n o l on ge r a uth ori se d TEVA Pharmaceutical Works Private Limited Company Pallagi út 13, 4042 Debrecen, Hungary Or: TEVA Pharmaceutical Works Private Limited Company H-2100 Gödöllő, Táncsics Mihály út 82 Hungary Or: TEVA UK Ltd Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG United Kingdom Or: Pharmachemie B.V. Swensweg 5, 2031 GA Haarlem The Netherlands Or: TEVA Santé, Rue Bellocier, 89100, Sens, France Or:Teva Czech Industries s.r.o. Ostravska 29, c.p. 305 747 70 Opava-Komarov Czech Republic For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Teva Pharma Belgium N.V./S.A./AG Tel/Tél: +32 3 820 73 73 Luxembourg/Luxemburg Teva Pharma Belgium S.A. Tél/Tel: +32 3 820 73 73 България Тева Фармасютикълс България ЕООД Teл: +359 2 489 95 82 Magyarország Teva Magyarország Zrt Tel.: +36 1 288 64 00 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251 007 111 Malta Drugsales Ltd Tel: +356 21 419 070/1/2 Danmark Teva Denmark A/S Tlf: +45 44 98 55 11 Nederland Teva Nederland B.V. Tel: +31 (0) 800 0228400 84 Me dic ina l p rod uc t n o l on ge r a uth ori se d 85 Deutschland Teva GmbH Tel: + 49 731 402 08 Norge Teva Norway AS Tlf: +46 66 77 55 90 Eesti Teva Eesti esindus UAB Sicor Biotech Eesti filiaal Tel: +372 6610801 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1 97 007 Ελλάδα Teva Ελλάς Α.Ε. Τηλ: +30 210 72 79 099 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel.: +(48) 22 345 93 00 España Teva Pharma, S.L.U Tél: +(34) 91 387 32 80 Portugal Teva Pharma - Produtos Farmacêuticos Lda Tel: (351) 214 235 910 France Teva Santé Tél: +(33) 1 55 91 7800 România Teva Pharmaceuticals S.R.L Tel: +4021 230 65 24 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)42 9395 892 Slovenija Pliva Ljubljana d.o.o. Tel: +386 1 58 90 390 Ísland Teva UK Limited Sími: +(44) 1323 501 111. Slovenská republika Teva Pharmaceuticals Slovakia s.r.o. Tel: +(421) 2 5726 7911 Italia Teva Italia S.r.l. Tel: +(39) 0289179805 Suomi/Finland ratiopharm Oy Puh/Tel: +(46) 42 12 11 00 Κύπρος Teva Ελλάς Α.Ε. Τηλ: +30 210 72 79 099 Sverige Teva Sweden AB Tel: +(46) 42 12 11 00 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 67 784 980 United Kingdom Teva UK Limited Tel: +(44) 1323 501 111 Lietuva UAB “Sicor Biotech” Tel: +370 5 266 02 03 This leaflet was last approved in {MM/YYYY}. Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to take rivastigmine teva', 'Section_Content': 'always take rivastigmine teva exactly as your doctor has told you. you should check with your doctor or pharmacist if you are not sure. how to start treatment your doctor will tell you what dose of rivastigmine teva to take. treatment usually starts with a low dose. your doctor will slowly increase your dose depending on how you respond to the treatment. the highest dose that should be taken is 6.0 mg twice a day. your doctor will regularly check if the medicine is working for you. your doctor will also monitor your weight whilst you are taking this medicine. if you have not taken rivastigmine teva for several days, do not take the next dose until you have talked to your doctor. taking this medicine tell your caregiver that you are taking rivastigmine teva. to benefit from your medicine, take it every day. take rivastigmine teva twice a day, in the morning and evening, with food. swallow the capsules whole with a drink. do not open or crush the capsules. if you take more rivastigmine teva than you should if you accidentally take more rivastigmine teva than you should, inform your doctor. you may require medical attention. some people who have accidentally taken too much rivastigmine teva have experienced feeling sick (nausea), being sick (vomiting), diarrhoea, high blood pressure and hallucinations. slow heart beat and fainting may also occur. if you forget to take rivastigmine teva if you find you have forgotten to take your dose of rivastigmine teva, wait and take the next dose at the usual time. do not take a double dose to make up for a forgotten dose.', 'Entity_Recognition': [{'Text': 'rivastigmine teva', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'rivastigmine teva', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 29}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 149, 'EndOffset': 158}, {'Text': 'rivastigmine teva', 'Type': 'TREATMENT', 'BeginOffset': 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, rivastigmine teva can cause side effects, although not everybody gets them. you may have side effects more often when you start your medicine or when your dose is increased. usually, the side effects slowly go away as your body gets used to the medicine. the frequencies are defined as: very common (affects more than 1 patient in 10) common (affects 1 to 10 patients in 100) uncommon (affects 1 to 10 patients in 1,000) rare (affects 1 to 10 patients in 10, 000) very rare (affects less than 1 patient in 10,000) not known (frequency cannot be estimated from the available data) very common feeling dizzy loss of appetite stomach problems such as feeling sick (nausea) or being sick (vomiting), diarrhoea common anxiety sweating headache heartburn weight loss stomach pain feeling agitated feeling tired or weak generally feeling unwell trembling or feeling confused uncommon depression difficulty in sleeping fainting or accidentally falling changes in how your liver is working 81 rare chest pain rash, itching fits (seizures) ulcers in your stomach or intestine very rare high blood pressure urinary tract infection seeing things that are not there (hallucinations) problems with your heartbeat such as fast or slow heartbeat bleeding in the gut - shows as blood in stools or when being sick inflammation of the pancreas the signs include serious upper stomach pain, often with feeling sick (nausea) or being sick (vomiting) the signs of parkinson's disease get worse or getting similar signs such as stiff muscles, difficulty in carrying out movements not known being violently sick (vomiting) that can cause tearing of the tube that connects your mouth with your stomach (oesophagus). dehydration (losing too much fluid) liver disorders (yellow skin, yellowing of the whites of eyes, abnormal darkening of the urine or unexplained nausea, vomiting, tiredness and loss of appetite) aggression , feeling restless uneven heartbeat patients with dementia and parkinson's disease these patients have some side effects more often. they also have some additional side effects: very common trembling common anxiety feeling restless, slow heartbeat difficulty in sleeping too much saliva and dehydration unusually slow movements or movements you cannot control the signs of parkinson's disease get worse or getting similar signs such as stiff muscles, difficulty in carrying out movements uncommon uneven heartbeat and poor control of movements other side effects seen with rivastigmine transdermal patches and which may occur with hard capsules: common fever severe confusion if you get any of these side effects, contact your doctor as you may need medical assistance. if any of these side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.", 'Entity_Recognition': [{'Text': 'rivastigmine teva', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, 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{'Title': '5. how to store rivastigmine teva', 'Section_Content': 'keep out of the reach and sight of children. do not use rivastigmine teva after the expiry date that is stated on the carton. the expiry date refers to the last day of that month. this medicinal product does not require any special storage conditions medicines should not be disposed of via wastewater or household waste. ask your pharmacist how to dispose of medicines no longer required. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'rivastigmine teva', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'rivastigmine teva', 'Type': 'TREATMENT', 'BeginOffset': 56, 'EndOffset': 73}, {'Text': 'any special storage conditions medicines', 'Type': 'TREATMENT', 'BeginOffset': 220, 'EndOffset': 260}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 360, 'EndOffset': 369}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 390, 'EndOffset': 404}]}

{'Title': '6. further information', 'Section_Content': 'what rivastigmine teva contains the active substance is rivastigmine rivastigmine teva 1.5 mg hard capsules contains 1.5 mg rivastigmine as rivastigmine hydrogen tartrate rivastigmine teva 3 mg hard capsules contains 3 mg rivastigmine as rivastigmine hydrogen tartrate rivastigmine teva 4.5 mg hard capsules contains 4.5 mg rivastigmine as rivastigmine hydrogen tartrate rivastigmine teva 6 mg hard capsules contains 6 mg rivastigmine as rivastigmine hydrogen tartrate the other ingredients are: capsule contents - microcrystalline cellulose, hypromellose, colloidal silicon dioxide, magnesium stearate. capsule shell titanium dioxide (e171), gelatin and ink used for imprinting black s-1-17822/s-1- 17823 (shellac glaze-45% in ethanol containing iron oxide black, n-butyl alcohol, isopropyl alcohol, propylene alcohol and ammonium hydroxide). in addition, rivastigmine teva 3 mg, 4.5 mg and 6 mg hard capsules contain red iron oxide (e172) and yellow iron oxide (e 172). what rivastigmine teva looks like and contents of the pack hard capsule - rivastigmine teva 1.5 mg hard capsules: white cap imprinted with "r" & white body imprinted with "1.5" - rivastigmine teva 3 mg hard capsules: flesh colour cap imprinted with "r" & flesh colour body imprinted with "3" - rivastigmine teva 4.5 mg hard capsules: orange colour cap imprinted with "r" & orange colour body imprinted with "4.5" - rivastigmine teva 6 mg hard capsules: orange cap imprinted with "r" & flesh colour body imprinted with "6" rivastigmine teva hard capsules are available in blister packs of 28, 56 and 112 capsules, perforated blisters containing 50 x 1 capsules, and bottles containing 250 capsules.', 'Entity_Recognition': [{'Text': 'rivastigmine teva', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'what rivastigmine teva', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 22}, {'Text': 'rivastigmine rivastigmine teva', 'Type': 'TREATMENT', 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75C161A3455F36F9417F2F8FF16A74A4

https://www.ema.europa.eu/documents/product-information/neurobloc-epar-product-information_en.pdf

NeuroBloc

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT NeuroBloc 5000 U/ml solution for injection. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each ml contains 5000 U Botulinum Toxin Type B. Each 0.5 ml vial contains 2500 U Botulinum Toxin Type B. Each 1.0 ml vial contains 5000 U Botulinum Toxin Type B. Each 2.0 ml vial contains 10,000 U Botulinum Toxin Type B. Produced in Clostridium botulinum Serotype B (Bean Strain) cells. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection. Clear and colourless to light yellow solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications NeuroBloc is indicated for the treatment of cervical dystonia (torticollis) in adults. 4.2 Posology and method of administration NeuroBloc should only be administered by a physician who is familiar with and experience in the treatment of cervical dystonia and in the use of botulinum toxins. Restricted to hospital use only. Posology The initial dose is 10,000 U and should be divided between the two to four most affected muscles. Data from clinical studies suggest that efficacy is dose dependent, but these trials, because they were not powered for a comparison, do not show a significant difference between 5000 U and 10,000 U. Therefore an initial dose of 5000 U may also be considered, but a dose of 10,000 U may increase the likelihood of clinical benefit. Injections should be repeated as required to maintain good function and minimise pain. In long term clinical studies, the average dosing frequency was approximately every 12 weeks, however this may vary between subjects, and a proportion of patients maintained a significant improvement relative to baseline for 16 weeks or longer. The dosing frequency should therefore be adapted based on the clinical assessment/response of an individual patient. For patients with reduced muscle mass the dose should be adjusted according to individual patient need. The potency of this medicinal product is expressed in NeuroBloc 5000 U/ml. These units are not interchangeable with the units used to express the potency of other botulinum toxin preparations (see section 4.4). Special populations Elderly No dose adjustment is required in older people ≥ 65 years of age. 3 Renal and hepatic impairment Studies have not been carried out in patients with hepatic or renal impairment. However, the pharmacological characteristics do not indicate any need to adjust the dose. Paediatric population The safety and efficacy of NeuroBloc in children aged less than 18 years have not yet been established. No data are available. Method of administration NeuroBloc must only be administered by intramuscular injection. Particular caution should be paid to ensure that it is not injected into a blood vessel. The initial dose of 10,000 U should be divided between the two to four most affected muscles. To allow division of the total dose between several injections, NeuroBloc may be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection and the solution used immediately. For instructions on dilution of the product before administration, see section 6.6. 4.3 Contraindications Individuals with known neuromuscular diseases (e.g. amyotrophic lateral sclerosis or peripheral neuropathy) or known neuromuscular junctional disorders (e.g. myasthenia gravis or Lambert-Eaton syndrome) must not be given NeuroBloc. Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use NeuroBloc is recommended for intramuscular administration only. The safety of NeuroBloc outside the approved indication has not been established. This warning includes use in children and in any other indication besides cervical dystonia. The risks, which can include death, may outweigh the potential benefits. Seroconversion As with many biological/biotechnology proteins used as therapeutic agents, repeated administration of NeuroBloc may be associated with development of antibodies to Botulinum Toxin Type B in some patients. Immunogenicity data from three long term clinical studies indicate that approximately one third of patients develop antibodies, as determined by the mouse neutralisation/mouse protection assay dependent on duration of exposure (see section 5.1). An investigation into the consequence of seroconversion showed that the presence of antibodies was not synonymous with a loss of clinical response, and did not have an impact on the overall safety profile. However, the clinical relevance of the presence of antibodies as determined by the mouse neutralisation / mouse protection assay is uncertain. Caution should be used in patients with bleeding disorders or receiving anticoagulant therapy. Spread of toxin effect Neuromuscular effects related to spread of toxin, distant from the site of administration have been reported (see section 4.8). These include dysphagia and breathing difficulties. 4 Pre-Existing neuromuscular disorders Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including severe dysphagia and respiratory compromise from typical doses of NeuroBloc (see section 4.3). There have been spontaneous reports of dysphagia, aspiration pneumonia and/or potentially fatal respiratory disease, after treatment with Botulinum Toxin Type A/B. Children (non approved use) and patients with underlying neuromuscular disorders including swallowing disorders are at increased risk of these adverse reactions. In patients with neuromuscular disorders or history of dysphagia and aspiration, botulinum toxins should only be used in an experimental setting under strict medical supervision. Following NeuroBloc treatment, all patients and caregivers should be advised to seek medical attention for respiratory difficulties, choking or any new or worsening dysphagia. Dysphagia has been reported following injection to sites other than the cervical musculature. Lack of interchangeability between botulinum toxin products The initial starting dose of 10,000 U (or 5000 U) is relevant only to NeuroBloc (Botulinum Toxin Type B). These dose units are specific to NeuroBloc only and are not relevant to preparations of Botulinum Toxin Type A. The unit dose recommendations for Botulinum Toxin Type A are significantly lower than those for NeuroBloc and administration of Botulinum Toxin Type A at the unit dose recommended for NeuroBloc may result in systemic toxicity and life-threatening clinical sequelae. 4.5 Interaction with other medicinal products and other forms of interaction The effect of administering different botulinum neurotoxin serotypes concurrently is unknown. However, in clinical studies, NeuroBloc was administered 16 weeks after the injection of Botulinum Toxin Type A. Co-administration of NeuroBloc and aminoglycosides or agents interfering with neuromuscular transmission (e.g. curare-like compounds) should be considered with caution. 4.6 Fertility, pregnancy and lactation Pregnancy Animal reproduction studies are insufficient with respect to effects on pregnancy and embryonal/foetal development. The potential risk for humans is unknown. NeuroBloc should not be used during pregnancy unless the clinical condition of the woman requires treatment with Botulinum Toxin Type B (see section 5.3). Breast-feeding It is unknown whether Botulinum Toxin Type B is excreted in human breast milk. The excretion of Botulinum Toxin Type B in milk has not been studied in animals. A decision must be made on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with NeuroBloc taking into account the benefit of breast-feeding to the child and the benefit of NeuroBloc therapy to the woman. Fertility No fertility studies have been performed and it is not known whether NeuroBloc can affect reproduction capacity. 5 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Neurobloc may impair the ability to drive or operate machinery in case of adverse reactions such as muscle weakness and eye disorders (blurred vision, eyelid ptosis). 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions associated with NeuroBloc treatment were dry mouth, dysphagia, dyspepsia, and injection site pain. Adverse reactions related to spread of toxin distant from the site of administration have been reported: exaggerated muscle weakness, dysphagia, dyspnoea, aspiration pneumonia with fatal outcome in some cases (see section 4.4). Tabulated list of adverse reactions Adverse reactions seen in all clinical studies are listed below according to MedDRA system organ class and in decreasing frequency which is defined as follows: Very Common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1000 to <1/100). System Organ Class Very Common Common Nervous system disorders dry mouth, headache torticollis (worsening from baseline), taste perversion Eye disorders blurred vision Respiratory thoracic and mediastinal disorders dysphonia Gastrointestinal disorders dysphagia dyspepsia Musculoskeletal connective tissue and bone disorders myasthenia General disorders and administration site conditions injection site pain neck pain influenza like illness In common with Botulinum Toxin Type A, electrophysiological jitter, which is not associated with clinical weakness or other electrophysiological abnormalities, may be experienced in some distant muscles. Post marketing experience Side effects related to spread of toxin distant from the site of administration have been reported (exaggerated muscle weakness, dysphagia, dyspnoea, aspiration pneumonia with fatal outcome in some cases) (see section 4.4). The following effects have also been reported during post marketing use: abnormal accommodation, ptosis, vomiting, constipation, flu-like symptoms, asthenia, angioedema, rash, urticaria and pruritus. The available reports indicate that the product has been used in the paediatric population. Case reports are more likely to be serious in children (40%) compared to those in adults and older people (12%), possibly as a result of using an inappropriately high dosage for the child (see section 4.9). 6 Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Cases of overdose (some with signs of systemic toxicity) have been reported. In the event of an overdose, general medical supportive measures should be instituted. Doses of up to 15,000 U have infrequently resulted in clinically significant systemic toxicity in adults. If botulism is clinically suspected, hospitalisation for the monitoring of respiratory function (incipient respiratory failure) may be required. In the event of an overdose or injection into a muscle that normally compensates for the cervical dystonia, it is conceivable that the dystonia may worsen. As with other botulinum toxins spontaneous recovery will occur over a period of time. Paediatric use (non approved): in children, clinically significant systemic toxicity has occurred at doses approved for the treatment of adult patients. The risk of spreading of effect is greater than in adults, and more frequently severe. This can be due to the high dosages usually used in this population. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: muscle relaxant, peripherally acting agents, ATC code: M03AX 01. Mechanism of action NeuroBloc is a neuromuscular blocking agent. The mechanism of action of NeuroBloc in blocking neuromuscular conduction occurs by a three-step process: 1. Extracellular binding of the toxin to specific acceptors on motor nerve terminals 2. Internalisation and release of the toxin into the cytosol of the nerve terminals 3. Inhibition of acetylcholine release from nerve terminals at the neuromuscular junction When injected directly into a muscle, NeuroBloc causes a localised paralysis that gradually reverses over time. The mechanism by which muscle paralysis is reversed over time remains unknown, but may be associated with the intraneuronal turnover of the affected protein and/or sprouting of the nerve ending. Clinical efficacy and safety A series of clinical studies have been conducted to evaluate the efficacy and safety of NeuroBloc in the treatment of cervical dystonia. These studies have demonstrated the activity of NeuroBloc in both treatment-naïve patients, and patients who have previously received treatment with Botulinum Toxin Type A, including those that were considered clinically resistant to Botulinum Toxin Type A. Two Phase III randomised, multicentre, double-blind, placebo-controlled studies were conducted in patients with cervical dystonia. Both studies enrolled adult patients (³ 18 years) who had a history of receiving Botulinum Toxin Type A. The first study enrolled patients who were clinically resistant to type A toxin (A-non responders), confirmed by a Frontalis Type A test. The second study enrolled patients who continued to respond to type A toxin (A-responders). In the first study, type A resistant patients (A-non responders) were randomised to receive placebo or 10,000 U of NeuroBloc and in the second, type A toxin responsive patients (A-responders) were randomised to receive placebo, 5000 U or 10,000 U of toxin. The medicinal product was injected on a single occasion into 2 to 4 of the https://view.officeapps.live.com/op/view.aspx?src=https%3A%2F%2Fwww.ema.europa.eu%2Fdocs%2Fen_GB%2Fdocument_library%2FTemplate_or_form%2F2013%2F03%2FWC500139752.doc 7 following muscles: splenius capitus, sternocleidomastoid, levator scapulae, trapezius, semispinalis capitus and scalene. The total dose was divided between the selected muscles and 1 to 5 injections per muscle were administered. There were 77 subjects enrolled into the first study and 109 subjects into the second. Patient evaluations continued for 16 weeks post injection. The primary efficacy outcome variable for both studies was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score (range of possible scores is 0-87) at Week 4. The secondary endpoints included Visual Analogue Scales (VAS) to quantify the Patient Global Assessment of change and the Physician Global Assessment of change, both from baseline to Week 4. On these scales, scores of 50 indicate no change, 0 much worse, and 100 much better. Results of comparisons of the primary and secondary efficacy variables are summarised in Table 1. Analysis of the TWSTRS sub scales revealed significant effects on the severity of cervical dystonia and its associated pain and disability. Table 1 Efficacy Results from Phase III NeuroBloc Studies STUDY 1 (A-Resistant Patients) STUDY 2 (A-Responsive Patients) Assessments Placebo 10,000 U Placebo 5000 U 10,000 U n = 38 n = 39 n = 36 n = 36 n = 37 TWSTRS-Total Mean At Baseline 51.2 52.8 43.6 46.4 46.9 Mean at Week 4 49.2 41.8 39.3 37.1 35.2 Change from Baseline -2.0 -11.1 -4.3 -9.3 -11.7 P-Value* 0.0001 0.0115 0.0004 Patient Global Mean at Week 4 39.5 60.2 43.6 60.6 64.6 P-Value* 0.0001 0.0010 0.0001 Physician Global Mean at Week 4 47.9 60.6 52.0 65.3 64.2 P-Value* 0.0001 0.0011 0.0038 * Analysis of covariance, two-tailed tests, a = 0.05 A further randomised, multicentre, double-blind study was conducted to compare the efficacy of NeuroBloc (10,000 U) to Botulinum Toxin Type A (150 U) in patients with cervical dystonia who have never previously received a botulinum toxin product. The primary efficacy assessment was the TWSTRS Total score, and secondary efficacy assessments included VAS assessment of change evaluated by patient and investigator, conducted at 4, 8 and 12 weeks after treatment. The study met the pre-defined criteria for non-inferiority of NeuroBloc compared to Botulinum Toxin Type A, both in terms of mean TWSTRS total score at week 4 after first and second treatment sessions, and in terms of duration of effect. The non-inferiority of NeuroBloc compared to Botulinum Toxin Type A was further supported by a responder analysis where similar percentages of subjects showed improvement in the TWSTRS score at Week 4 of Session 1 (86% NeuroBloc and 85% Botox), and a similar proportion of subjects experienced at least a 20% decrease from baseline in the TWSTRS score at Week 4 of Session 1 (51% NeuroBloc, 47% Botox). Further clinical studies and open label follow-up have shown that subjects can continue to respond to NeuroBloc for prolonged periods of time, with some subjects receiving more than 14 treatment sessions over a period of more than 3.5 years. In addition to improved function as demonstrated by a reduction in TWSTRS-total score, treatment with NeuroBloc was associated with a significant reduction in TWSTRS-Pain and pain VAS scores at each treatment session at weeks 4, 8 and 12 relative to baseline. In these studies, the average dosing frequency was approximately every 12 weeks. 8 The immunogenicity of NeuroBloc has been evaluated in two clinical studies and an open-label extension study. The presence of antibodies in these studies was assessed using the mouse protection assay (also known as the Mouse Neutralization Assay, MNA). Immunogenicity data from three long-term clinical studies indicate that approximately one third of patients develop antibodies, as determined by the mouse neutralisation/ mouse protection assay dependent on duration of exposure. Specifically, these studies showed approximately 19-25% seroconverted within 18 months of initiation of treatment, increasing to approximately 33-44% with up to 45 months of treatment. An investigation into the consequence of seroconversion showed that the presence of antibodies was not synonymous with a loss of clinical response, and did not have an impact on the overall safety profile. However, the clinical relevance of the presence of antibodies as determined by the mouse neutralisation/ mouse protection assay is uncertain. The extent and time course of seroconversion were similar in patients with prior toxin A exposure and those who were toxin A naïve, and between toxin A resistant and toxin A responsive patients. 5.2 Pharmacokinetic properties NeuroBloc injected intramuscularly produces localised muscle weakness by chemical denervation. Following local intramuscular injection of NeuroBloc serious adverse events that may have been due to systemic effects of Botulinum Toxin Type B, were observed in 12% of adverse reaction cases reported during the post-marketing experience (including the following adverse reactions: dry mouth, dysphagia and blurred vision). However, no pharmacokinetic or Absorption, Distribution, Metabolism and Excretion (ADME) studies have been performed. 5.3 Preclinical safety data Single dose pharmacology studies in cynomolgus monkeys have shown no effects other than the anticipated dose-dependent paralysis of injected muscles, together with some diffusion of toxin at high doses producing similar effects in neighbouring non-injected muscles. Single dose intramuscular toxicology studies have been performed in cynomolgus monkeys. The systemic No Observed Effect Level (NOEL) was shown to be approximately 960 U/kg. The dose resulting in death was 2400 U/kg. Because of the nature of the product, no animal studies have been carried out to establish the carcinogenic effects of NeuroBloc. Standard tests to investigate the mutagenicity of NeuroBloc have not been performed. Development studies in rats and rabbits have shown no evidence of foetal malformations or changes to fertility. In the development studies, the No Observed Adverse Effect Dose Level (NOAEL) in rats was 1000 U/kg/day for maternal effects and 3000 U/kg/day for foetal effects. In rabbits, the NOAEL was 0.1 U/kg/day for maternal effects and 0.3 U/kg/day for foetal effects. In the fertility studies the NOAEL was 300 U/kg/day for general toxicity in both males and females and 1000 U/kg/day for fertility and reproductive performance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Disodium succinate Sodium chloride Human serum albumin Hydrochloric acid (for pH adjustment) Water for injections 9 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 5 years, as packaged for sale. Use immediately if diluted (see section 4.2 and section 6.6). From a microbiological point of view, unless the method of opening/dilution precludes the risk of microbial contamination the product should be used immediately. 6.4 Special precautions for storage Store in a refrigerator at 2oC-8oC. Do not freeze. Keep the container in the outer carton in order to protect from light. Within its shelf-life, the product may be removed from the refrigerator for a single period of up to 3 months at a temperature not above 25°C, without being refrigerated again. At the end of this period, the product should not be put back in the refrigerator and should be disposed of. For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 0.5 ml, 1 ml or 2 ml solution in a 3.5 ml Type I glass vial, with siliconised butyl rubber stoppers oversealed by aluminium crimped caps. Pack size of 1. 6.6 Special precautions for disposal and other handling NeuroBloc is provided in vials for single use only. The medicinal product is ready to use and no reconstitution is required. Do not shake. To allow division of the total dose between several injections, NeuroBloc may be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection (see section 4.2). Such dilutions with sodium chloride should be done in a syringe, pulling out the desired amount of Neurobloc into the syringe first, and then adding sodium chloride to the syringe. In non clinical experiments, NeuroBloc solution has been diluted up to 6-fold without any resulting change in potency. Once diluted, the medicinal product must be used immediately as the formulation does not contain a preservative. Any unused solution, all vials of expired NeuroBloc and equipment used in the administration of the medicinal product should be carefully discarded as Medical Bioharzardous Waste in accordance with local requirements. Vials should be visually inspected prior to use. If the NeuroBloc solution is not clear and colourless/light yellow or if the vial appears damaged, the product should not be used, but discarded as Medical Biohazardous Waste in accordance with local requirements. Decontaminate any spill with 10% caustic solution, or sodium hypochlorite (household chlorine bleach –2 ml (0.5%): 1 litre water) solution. Wear waterproof gloves and soak up the liquid with an appropriate absorbent. Place the absorbed toxin in an autoclave bag, seal it and process as Medical Biohazardous Waste in accordance with local requirements. 10 7. MARKETING AUTHORISATION HOLDER Sloan Pharma S.à.r.l. 33, Rue du Puits Romain 8070 Bertrange Luxembourg 8. MARKETING AUTHORISATION NUMBER(S) EU/1/00/166/001 – 2500 U EU/1/00/166/002 – 5000 U EU/1/00/166/003 – 10,000 U 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 22 January 2001 Date of latest renewal: 29 November 2010 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 11 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 12 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Merz Pharma GmbH & Co. KGaA AmPharmapark Dessau-Rosslau Germany Name and address of the manufacturer responsible for batch release Almac Pharma Services Limited Seagoe Industrial Estate Portadown Craigavon BT63 5UA United Kingdom And Almac Pharma Services (Ireland) Limited Finnabair Industrial Estate Dundalk Co. Louth A91 P9KD Ireland The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; 13 • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. 14 ANNEX III LABELLING AND PACKAGE LEAFLET 15 A. LABELLING 16 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 0.5 ml vial 1. NAME OF THE MEDICINAL PRODUCT NeuroBloc 5000 U/ml solution for injection Botulinum Toxin Type B 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml contains 5000 U Botulinum Toxin Type B. One vial of 0.5 ml contains 2500 U of Botulinum Toxin Type B. 3. LIST OF EXCIPIENTS Disodium succinate, sodium chloride, human serum albumin solution, hydrochloric acid and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Do not shake. Read the package leaflet before use. Intramuscular use. For single use only. 6. SPECIAL WARNINGS THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY The potency of Neurobloc is 5000 U/ml. The units expressed are Type B Units, which are not interchangeable with the units used to express the potency of other Botulinum toxin preparations. 8. EXPIRY DATE EXP After dilution, use immediately 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator (2°C-8°C). Do not freeze. 17 Keep the container in the outer carton in order to protect from light. Within its shelf-life, the product may be removed from the refrigerator for one single period of up to 3 months at a temperature not above 25°C without being refrigerated again. At the end of this period, the product should not be put back in the refrigerator and should be disposed of. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Read package leaflet for special precautions for handling, in-use storage and disposal. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: Sloan Pharma S.à.r.l. 33, Rue du Puits Romain 8070 Bertrange Luxembourg 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/166/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 18 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 0.5 ml vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION NeuroBloc 5000 U/ml solution for injection IM 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2500 U 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1.0 ml vial 1. NAME OF THE MEDICINAL PRODUCT NeuroBloc 5000 U/ml Solution for injection Botulinum Toxin Type B 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml contains 5000 U Botulinum Toxin Type B. One vial of 1 ml contains 5000 U of Botulinum Toxin Type B. 3. LIST OF EXCIPIENTS Disodium succinate, sodium chloride, human serum albumin solution, hydrochloric acid and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Do not shake. Read the package leaflet before use. Intramuscular use. For single use only. 6. SPECIAL WARNINGS THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY The potency of Neurobloc is 5000 U/ml. The units expressed are Type B Units, which are not interchangeable with the units used to express the potency of other Botulinum toxin preparations. 8. EXPIRY DATE EXP After dilution, use immediately 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator (2°C-8°C). Do not freeze. 20 Keep the container in the outer carton in order to protect from light. Within its shelf-life, the product may be removed from the refrigerator for one single period of up to 3 months at a temperature not above 25°C without being refrigerated again. At the end of this period, the product should not be put back in the refrigerator and should be disposed of. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Read package leaflet for special precautions for handling, in-use storage and disposal. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: Sloan Pharma S.à.r.l. 33, Rue du Puits Romain 8070 Bertrange Luxembourg 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/166/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 21 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 1.0 ml vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION NeuroBloc 5000 U/ml solution for injection IM 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 5000 U 22 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 2.0 ml vial 1. NAME OF THE MEDICINAL PRODUCT NeuroBloc 5000 U/ml Solution for injection Botulinum Toxin Type B 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml contains 5000 U of Botulinum Toxin Type B. One vial of 2 ml contains 10,000 U of Botulinum Toxin Type B. 3. LIST OF EXCIPIENTS Disodium succinate, sodium chloride, human serum albumin solution, hydrochloric acid and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Do not shake. Read the package leaflet before use. Intramuscular use. For single use only. 6. SPECIAL WARNINGS THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY The potency of Neurobloc is 5000 U/ml. The units expressed are Type B Units, which are not interchangeable with the units used to express the potency of other Botulinum toxin preparations. 8. EXPIRY DATE EXP After dilution, use immediately 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator (2°C-8°C). Do not freeze. 23 Keep the container in the outer carton in order to protect from light. Within its shelf-life, the product may be removed from the refrigerator for one single period of up to 3 months at a temperature not above 25°C without being refrigerated again. At the end of this period, the product should not be put back in the refrigerator and should be disposed of. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Read package leaflet for special precautions for handling, in-use storage and disposal. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: Sloan Pharma S.à.r.l. 33, Rue du Puits Romain 8070 Bertrange Luxembourg 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/166/003 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 24 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 2.0 ml vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION NeuroBloc 5000 U/ml solution for injection IM 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10,000 U 25 B. PACKAGE LEAFLET 26 Package leaflet: Information for the user NeuroBloc 5000 U/ml Solution for Injection Botulinum Toxin Type B Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have further questions, please ask your doctor or pharmacist. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What NeuroBloc is and what it is used for 2. What you need to know before you use NeuroBloc 3. How to use NeuroBloc 4. Possible side effects 5. How to store NeuroBloc 6. Contents of the pack and other information 1. What NeuroBloc is and what it is used for NeuroBloc injection works by reducing or stopping muscle contractions. It contains the active ingredient ‘Botulinum Toxin Type B’. NeuroBloc is used to treat an illness called cervical dystonia (torticollis). This is where you have contractions of your neck or shoulder muscles that you cannot control. 2. What you need to know before you use NeuroBloc Do not use NeuroBloc: - if you are allergic to Botulinum Toxin Type B or any of the other ingredients of NeuroBloc (listed in section 6) - if you have other problems with your nerves or muscles, such as amyotrophic lateral sclerosis (Lou Gehrig's disease), peripheral neuropathy, myasthenia gravis or Lambert-Eaton syndrome (muscle weakness or numbness or pain) - if you have been experiencing shortness of breath or difficulty swallowing You must not be given NeuroBloc if any of the above applies to you. If you are not sure talk to your doctor or pharmacist. Warnings and precautions Talk to your doctor or pharmacist before using NeuroBloc: - if you have a bleeding problem such as haemophilia - if you have lung problems - if you have difficulty swallowing. This is because swallowing problems could make you breathe food or liquids into your lungs, which could then cause very serious pneumonia 27 General precaution: NeuroBloc has been approved for the treatment of cervical dystonia only and should not be used to treat anything else. The safety of NeuroBloc when used to treat other conditions is not known: some side effects may be fatal. Children and adolescents NeuroBloc is not to be used in children aged less than18 years. Other medicines and NeuroBloc Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because NeuroBloc can affect the way some medicines work and other medicines can also affect the way NeuroBloc works. In particular, tell your doctor or pharmacist if you are taking any of the following medicines: - aminoglycoside antibiotics for an infection - medicines to stop blood clotting, such as warfarin If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before you are given NeuroBloc. Before having an operation If you are going to have an operation, please tell your doctor that you have been given NeuroBloc. This is because NeuroBloc can affect the medicines you may be given before a general anaesthetic. Pregnancy, breast-feeding and fertility - you will not normally be given NeuroBloc if you are pregnant or breast-feeding. This is because it is not known how NeuroBloc affects patients who are pregnant and it is not known if NeuroBloc passes into a nursing mother’s breast milk - if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine Driving and using machines You may have muscle weakness or eye problems such as blurred vision or eyelid drooping after being given NeuroBloc. If this happens, do not drive or use any tools or machines. NeuroBloc contains less than 1 mmol sodium (23 mg) per 10,000 units of NeuroBloc. This means it is essentially “sodium free”. 3. How to use NeuroBloc NeuroBloc will be given to you by a doctor with specialist experience in the treatment of cervical dystonia and in the use of botulinum toxins. How much will be given - your doctor will decide how much NeuroBloc to give you - the usual dose is 10,000 units, however, it can be higher or lower - if you have had NeuroBloc injections before, your doctor will take into account how well it worked the other times How NeuroBloc is given - NeuroBloc will be injected into your neck or shoulder muscles, depending on which ones are causing the problem - your doctor may inject part of the dose into different places in your muscles Having more injections of NeuroBloc - the effects of NeuroBloc will usually last about 12 to 16 weeks - your doctor will decide if you need another injection and how much to give you If you think that the effect of NeuroBloc is too strong or too weak, talk to your doctor. 28 If you are given more NeuroBloc than you should - if you have been given more NeuroBloc than you need, some of your muscles that were not injected may feel weak or you may develop symptoms away from the injected muscles, like difficulty in swallowing or breathing. This may occur when higher doses of up to 15,000 units are given - if you have difficulty breathing or you are worried by any symptoms you develop away from the place of the injection, talk to your doctor immediately. If he/she is unavailable seek emergency assistance. You may need urgent medical treatment A serious condition called “botulism” which causes paralysis of muscles and respiratory failure could occur if too much of the active ingredient (botulinum toxin) is injected into the body. If your doctor suspects that botulism may have occurred, you will be admitted to hospital and your breathing (respiratory function) will be monitored. Recovery usually takes place over a period of time. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. They may happen days to weeks after you have had the injection. You may feel pain at the place where you had the injection, but this should wear off after a few minutes. You may get a dry mouth and it might become difficult to swallow. In rare cases difficulty in swallowing may be severe and choking is possible. If your swallowing difficulty gets worse or you have choking or breathing problems, see a doctor immediately. You may need urgent medical treatment. Aspiration pneumonia caused by food particles or vomit entering into the lungs, and respiratory disease, have been reported after treatment with botulinum toxins (Type A and Type B). These side effects have sometimes resulted in death and are possibly related to the spread of botulinum toxin to body parts away from the place where the injection is given. Other side effects include: Very common (may affect more than 1 in 10 people) - dry mouth - difficulty swallowing - headache Common (may affect up to 1 in 10 people) - blurred vision or drooping of your upper eyelid - indigestion or being sick (vomiting) - constipation - neck pain - feeling weak, pain or stiff muscles around your body - loss of strength or energy - changes in the taste of your food and drink - changes in the sound of your voice - flu-like symptoms Skin allergies such as rash with or without paleness, redness, patches, severe itching; and skin eruptions such as welts or hives have also been reported after receiving NeuroBloc. The frequency of these side effects is not known. It is possible that cervical dystonia could become worse after you have had your injection. 29 Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store NeuroBloc - keep this medicine out of the sight and reach of children - do not use this medicine after the expiry date which is stated on the carton and on the vial after EXP - store in a refrigerator (2°C-8°C). Do not freeze - keep the vial in the outer carton in order to protect from light - within its shelf-life, NeuroBloc may be removed from the refrigerator for a single period of up to 3 months at a temperature not above 25oC. At the end of this period, the product should not be put back in the refrigerator and should be disposed of - the date at which the medicine was taken out from the refrigerator will be put on the outer carton - if the medicine is diluted, the doctor will use it immediately - before using the medicine the doctor will check that the solution is clear and colourless/light yellow. If there are any visible signs of deterioration, the medicine should not be used, but discarded - any unused solution should be discarded - due to the special nature of NeuroBloc, the doctor will ensure that all used vials, needles and syringes must be processed as Medical Biohazardous Waste in accordance with local requirements 6. Contents of the pack and other information What NeuroBloc contains The active substance is Botulinum Toxin Type B. One millilitre (ml) contains 5000 U. One vial of 0.5 ml contains 2500 U of Botulinum Toxin Type B. One vial of 1 ml contains 5000 U of Botulinum Toxin Type B. One vial of 2 ml contains 10,000 U of Botulinum Toxin Type B. The other ingredients are disodium succinate, sodium chloride, human serum albumin solution, hydrochloric acid (for pH adjustment) and water for injections. What NeuroBloc looks like and contents of the pack NeuroBloc is presented as a solution for injection in a vial that contains 0.5 ml (2500 Units), 1.0 ml (5000 Units) or 2.0 ml (10,000 Units). The solution is clear and colourless to pale yellow. Pack size of 1. Marketing Authorisation holder Sloan Pharma S.à.r.l. 33, Rue du Puits Romain 8070 Bertrange Luxembourg https://view.officeapps.live.com/op/view.aspx?src=https%3A%2F%2Fwww.ema.europa.eu%2Fdocs%2Fen_GB%2Fdocument_library%2FTemplate_or_form%2F2013%2F03%2FWC500139752.doc 30 Manufacturer Almac Pharma Services Limited Seagoe Industrial Estate Portadown Craigavon BT63 5UA United Kingdom And Almac Pharma Services (Ireland) Limited Finnabair Industrial Estate Dundalk Co. Louth A91 P9KD Ireland For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: ae@sloanpharma.com This leaflet was last revised in <{MM/YYYY}> <{month YYYY}> Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. 31 ------------------------------------------------------------------------------------------------------------------------- The following information is intended for healthcare professionals only: INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL NeuroBloc is provided in vials for single use only. The medicinal product is ready to use and no reconstitution is required. Do not shake. To allow division of the total dose between several injections, NeuroBloc may be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection (see section 4.2 of Summary of Product Characteristics). Such dilutions with sodium chloride should be done in a syringe, pulling out the desired amount of NeuroBloc into the syringe first, and then adding sodium chloride to the syringe. In non clinical experiments, NeuroBloc solution has been diluted up to 6-fold without any resulting change in potency. Once diluted, the medicinal product must be used immediately as the formulation does not contain a preservative. Any unused solution, all vials of expired NeuroBloc and equipment used in the administration of the medicinal product should be carefully discarded as Medical Biohazardous Waste in accordance with local requirements. Vials should be visually inspected prior to use. If the NeuroBloc solution is not clear and colourless/light yellow or if the vial appears damaged, the product should not be used, but discarded as Medical Biohazardous Waste in accordance with local requirements. Decontaminate any spill with 10% caustic solution, or sodium hypochlorite (household chlorine bleach –2 ml (0.5%): 1 litre water) solution. Wear waterproof gloves and soak up the liquid with an appropriate absorbent. Place the absorbed toxin in an autoclave bag, seal it and process as Medical Biohazardous Waste in accordance with local requirements. Do not use after the expiration date stamped on the vial. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE ANDMANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to use neurobloc', 'Section_Content': 'neurobloc will be given to you by a doctor with specialist experience in the treatment of cervical dystonia and in the use of botulinum toxins. how much will be given - your doctor will decide how much neurobloc to give you - the usual dose is 10,000 units, however, it can be higher or lower - if you have had neurobloc injections before, your doctor will take into account how well it worked the other times how neurobloc is given - neurobloc will be injected into your neck or shoulder muscles, depending on which ones are causing the problem - your doctor may inject part of the dose into different places in your muscles having more injections of neurobloc - the effects of neurobloc will usually last about 12 to 16 weeks - your doctor will decide if you need another injection and how much to give you if you think that the effect of neurobloc is too strong or too weak, talk to your doctor. if you are given more neurobloc than you should - if you have been given more neurobloc than you need, some of your muscles that were not injected may feel weak or you may develop symptoms away from the injected muscles, like difficulty in swallowing or breathing. this may occur when higher doses of up to 15,000 units are given - if you have difficulty breathing or you are worried by any symptoms you develop away from the place of the injection, talk to your doctor immediately. if he/she is unavailable seek emergency assistance. you may need urgent medical treatment a serious condition called "botulism" which causes paralysis of muscles and respiratory failure could occur if too much of the active ingredient (botulinum toxin) is injected into the body. if your doctor suspects that botulism may have occurred, you will be admitted to hospital and your breathing (respiratory function) will be monitored. recovery usually takes place over a period of time.', 'Entity_Recognition': [{'Text': 'neurobloc', 'Type': 'PRODUCT_NAME', 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. they may happen days to weeks after you have had the injection. you may feel pain at the place where you had the injection, but this should wear off after a few minutes. you may get a dry mouth and it might become difficult to swallow. in rare cases difficulty in swallowing may be severe and choking is possible. if your swallowing difficulty gets worse or you have choking or breathing problems, see a doctor immediately. you may need urgent medical treatment. aspiration pneumonia caused by food particles or vomit entering into the lungs, and respiratory disease, have been reported after treatment with botulinum toxins (type a and type b). these side effects have sometimes resulted in death and are possibly related to the spread of botulinum toxin to body parts away from the place where the injection is given. other side effects include: very common (may affect more than 1 in 10 people) - dry mouth - difficulty swallowing - headache common (may affect up to 1 in 10 people) - blurred vision or drooping of your upper eyelid - indigestion or being sick (vomiting) - constipation - neck pain - feeling weak, pain or stiff muscles around your body - loss of strength or energy - changes in the taste of your food and drink - changes in the sound of your voice - flu-like symptoms skin allergies such as rash with or without paleness, redness, patches, severe itching; and skin eruptions such as welts or hives have also been reported after receiving neurobloc. the frequency of these side effects is not known. it is possible that cervical dystonia could become worse after you have had your injection. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system 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'Category': 'ANATOMY', 'Traits': []}, {'Type': 'DIRECTION', 'Score': 0.3819420039653778, 'RelationshipScore': 0.9668542146682739, 'RelationshipType': 'DIRECTION', 'Id': 7, 'BeginOffset': 1232, 'EndOffset': 1238, 'Text': 'around', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9819674491882324, 'RelationshipScore': 0.8373110294342041, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 8, 'BeginOffset': 1244, 'EndOffset': 1248, 'Text': 'body', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 47, 'BeginOffset': 1271, 'EndOffset': 1287, 'Score': 0.8393257856369019, 'Text': 'energy - changes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6927152872085571}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.3819420039653778, 'RelationshipScore': 0.5969022512435913, 'RelationshipType': 'DIRECTION', 'Id': 7, 'BeginOffset': 1232, 'EndOffset': 1238, 'Text': 'around', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9819674491882324, 'RelationshipScore': 0.6863275766372681, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 8, 'BeginOffset': 1244, 'EndOffset': 1248, 'Text': 'body', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 48, 'BeginOffset': 1295, 'EndOffset': 1333, 'Score': 0.53343665599823, 'Text': 'taste of your food and drink - changes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5473049879074097}]}, {'Text': 'your voice', 'Type': 'PROBLEM', 'BeginOffset': 1350, 'EndOffset': 1360}, {'Id': 49, 'BeginOffset': 1363, 'EndOffset': 1380, 'Score': 0.5742726922035217, 'Text': 'flu-like symptoms', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6737021803855896}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9769901037216187, 'RelationshipScore': 0.8334227800369263, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 9, 'BeginOffset': 1381, 'EndOffset': 1385, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 50, 'BeginOffset': 1381, 'EndOffset': 1395, 'Score': 0.7149406671524048, 'Text': 'skin allergies', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9481430053710938}]}, {'Id': 51, 'BeginOffset': 1404, 'EndOffset': 1408, 'Score': 0.9981539845466614, 'Text': 'rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9642156958580017}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9769901037216187, 'RelationshipScore': 0.763334333896637, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 9, 'BeginOffset': 1381, 'EndOffset': 1385, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 52, 'BeginOffset': 1425, 'EndOffset': 1433, 'Score': 0.9662381410598755, 'Text': 'paleness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9657553434371948}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9769901037216187, 'RelationshipScore': 0.8458593487739563, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 9, 'BeginOffset': 1381, 'EndOffset': 1385, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 53, 'BeginOffset': 1435, 'EndOffset': 1442, 'Score': 0.9965084195137024, 'Text': 'redness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9764436483383179}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9769901037216187, 'RelationshipScore': 0.6170431971549988, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 9, 'BeginOffset': 1381, 'EndOffset': 1385, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 54, 'BeginOffset': 1444, 'EndOffset': 1451, 'Score': 0.962537407875061, 'Text': 'patches', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9581831693649292}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9769901037216187, 'RelationshipScore': 0.7699810862541199, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 9, 'BeginOffset': 1381, 'EndOffset': 1385, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'severe itching', 'Type': 'PROBLEM', 'BeginOffset': 1453, 'EndOffset': 1467}, {'Id': 56, 'BeginOffset': 1473, 'EndOffset': 1487, 'Score': 0.9147164225578308, 'Text': 'skin eruptions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9380122423171997}]}, {'Id': 57, 'BeginOffset': 1496, 'EndOffset': 1501, 'Score': 0.8090776801109314, 'Text': 'welts', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8497173190116882}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9937946796417236, 'RelationshipScore': 0.8890371918678284, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 10, 'BeginOffset': 1473, 'EndOffset': 1477, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 58, 'BeginOffset': 1505, 'EndOffset': 1510, 'Score': 0.9956047534942627, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.866344153881073}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9937946796417236, 'RelationshipScore': 0.3978477418422699, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 10, 'BeginOffset': 1473, 'EndOffset': 1477, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'neurobloc', 'Type': 'TREATMENT', 'BeginOffset': 1551, 'EndOffset': 1560}, {'Id': 59, 'BeginOffset': 1566, 'EndOffset': 1575, 'Score': 0.4274401366710663, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'these side effects', 'Type': 'PROBLEM', 'BeginOffset': 1579, 'EndOffset': 1597}, {'Id': 61, 'BeginOffset': 1632, 'EndOffset': 1649, 'Score': 0.9632828235626221, 'Text': 'cervical dystonia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8206681609153748}]}, {'Text': 'your injection', 'Type': 'TREATMENT', 'BeginOffset': 1688, 'EndOffset': 1702}, {'Id': 62, 'BeginOffset': 1717, 'EndOffset': 1729, 'Score': 0.9497020244598389, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8409645557403564}]}, {'Id': 63, 'BeginOffset': 1745, 'EndOffset': 1757, 'Score': 0.9308897852897644, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8118677139282227}]}, {'Id': 64, 'BeginOffset': 1821, 'EndOffset': 1833, 'Score': 0.9575835466384888, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6931730508804321}]}, {'Id': 65, 'BeginOffset': 1882, 'EndOffset': 1894, 'Score': 0.8744877576828003, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7286961078643799}]}, {'Id': 66, 'BeginOffset': 1948, 'EndOffset': 1959, 'Score': 0.39812666177749634, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.685549795627594}]}, {'Id': 67, 'BeginOffset': 1973, 'EndOffset': 1985, 'Score': 0.8977246880531311, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7824901342391968}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2041, 'EndOffset': 2054}]}

{'Title': '5. how to store neurobloc', 'Section_Content': '- keep this medicine out of the sight and reach of children - do not use this medicine after the expiry date which is stated on the carton and on the vial after exp - store in a refrigerator (2-8). do not freeze - keep the vial in the outer carton in order to protect from light - within its shelf-life, neurobloc may be removed from the refrigerator for a single period of up to 3 months at a temperature not above 25oc. at the end of this period, the product should not be put back in the refrigerator and should be disposed of - the date at which the medicine was taken out from the refrigerator will be put on the outer carton - if the medicine is diluted, the doctor will use it immediately - before using the medicine the doctor will check that the solution is clear and colourless/light yellow. if there are any visible signs of deterioration, the medicine should not be used, but discarded - any unused solution should be discarded - due to the special nature of neurobloc, the doctor will ensure that all used vials, needles and syringes must be processed as medical biohazardous waste in accordance with local requirements', 'Entity_Recognition': [{'Text': 'neurobloc', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 73, 'EndOffset': 86}, {'Text': 'neurobloc', 'Type': 'TREATMENT', 'BeginOffset': 304, 'EndOffset': 313}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 380, 'EndOffset': 381}, {'Id': 0, 'BeginOffset': 394, 'EndOffset': 405, 'Score': 0.7470605373382568, 'Text': 'temperature', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'deterioration', 'Type': 'PROBLEM', 'BeginOffset': 836, 'EndOffset': 849}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 851, 'EndOffset': 863}, {'Text': 'any unused solution', 'Type': 'TREATMENT', 'BeginOffset': 900, 'EndOffset': 919}, {'Text': 'needles and syringes', 'Type': 'TREATMENT', 'BeginOffset': 1026, 'EndOffset': 1046}, {'Text': 'medical biohazardous waste', 'Type': 'TREATMENT', 'BeginOffset': 1068, 'EndOffset': 1094}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what neurobloc contains the active substance is botulinum toxin type b. one millilitre (ml) contains 5000 u. one vial of 0.5 ml contains 2500 u of botulinum toxin type b. one vial of 1 ml contains 5000 u of botulinum toxin type b. one vial of 2 ml contains 10,000 u of botulinum toxin type b. the other ingredients are disodium succinate, sodium chloride, human serum albumin solution, hydrochloric acid (for ph adjustment) and water for injections. what neurobloc looks like and contents of the pack neurobloc is presented as a solution for injection in a vial that contains 0.5 ml (2500 units), 1.0 ml (5000 units) or 2.0 ml (10,000 units). the solution is clear and colourless to pale yellow. pack size of 1.', 'Entity_Recognition': [{'Text': 'neurobloc', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 48, 'EndOffset': 63, 'Score': 0.9684599041938782, 'Text': 'botulinum toxin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8053467869758606, 'RelationshipScore': 1.0, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 72, 'EndOffset': 86, 'Text': 'one millilitre', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.40811604261398315, 'RelationshipScore': 0.9999818801879883, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 101, 'EndOffset': 117, 'Text': '5000 u. one vial', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8968303203582764, 'RelationshipScore': 0.9999955892562866, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 121, 'EndOffset': 127, 'Text': '0.5 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '5000', 'Type': 'NUMBER', 'BeginOffset': 101, 'EndOffset': 105}, {'Text': '0.5', 'Type': 'NUMBER', 'BeginOffset': 121, 'EndOffset': 124}, {'Text': '2500', 'Type': 'NUMBER', 'BeginOffset': 137, 'EndOffset': 141}, {'Text': 'botulinum toxin type b.', 'Type': 'TREATMENT', 'BeginOffset': 147, 'EndOffset': 170}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 183, 'EndOffset': 184}, {'Text': '5000', 'Type': 'NUMBER', 'BeginOffset': 197, 'EndOffset': 201}, {'Text': 'botulinum toxin type b.', 'Type': 'TREATMENT', 'BeginOffset': 207, 'EndOffset': 230}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 243, 'EndOffset': 244}, {'Text': '10,000', 'Type': 'NUMBER', 'BeginOffset': 257, 'EndOffset': 263}, {'Text': 'botulinum toxin type b.', 'Type': 'TREATMENT', 'BeginOffset': 269, 'EndOffset': 292}, {'Id': 14, 'BeginOffset': 319, 'EndOffset': 337, 'Score': 0.9918563365936279, 'Text': 'disodium succinate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 339, 'EndOffset': 354, 'Score': 0.9996576309204102, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'human serum albumin solution', 'Type': 'TREATMENT', 'BeginOffset': 356, 'EndOffset': 384}, {'Id': 18, 'BeginOffset': 386, 'EndOffset': 403, 'Score': 0.9945949912071228, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ph adjustment', 'Type': 'TREATMENT', 'BeginOffset': 409, 'EndOffset': 422}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 438, 'EndOffset': 448}, {'Text': 'the pack neurobloc', 'Type': 'TREATMENT', 'BeginOffset': 492, 'EndOffset': 510}, {'Text': 'a solution for injection in a vial', 'Type': 'TREATMENT', 'BeginOffset': 527, 'EndOffset': 561}, {'Text': '0.5', 'Type': 'NUMBER', 'BeginOffset': 576, 'EndOffset': 579}, {'Text': '2500', 'Type': 'NUMBER', 'BeginOffset': 584, 'EndOffset': 588}, {'Text': '1.0', 'Type': 'NUMBER', 'BeginOffset': 597, 'EndOffset': 600}, {'Text': '5000', 'Type': 'NUMBER', 'BeginOffset': 605, 'EndOffset': 609}, {'Text': '2.0', 'Type': 'NUMBER', 'BeginOffset': 620, 'EndOffset': 623}, {'Text': '10,000', 'Type': 'NUMBER', 'BeginOffset': 628, 'EndOffset': 634}, {'Text': 'the solution', 'Type': 'TREATMENT', 'BeginOffset': 643, 'EndOffset': 655}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 709, 'EndOffset': 710}]}

4406F5E84C9A761C89602A0DE3C1F08E

https://www.ema.europa.eu/documents/product-information/exjade-epar-product-information_en.pdf

Exjade

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT EXJADE 125 mg dispersible tablets EXJADE 250 mg dispersible tablets EXJADE 500 mg dispersible tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION EXJADE 125 mg dispersible tablets Each dispersible tablet contains 125 mg deferasirox. Excipient with known effect: Each dispersible tablet contains 136 mg lactose. EXJADE 250 mg dispersible tablets Each dispersible tablet contains 250 mg deferasirox. Excipient with known effect: Each dispersible tablet contains 272 mg lactose. EXJADE 500 mg dispersible tablets Each dispersible tablet contains 500 mg deferasirox. Excipient with known effect: Each dispersible tablet contains 544 mg lactose. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Dispersible tablet EXJADE 125 mg dispersible tablets White to slightly yellow, round, flat tablets with bevelled edges and imprints (NVR on one face and J 125 on the other). Approximate tablet dimensions 12 mm x 3.6 mm. EXJADE 250 mg dispersible tablets White to slightly yellow, round, flat tablets with bevelled edges and imprints (NVR on one face and J 250 on the other). Approximate tablet dimensions 15 mm x 4.7 mm. EXJADE 500 mg dispersible tablets White to slightly yellow, round, flat tablets with bevelled edges and imprints (NVR on one face and J 500 on the other). Approximate tablet dimensions 20 mm x 5.6 mm. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications EXJADE is indicated for the treatment of chronic iron overload due to frequent blood transfusions (7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and older. EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups: - in paediatric patients with beta thalassaemia major with iron overload due to frequent blood transfusions (7 ml/kg/month of packed red blood cells) aged 2 to 5 years, - in adult and paediatric patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older, - in adult and paediatric patients with other anaemias aged 2 years and older. EXJADE is also indicated for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older. 4.2 Posology and method of administration Treatment with EXJADE should be initiated and maintained by physicians experienced in the treatment of chronic iron overload. Posology Transfusional iron overload It is recommended that treatment be started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells (PRBC) or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1,000 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size. The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and, as required, to reduce the existing iron burden. Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients (see section 4.4). In case of switching from film-coated tablets/granules to dispersible tablets, the dose of dispersible tablets should be 40% higher than the dose of film-coated tablets/granules, rounded to the nearest whole tablet. The corresponding doses for the different formulations are shown in the table below. 4 Table 1 Recommended doses for transfusional iron overload Film-coated tablets/granules Dispersible tablets Transfusions Serum ferritin Starting dose 14 mg/kg/day 20 mg/kg/day After 20 units (about 100 ml/kg) of PRBC or >1,000 µg/l Alternative starting doses 21 mg/kg/day 30 mg/kg/day >14 ml/kg/month of PRBC (approx. >4 units/month for an adult) 7 mg/kg/day 10 mg/kg/day <7 ml/kg/month of PRBC (approx. <2 units/month for an adult) For patients well managed on deferoxamine One third of deferoxamine dose Half of deferoxamine dose Monitoring Monthly Target range 500-1,000 µg/l Adjustment steps (every 3-6 months) Increase >2,500 µg/l 3.5 - 7 mg/kg/day Up to 28 mg/kg/day 5-10 mg/kg/day Up to 40 mg/kg/day Decrease 3.5 - 7 mg/kg/day 5-10 mg/kg/day <2,500 µg/l In patients treated with doses >21 mg/kg/day In patients treated with doses >30 mg/kg/day - When target is reached 500-1,000 µg/l Maximum dose 28 mg/kg/day 40 mg/kg/day Consider interruption <500 µg/l Starting dose The recommended initial daily dose of EXJADE dispersible tablets is 20 mg/kg body weight. An initial daily dose of 30 mg/kg may be considered for patients who require reduction of elevated body iron levels and who are also receiving more than 14 ml/kg/month of packed red blood cells (approximately >4 units/month for an adult). An initial daily dose of 10 mg/kg may be considered for patients who do not require reduction of body iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells (approximately <2 units/month for an adult). The patient’s response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1). For patients already well managed on treatment with deferoxamine, a starting dose of EXJADE dispersible tablets that is numerically half that of the deferoxamine dose could be considered (e.g. a patient receiving 40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting daily dose of 20 mg/kg/day of EXJADE dispersible tablets). When this results in a daily dose less than 20 mg/kg body weight, the patient’s response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1). 5 Dose adjustment It is recommended that serum ferritin be monitored every month and that the dose of EXJADE be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments may be made in steps of 5 to 10 mg/kg and are to be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with doses of 30 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a decreasing trend over time), doses of up to 40 mg/kg may be considered. The availability of long-term efficacy and safety data with EXJADE dispersible tablets used at doses above 30 mg/kg is currently limited (264 patients followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is achieved at doses up to 30 mg/kg, a further increase (to a maximum of 40 mg/kg) may not achieve satisfactory control, and alternative treatment options may be considered. If no satisfactory control is achieved at doses above 30 mg/kg, treatment at such doses should not be maintained and alternative treatment options should be considered whenever possible. Doses above 40 mg/kg are not recommended because there is only limited experience with doses above this level. In patients treated with doses greater than 30 mg/kg, dose reductions in steps of 5 to 10 mg/kg should be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l and showing a decreasing trend over time). In patients whose serum ferritin level has reached the target (usually between 500 and 1,000 µg/l), dose reductions in steps of 5 to 10 mg/kg should be considered to maintain serum ferritin levels within the target range and to minimise the risk of overchelation. If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should be considered (see section 4.4). Non-transfusion-dependent thalassaemia syndromes Chelation therapy should only be initiated when there is evidence of iron overload (liver iron concentration [LIC] ≥5 mg Fe/g dry weight [dw] or serum ferritin consistently >800 µg/l). LIC is the preferred method of iron overload determination and should be used wherever available. Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients (see section 4.4). In case of switching from film-coated tablets/granules to dispersible tablets, the dose of dispersible tablets should be 40% higher than the dose of film-coated tablets/granules, rounded to the nearest whole tablet. The corresponding doses for the different formulations are shown in the table below. Table 2 Recommended doses for non-transfusion-dependent thalassaemia syndromes Film-coated tablets/granules Dispersible tablets Liver iron concentration (LIC)* Serum ferritin Starting dose 7 mg/kg/day 10 mg/kg/day ≥5 mg Fe/g dw or >800 µg/l Monitoring Monthly Adjustment steps (every 3-6 months) Increase ≥7 mg Fe/g dw or >2,000 µg/l 3.5 - 7 mg/kg/day 5-10 mg/kg/day Decrease <7 mg Fe/g dw or ≤2,000 µg/l 3.5 - 7 mg/kg/day 5-10 mg/kg/day Maximum dose 14 mg/kg/day 20 mg/kg/day 7 mg/kg/day 10 mg/kg/day For adults not assessed and ≤2,000 µg/l For paediatric patients Interruption <3 mg Fe/g dw or <300 µg/l Retreatment Not recommended *LIC is the preferred method of iron overload determination. 6 Starting dose The recommended initial daily dose of EXJADE dispersible tablets in patients with non-transfusion-dependent thalassaemia syndromes is 10 mg/kg body weight. Dose adjustment It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimise the risk of overchelation (see section 4.4). After every 3 to 6 months of treatment, a dose increase in increments of 5 to 10 mg/kg should be considered if the patient’s LIC is ≥7 mg Fe/g dw, or if serum ferritin is consistently >2,000 µg/l and not showing a downward trend, and the patient is tolerating the medicinal product well. Doses above 20 mg/kg are not recommended because there is no experience with doses above this level in patients with non-transfusion-dependent thalassaemia syndromes. In patients in whom LIC was not assessed and serum ferritin is ≤2,000 µg/l, dosing should not exceed 10 mg/kg. For patients in whom the dose was increased to >10 mg/kg, dose reduction to 10 mg/kg or less is recommended when LIC is <7 mg Fe/g dw or serum ferritin is ≤2,000 µg/l. Treatment cessation Once a satisfactory body iron level has been achieved (LIC <3 mg Fe/g dw or serum ferritin <300 µg/l), treatment should be stopped. There are no data available on the retreatment of patients who reaccumulate iron after having achieved a satisfactory body iron level and therefore retreatment cannot be recommended. Special populations Elderly patients (≥65 years of age) The dosing recommendations for elderly patients are the same as described above. In clinical studies, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular, diarrhoea) and should be monitored closely for adverse reactions that may require a dose adjustment. Paediatric population Transfusional iron overload: The dosing recommendations for paediatric patients aged 2 to 17 years with transfusional iron overload are the same as for adult patients (see section 4.2). It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimise the risk of overchelation (see section 4.4). Changes in weight of paediatric patients over time must be taken into account when calculating the dose. In children with transfusional iron overload aged between 2 and 5 years, exposure is lower than in adults (see section 5.2). This age group may therefore require higher doses than are necessary in adults. However, the initial dose should be the same as in adults, followed by individual titration. Non-transfusion-dependent thalassaemia syndromes: In paediatric patients with non-transfusion-dependent thalassaemia syndromes, dosing should not exceed 10 mg/kg. In these patients, closer monitoring of LIC and serum ferritin is essential to avoid overchelation (see section 4.4). In addition to monthly serum ferritin assessments, LIC should be monitored every three months when serum ferritin is ≤800 µg/l. Children from birth to 23 months: The safety and efficacy of EXJADE in children from birth to 23 months of age have not been established. No data are available. 7 Patients with renal impairment EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4). Patients with hepatic impairment EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be considerably reduced followed by progressive increase up to a limit of 50% (see sections 4.4 and 5.2), and EXJADE must be used with caution in such patients. Hepatic function in all patients should be monitored before treatment, every 2 weeks during the first month and then every month (see section 4.4). Method of administration For oral use. EXJADE dispersible tablets must be taken once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day (see sections 4.5 and 5.2). The dispersible tablets are dispersed by stirring in a glass of water or orange or apple juice (100 to 200 ml) until a fine suspension is obtained. After the suspension has been swallowed, any residue must be resuspended in a small volume of water or juice and swallowed. The tablets must not be chewed or swallowed whole (see also section 6.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Combination with other iron chelator therapies as the safety of such combinations has not been established (see section 4.5). Patients with estimated creatinine clearance <60 ml/min. 4.4 Special warnings and precautions for use Renal function Deferasirox has been studied only in patients with baseline serum creatinine within the age-appropriate normal range. During clinical studies, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes above the upper limit of the normal range, occurred in about 36% of patients. These were dose-dependent. About two-thirds of the patients showing serum creatinine increase returned below the 33% level without dose adjustment. In the remaining third the serum creatinine increase did not always respond to a dose reduction or a dose interruption. In some cases, only a stabilisation of the serum creatinine values has been observed after dose reduction. Cases of acute renal failure have been reported following post-marketing use of deferasirox (see section 4.8). In some post-marketing cases, renal function deterioration has led to renal failure requiring temporary or permanent dialysis. The causes of the rises in serum creatinine have not been elucidated. Particular attention should therefore be paid to monitoring of serum creatinine in patients who are concomitantly receiving medicinal products that depress renal function, and in patients who are receiving high doses of deferasirox and/or low rates of transfusion (<7 ml/kg/month of packed red blood cells or <2 units/month for an adult). While no increase in renal adverse events was observed after dose escalation of EXJADE dispersible tablets to doses above 30 mg/kg in clinical studies, an increased risk of renal adverse events with EXJADE dispersible tablet doses above 30 mg/kg cannot be excluded. 8 It is recommended that serum creatinine be assessed in duplicate before initiating therapy. Serum creatinine, creatinine clearance (estimated with the Cockcroft-Gault or MDRD formula in adults and with the Schwartz formula in children) and/or plasma cystatin C levels should be monitored prior to therapy, weekly in the first month after initiation or modification of therapy with EXJADE (including switch of formulation), and monthly thereafter. Patients with pre-existing renal conditions and patients who are receiving medicinal products that depress renal function may be more at risk of complications. Care should be taken to maintain adequate hydration in patients who develop diarrhoea or vomiting. There have been post-marketing reports of metabolic acidosis occurring during treatment with deferasirox. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication. Acid-base balance should be monitored as clinically indicated in these populations. Interruption of EXJADE therapy should be considered in patients who develop metabolic acidosis. Post-marketing cases of severe forms of renal tubulopathy (such as Fanconi syndrome) and renal failure associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported in patients treated with deferasirox, mainly in children. It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on Exjade therapy. Table 3 Dose adjustment and interruption of treatment for renal monitoring Treatment may be reinitiated depending on the individual clinical circumstances. Serum creatinine Creatinine clearance Before initiation of therapy Twice (2x) and Once (1x) Contraindicated <60 ml/min Monitoring - First month after start of therapy or dose modification (including switch of formulation) Weekly and Weekly - Thereafter Monthly and Monthly Reduction of daily dose by 10 mg/kg/day (dispersible tablet formulation), if following renal parameters are observed at two consecutive visits and cannot be attributed to other causes Adult patients >33% above pre- treatment average and Decreases <LLN* (<90 ml/min) Paediatric patients > age appropriate ULN** and/or Decreases <LLN* (<90 ml/min) After dose reduction, interrupt treatment, if Adult and paediatric Remains >33% above pre-treatment average and/or Decreases <LLN* (<90 ml/min) *LLN: lower limit of the normal range **ULN: upper limit of the normal range 9 Dose reduction or interruption may be also considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated: • Proteinuria (test should be performed prior to therapy and monthly thereafter) • Glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria (monitor as needed). Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with EXJADE. Patients should be referred to a renal specialist, and further specialised investigations (such as renal biopsy) may be considered if the following occur despite dose reduction and interruption: • Serum creatinine remains significantly elevated and • Persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi Syndrome). Hepatic function Liver function test elevations have been observed in patients treated with deferasirox. Post-marketing cases of hepatic failure, some of which were fatal, have been reported. Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy, may occur in patients treated with deferasirox, particularly in children. It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on Exjade therapy. Care should be taken to maintain adequate hydration in patients who experience volume-depleting events (such as diarrhoea or vomiting), particularly in children with acute illness. Most reports of hepatic failure involved patients with significant comorbidities including pre-existing chronic liver conditions (including cirrhosis and hepatitis C) and multi-organ failure. The role of deferasirox as a contributing or aggravating factor cannot be excluded (see section 4.8). It is recommended that serum transaminases, bilirubin and alkaline phosphatase be checked before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a persistent and progressive increase in serum transaminase levels that cannot be attributed to other causes, EXJADE should be interrupted. Once the cause of the liver function test abnormalities has been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered. EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) (see section 5.2). 10 Table 4 Summary of safety monitoring recommendations In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when co-morbidities could increase the risk of adverse events, the benefit of EXJADE might be limited and may be inferior to risks. As a consequence, treatment with EXJADE is not recommended in these patients. Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular, diarrhoea). Data in children with non-transfusion-dependent thalassaemia are very limited (see section 5.1). As a consequence, EXJADE therapy should be closely monitored to detect adverse reactions and to follow iron burden in the paediatric population. In addition, before treating heavily iron-overloaded children with non-transfusion-dependent thalassaemia with EXJADE, the physician should be aware that the consequences of long-term exposure in such patients are currently not known. Gastrointestinal disorders Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Multiple ulcers have been observed in some patients (see section 4.8). There have been reports of ulcers complicated with digestive perforation. Also, there have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who had haematological malignancies and/or low platelet counts. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during EXJADE therapy. In case of gastrointestinal ulceration or haemorrhage, EXJADE should be discontinued and additional evaluation and treatment must be promptly initiated. Caution should be exercised in patients who are taking EXJADE in combination with substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below 50,000/mm3 (50 x 109/l) (see section 4.5). Test Frequency Serum creatinine In duplicate prior to therapy. Weekly during first month of therapy or after dose modification (including switch of formulation). Monthly thereafter. Creatinine clearance and/or plasma cystatin C Prior to therapy. Weekly during first month of therapy or after dose modification (including switch of formulation). Monthly thereafter. Proteinuria Prior to therapy. Monthly thereafter. Other markers of renal tubular function (such as glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria) As needed. Serum transaminases, bilirubin, alkaline phosphatase Prior to therapy. Every 2 weeks during first month of therapy. Monthly thereafter. Auditory and ophthalmic testing Prior to therapy. Annually thereafter. Body weight, height and sexual development Prior to therapy. Annually in paediatric patients. 11 Skin disorders Skin rashes may appear during EXJADE treatment. The rashes resolve spontaneously in most cases. When interruption of treatment may be necessary, treatment may be reintroduced after resolution of the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could be conducted in combination with a short period of oral steroid administration. Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported. If any SCAR is suspected, EXJADE should be discontinued immediately and should not be reintroduced. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. Hypersensitivity reactions Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving deferasirox, with the onset of the reaction occurring in the majority of cases within the first month of treatment (see section 4.8). If such reactions occur, EXJADE should be discontinued and appropriate medical intervention instituted. Deferasirox should not be reintroduced in patients who have experienced a hypersensitivity reaction due to the risk of anaphylactic shock (see section 4.3). Vision and hearing Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section 4.8). Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption may be considered. Blood disorders There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia (or aggravation of these cytopenias) and of aggravated anaemia in patients treated with deferasirox. Most of these patients had pre-existing haematological disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained cytopenia. Other considerations Monthly monitoring of serum ferritin is recommended in order to assess the patient’s response to therapy and to avoid overchelation (see section 4.2). Dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels are recommended during periods of treatment with high doses and when serum ferritin levels are close to the target range. If serum ferritin falls consistently below 500 µg/l (in transfusional iron overload) or below 300 µg/l (in non-transfusion-dependent thalassaemia syndromes), an interruption of treatment should be considered. The results of the tests for serum creatinine, serum ferritin and serum transaminases should be recorded and regularly assessed for trends. In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.8). However, as a general precautionary measure in the management of paediatric patients with transfusional iron overload, body weight, height and sexual development should be monitored prior to therapy and at regular intervals (every 12 months). Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be monitored in patients with severe iron overload during long-term treatment with EXJADE. Lactose content The dispersible tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 12 4.5 Interaction with other medicinal products and other forms of interaction The safety of deferasirox in combination with other iron chelators has not been established. Therefore, it must not be combined with other iron chelator therapies (see section 4.3). Interaction with food The bioavailability of deferasirox was increased to a variable extent when taken along with food. EXJADE dispersible tablets must therefore be taken on an empty stomach at least 30 minutes before food, preferably at the same time each day (see sections 4.2 and 5.2). Agents that may decrease EXJADE systemic exposure Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant administration of deferasirox (single dose of 30 mg/kg, dispersible tablet formulation) and the potent UGT inducer, rifampicin, (repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37% - 51%). Therefore, the concomitant use of EXJADE with potent UGT inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in EXJADE efficacy. The patient’s serum ferritin should be monitored during and after the combination, and the dose of EXJADE adjusted if necessary. Cholestyramine significantly reduced the deferasirox exposure in a mechanistic study to determine the degree of enterohepatic recycling (see section 5.2). Interaction with midazolam and other agents metabolised by CYP3A4 In a healthy volunteer study, the concomitant administration of deferasirox dispersible tablets and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8% - 26%). In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with substances metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine). Interaction with repaglinide and other agents metabolised by CYP2C8 In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8 inhibitor (30 mg/kg daily, dispersible tablet formulation), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg, increased repaglinide AUC and Cmax about 2.3-fold (90% CI [2.03-2.63]) and 1.6-fold (90% CI [1.42-1.84]), respectively. Since the interaction has not been established with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed (see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded. Interaction with theophylline and other agents metabolised by CYP1A2 In a healthy volunteer study, the concomitant administration of deferasirox as a CYP1A2 inhibitor (repeated dose of 30 mg/kg/day, dispersible tablet formulation) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose Cmax was not affected, but an increase of theophylline Cmax is expected to occur with chronic dosing. Therefore, the concomitant use of deferasirox with theophylline is not recommended. If deferasirox and theophylline are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction should be considered. An interaction between deferasirox and other CYP1A2 substrates cannot be excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline. 13 Other information The concomitant administration of deferasirox and aluminium-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not recommended to take deferasirox tablets with aluminium-containing antacid preparations. The concomitant administration of deferasirox with substances that have known ulcerogenic potential, such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). The concomitant administration of deferasirox with anticoagulants may also increase the risk of gastrointestinal haemorrhage. Close clinical monitoring is required when deferasirox is combined with these substances. Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC), but the mechanism of the interaction remains unclear. If possible, evaluation of the pharmacokinetics (AUC, clearance) of a busulfan test dose should be performed to allow dose adjustment. 4.6 Fertility, pregnancy and lactation Pregnancy No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is unknown. As a precaution, it is recommended that EXJADE is not used during pregnancy unless clearly necessary. EXJADE may decrease the efficacy of hormonal contraceptives (see section 4.5). Women of childbearing potential are recommended to use additional or alternative non-hormonal methods of contraception when using EXJADE. Breast-feeding In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-feeding while taking EXJADE is not recommended. Fertility No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found (see section 5.3). 4.7 Effects on ability to drive and use machines EXJADE has minor influence on the ability to drive and use machines. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machines (see section 4.8). 14 4.8 Undesirable effects Summary of the safety profile The most frequent reactions reported during chronic treatment with deferasirox dispersible tablets in adult and paediatric patients include gastrointestinal disturbances (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued. During clinical studies, dose-dependent increases in serum creatinine occurred in about 36% of patients, though most remained within the normal range. Decreases in mean creatinine clearance have been observed in both paediatric and adult patients with beta-thalassemia and iron overload during the first year of treatment, but there is evidence that this does not decrease further in subsequent years of treatment. Elevations of liver transaminases have been reported. Safety monitoring schedules for renal and liver parameters are recommended. Auditory (decreased hearing) and ocular (lens opacities) disturbances are uncommon, and yearly examinations are also recommended (see section 4.4). Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of EXJADE (see section 4.4). Tabulated list of adverse reactions Adverse reactions are ranked below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 15 Table 5 Blood and lymphatic system disorders Not known: Pancytopenia1, thrombocytopenia1, anaemia aggravated1, neutropenia1 Immune system disorders Not known: Hypersensitivity reactions (including anaphylactic reactions and angioedema)1 Metabolism and nutrition disorders Not known: Metabolic acidosis1 Psychiatric disorders Uncommon: Anxiety, sleep disorder Nervous system disorders Common: Headache Uncommon: Dizziness Eye disorders Uncommon: Cataract, maculopathy Rare: Optic neuritis Ear and labyrinth disorders Uncommon: Deafness Respiratory, thoracic and mediastinal disorders Uncommon: Laryngeal pain Gastrointestinal disorders Common: Diarrhoea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia Uncommon: Gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis Rare: Oesophagitis Not known: Gastrointestinal perforation1, acute pancreatitis1 Hepatobiliary disorders Common: Transaminases increased Uncommon: Hepatitis, cholelithiasis Not known: Hepatic failure1, 2 Skin and subcutaneous tissue disorders Common: Rash, pruritus Uncommon: Pigmentation disorder Rare: Drug reaction with eosinophilia and systemic symptoms (DRESS) Not known: Stevens-Johnson syndrome1, hypersensitivity vasculitis1, urticaria1, erythema multiforme1, alopecia1, toxic epidermal necrolysis (TEN)1 Renal and urinary disorders Very common: Blood creatinine increased Common: Proteinuria Uncommon: Renal tubular disorder2 (acquired Fanconi syndrome), glycosuria Not known: Acute renal failure1, 2, tubulointerstitial nephritis1, nephrolithiasis1, renal tubular necrosis1 General disorders and administration site conditions Uncommon: Pyrexia, oedema, fatigue 1 Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product. 2 Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported. 16 Description of selected adverse reactions Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During post-marketing experience, hepatic failure, sometimes fatal, has been reported with deferasirox (see section 4.4). There have been post-marketing reports of metabolic acidosis. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication (see section 4.4). Cases of serious acute pancreatitis were observed without documented underlying biliary conditions. As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with deferasirox (see section 4.4). Creatinine clearance in transfusional iron overload In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with transfusional iron overload treated with deferasirox dispersible tablets in two randomised and four open label studies of up to five years’ duration, a mean creatinine clearance decrease of 13.2% in adult patients (95% CI: -14.4% to -12.1%; n=935) and 9.9% (95% CI: -11.1% to -8.6%; n=1,142) in paediatric patients was observed during the first year of treatment. In 250 patients who were followed for up to five years, no further decrease in mean creatinine clearance levels was observed. Clinical study in patients with non-transfusion-dependent thalassaemia syndromes In a 1-year study in patients with non-transfusion-dependent thalassaemia syndromes and iron overload (dispersible tablets at a dose of 10 mg/kg/day), diarrhoea (9.1%), rash (9.1%), and nausea (7.3%) were the most frequent study drug-related adverse events. Abnormal serum creatinine and creatinine clearance values were reported in 5.5% and 1.8% of patients, respectively. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were reported in 1.8% of patients. Paediatric population In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.4). Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients. Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with deferasirox. In post-marketing reports, a high proportion of cases of metabolic acidosis occurred in children in the context of Fanconi syndrome. Acute pancreatitis has been reported, particularly in children and adolescents. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Early signs of acute overdose are digestive effects such as abdominal pain, diarrhoea, nausea and vomiting. Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment. There is no specific antidote for deferasirox. Standard procedures for management of overdose may be indicated as well as symptomatic treatment, as medically appropriate. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 17 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Iron chelating agents, ATC code: V03AC03 Mechanism of action Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals. Pharmacodynamic effects In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, deferasirox at daily doses of 10, 20 and 40 mg/kg (dispersible tablet formulation) induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg body weight/day, respectively. Clinical efficacy and safety Clinical efficacy studies were conducted with deferasirox dispersible tablets. Deferasirox has been investigated in 411 adult (age 16 years) and 292 paediatric patients (aged 2 to <16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle cell disease and other congenital and acquired anaemias (myelodysplastic syndromes [MDS], Diamond-Blackfan syndrome, aplastic anaemia and other very rare anaemias). Daily treatment with the deferasirox dispersible tablet formulation at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average, respectively, and serum ferritin was reduced by about -36 and -926 µg/l on average, respectively. At these same doses the ratios of iron excretion: iron intake were 1.02 (indicating net iron balance) and 1.67 (indicating net iron removal), respectively. Deferasirox induced similar responses in iron-overloaded patients with other anaemias. Daily doses of 10 mg/kg (dispersible tablet formulation) for one year could maintain liver iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with deferasirox 10-30 mg/kg/day (dispersible tablet formulation) for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds). The principal analysis of the pivotal comparative study in 586 patients suffering from beta-thalassaemia and transfusional iron overload did not demonstrate non-inferiority of deferasirox dispersible tablets to deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with deferasirox dispersible tablets (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with deferasirox dispersible tablets (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-six patients under the age of 6 years participated in this pivotal study, 28 of them receiving deferasirox dispersible tablets. 18 It appeared from preclinical and clinical studies that deferasirox dispersible tablets could be as active as deferoxamine when used in a dose ratio of 2:1 (i.e. a dose of deferasirox dispersible tablets that is numerically half of the deferoxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical studies. In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or sickle cell disease, deferasirox dispersible tablets up to 20 and 30 mg/kg produced a decrease in liver iron concentration and serum ferritin comparable to that obtained in patients with beta-thalassaemia. A placebo-controlled randomised study was performed in 225 patients with MDS (Low/Int-1 risk) and transfusional iron overload. The results of this study suggest that there is a positive impact of deferasirox on event-free survival (EFS, a composite endpoint including non-fatal cardiac or liver events) and serum ferritin levels. The safety profile was consistent with previous studies in adult MDS patients. In a 5-year observational study in which 267 children aged 2 to <6 years (at enrollment) with transfusional haemosiderosis received deferasirox, there were no clinically meaningful differences in the safety and tolerability profile of Exjade in paediatric patients aged 2 to <6 years compared to the overall adult and older paediatric population, including increases in serum creatinine of >33% and above the upper limit of normal on ≥2 consecutive occasions (3.1%), and elevation of alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (4.3%). Single events of increase in ALT and aspartate aminotransferase were reported in 20.0% and 8.3%, respectively, of the 145 patients who completed the study. In a study to assess the safety of deferasirox film-coated and dispersible tablets, 173 adult and paediatric patients with transfusion dependent thalassaemia or myelodysplastic syndrome were treated for 24 weeks. A comparable safety profile for film-coated and dispersible tablets was observed. In patients with non-transfusion-dependent thalassaemia syndromes and iron overload, treatment with deferasirox dispersible tablets was assessed in a 1-year, randomised, double-blind, placebo-controlled study. The study compared the efficacy of two different deferasirox dispersible tablet regimens (starting doses of 5 and 10 mg/kg/day, 55 patients in each arm) and of matching placebo (56 patients). The study enrolled 145 adult and 21 paediatric patients. The primary efficacy parameter was the change in liver iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy parameters was the change in serum ferritin between baseline and fourth quarter. At a starting dose of 10 mg/kg/day, deferasirox dispersible tablets led to reductions in indicators of total body iron. On average, liver iron concentration decreased by 3.80 mg Fe/g dw in patients treated with deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 0.38 mg Fe/g dw in patients treated with placebo (p<0.001). On average, serum ferritin decreased by 222.0 µg/l in patients treated with deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 115 µg/l in patients treated with placebo (p<0.001). 5.2 Pharmacokinetic properties Absorption Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox (dispersible tablet formulation) is about 70% compared to an intravenous dose. Total exposure (AUC) was approximately doubled when taken along with a high-fat breakfast (fat content >50% of calories) and by about 50% when taken along with a standard breakfast. The bioavailability (AUC) of deferasirox was moderately (approx. 13–25%) elevated when taken 30 minutes before meals with normal or high fat content. Distribution Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 litres in adults. 19 Biotransformation Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur: in a healthy volunteer study, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC). Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed in vitro. Elimination Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox. Linearity / non-linearity The Cmax and AUC0-24h of deferasirox increase approximately linearly with dose under steady-state conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3. Characteristics in patients Paediatric patients The overall exposure of adolescents (12 to ≤17 years) and children (2 to <12 years) to deferasirox after single and multiple doses was lower than that in adult patients. In children younger than 6 years old exposure was about 50% lower than in adults. Since dosing is individually adjusted according to response this is not expected to have clinical consequences. Gender Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this is not expected to have clinical consequences. Elderly patients The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older). Renal or hepatic impairment The pharmacokinetics of deferasirox have not been studied in patients with renal impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the upper limit of the normal range. In a clinical study using single doses of 20 mg/kg deferasirox dispersible tablets, the average exposure was increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic function. The average Cmax of deferasirox in subjects with mild or moderate hepatic impairment was increased by 22%. Exposure was increased 2.8-fold in one subject with severe hepatic impairment (Child-Pugh Class C) (see sections 4.2 and 4.4). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that were not previously overloaded with iron. 20 Tests of genotoxicity in vitro were negative (Ames test, chromosomal aberration test) while deferasirox caused formation of micronuclei in vivo in the bone marrow, but not liver, of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats. Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/- heterozygous mice in a 6-month study. The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other effects on fertility or reproduction. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Crospovidone type A Cellulose, microcrystalline Povidone Sodium laurilsulfate Silica, colloidal anhydrous Magnesium stearate 6.2 Incompatibilities Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion, respectively. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container PVC/PE/PVDC/Aluminium blisters. EXJADE 125 mg dispersible tablets Packs containing 28, 84 or 252 dispersible tablets. EXJADE 250 mg dispersible tablets Packs containing 28, 84 or 252 dispersible tablets. EXJADE 500 mg dispersible tablets Unit packs containing 28, 84 or 252 dispersible tablets and multipacks containing 294 (3 packs of 98) dispersible tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 21 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EXJADE 125 mg dispersible tablets EU/1/06/356/001 EU/1/06/356/002 EU/1/06/356/007 EXJADE 250 mg dispersible tablets EU/1/06/356/003 EU/1/06/356/004 EU/1/06/356/008 EXJADE 500 mg dispersible tablets EU/1/06/356/005 EU/1/06/356/006 EU/1/06/356/009 EU/1/06/356/010 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 28 August 2006 Date of latest renewal: 18 April 2016 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/ 22 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT EXJADE 90 mg film-coated tablets EXJADE 180 mg film-coated tablets EXJADE 360 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION EXJADE 90 mg film-coated tablets Each film-coated tablet contains 90 mg deferasirox. EXJADE 180 mg film-coated tablets Each film-coated tablet contains 180 mg deferasirox. EXJADE 360 mg film-coated tablets Each film-coated tablet contains 360 mg deferasirox. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet EXJADE 90 mg film-coated tablets Light blue, ovaloid, biconvex film-coated tablet with bevelled edges and imprints (NVR on one face and 90 on the other). Approximate tablet dimensions 10.7 mm x 4.2 mm. EXJADE 180 mg film-coated tablets Medium blue, ovaloid, biconvex film-coated tablet with bevelled edges and imprints (NVR on one face and 180 on the other). Approximate tablet dimensions 14 mm x 5.5 mm. EXJADE 360 mg film-coated tablets Dark blue, ovaloid, biconvex film-coated tablet with bevelled edges and imprints (NVR on one face and 360 on the other). Approximate tablet dimensions 17 mm x 6.7 mm. 23 4. CLINICAL PARTICULARS 4.1 Therapeutic indications EXJADE is indicated for the treatment of chronic iron overload due to frequent blood transfusions (7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and older. EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups: - in paediatric patients with beta thalassaemia major with iron overload due to frequent blood transfusions (7 ml/kg/month of packed red blood cells) aged 2 to 5 years, - in adult and paediatric patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older, - in adult and paediatric patients with other anaemias aged 2 years and older. EXJADE is also indicated for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older. 4.2 Posology and method of administration Treatment with EXJADE should be initiated and maintained by physicians experienced in the treatment of chronic iron overload. Posology Transfusional iron overload It is recommended that treatment be started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells (PRBC) or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1,000 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size. The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and, as required, to reduce the existing iron burden. Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients (see section 4.4). EXJADE film-coated tablets demonstrate higher bioavailability compared to the EXJADE dispersible tablet formulation (see section 5.2). In case of switching from dispersible tablets to film-coated tablets, the dose of the film-coated tablets should be 30% lower than the dose of the dispersible tablets, rounded to the nearest whole tablet. The corresponding doses for the different formulations are shown in the table below. 24 Table 1 Recommended doses for transfusional iron overload Film-coated tablets/granules Dispersible tablets Transfusions Serum ferritin Starting dose 14 mg/kg/day 20 mg/kg/day After 20 units (about 100 ml/kg) of PRBC or >1,000 µg/l Alternative starting doses 21 mg/kg/day 30 mg/kg/day >14 ml/kg/month of PRBC (approx. >4 units/month for an adult) 7 mg/kg/day 10 mg/kg/day <7 ml/kg/month of PRBC (approx. <2 units/month for an adult) For patients well managed on deferoxamine One third of deferoxamine dose Half of deferoxamine dose Monitoring Monthly Target range 500-1,000 µg/l Adjustment steps (every 3-6 months) Increase >2,500 µg/l 3.5 - 7 mg/kg/day Up to 28 mg/kg/day 5-10 mg/kg/day Up to 40 mg/kg/day Decrease 3.5 - 7 mg/kg/day 5-10 mg/kg/day <2,500 µg/l In patients treated with doses >21 mg/kg/day In patients treated with doses >30 mg/kg/day - When target is reached 500-1,000 µg/l Maximum dose 28 mg/kg/day 40 mg/kg/day Consider interruption <500 µg/l 25 Starting dose The recommended initial daily dose of EXJADE film-coated tablets is 14 mg/kg body weight. An initial daily dose of 21 mg/kg may be considered for patients who require reduction of elevated body iron levels and who are also receiving more than 14 ml/kg/month of packed red blood cells (approximately >4 units/month for an adult). An initial daily dose of 7 mg/kg may be considered for patients who do not require reduction of body iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells (approximately <2 units/month for an adult). The patient’s response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1). For patients already well managed on treatment with deferoxamine, a starting dose of EXJADE film-coated tablets that is numerically one third that of the deferoxamine dose could be considered (e.g. a patient receiving 40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting daily dose of 14 mg/kg/day of EXJADE film-coated tablets). When this results in a daily dose less than 14 mg/kg body weight, the patient’s response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1). Dose adjustment It is recommended that serum ferritin be monitored every month and that the dose of EXJADE be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments may be made in steps of 3.5 to 7 mg/kg and are to be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with doses of 21 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a decreasing trend over time), doses of up to 28 mg/kg may be considered. The availability of long-term efficacy and safety data from clinical studies conducted with EXJADE dispersible tablets used at doses above 30 mg/kg is currently limited (264 patients followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is achieved at doses up to 21 mg/kg, a further increase (to a maximum of 28 mg/kg) may not achieve satisfactory control, and alternative treatment options may be considered. If no satisfactory control is achieved at doses above 21 mg/kg, treatment at such doses should not be maintained and alternative treatment options should be considered whenever possible. Doses above 28 mg/kg are not recommended because there is only limited experience with doses above this level (see section 5.1). In patients treated with doses greater than 21 mg/kg, dose reductions in steps of 3.5 to 7 mg/kg should be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l and showing a decreasing trend over time). In patients whose serum ferritin level has reached the target (usually between 500 and 1,000 µg/l), dose reductions in steps of 3.5 to 7 mg/kg should be considered to maintain serum ferritin levels within the target range and to minimise the risk of overchelation. If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should be considered (see section 4.4). Non-transfusion-dependent thalassaemia syndromes Chelation therapy should only be initiated when there is evidence of iron overload (liver iron concentration [LIC] ≥5 mg Fe/g dry weight [dw] or serum ferritin consistently >800 µg/l). LIC is the preferred method of iron overload determination and should be used wherever available. Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients (see section 4.4). EXJADE film-coated tablets demonstrate higher bioavailability compared to the EXJADE dispersible tablet formulation (see section 5.2). In case of switching from dispersible tablets to film-coated tablets, the dose of the film-coated tablets should be 30% lower than the dose of the dispersible tablets, rounded to the nearest whole tablet. The corresponding doses for the different formulations are shown in the table below. 26 Table 2 Recommended doses for non-transfusion-dependent thalassaemia syndromes Film-coated tablets/granules Dispersible tablets Liver iron concentration (LIC)* Serum ferritin Starting dose 7 mg/kg/day 10 mg/kg/day ≥5 mg Fe/g dw or >800 µg/l Monitoring Monthly Adjustment steps (every 3-6 months) Increase ≥7 mg Fe/g dw or >2,000 µg/l 3.5 - 7 mg/kg/day 5-10 mg/kg/day Decrease <7 mg Fe/g dw or ≤2,000 µg/l 3.5 - 7 mg/kg/day 5-10 mg/kg/day Maximum dose 14 mg/kg/day 20 mg/kg/day 7 mg/kg/day 10 mg/kg/day For adults not assessed and ≤2,000 µg/l For paediatric patients Interruption <3 mg Fe/g dw or <300 µg/l Retreatment Not recommended *LIC is the preferred method of iron overload determination. Starting dose The recommended initial daily dose of EXJADE film-coated tablets in patients with non-transfusion-dependent thalassaemia syndromes is 7 mg/kg body weight. Dose adjustment It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimise the risk of overchelation (see section 4.4). After every 3 to 6 months of treatment, a dose increase in increments of 3.5 to 7 mg/kg should be considered if the patient’s LIC is ≥7 mg Fe/g dw, or if serum ferritin is consistently >2,000 µg/l and not showing a downward trend, and the patient is tolerating the medicinal product well. Doses above 14 mg/kg are not recommended because there is no experience with doses above this level in patients with non-transfusion-dependent thalassaemia syndromes. In patients in whom LIC was not assessed and serum ferritin is ≤2,000 µg/l, dosing should not exceed 7 mg/kg. For patients in whom the dose was increased to >7 mg/kg, dose reduction to 7 mg/kg or less is recommended when LIC is <7 mg Fe/g dw or serum ferritin is ≤2,000 µg/l. Treatment cessation Once a satisfactory body iron level has been achieved (LIC <3 mg Fe/g dw or serum ferritin <300 µg/l), treatment should be stopped. There are no data available on the retreatment of patients who reaccumulate iron after having achieved a satisfactory body iron level and therefore retreatment cannot be recommended. Special populations Elderly patients (≥65 years of age) The dosing recommendations for elderly patients are the same as described above. In clinical studies, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular, diarrhoea) and should be monitored closely for adverse reactions that may require a dose adjustment. 27 Paediatric population Transfusional iron overload: The dosing recommendations for paediatric patients aged 2 to 17 years with transfusional iron overload are the same as for adult patients (see section 4.2). It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimise the risk of overchelation (see section 4.4). Changes in weight of paediatric patients over time must be taken into account when calculating the dose. In children with transfusional iron overload aged between 2 and 5 years, exposure is lower than in adults (see section 5.2). This age group may therefore require higher doses than are necessary in adults. However, the initial dose should be the same as in adults, followed by individual titration. Non-transfusion-dependent thalassaemia syndromes: In paediatric patients with non-transfusion-dependent thalassaemia syndromes, dosing should not exceed 7 mg/kg. In these patients, closer monitoring of LIC and serum ferritin is essential to avoid overchelation (see section 4.4). In addition to monthly serum ferritin assessments, LIC should be monitored every three months when serum ferritin is ≤800 µg/l. Children from birth to 23 months: The safety and efficacy of EXJADE in children from birth to 23 months of age have not been established. No data are available. Patients with renal impairment EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4). Patients with hepatic impairment EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be considerably reduced followed by progressive increase up to a limit of 50% (see sections 4.4 and 5.2), and EXJADE must be used with caution in such patients. Hepatic function in all patients should be monitored before treatment, every 2 weeks during the first month and then every month (see section 4.4). Method of administration For oral use. The film-coated tablets should be swallowed whole with some water. For patients who are unable to swallow whole tablets, the film-coated tablets may be crushed and administered by sprinkling the full dose onto soft food, e.g. yogurt or apple sauce (pureed apple). The dose should be immediately and completely consumed, and not stored for future use. The film-coated tablets should be taken once a day, preferably at the same time each day, and may be taken on an empty stomach or with a light meal (see sections 4.5 and 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Combination with other iron chelator therapies as the safety of such combinations has not been established (see section 4.5). Patients with estimated creatinine clearance <60 ml/min. 28 4.4 Special warnings and precautions for use Renal function Deferasirox has been studied only in patients with baseline serum creatinine within the age-appropriate normal range. During clinical studies, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes above the upper limit of the normal range, occurred in about 36% of patients. These were dose-dependent. About two-thirds of the patients showing serum creatinine increase returned below the 33% level without dose adjustment. In the remaining third the serum creatinine increase did not always respond to a dose reduction or a dose interruption. In some cases, only a stabilisation of the serum creatinine values has been observed after dose reduction. Cases of acute renal failure have been reported following post-marketing use of deferasirox (see section 4.8). In some post-marketing cases, renal function deterioration has led to renal failure requiring temporary or permanent dialysis. The causes of the rises in serum creatinine have not been elucidated. Particular attention should therefore be paid to monitoring of serum creatinine in patients who are concomitantly receiving medicinal products that depress renal function, and in patients who are receiving high doses of deferasirox and/or low rates of transfusion (<7 ml/kg/month of packed red blood cells or <2 units/month for an adult). While no increase in renal adverse events was observed after dose escalation of EXJADE dispersible tablets to doses above 30 mg/kg in clinical studies, an increased risk of renal adverse events with film-coated tablet doses above 21 mg/kg cannot be excluded. It is recommended that serum creatinine be assessed in duplicate before initiating therapy. Serum creatinine, creatinine clearance (estimated with the Cockcroft-Gault or MDRD formula in adults and with the Schwartz formula in children) and/or plasma cystatin C levels should be monitored prior to therapy, weekly in the first month after initiation or modification of therapy with EXJADE (including switch of formulation), and monthly thereafter. Patients with pre-existing renal conditions and patients who are receiving medicinal products that depress renal function may be more at risk of complications. Care should be taken to maintain adequate hydration in patients who develop diarrhoea or vomiting. There have been post-marketing reports of metabolic acidosis occurring during treatment with deferasirox. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication. Acid-base balance should be monitored as clinically indicated in these populations. Interruption of EXJADE therapy should be considered in patients who develop metabolic acidosis. Post-marketing cases of severe forms of renal tubulopathy (such as Fanconi syndrome) and renal failure associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported in patients treated with deferasirox, mainly in children. It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on Exjade therapy. 29 Table 3 Dose adjustment and interruption of treatment for renal monitoring Treatment may be reinitiated depending on the individual clinical circumstances. Dose reduction or interruption may be also considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated: • Proteinuria (test should be performed prior to therapy and monthly thereafter) • Glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria (monitor as needed). Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with EXJADE. Patients should be referred to a renal specialist, and further specialised investigations (such as renal biopsy) may be considered if the following occur despite dose reduction and interruption: • Serum creatinine remains significantly elevated and • Persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi Syndrome). Hepatic function Liver function test elevations have been observed in patients treated with deferasirox. Post-marketing cases of hepatic failure, some of which were fatal, have been reported. Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy, may occur in patients treated with deferasirox, particularly in children. It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on Exjade therapy. Care should be taken to maintain adequate hydration in patients who experience volume-depleting events (such as diarrhoea or vomiting), particularly in children with acute illness. Most reports of hepatic failure involved patients with significant comorbidities including pre-existing chronic liver conditions (including cirrhosis and hepatitis C) and multi-organ failure. The role of deferasirox as a contributing or aggravating factor cannot be excluded (see section 4.8). Serum creatinine Creatinine clearance Before initiation of therapy Twice (2x) and Once (1x) Contraindicated <60 ml/min Monitoring - First month after start of therapy or dose modification (including switch of formulation) Weekly and Weekly - Thereafter Monthly and Monthly Reduction of daily dose by 7 mg/kg/day (film-coated tablet formulation), if following renal parameters are observed at two consecutive visits and cannot be attributed to other causes Adult patients >33% above pre- treatment average and Decreases <LLN* (<90 ml/min) Paediatric patients > age appropriate ULN** and/or Decreases <LLN* (<90 ml/min) After dose reduction, interrupt treatment, if Adult and paediatric Remains >33% above pre-treatment average and/or Decreases <LLN* (<90 ml/min) *LLN: lower limit of the normal range **ULN: upper limit of the normal range 30 It is recommended that serum transaminases, bilirubin and alkaline phosphatase be checked before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a persistent and progressive increase in serum transaminase levels that cannot be attributed to other causes, EXJADE should be interrupted. Once the cause of the liver function test abnormalities has been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered. EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) (see section 5.2). Table 4 Summary of safety monitoring recommendations In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when co-morbidities could increase the risk of adverse events, the benefit of EXJADE might be limited and may be inferior to risks. As a consequence, treatment with EXJADE is not recommended in these patients. Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular, diarrhoea). Data in children with non-transfusion-dependent thalassaemia are very limited (see section 5.1). As a consequence, EXJADE therapy should be closely monitored to detect adverse reactions and to follow iron burden in the paediatric population. In addition, before treating heavily iron-overloaded children with non-transfusion-dependent thalassaemia with EXJADE, the physician should be aware that the consequences of long-term exposure in such patients are currently not known. Test Frequency Serum creatinine In duplicate prior to therapy. Weekly during first month of therapy or after dose modification (including switch of formulation). Monthly thereafter. Creatinine clearance and/or plasma cystatin C Prior to therapy. Weekly during first month of therapy or after dose modification (including switch of formulation). Monthly thereafter. Proteinuria Prior to therapy. Monthly thereafter. Other markers of renal tubular function (such as glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria) As needed. Serum transaminases, bilirubin, alkaline phosphatase Prior to therapy. Every 2 weeks during first month of therapy. Monthly thereafter. Auditory and ophthalmic testing Prior to therapy. Annually thereafter. Body weight, height and sexual development Prior to therapy. Annually in paediatric patients. 31 Gastrointestinal disorders Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Multiple ulcers have been observed in some patients (see section 4.8). There have been reports of ulcers complicated with digestive perforation. Also, there have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who had haematological malignancies and/or low platelet counts. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during EXJADE therapy. In case of gastrointestinal ulceration or haemorrhage, EXJADE should be discontinued and additional evaluation and treatment must be promptly initiated. Caution should be exercised in patients who are taking EXJADE in combination with substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below 50,000/mm3 (50 x 109/l) (see section 4.5). Skin disorders Skin rashes may appear during EXJADE treatment. The rashes resolve spontaneously in most cases. When interruption of treatment may be necessary, treatment may be reintroduced after resolution of the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could be conducted in combination with a short period of oral steroid administration. Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life- threatening or fatal, have been reported. If any SCAR is suspected, EXJADE should be discontinued immediately and should not be reintroduced. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. Hypersensitivity reactions Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving deferasirox, with the onset of the reaction occurring in the majority of cases within the first month of treatment (see section 4.8). If such reactions occur, EXJADE should be discontinued and appropriate medical intervention instituted. Deferasirox should not be reintroduced in patients who have experienced a hypersensitivity reaction due to the risk of anaphylactic shock (see section 4.3). Vision and hearing Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section 4.8). Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption may be considered. Blood disorders There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia (or aggravation of these cytopenias) and of aggravated anaemia in patients treated with deferasirox. Most of these patients had pre-existing haematological disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained cytopenia. Other considerations Monthly monitoring of serum ferritin is recommended in order to assess the patient’s response to therapy and to avoid overchelation (see section 4.2). Dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels are recommended during periods of treatments with high doses and when serum ferritin levels are close to the target range. If serum ferritin falls consistently below 500 µg/l (in transfusional iron overload) or below 300 µg/l (in non-transfusion-dependent thalassaemia syndromes), an interruption of treatment should be considered. The results of the tests for serum creatinine, serum ferritin and serum transaminases should be recorded and regularly assessed for trends. 32 In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.8). However, as a general precautionary measure in the management of paediatric patients with transfusional iron overload, body weight, height and sexual development should be monitored prior to therapy and at regular intervals (every 12 months). Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be monitored in patients with severe iron overload during long-term treatment with EXJADE. 4.5 Interaction with other medicinal products and other forms of interaction The safety of deferasirox in combination with other iron chelators has not been established. Therefore, it must not be combined with other iron chelator therapies (see section 4.3). Interaction with food The Cmax of deferasirox film-coated tablets was increased (by 29%) when taken with a high-fat meal. EXJADE film-coated tablets may be taken either on an empty stomach or with a light meal, preferably at the same time each day (see sections 4.2 and 5.2). Agents that may decrease EXJADE systemic exposure Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant administration of deferasirox (single dose of 30 mg/kg, dispersible tablet formulation) and the potent UGT inducer, rifampicin, (repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37% - 51%). Therefore, the concomitant use of EXJADE with potent UGT inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in EXJADE efficacy. The patient’s serum ferritin should be monitored during and after the combination, and the dose of EXJADE adjusted if necessary. Cholestyramine significantly reduced the deferasirox exposure in a mechanistic study to determine the degree of enterohepatic recycling (see section 5.2). Interaction with midazolam and other agents metabolised by CYP3A4 In a healthy volunteer study, the concomitant administration of deferasirox dispersible tablets and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8% - 26%). In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with substances metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine). Interaction with repaglinide and other agents metabolised by CYP2C8 In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8 inhibitor (30 mg/kg daily, dispersible tablet formulation), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg, increased repaglinide AUC and Cmax about 2.3-fold (90% CI [2.03-2.63]) and 1.6-fold (90% CI [1.42-1.84]), respectively. Since the interaction has not been established with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed (see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded. 33 Interaction with theophylline and other agents metabolised by CYP1A2 In a healthy volunteer study, the concomitant administration of deferasirox as a CYP1A2 inhibitor (repeated dose of 30 mg/kg/day, dispersible tablet formulation) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose Cmax was not affected, but an increase of theophylline Cmax is expected to occur with chronic dosing. Therefore, the concomitant use of deferasirox with theophylline is not recommended. If deferasirox and theophylline are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction should be considered. An interaction between deferasirox and other CYP1A2 substrates cannot be excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline. Other information The concomitant administration of deferasirox and aluminium-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not recommended to take deferasirox tablets with aluminium-containing antacid preparations. The concomitant administration of deferasirox with substances that have known ulcerogenic potential, such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). The concomitant administration of deferasirox with anticoagulants may also increase the risk of gastrointestinal haemorrhage. Close clinical monitoring is required when deferasirox is combined with these substances. Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC), but the mechanism of the interaction remains unclear. If possible, evaluation of the pharmacokinetics (AUC, clearance) of a busulfan test dose should be performed to allow dose adjustment. 4.6 Fertility, pregnancy and lactation Pregnancy No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is unknown. As a precaution, it is recommended that EXJADE is not used during pregnancy unless clearly necessary. EXJADE may decrease the efficacy of hormonal contraceptives (see section 4.5). Women of childbearing potential are recommended to use additional or alternative non-hormonal methods of contraception when using EXJADE. Breast-feeding In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-feeding while taking EXJADE is not recommended. Fertility No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found (see section 5.3). 34 4.7 Effects on ability to drive and use machines EXJADE has minor influence on the ability to drive and use machines. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machines (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The most frequent reactions reported during chronic treatment in clinical studies conducted with deferasirox dispersible tablets in adult and paediatric patients include gastrointestinal disturbances (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued. During clinical studies dose-dependent increases in serum creatinine occurred in about 36% of patients, though most remained within the normal range. Decreases in mean creatinine clearance have been observed in both paediatric and adult patients with beta-thalassemia and iron overload during the first year of treatment, but there is evidence that this does not decrease further in subsequent years of treatment. Elevations of liver transaminases have been reported. Safety monitoring schedules for renal and liver parameters are recommended. Auditory (decreased hearing) and ocular (lens opacities) disturbances are uncommon, and yearly examinations are also recommended (see section 4.4). Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of EXJADE (see section 4.4). Tabulated list of adverse reactions Adverse reactions are ranked below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 35 Table 5 Blood and lymphatic system disorders Not known: Pancytopenia1, thrombocytopenia1, anaemia aggravated1, neutropenia1 Immune system disorders Not known: Hypersensitivity reactions (including anaphylactic reactions and angioedema)1 Metabolism and nutrition disorders Not known: Metabolic acidosis1 Psychiatric disorders Uncommon: Anxiety, sleep disorder Nervous system disorders Common: Headache Uncommon: Dizziness Eye disorders Uncommon: Cataract, maculopathy Rare: Optic neuritis Ear and labyrinth disorders Uncommon: Deafness Respiratory, thoracic and mediastinal disorders Uncommon: Laryngeal pain Gastrointestinal disorders Common: Diarrhoea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia Uncommon: Gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis Rare: Oesophagitis Not known: Gastrointestinal perforation1, acute pancreatitis1 Hepatobiliary disorders Common: Transaminases increased Uncommon: Hepatitis, cholelithiasis Not known: Hepatic failure1, 2 Skin and subcutaneous tissue disorders Common: Rash, pruritus Uncommon: Pigmentation disorder Rare: Drug reaction with eosinophilia and systemic symptoms (DRESS) Not known: Stevens-Johnson syndrome1, hypersensitivity vasculitis1, urticaria1, erythema multiforme1, alopecia1, toxic epidermal necrolysis (TEN)1 Renal and urinary disorders Very common: Blood creatinine increased Common: Proteinuria Uncommon: Renal tubular disorder2 (acquired Fanconi syndrome), glycosuria Not known: Acute renal failure1, 2, tubulointerstitial nephritis1, nephrolithiasis1, renal tubular necrosis1 General disorders and administration site conditions Uncommon: Pyrexia, oedema, fatigue 1 Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product. 2 Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported. 36 Description of selected adverse reactions Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During post-marketing experience, hepatic failure, sometimes fatal, has been reported with deferasirox (see section 4.4). There have been post-marketing reports of metabolic acidosis. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication (see section 4.4). Cases of serious acute pancreatitis were observed without documented underlying biliary conditions. As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with deferasirox (see section 4.4). Creatinine clearance in transfusional iron overload In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with transfusional iron overload treated with deferasirox dispersible tablets in two randomised and four open label studies of up to five years’ duration, a mean creatinine clearance decrease of 13.2% in adult patients (95% CI: -14.4% to -12.1%; n=935) and 9.9% (95% CI: -11.1% to -8.6%; n=1,142) in paediatric patients was observed during the first year of treatment. In 250 patients who were followed for up to five years, no further decrease in mean creatinine clearance levels was observed. Clinical study in patients with non-transfusion-dependent thalassaemia syndromes In a 1-year study in patients with non-transfusion-dependent thalassaemia syndromes and iron overload (dispersible tablets at a dose of 10 mg/kg/day), diarrhoea (9.1%), rash (9.1%), and nausea (7.3%) were the most frequent study drug-related adverse events. Abnormal serum creatinine and creatinine clearance values were reported in 5.5% and 1.8% of patients, respectively. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were reported in 1.8% of patients. Paediatric population In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.4). Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients. Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with deferasirox. In post-marketing reports, a high proportion of cases of metabolic acidosis occurred in children in the context of Fanconi syndrome. Acute pancreatitis has been reported, particularly in children and adolescents. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Early signs of acute overdose are digestive effects such as abdominal pain, diarrhoea, nausea and vomiting. Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment. There is no specific antidote for deferasirox. Standard procedures for management of overdose may be indicated as well as symptomatic treatment, as medically appropriate. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 37 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Iron chelating agents, ATC code: V03AC03 Mechanism of action Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals. Pharmacodynamic effects In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, deferasirox at daily doses of 10, 20 and 40 mg/kg (dispersible tablet formulation) induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg body weight/day, respectively. Clinical efficacy and safety Clinical efficacy studies were conducted with deferasirox dispersible tablets. Deferasirox has been investigated in 411 adult (age 16 years) and 292 paediatric patients (aged 2 to <16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle cell disease and other congenital and acquired anaemias (myelodysplastic syndromes [MDS], Diamond-Blackfan syndrome, aplastic anaemia and other very rare anaemias). Daily treatment with the deferasirox dispersible tablet formulation at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average, respectively, and serum ferritin was reduced by about -36 and -926 µg/l on average, respectively. At these same doses the ratios of iron excretion: iron intake were 1.02 (indicating net iron balance) and 1.67 (indicating net iron removal), respectively. Deferasirox induced similar responses in iron-overloaded patients with other anaemias. Daily doses of 10 mg/kg (dispersible tablet formulation) for one year could maintain liver iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with deferasirox 10-30 mg/kg/day (dispersible tablet formulation) for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds). The principal analysis of the pivotal comparative study in 586 patients suffering from beta-thalassaemia and transfusional iron overload did not demonstrate non-inferiority of deferasirox dispersible tablets to deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with deferasirox dispersible tablets (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with deferasirox dispersible tablets (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-six patients under the age of 6 years participated in this pivotal study, 28 of them receiving deferasirox dispersible tablets. 38 It appeared from preclinical and clinical studies that deferasirox dispersible tablets could be as active as deferoxamine when used in a dose ratio of 2:1 (i.e. a dose of deferasirox dispersible tablets that is numerically half of the deferoxamine dose). For deferasirox film-coated tablets, a dose ratio of 3:1 can be considered (i.e. a dose of deferasirox film-coated tablets that is numerically one third of the deferoxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical studies. In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or sickle cell disease, deferasirox dispersible tablets up to 20 and 30 mg/kg produced a decrease in liver iron concentration and serum ferritin comparable to that obtained in patients with beta-thalassaemia. A placebo-controlled randomised study was performed in 225 patients with MDS (Low/Int-1 risk) and transfusional iron overload. The results of this study suggest that there is a positive impact of deferasirox on event-free survival (EFS, a composite endpoint including non-fatal cardiac or liver events) and serum ferritin levels. The safety profile was consistent with previous studies in adult MDS patients. In a 5-year observational study in which 267 children aged 2 to <6 years (at enrollment) with transfusional haemosiderosis received deferasirox, there were no clinically meaningful differences in the safety and tolerability profile of Exjade in paediatric patients aged 2 to <6 years compared to the overall adult and older paediatric population, including increases in serum creatinine of >33% and above the upper limit of normal on ≥2 consecutive occasions (3.1%), and elevation of alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (4.3%). Single events of increase in ALT and aspartate aminotransferase were reported in 20.0% and 8.3%, respectively, of the 145 patients who completed the study. In a study to assess the safety of deferasirox film-coated and dispersible tablets, 173 adult and paediatric patients with transfusion dependent thalassaemia or myelodysplastic syndrome were treated for 24 weeks. A comparable safety profile for film-coated and dispersible tablets was observed. In patients with non-transfusion-dependent thalassaemia syndromes and iron overload, treatment with deferasirox dispersible tablets was assessed in a 1-year, randomised, double-blind, placebo-controlled study. The study compared the efficacy of two different deferasirox dispersible tablet regimens (starting doses of 5 and 10 mg/kg/day, 55 patients in each arm) and of matching placebo (56 patients). The study enrolled 145 adult and 21 paediatric patients. The primary efficacy parameter was the change in liver iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy parameters was the change in serum ferritin between baseline and fourth quarter. At a starting dose of 10 mg/kg/day, deferasirox dispersible tablets led to reductions in indicators of total body iron. On average, liver iron concentration decreased by 3.80 mg Fe/g dw in patients treated with deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 0.38 mg Fe/g dw in patients treated with placebo (p<0.001). On average, serum ferritin decreased by 222.0 µg/l in patients treated with deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 115 µg/l in patients treated with placebo (p<0.001). 5.2 Pharmacokinetic properties EXJADE film-coated tablets demonstrate higher bioavailability compared to the EXJADE dispersible tablet formulation. After adjustment of the strength, the film-coated tablet formulation (360 mg strength) was equivalent to EXJADE dispersible tablets (500 mg strength) with respect to the mean area under the plasma concentration time curve (AUC) under fasting conditions. The Cmax was increased by 30% (90% CI: 20.3% - 40.0%); however a clinical exposure/response analysis revealed no evidence of clinically relevant effects of such an increase. 39 Absorption Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox (dispersible tablet formulation) is about 70% compared to an intravenous dose. The absolute bioavailability of the film-coated tablet formulation has not been determined. Bioavailability of deferasirox film-coated tablets was 36% greater than that with dispersible tablets. A food-effect study involving administration of the film-coated tablets to healthy volunteers under fasting conditions and with a low-fat (fat content <10% of calories) or high-fat (fat content >50% of calories) meal indicated that the AUC and Cmax were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were increased (by 18% and 29%, respectively). The increases in Cmax due to the change in formulation and due to the effect of a high-fat meal may be additive and therefore, it is recommended that the film-coated tablets should be taken either on an empty stomach or with a light meal. Distribution Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 litres in adults. Biotransformation Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur: in a healthy volunteer study, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC). Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed in vitro. Elimination Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox. Linearity / non-linearity The Cmax and AUC0-24h of deferasirox increase approximately linearly with dose under steady-state conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3. Characteristics in patients Paediatric patients The overall exposure of adolescents (12 to ≤17 years) and children (2 to <12 years) to deferasirox after single and multiple doses was lower than that in adult patients. In children younger than 6 years old exposure was about 50% lower than in adults. Since dosing is individually adjusted according to response this is not expected to have clinical consequences. Gender Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this is not expected to have clinical consequences. Elderly patients The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older). 40 Renal or hepatic impairment The pharmacokinetics of deferasirox have not been studied in patients with renal impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the upper limit of the normal range. In a clinical study using single doses of 20 mg/kg deferasirox dispersible tablets, the average exposure was increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic function. The average Cmax of deferasirox in subjects with mild or moderate hepatic impairment was increased by 22%. Exposure was increased 2.8-fold in one subject with severe hepatic impairment (Child-Pugh Class C) (see sections 4.2 and 4.4). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that were not previously overloaded with iron. Tests of genotoxicity in vitro were negative (Ames test, chromosomal aberration test) while deferasirox caused formation of micronuclei in vivo in the bone marrow, but not liver, of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats. Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/- heterozygous mice in a 6-month study. The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other effects on fertility or reproduction. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Cellulose, microcrystalline Crospovidone Povidone Magnesium stearate Silica, colloidal anhydrous Poloxamer Coating material: Hypromellose Titanium dioxide (E171) Macrogol (4000) Talc Indigo carmine aluminium lake (E132) 6.2 Incompatibilities Not applicable. 41 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container PVC/PVDC/Aluminium blisters. Unit packs containing 30 or 90 film-coated tablets or multipacks containing 300 (10 packs of 30) film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EXJADE 90 mg film-coated tablets EU/1/06/356/011 EU/1/06/356/012 EU/1/06/356/013 EXJADE 180 mg film-coated tablets EU/1/06/356/014 EU/1/06/356/015 EU/1/06/356/016 EXJADE 360 mg film-coated tablets EU/1/06/356/017 EU/1/06/356/018 EU/1/06/356/019 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 28 August 2006 Date of latest renewal: 18 April 2016 42 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/ 43 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT EXJADE 90 mg granules in sachet EXJADE 180 mg granules in sachet EXJADE 360 mg granules in sachet 2. QUALITATIVE AND QUANTITATIVE COMPOSITION EXJADE 90 mg granules Each sachet contains 90 mg deferasirox. EXJADE 180 mg granules Each sachet contains 180 mg deferasirox. EXJADE 360 mg granules Each sachet contains 360 mg deferasirox. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Granules in sachet (granules) White to almost white granules 4. CLINICAL PARTICULARS 4.1 Therapeutic indications EXJADE is indicated for the treatment of chronic iron overload due to frequent blood transfusions (7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and older. EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups: - in paediatric patients with beta thalassaemia major with iron overload due to frequent blood transfusions (7 ml/kg/month of packed red blood cells) aged 2 to 5 years, - in adult and paediatric patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older, - in adult and paediatric patients with other anaemias aged 2 years and older. EXJADE is also indicated for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older. 44 4.2 Posology and method of administration Treatment with EXJADE should be initiated and maintained by physicians experienced in the treatment of chronic iron overload. Posology Transfusional iron overload It is recommended that treatment be started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells (PRBC) or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1,000 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole sachet size. The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and, as required, to reduce the existing iron burden. Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients (see section 4.4). EXJADE granules demonstrate higher bioavailability compared to the EXJADE dispersible tablet formulation (see section 5.2). In case of switching from dispersible tablets to granules, the dose of the granules should be 30% lower than the dose of the dispersible tablets, rounded to the nearest whole sachet. The corresponding doses for the different formulations are shown in the table below. 45 Table 1 Recommended doses for transfusional iron overload Film-coated tablets/granules Dispersible tablets Transfusions Serum ferritin Starting dose 14 mg/kg/day 20 mg/kg/day After 20 units (about 100 ml/kg) of PRBC or >1,000 µg/l Alternative starting doses 21 mg/kg/day 30 mg/kg/day >14 ml/kg/month of PRBC (approx. >4 units/month for an adult) 7 mg/kg/day 10 mg/kg/day <7 ml/kg/month of PRBC (approx. <2 units/month for an adult) For patients well managed on deferoxamine One third of deferoxamine dose Half of deferoxamine dose Monitoring Monthly Target range 500-1,000 µg/l Adjustment steps (every 3-6 months) Increase >2,500 µg/l 3.5 - 7 mg/kg/day Up to 28 mg/kg/day 5-10 mg/kg/day Up to 40 mg/kg/day Decrease 3.5 - 7 mg/kg/day 5-10 mg/kg/day <2,500 µg/l In patients treated with doses >21 mg/kg/day In patients treated with doses >30 mg/kg/day - When target is reached 500-1,000 µg/l Maximum dose 28 mg/kg/day 40 mg/kg/day Consider interruption <500 µg/l 46 Starting dose The recommended initial daily dose of EXJADE granules is 14 mg/kg body weight. An initial daily dose of 21 mg/kg may be considered for patients who require reduction of elevated body iron levels and who are also receiving more than 14 ml/kg/month of packed red blood cells (approximately >4 units/month for an adult). An initial daily dose of 7 mg/kg may be considered for patients who do not require reduction of body iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells (approximately <2 units/month for an adult). The patient’s response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1). For patients already well managed on treatment with deferoxamine, a starting dose of EXJADE granules that is numerically one third that of the deferoxamine dose could be considered (e.g. a patient receiving 40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting daily dose of 14 mg/kg/day of EXJADE granules). When this results in a daily dose less than 14 mg/kg body weight, the patient’s response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1). Dose adjustment It is recommended that serum ferritin be monitored every month and that the dose of EXJADE be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments may be made in steps of 3.5 to 7 mg/kg and are to be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with doses of 21 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a decreasing trend over time), doses of up to 28 mg/kg may be considered. The availability of long-term efficacy and safety data from clinical studies conducted with EXJADE dispersible tablets used at doses above 30 mg/kg is currently limited (264 patients followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is achieved at doses up to 21 mg/kg, a further increase (to a maximum of 28 mg/kg) may not achieve satisfactory control, and alternative treatment options may be considered. If no satisfactory control is achieved at doses above 21 mg/kg, treatment at such doses should not be maintained and alternative treatment options should be considered whenever possible. Doses above 28 mg/kg are not recommended because there is only limited experience with doses above this level (see section 5.1). In patients treated with doses greater than 21 mg/kg, dose reductions in steps of 3.5 to 7 mg/kg should be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l and showing a decreasing trend over time). In patients whose serum ferritin level has reached the target (usually between 500 and 1,000 µg/l), dose reductions in steps of 3.5 to 7 mg/kg should be considered to maintain serum ferritin levels within the target range and to minimise the risk of overchelation. If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should be considered (see section 4.4). Non-transfusion-dependent thalassaemia syndromes Chelation therapy should only be initiated when there is evidence of iron overload (liver iron concentration [LIC] ≥5 mg Fe/g dry weight [dw] or serum ferritin consistently >800 µg/l). LIC is the preferred method of iron overload determination and should be used wherever available. Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients (see section 4.4). EXJADE granules demonstrate higher bioavailability compared to the EXJADE dispersible tablet formulation (see section 5.2). In case of switching from dispersible tablets to granules, the dose of the granules should be 30% lower than the dose of the dispersible tablets, rounded to the nearest whole sachet. The corresponding doses for the different formulations are shown in the table below. 47 Table 2 Recommended doses for non-transfusion-dependent thalassaemia syndromes Film-coated tablets/granules Dispersible tablets Liver iron concentration (LIC)* Serum ferritin Starting dose 7 mg/kg/day 10 mg/kg/day ≥5 mg Fe/g dw or >800 µg/l Monitoring Monthly Adjustment steps (every 3-6 months) Increase ≥7 mg Fe/g dw or >2,000 µg/l 3.5 - 7 mg/kg/day 5-10 mg/kg/day Decrease <7 mg Fe/g dw or ≤2,000 µg/l 3.5 - 7 mg/kg/day 5-10 mg/kg/day Maximum dose 14 mg/kg/day 20 mg/kg/day 7 mg/kg/day 10 mg/kg/day For adults not assessed and ≤2,000 µg/l For paediatric patients Interruption <3 mg Fe/g dw or <300 µg/l Retreatment Not recommended *LIC is the preferred method of iron overload determination. Starting dose The recommended initial daily dose of EXJADE granules in patients with non-transfusion-dependent thalassaemia syndromes is 7 mg/kg body weight. Dose adjustment It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimise the risk of overchelation (see section 4.4). After every 3 to 6 months of treatment, a dose increase in increments of 3.5 to 7 mg/kg should be considered if the patient’s LIC is ≥7 mg Fe/g dw, or if serum ferritin is consistently >2,000 µg/l and not showing a downward trend, and the patient is tolerating the medicinal product well. Doses above 14 mg/kg are not recommended because there is no experience with doses above this level in patients with non-transfusion-dependent thalassaemia syndromes. In patients in whom LIC was not assessed and serum ferritin is ≤2,000 µg/l, dosing should not exceed 7 mg/kg. For patients in whom the dose was increased to >7 mg/kg, dose reduction to 7 mg/kg or less is recommended when LIC is <7 mg Fe/g dw or serum ferritin is ≤2,000 µg/l. Treatment cessation Once a satisfactory body iron level has been achieved (LIC <3 mg Fe/g dw or serum ferritin <300 µg/l), treatment should be stopped. There are no data available on the retreatment of patients who reaccumulate iron after having achieved a satisfactory body iron level and therefore retreatment cannot be recommended. Special populations Elderly patients (≥65 years of age) The dosing recommendations for elderly patients are the same as described above. In clinical studies, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular, diarrhoea) and should be monitored closely for adverse reactions that may require a dose adjustment. 48 Paediatric population Transfusional iron overload: The dosing recommendations for paediatric patients aged 2 to 17 years with transfusional iron overload are the same as for adult patients (see section 4.2). It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimise the risk of overchelation (see section 4.4). Changes in weight of paediatric patients over time must be taken into account when calculating the dose. In children with transfusional iron overload aged between 2 and 5 years, exposure is lower than in adults (see section 5.2). This age group may therefore require higher doses than are necessary in adults. However, the initial dose should be the same as in adults, followed by individual titration. Non-transfusion-dependent thalassaemia syndromes: In paediatric patients with non-transfusion-dependent thalassaemia syndromes, dosing should not exceed 7 mg/kg. In these patients, closer monitoring of LIC and serum ferritin is essential to avoid overchelation (see section 4.4). In addition to monthly serum ferritin assessments, LIC should be monitored every three months when serum ferritin is ≤800 µg/l. Children from birth to 23 months: The safety and efficacy of EXJADE in children from birth to 23 months of age have not been established. No data are available. Patients with renal impairment EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4). Patients with hepatic impairment EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be considerably reduced followed by progressive increase up to a limit of 50% (see sections 4.4 and 5.2), and EXJADE must be used with caution in such patients. Hepatic function in all patients should be monitored before treatment, every 2 weeks during the first month and then every month (see section 4.4). Method of administration For oral use. The granules should be administered by sprinkling the full dose onto soft food, e.g. yogurt or apple sauce (pureed apple). The dose should be immediately and completely consumed, and not stored for future use. The soft food containing the granules should be taken with or without a light meal, once a day, preferably at the same time each day (see sections 4.5 and 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Combination with other iron chelator therapies as the safety of such combinations has not been established (see section 4.5). Patients with estimated creatinine clearance <60 ml/min. 49 4.4 Special warnings and precautions for use Renal function Deferasirox has been studied only in patients with baseline serum creatinine within the age-appropriate normal range. During clinical studies, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes above the upper limit of the normal range, occurred in about 36% of patients. These were dose-dependent. About two-thirds of the patients showing serum creatinine increase returned below the 33% level without dose adjustment. In the remaining third the serum creatinine increase did not always respond to a dose reduction or a dose interruption. In some cases, only a stabilisation of the serum creatinine values has been observed after dose reduction. Cases of acute renal failure have been reported following post-marketing use of deferasirox (see section 4.8). In some post-marketing cases, renal function deterioration has led to renal failure requiring temporary or permanent dialysis. The causes of the rises in serum creatinine have not been elucidated. Particular attention should therefore be paid to monitoring of serum creatinine in patients who are concomitantly receiving medicinal products that depress renal function, and in patients who are receiving high doses of deferasirox and/or low rates of transfusion (<7 ml/kg/month of packed red blood cells or <2 units/month for an adult). While no increase in renal adverse events was observed after dose escalation of EXJADE dispersible tablets to doses above 30 mg/kg in clinical studies, an increased risk of renal adverse events with granule doses above 21 mg/kg cannot be excluded. It is recommended that serum creatinine be assessed in duplicate before initiating therapy. Serum creatinine, creatinine clearance (estimated with the Cockcroft-Gault or MDRD formula in adults and with the Schwartz formula in children) and/or plasma cystatin C levels should be monitored prior to therapy, weekly in the first month after initiation or modification of therapy with EXJADE (including switch of formulation), and monthly thereafter. Patients with pre-existing renal conditions and patients who are receiving medicinal products that depress renal function may be more at risk of complications. Care should be taken to maintain adequate hydration in patients who develop diarrhoea or vomiting. There have been post-marketing reports of metabolic acidosis occurring during treatment with deferasirox. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication. Acid-base balance should be monitored as clinically indicated in these populations. Interruption of EXJADE therapy should be considered in patients who develop metabolic acidosis. Post-marketing cases of severe forms of renal tubulopathy (such as Fanconi syndrome) and renal failure associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported in patients treated with deferasirox, mainly in children. It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on Exjade therapy. 50 Table 3 Dose adjustment and interruption of treatment for renal monitoring Treatment may be reinitiated depending on the individual clinical circumstances. Dose reduction or interruption may be also considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated: • Proteinuria (test should be performed prior to therapy and monthly thereafter) • Glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria (monitor as needed). Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with EXJADE. Patients should be referred to a renal specialist, and further specialised investigations (such as renal biopsy) may be considered if the following occur despite dose reduction and interruption: • Serum creatinine remains significantly elevated and • Persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi Syndrome). Hepatic function Liver function test elevations have been observed in patients treated with deferasirox. Post-marketing cases of hepatic failure, some of which were fatal, have been reported. Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy, may occur in patients treated with deferasirox, particularly in children. It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on Exjade therapy. Care should be taken to maintain adequate hydration in patients who experience volume-depleting events (such as diarrhoea or vomiting), particularly in children with acute illness. Most reports of hepatic failure involved patients with significant comorbidities including pre-existing chronic liver conditions (including cirrhosis and hepatitis C) and multi-organ failure. The role of deferasirox as a contributing or aggravating factor cannot be excluded (see section 4.8). Serum creatinine Creatinine clearance Before initiation of therapy Twice (2x) and Once (1x) Contraindicated <60 ml/min Monitoring - First month after start of therapy or dose modification (including switch of formulation) Weekly and Weekly - Thereafter Monthly and Monthly Reduction of daily dose by 7 mg/kg/day (film-coated tablet formulation), if following renal parameters are observed at two consecutive visits and cannot be attributed to other causes Adult patients >33% above pre- treatment average and Decreases <LLN* (<90 ml/min) Paediatric patients > age appropriate ULN** and/or Decreases <LLN* (<90 ml/min) After dose reduction, interrupt treatment, if Adult and paediatric Remains >33% above pre-treatment average and/or Decreases <LLN* (<90 ml/min) *LLN: lower limit of the normal range **ULN: upper limit of the normal range 51 It is recommended that serum transaminases, bilirubin and alkaline phosphatase be checked before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a persistent and progressive increase in serum transaminase levels that cannot be attributed to other causes, EXJADE should be interrupted. Once the cause of the liver function test abnormalities has been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered. EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) (see section 5.2). Table 4 Summary of safety monitoring recommendations In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when co-morbidities could increase the risk of adverse events, the benefit of EXJADE might be limited and may be inferior to risks. As a consequence, treatment with EXJADE is not recommended in these patients. Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular, diarrhoea). Data in children with non-transfusion-dependent thalassaemia are very limited (see section 5.1). As a consequence, EXJADE therapy should be closely monitored to detect adverse reactions and to follow iron burden in the paediatric population. In addition, before treating heavily iron-overloaded children with non-transfusion-dependent thalassaemia with EXJADE, the physician should be aware that the consequences of long-term exposure in such patients are currently not known. Test Frequency Serum creatinine In duplicate prior to therapy. Weekly during first month of therapy or after dose modification (including switch of formulation). Monthly thereafter. Creatinine clearance and/or plasma cystatin C Prior to therapy. Weekly during first month of therapy or after dose modification (including switch of formulation). Monthly thereafter. Proteinuria Prior to therapy. Monthly thereafter. Other markers of renal tubular function (such as glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria) As needed. Serum transaminases, bilirubin, alkaline phosphatase Prior to therapy. Every 2 weeks during first month of therapy. Monthly thereafter. Auditory and ophthalmic testing Prior to therapy. Annually thereafter. Body weight, height and sexual development Prior to therapy. Annually in paediatric patients. 52 Gastrointestinal disorders Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Multiple ulcers have been observed in some patients (see section 4.8). There have been reports of ulcers complicated with digestive perforation. Also, there have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who had haematological malignancies and/or low platelet counts. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during EXJADE therapy. In case of gastrointestinal ulceration or haemorrhage, EXJADE should be discontinued and additional evaluation and treatment must be promptly initiated. Caution should be exercised in patients who are taking EXJADE in combination with substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below 50,000/mm3 (50 x 109/l) (see section 4.5). Skin disorders Skin rashes may appear during EXJADE treatment. The rashes resolve spontaneously in most cases. When interruption of treatment may be necessary, treatment may be reintroduced after resolution of the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could be conducted in combination with a short period of oral steroid administration. Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported. If any SCAR is suspected, EXJADE should be discontinued immediately and should not be reintroduced. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. Hypersensitivity reactions Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving deferasirox, with the onset of the reaction occurring in the majority of cases within the first month of treatment (see section 4.8). If such reactions occur, EXJADE should be discontinued and appropriate medical intervention instituted. Deferasirox should not be reintroduced in patients who have experienced a hypersensitivity reaction due to the risk of anaphylactic shock (see section 4.3). Vision and hearing Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section 4.8). Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption may be considered. Blood disorders There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia (or aggravation of these cytopenias) and of aggravated anaemia in patients treated with deferasirox. Most of these patients had pre-existing haematological disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained cytopenia. Other considerations Monthly monitoring of serum ferritin is recommended in order to assess the patient’s response to therapy and to avoid overchelation (see section 4.2). Dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels are recommended during periods of treatments with high doses and when serum ferritin levels are close to the target range. If serum ferritin falls consistently below 500 µg/l (in transfusional iron overload) or below 300 µg/l (in non-transfusion-dependent thalassaemia syndromes), an interruption of treatment should be considered. The results of the tests for serum creatinine, serum ferritin and serum transaminases should be recorded and regularly assessed for trends. 53 In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.8). However, as a general precautionary measure in the management of paediatric patients with transfusional iron overload, body weight, height and sexual development should be monitored prior to therapy and at regular intervals (every 12 months). Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be monitored in patients with severe iron overload during long-term treatment with EXJADE. 4.5 Interaction with other medicinal products and other forms of interaction The safety of deferasirox in combination with other iron chelators has not been established. Therefore, it must not be combined with other iron chelator therapies (see section 4.3). Interaction with food There were no clinically relevant changes in deferasirox pharmacokinetics when EXJADE granules were administered with food. Although there was no significant effect (increase in the extent of absorption AUC by 18-19%; no change in Cmax) of a high-fat meal on deferasirox pharmacokinetics, it is recommended that deferasirox granules be taken either with or without a light meal (see section 5.2). Agents that may decrease EXJADE systemic exposure Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant administration of deferasirox (single dose of 30 mg/kg, dispersible tablet formulation) and the potent UGT inducer, rifampicin, (repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37% - 51%). Therefore, the concomitant use of EXJADE with potent UGT inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in EXJADE efficacy. The patient’s serum ferritin should be monitored during and after the combination, and the dose of EXJADE adjusted if necessary. Cholestyramine significantly reduced the deferasirox exposure in a mechanistic study to determine the degree of enterohepatic recycling (see section 5.2). Interaction with midazolam and other agents metabolised by CYP3A4 In a healthy volunteer study, the concomitant administration of deferasirox dispersible tablets and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8% - 26%). In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with substances metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine). Interaction with repaglinide and other agents metabolised by CYP2C8 In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8 inhibitor (30 mg/kg daily, dispersible tablet formulation), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg, increased repaglinide AUC and Cmax about 2.3-fold (90% CI [2.03-2.63]) and 1.6-fold (90% CI [1.42-1.84]), respectively. Since the interaction has not been established with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed (see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded. 54 Interaction with theophylline and other agents metabolised by CYP1A2 In a healthy volunteer study, the concomitant administration of deferasirox as a CYP1A2 inhibitor (repeated dose of 30 mg/kg/day, dispersible tablet formulation) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose Cmax was not affected, but an increase of theophylline Cmax is expected to occur with chronic dosing. Therefore, the concomitant use of deferasirox with theophylline is not recommended. If deferasirox and theophylline are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction should be considered. An interaction between deferasirox and other CYP1A2 substrates cannot be excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline. Other information The concomitant administration of deferasirox and aluminium-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not recommended to take deferasirox granules with aluminium-containing antacid preparations. The concomitant administration of deferasirox with substances that have known ulcerogenic potential, such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). The concomitant administration of deferasirox with anticoagulants may also increase the risk of gastrointestinal haemorrhage. Close clinical monitoring is required when deferasirox is combined with these substances. Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC), but the mechanism of the interaction remains unclear. If possible, evaluation of the pharmacokinetics (AUC, clearance) of a busulfan test dose should be performed to allow dose adjustment. 4.6 Fertility, pregnancy and lactation Pregnancy No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is unknown. As a precaution, it is recommended that EXJADE is not used during pregnancy unless clearly necessary. EXJADE may decrease the efficacy of hormonal contraceptives (see section 4.5). Women of childbearing potential are recommended to use additional or alternative non-hormonal methods of contraception when using EXJADE. Breast-feeding In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-feeding while taking EXJADE is not recommended. Fertility No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found (see section 5.3). 55 4.7 Effects on ability to drive and use machines EXJADE has minor influence on the ability to drive and use machines. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machines (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The most frequent reactions reported during chronic treatment in clinical studies conducted with deferasirox dispersible tablets in adult and paediatric patients include gastrointestinal disturbances (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued. During clinical studies dose-dependent increases in serum creatinine occurred in about 36% of patients, though most remained within the normal range. Decreases in mean creatinine clearance have been observed in both paediatric and adult patients with beta-thalassemia and iron overload during the first year of treatment, but there is evidence that this does not decrease further in subsequent years of treatment. Elevations of liver transaminases have been reported. Safety monitoring schedules for renal and liver parameters are recommended. Auditory (decreased hearing) and ocular (lens opacities) disturbances are uncommon, and yearly examinations are also recommended (see section 4.4). Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of EXJADE (see section 4.4). Tabulated list of adverse reactions Adverse reactions are ranked below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 56 Table 5 Blood and lymphatic system disorders Not known: Pancytopenia1, thrombocytopenia1, anaemia aggravated1, neutropenia1 Immune system disorders Not known: Hypersensitivity reactions (including anaphylactic reactions and angioedema)1 Metabolism and nutrition disorders Not known: Metabolic acidosis1 Psychiatric disorders Uncommon: Anxiety, sleep disorder Nervous system disorders Common: Headache Uncommon: Dizziness Eye disorders Uncommon: Cataract, maculopathy Rare: Optic neuritis Ear and labyrinth disorders Uncommon: Deafness Respiratory, thoracic and mediastinal disorders Uncommon: Laryngeal pain Gastrointestinal disorders Common: Diarrhoea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia Uncommon: Gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis Rare: Oesophagitis Not known: Gastrointestinal perforation1, acute pancreatitis1 Hepatobiliary disorders Common: Transaminases increased Uncommon: Hepatitis, cholelithiasis Not known: Hepatic failure1, 2 Skin and subcutaneous tissue disorders Common: Rash, pruritus Uncommon: Pigmentation disorder Rare: Drug reaction with eosinophilia and systemic symptoms (DRESS) Not known: Stevens-Johnson syndrome1, hypersensitivity vasculitis1, urticaria1, erythema multiforme1, alopecia1, toxic epidermal necrolysis (TEN)1 Renal and urinary disorders Very common: Blood creatinine increased Common: Proteinuria Uncommon: Renal tubular disorder2 (acquired Fanconi syndrome), glycosuria Not known: Acute renal failure1, 2, tubulointerstitial nephritis1, nephrolithiasis1, renal tubular necrosis1 General disorders and administration site conditions Uncommon: Pyrexia, oedema, fatigue 1 Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product. 2 Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported. 57 Description of selected adverse reactions Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During post-marketing experience, hepatic failure, sometimes fatal, has been reported with deferasirox (see section 4.4). There have been post-marketing reports of metabolic acidosis. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication (see section 4.4). Cases of serious acute pancreatitis were observed without documented underlying biliary conditions. As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with deferasirox (see section 4.4). Creatinine clearance in transfusional iron overload In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with transfusional iron overload treated with deferasirox dispersible tablets in two randomised and four open label studies of up to five years’ duration, a mean creatinine clearance decrease of 13.2% in adult patients (95% CI: -14.4% to -12.1%; n=935) and 9.9% (95% CI: -11.1% to -8.6%; n=1,142) in paediatric patients was observed during the first year of treatment. In 250 patients who were followed for up to five years, no further decrease in mean creatinine clearance levels was observed. Clinical study in patients with non-transfusion-dependent thalassaemia syndromes In a 1-year study in patients with non-transfusion-dependent thalassaemia syndromes and iron overload (dispersible tablets at a dose of 10 mg/kg/day), diarrhoea (9.1%), rash (9.1%), and nausea (7.3%) were the most frequent study drug-related adverse events. Abnormal serum creatinine and creatinine clearance values were reported in 5.5% and 1.8% of patients, respectively. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were reported in 1.8% of patients. Paediatric population In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.4). Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients. Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with deferasirox. In post-marketing reports, a high proportion of cases of metabolic acidosis occurred in children in the context of Fanconi syndrome. Acute pancreatitis has been reported, particularly in children and adolescents. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Early signs of acute overdose are digestive effects such as abdominal pain, diarrhoea, nausea and vomiting. Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment. There is no specific antidote for deferasirox. Standard procedures for management of overdose may be indicated as well as symptomatic treatment, as medically appropriate. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 58 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Iron chelating agents, ATC code: V03AC03 Mechanism of action Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals. Pharmacodynamic effects In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, deferasirox at daily doses of 10, 20 and 40 mg/kg (dispersible tablet formulation) induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg body weight/day, respectively. Clinical efficacy and safety Clinical efficacy studies were conducted with deferasirox dispersible tablets. Deferasirox has been investigated in 411 adult (age 16 years) and 292 paediatric patients (aged 2 to <16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle cell disease and other congenital and acquired anaemias (myelodysplastic syndromes [MDS], Diamond-Blackfan syndrome, aplastic anaemia and other very rare anaemias). Daily treatment with the deferasirox dispersible tablet formulation at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average, respectively, and serum ferritin was reduced by about -36 and -926 µg/l on average, respectively. At these same doses the ratios of iron excretion: iron intake were 1.02 (indicating net iron balance) and 1.67 (indicating net iron removal), respectively. Deferasirox induced similar responses in iron-overloaded patients with other anaemias. Daily doses of 10 mg/kg (dispersible tablet formulation) for one year could maintain liver iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with deferasirox 10-30 mg/kg/day (dispersible tablet formulation) for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds). The principal analysis of the pivotal comparative study in 586 patients suffering from beta-thalassaemia and transfusional iron overload did not demonstrate non-inferiority of deferasirox dispersible tablets to deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with deferasirox dispersible tablets (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with deferasirox dispersible tablets (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-six patients under the age of 6 years participated in this pivotal study, 28 of them receiving deferasirox dispersible tablets. 59 It appeared from preclinical and clinical studies that deferasirox dispersible tablets could be as active as deferoxamine when used in a dose ratio of 2:1 (i.e. a dose of deferasirox dispersible tablets that is numerically half of the deferoxamine dose). For deferasirox granules, a dose ratio of 3:1 can be considered (i.e. a dose of deferasirox granules that is numerically one third of the deferoxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical studies. In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or sickle cell disease, deferasirox dispersible tablets up to 20 and 30 mg/kg produced a decrease in liver iron concentration and serum ferritin comparable to that obtained in patients with beta-thalassaemia. A placebo-controlled randomised study was performed in 225 patients with MDS (Low/Int-1 risk) and transfusional iron overload. The results of this study suggest that there is a positive impact of deferasirox on event-free survival (EFS, a composite endpoint including non-fatal cardiac or liver events) and serum ferritin levels. The safety profile was consistent with previous studies in adult MDS patients. In a 5-year observational study in which 267 children aged 2 to <6 years (at enrollment) with transfusional haemosiderosis received deferasirox, there were no clinically meaningful differences in the safety and tolerability profile of Exjade in paediatric patients aged 2 to <6 years compared to the overall adult and older paediatric population, including increases in serum creatinine of >33% and above the upper limit of normal on ≥2 consecutive occasions (3.1%), and elevation of alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (4.3%). Single events of increase in ALT and aspartate aminotransferase were reported in 20.0% and 8.3%, respectively, of the 145 patients who completed the study. In a study to assess the safety of deferasirox film-coated and dispersible tablets, 173 adult and paediatric patients with transfusion dependent thalassaemia or myelodysplastic syndrome were treated for 24 weeks. A comparable safety profile for film-coated and dispersible tablets was observed. In patients with non-transfusion-dependent thalassaemia syndromes and iron overload, treatment with deferasirox dispersible tablets was assessed in a 1-year, randomised, double-blind, placebo-controlled study. The study compared the efficacy of two different deferasirox dispersible tablet regimens (starting doses of 5 and 10 mg/kg/day, 55 patients in each arm) and of matching placebo (56 patients). The study enrolled 145 adult and 21 paediatric patients. The primary efficacy parameter was the change in liver iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy parameters was the change in serum ferritin between baseline and fourth quarter. At a starting dose of 10 mg/kg/day, deferasirox dispersible tablets led to reductions in indicators of total body iron. On average, liver iron concentration decreased by 3.80 mg Fe/g dw in patients treated with deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 0.38 mg Fe/g dw in patients treated with placebo (p<0.001). On average, serum ferritin decreased by 222.0 µg/l in patients treated with deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 115 µg/l in patients treated with placebo (p<0.001). 5.2 Pharmacokinetic properties EXJADE granules demonstrate higher bioavailability compared to the EXJADE dispersible tablet formulation. After adjustment of the strength, the granules formulation (4 x 90 mg strength) was equivalent to EXJADE dispersible tablets (500 mg strength) with respect to the mean area under the plasma concentration time curve (AUC) under fasting conditions. The Cmax was increased by 34% (90% CI: 27.9% - 40.3%); however a clinical exposure/response analysis revealed no evidence of clinically relevant effects of such an increase. 60 Absorption Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox (dispersible tablet formulation) is about 70% compared to an intravenous dose. The absolute bioavailability of the granule formulation has not been determined. Bioavailability of deferasirox granules was 52% greater than that with dispersible tablets. A food-effect study involving administration of the granules to healthy volunteers under fasting conditions and with a low-fat (fat content = approximately 30% of calories) or high-fat (fat content >50% of calories) meal indicated that the AUC and Cmax were slightly decreased after a low-fat meal (by 10% and 11%, respectively). After a high-fat meal, only AUC was mildly increased (by 18%). When the granules were administered with apple sauce or yogurt, a food effect was absent. Distribution Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 litres in adults. Biotransformation Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur: in a healthy volunteer study, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC). Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed in vitro. Elimination Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox. Linearity / non-linearity The Cmax and AUC0-24h of deferasirox increase approximately linearly with dose under steady-state conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3. Characteristics in patients Paediatric patients The overall exposure of adolescents (12 to ≤17 years) and children (2 to <12 years) to deferasirox after single and multiple doses was lower than that in adult patients. In children younger than 6 years old exposure was about 50% lower than in adults. Since dosing is individually adjusted according to response this is not expected to have clinical consequences. Gender Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this is not expected to have clinical consequences. Elderly patients The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older). Renal or hepatic impairment The pharmacokinetics of deferasirox have not been studied in patients with renal impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the upper limit of the normal range. 61 In a clinical study using single doses of 20 mg/kg deferasirox dispersible tablets, the average exposure was increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic function. The average Cmax of deferasirox in subjects with mild or moderate hepatic impairment was increased by 22%. Exposure was increased 2.8-fold in one subject with severe hepatic impairment (Child-Pugh Class C) (see sections 4.2 and 4.4). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that were not previously overloaded with iron. Tests of genotoxicity in vitro were negative (Ames test, chromosomal aberration test) while deferasirox caused formation of micronuclei in vivo in the bone marrow, but not liver, of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats. Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/- heterozygous mice in a 6-month study. The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other effects on fertility or reproduction. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Cellulose, microcrystalline Crospovidone Povidone Magnesium stearate Silica, colloidal anhydrous Poloxamer 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Sachets of polyethylene terephthalate (PET)/Aluminium/polyethylene (PE) foil. Unit packs containing 30 sachets. 62 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EXJADE 90 mg granules EU/1/06/356/020 EXJADE 180 mg granules EU/1/06/356/021 EXJADE 360 mg granules EU/1/06/356/022 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 28 August 2006 Date of latest renewal: 18 April 2016 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/ 63 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 64 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release EXJADE 125 mg, 250 mg and 500 mg dispersible tablets Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany EXJADE 90 mg, 180 mg and 360 mg film-coated tablets Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany Novartis Farmacéutica SA Ronda de Santa Maria 158 08210 Barberà del Vallès, Barcelona Spain EXJADE 90 mg, 180 mg and 360 mg granules in sachet Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and and any subsequent updates published on the European medicines web-portal. 65 D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.  Additional risk minimisation measures The MAH must inform the European Medicines Agency and the CHMP of the results of the surveillance programme in each Member State. Prior to launch of EXJADE in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority. The educational programme is aimed to inform healthcare professionals and patients to minimise the risks of:  Non-compliance of the posology and biological monitoring  Medication errors due to switching between formulations (dispersible tablets and film-coated tablets/granules). The MAH shall ensure that, at launch, in each Member State where EXJADE is marketed, all healthcare professionals and patients who are expected to prescribe, dispense and use EXJADE are provided with the following educational package for all available formulations (e.g. dispersible tablets, film-coated tablets and granules) for all indications:  Physician educational material  Patient information pack Additional periodic distributions after launch should be performed, notably after substantial safety modifications of the product information justifying educational material updates. The MAH shall use distinct outer cartons, blisters and tablets for all formulations (dispersible tablets and film-coated tablets/granules). The physician educational material should contain:  The Summary of Product Characteristics  Guide for healthcare professionals The Guide for healthcare professionals shall contain the following key elements:  Description of available deferasirox formulations (e.g. dispersible tablets, film-coated tablets and granules) o Different posology regimen o Different conditions of administration o Dose conversion table when switching from one formulation to another  The recommended doses and the rules for starting treatment  The need to monitor serum ferritin monthly 66  That deferasirox causes rises in serum creatinine in some patients o The need to monitor serum creatinine  On two occasions prior to initiation of treatment  Every week during the first month of initiation of treatment or after therapy modification  Monthly thereafter o The need to reduce by 10 mg/kg the dose if serum creatinine rises:  Adults: >33% above baseline and creatinine clearance <LLN (90 ml/min)  Paediatrics: either >ULN or creatinine clearance falls to <LLN at two consecutive visits. o The need to interrupt treatment after a dose reduction if serum creatinine rises:  Adults and Paediatrics: remain >33% above baseline or creatinine clearance <LLN (90 ml/min) o The need to consider renal biopsy:  When serum creatinine is elevated and if another abnormality has been detected (e.g. proteinuria, signs of Fanconi syndrome).  The importance of measuring creatinine clearance  Brief overview of methods of measuring creatinine clearance  That rises in serum transaminases may occur in patients treated with EXJADE o The need for liver function tests prior to prescription, then at monthly intervals or more often if clinically indicated o Not to prescribe to patients with pre-existing severe hepatic disease o The need to interrupt treatment if persistent and progressive increase in liver enzyme were noted.  The need for annual auditory and ophthalmic testing  The need for a guidance table highlighting pre-treatment measurements of serum creatinine, creatinine clearance, proteinuria, hepatic enzymes, ferritin, such as: Before initiating treatment Serum creatinine at Day - X Value 1 Serum creatinine at Day - Y Value 2 X and Y are the days (to be determined) when pre-treatment measurements should be performed.  A warning on the risk of overchelation and on the necessity of close monitoring of serum ferritin levels and renal and hepatic function.  The rules for treatment dose adjustments and interruption when target serum ferritin +/- liver iron concentration are reached.  Recommendations for treatment of non-transfusion-dependent thalassaemia (NTDT) syndromes: o Information that only one course of treatment is proposed for NTDT patients o A warning on the necessity of closer monitoring of liver iron concentration and serum ferritin in the paediatric population o A warning on the currently unknown safety consequences of long-term treatment in the paediatric population 67 Prior to launch of deferasirox film-coated tablets, healthcare professionals will receive introductory notification letters as follows:  Pharmacists - a detailed letter explaining the switch between formulations  Prescribers - a letter including the following dossiers: o A prescribers’ guide informing about the switch between formulations in order to address the important potential risk of medication error for deferasirox o A patient’s guide informing about the possibility of co-existing formulations in the EU market, and the differences concerning their administration, in order to address the important potential risk of medication error for deferasirox Additionally, prescribers and pharmacists will be informed via a specific letter regarding the timelines for removing EXJADE dispersible tablets from the EU market. The patient information pack should contain:  Patient information leaflet  Patient guide Patient guide should contain the following key elements: o Information on the need for regular monitoring, and when it should be carried out, of serum creatinine, creatinine clearance, proteinuria, hepatic enzymes, ferritin o Information that renal biopsy may be considered if significant renal abnormalities occur o Availability of several oral formulations (e.g. dispersible tablets, film-coated tablets and granules) and the main differences associated with these formulations (i.e., different posology regimen, different conditions of administration notably with food)  Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date Non-interventional post-authorisation safety study (PASS): In order to assess the long-term exposure and safety of deferasirox dispersible and film-coated tablets, the MAH should conduct an observational cohort study in paediatric non-transfusion-dependent thalassaemia patients over 10 years old for whom deferoxamine is contraindicated or inadequate conducted according to a CHMP-agreed protocol. The clinical study report should be submitted by June 2021 68 ANNEX III LABELLING AND PACKAGE LEAFLET 69 A. LABELLING 70 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT EXJADE 125 mg dispersible tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each dispersible tablet contains 125 mg of deferasirox. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Dispersible tablets 28 dispersible tablets 84 dispersible tablets 252 dispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Take this medicine on an empty stomach. Disperse tablets in water or fruit juice before swallowing. Do not swallow whole or chew. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 71 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/001 28 dispersible tablets EU/1/06/356/002 84 dispersible tablets EU/1/06/356/007 252 dispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE EXJADE 125 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 72 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 73 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT EXJADE 125 mg dispersible tablets deferasirox 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 74 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT EXJADE 250 mg dispersible tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each dispersible tablet contains 250 mg of deferasirox. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Dispersible tablets 28 dispersible tablets 84 dispersible tablets 252 dispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Take this medicine on an empty stomach. Disperse tablets in water or fruit juice before swallowing. Do not swallow whole or chew. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 75 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/003 28 dispersible tablets EU/1/06/356/004 84 dispersible tablets EU/1/06/356/008 252 dispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE EXJADE 250 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 76 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 77 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT EXJADE 250 mg dispersible tablets deferasirox 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 78 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT EXJADE 500 mg dispersible tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each dispersible tablet contains 500 mg of deferasirox. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Dispersible tablets 28 dispersible tablets 84 dispersible tablets 252 dispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Take this medicine on an empty stomach. Disperse tablets in water or fruit juice before swallowing. Do not swallow whole or chew. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 79 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/005 28 dispersible tablets EU/1/06/356/006 84 dispersible tablets EU/1/06/356/009 252 dispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE EXJADE 500 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 80 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 81 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (including blue box) 1. NAME OF THE MEDICINAL PRODUCT EXJADE 500 mg dispersible tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each dispersible tablet contains 500 mg of deferasirox. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Dispersible tablets Multipack: 294 (3 packs of 98) dispersible tablets. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Take this medicine on an empty stomach. Disperse tablets in water or fruit juice before swallowing. Do not swallow whole or chew. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 82 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/010 294 (3 packs of 98) dispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE EXJADE 500 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 83 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (without blue box) 1. NAME OF THE MEDICINAL PRODUCT EXJADE 500 mg dispersible tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each dispersible tablet contains 500 mg of deferasirox. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Dispersible tablets 98 dispersible tablets. Component of a multipack. Cannot be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Take this medicine on an empty stomach. Disperse tablets in water or fruit juice before swallowing. Do not swallow whole or chew. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 84 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/010 294 (3 packs of 98) dispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE EXJADE 500 mg 85 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT EXJADE 500 mg dispersible tablets deferasirox 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 86 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Exjade 90 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 90 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets 30 film-coated tablets 90 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 87 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/011 30 film-coated tablets EU/1/06/356/012 90 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 90 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 88 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Exjade 90 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 90 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets Multipack: 300 (10 packs of 30) film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 89 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/013 300 (10 packs of 30) film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 90 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 90 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Exjade 90 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 90 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets 30 film-coated tablets. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 91 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/013 300 (10 packs of 30) film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 90 mg 92 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Exjade 90 mg film-coated tablets deferasirox 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 93 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Exjade 180 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 180 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets 30 film-coated tablets 90 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 94 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/014 30 film-coated tablets EU/1/06/356/015 90 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 180 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 95 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Exjade 180 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 180 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets Multipack: 300 (10 packs of 30) film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 96 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/016 300 (10 packs of 30) film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 180 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 97 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Exjade 180 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 180 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets 30 film-coated tablets. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 98 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/016 300 (10 packs of 30) film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 180 mg 99 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Exjade 180 mg film-coated tablets deferasirox 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 100 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Exjade 360 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 360 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets 30 film-coated tablets 90 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 101 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/017 30 film-coated tablets EU/1/06/356/018 90 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 360 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 102 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Exjade 360 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 360 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets Multipack: 300 (10 packs of 30) film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 103 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/019 300 (10 packs of 30) film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 360 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 104 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Exjade 360 mg film-coated tablets deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 360 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablets 30 film-coated tablets. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 105 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/019 300 (10 packs of 30) film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 360 mg 106 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Exjade 360 mg film-coated tablets deferasirox 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 107 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Exjade 90 mg granules in sachet deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sachet contains 90 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Granules in sachet 30 sachets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 108 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/020 30 sachets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 90 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 109 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SACHETS 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Exjade 90 mg granules deferasirox Oral use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 162 mg 6. OTHER 110 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Exjade 180 mg granules in sachet deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sachet contains 180 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Granules in sachet 30 sachets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 111 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/021 30 sachets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 180 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 112 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SACHETS 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Exjade 180 mg granules deferasirox Oral use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 324 mg 6. OTHER 113 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Exjade 360 mg granules in sachet deferasirox 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sachet contains 360 mg of deferasirox. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS Granules in sachet 30 sachets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 114 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/06/356/022 30 sachets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Exjade 360 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 115 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SACHETS 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Exjade 360 mg granules deferasirox Oral use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 648 mg 6. OTHER 116 B. PACKAGE LEAFLET 117 Package leaflet: Information for the user EXJADE 125 mg dispersible tablets EXJADE 250 mg dispersible tablets EXJADE 500 mg dispersible tablets Deferasirox This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed only for you or your child. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What EXJADE is and what it is used for 2. What you need to know before you take EXJADE 3. How to take EXJADE 4. Possible side effects 5. How to store EXJADE 6. Contents of the pack and other information 1. What EXJADE is and what it is used for What EXJADE is EXJADE contains an active substance called deferasirox. It is an iron chelator which is a medicine used to remove the excess iron from the body (also called iron overload). It traps and removes excess iron which is then excreted mainly in the stools. What EXJADE is used for Repeated blood transfusions may be necessary in patients with various types of anaemia (for example thalassaemia, sickle cell disease or myelodysplastic syndromes (MDS)). However, repeated blood transfusions can cause a build-up of excess iron. This is because blood contains iron and your body does not have a natural way to remove the excess iron you get with your blood transfusions. In patients with non-transfusion-dependent thalassaemia syndromes, iron overload may also develop over time, mainly due to increased absorption of dietary iron in response to low blood cell counts. Over time, the excess iron can damage important organs such as the liver and heart. Medicines called iron chelators are used to remove the excess iron and reduce the risk of it causing organ damage. EXJADE is used to treat chronic iron overload caused by frequent blood transfusions in patients with beta thalassaemia major aged 6 years and older. EXJADE is also used to treat chronic iron overload when deferoxamine therapy is contraindicated or inadequate in patients with beta thalassaemia major with iron overload caused by infrequent blood transfusions, in patients with other types of anaemias, and in children aged 2 to 5 years. EXJADE is also used when deferoxamine therapy is contraindicated or inadequate to treat patients aged 10 years or older who have iron overload associated with their thalassaemia syndromes, but who are not transfusion dependent. 118 2. What you need to know before you take EXJADE Do not take EXJADE - if you are allergic to deferasirox or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor before taking EXJADE. If you think you may be allergic, ask your doctor for advice. - if you have moderate or severe kidney disease. - if you are currently taking any other iron chelator medicines. EXJADE is not recommended - if you are at an advanced stage of myelodysplastic syndrome (MDS; decreased production of blood cells by the bone marrow) or have advanced cancer. Warnings and precautions Talk to your doctor or pharmacist before taking EXJADE: - if you have a kidney or liver problem. - if you have a cardiac problem due to iron overload. - if you notice a marked decrease in your urine output (sign of kidney problem). - if you develop a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction, see also section 4 “Possible side effects”). - if you experience a combination of any of the following symptoms: rash, red skin, blistering of the lips, eyes, or mouth, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes (signs of severe skin reaction, see also section 4 “Possible side effects”). - if you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems). - if you experience difficulty thinking, remembering information, or solving problems, being less alert or aware or feeling very sleepy with low energy (signs of a high level of ammonia in your blood, which may be associated with liver or renal problems, see also section 4 “Possible side effects”). - if you vomit blood and/or have black stools. - if you experience frequent abdominal pain, particularly after eating or taking EXJADE. - if you experience frequent heartburn. - if you have a low level of platelets or white blood cells in your blood test. - if you have blurred vision. - if you have diarrhoea or vomiting. If any of these apply to you, tell your doctor straight away. Monitoring your EXJADE treatment You will have regular blood and urine tests during treatment. These will monitor the amount of iron in your body (blood level of ferritin) to see how well EXJADE is working. The tests will also monitor your kidney function (blood level of creatinine, presence of protein in the urine) and liver function (blood level of transaminases). Your doctor may require you to undergo a kidney biopsy, if he/she suspects significant kidney damage. You may also have MRI (magnetic resonance imaging) tests to determine the amount of iron in your liver. Your doctor will take these tests into consideration when deciding on the dose of EXJADE most suitable for you and will also use these tests to decide when you should stop taking EXJADE. Your eyesight and hearing will be tested each year during treatment as a precautionary measure. 119 Other medicines and EXJADE Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes in particular: - other iron chelators, which must not be taken with EXJADE, - antacids (medicines used to treat heartburn) containing aluminium, which should not be taken at the same time of day as EXJADE, - ciclosporin (used to prevent the body rejecting a transplanted organ or for other conditions, such as rheumatoid arthritis or atopic dermatitis), - simvastatin (used to lower cholesterol), - certain painkillers or anti-inflammatory medicines (e.g. aspirin, ibuprofen, corticosteroids), - oral bisphosphonates (used to treat osteoporosis), - anticoagulant medicines (used to prevent or treat blood clotting), - hormonal contraceptive agents (birth control medicines), - bepridil, ergotamine (used for heart problems and migraines), - repaglinide (used to treat diabetes), - rifampicin (used to treat tuberculosis), - phenytoin, phenobarbital, carbamazepine (used to treat epilepsy), - ritonavir (used in the treatment of HIV infection), - paclitaxel (used in cancer treatment), - theophylline (used to treat respiratory diseases such as asthma), - clozapine (used to treat psychiatric disorders such as schizophrenia), - tizanidine (used as a muscle relaxant), - cholestyramine (used to lower cholesterol levels in the blood), - busulfan (used as a treatment prior to transplantation in order to destroy the original bone marrow before the transplant). Additional tests may be required to monitor the blood levels of some of these medicines. Older people (age 65 years and over) EXJADE can be used by people aged 65 years and over at the same dose as for other adults. Elderly patients may experience more side effects (in particular diarrhoea) than younger patients. They should be monitored closely by their doctor for side effects that may require a dose adjustment. Children and adolescents EXJADE can be used in children and adolescents receiving regular blood transfusions aged 2 years and over and in children and adolescents not receiving regular blood transfusions aged 10 years and over. As the patient grows the doctor will adjust the dose. EXJADE is not recommended for children aged under 2 years. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. EXJADE is not recommended during pregnancy unless clearly necessary. If you are currently using an oral contraceptive or using a patch contraceptive to prevent pregnancy, you should use an additional or different type of contraception (e.g. condom), as EXJADE may reduce the effectiveness of oral and patch contraceptives. Breast-feeding is not recommended during treatment with EXJADE. Driving and using machines If you feel dizzy after taking EXJADE, do not drive or operate any tools or machines until you are feeling normal again. 120 EXJADE contains lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. 3. How to take EXJADE Treatment with EXJADE will be overseen by a doctor who is experienced in the treatment of iron overload caused by blood transfusions. Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. How much EXJADE to take The dose of EXJADE is related to body weight for all patients. Your doctor will calculate the dose you need and tell you how many tablets to take each day.  The usual daily dose for EXJADE dispersible tablets at the start of the treatment for patients receiving regular blood transfusions is 20 mg per kilogram body weight. A higher or lower starting dose may be recommended by your doctor based on your individual treatment needs.  The usual daily dose for EXJADE dispersible tablets at the start of the treatment for patients not receiving regular blood transfusions is 10 mg per kilogram body weight.  Depending on how you respond to treatment, your doctor may later adjust your treatment to a higher or lower dose.  The maximum recommended daily dose for EXJADE dispersible tablets is 40 mg per kilogram body weight for patients receiving regular blood transfusions, 20 mg per kilogram body weight for adult patients not receiving regular blood transfusions and 10 mg per kilogram body weight for children and adolescents not receiving regular blood transfusions. Deferasirox also comes as “film-coated” tablets and granules. If you are switching from the film-coated tablets or granules to these dispersible tablets, you will need an adjustment of the dose. When to take EXJADE  Take EXJADE once a day, every day, at about the same time each day.  Take the EXJADE dispersible tablets on an empty stomach.  Then wait at least 30 minutes before eating any food. Taking EXJADE at the same time each day will also help you remember when to take your tablets. How to take EXJADE:  Drop the tablet(s) into a glass of water, or apple or orange juice (100 to 200 ml).  Stir until the tablet(s) dissolve completely. The liquid in the glass will look cloudy.  Drink everything in the glass. Then add a little water or juice to what is left in the glass, swirl the liquid around and drink that too. Do not dissolve the tablets in fizzy drinks or milk. Do not chew, break or crush the tablets. Do not swallow the tablets whole. 121 How long to take EXJADE Continue taking EXJADE every day for as long as your doctor tells you. This is a long-term treatment, possibly lasting for months or years. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect (see also section 2: “Monitoring your EXJADE treatment”). If you have questions about how long to take EXJADE, talk to your doctor. If you take more EXJADE than you should If you have taken too much EXJADE, or if someone else accidentally takes your tablets, contact your doctor or hospital for advice straight away. Show the doctor the pack of tablets. Urgent medical treatment may be necessary. You may experience effects such as abdominal pain, diarrhoea, nausea and vomiting and kidney or liver problems that can be serious. If you forget to take EXJADE If you miss a dose, take it as soon as you remember on that day. Take your next dose as scheduled. Do not take a double dose on the next day to make up for the forgotten tablet(s). If you stop taking EXJADE Do not stop taking EXJADE unless your doctor tells you to. If you stop taking it, the excess iron will no longer be removed from your body (see also above section “How long to take EXJADE”). 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of the side effects are mild to moderate and will generally disappear after a few days to a few weeks of treatment. Some side effects could be serious and need immediate medical attention. These side effects are uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people).  If you get a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction),  If you experience a combination of any of the following symptoms: rash, red skin, blistering of the lips, eyes, or mouth, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes, (signs of severe skin reactions),  If you notice a marked decrease in your urine output (sign of kidney problem),  If you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems),  If you experience difficulty thinking, remembering information, or solving problems, being less alert or aware or feeling very sleepy with low energy (signs of a high level of ammonia in your blood, which may be associated with liver or renal problems and lead to a change in your brain function),  If you vomit blood and/or have black stools,  If you experience frequent abdominal pain, particularly after eating or taking EXJADE,  If you experience frequent heartburn,  If you experience partial loss of vision,  If you experience severe upper stomach pain (pancreatitis), stop taking this medicine and tell your doctor straight away. Some side effects could become serious. These side effects are uncommon.  If you get blurred or cloudy eyesight,  If you get reduced hearing, tell your doctor as soon as possible. 122 Other side effects Very common (may affect more than 1 in 10 people)  Disturbance in kidney function tests. Common (may affect up to 1 in 10 people)  Gastrointestinal disorders, such as nausea, vomiting, diarrhoea, pain in the abdomen, bloating, constipation, indigestion  Rash  Headache  Disturbance in liver function tests  Itching  Disturbance in urine test (protein in the urine) If any of these affects you severely, tell your doctor. Uncommon (may affect up to 1 in 100 people)  Dizziness  Fever  Sore throat  Swelling of arms or legs  Change in the colour of the skin  Anxiety  Sleep disorder  Tiredness If any of these affects you severely, tell your doctor. Frequency not known (cannot be estimated from the available data).  A decrease in the number of cells involved in blood clotting (thrombocytopenia), in the number of red blood cells (anaemia aggravated), in the number of white blood cells (neutropenia) or in the number of all kinds of blood cells (pancytopenia)  Hair loss  Kidney stones  Low urine output  Tear in stomach or intestine wall that can be painful and cause nausea  Severe upper stomach pain (pancreatitis)  Abnormal level of acid in blood Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store EXJADE  Keep this medicine out of the sight and reach of children.  Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP. The expiry date refers to the last day of that month.  Store in the original package in order to protect from moisture.  Do not use any pack that is damaged or shows signs of tampering.  Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 123 6. Contents of the pack and other information What EXJADE contains The active substance is deferasirox.  Each dispersible tablet of EXJADE 125 mg contains 125 mg deferasirox.  Each dispersible tablet of EXJADE 250 mg contains 250 mg deferasirox.  Each dispersible tablet of EXJADE 500 mg contains 500 mg deferasirox. The other ingredients are lactose monohydrate, crospovidone type A, povidone, sodium laurilsulfate, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate. What EXJADE looks like and contents of the pack EXJADE is supplied as dispersible tablets. The tablets are white to slightly yellow, round and flat.  EXJADE 125 mg tablets are stamped “J 125” on one side and “NVR” on the other.  EXJADE 250 mg tablets are stamped “J 250” on one side and “NVR” on the other.  EXJADE 500 mg tablets are stamped “J 500” on one side and “NVR” on the other. EXJADE 125 mg, 250 mg and 500 mg dispersible tablets are available in unit packs containing 28, 84 or 252 dispersible tablets. EXJADE 500 mg dispersible tablets are also available in multipacks containing 294 (3 packs of 98) dispersible tablets. Not all pack sizes or strengths may be available in your country. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva Novartis Pharma Services Inc. Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел.: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 124 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 26 37 82 555 Eesti Novartis Pharma Services Inc. Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA “Novartis Baltics” Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu http://www.ema.europa.eu/ 125 Package leaflet: Information for the user EXJADE 90 mg film-coated tablets EXJADE 180 mg film-coated tablets EXJADE 360 mg film-coated tablets Deferasirox This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed only for you or your child. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What EXJADE is and what it is used for 2. What you need to know before you take EXJADE 3. How to take EXJADE 4. Possible side effects 5. How to store EXJADE 6. Contents of the pack and other information 1. What EXJADE is and what it is used for What EXJADE is EXJADE contains an active substance called deferasirox. It is an iron chelator which is a medicine used to remove the excess iron from the body (also called iron overload). It traps and removes excess iron which is then excreted mainly in the stools. What EXJADE is used for Repeated blood transfusions may be necessary in patients with various types of anaemia (for example thalassaemia, sickle cell disease or myelodysplastic syndromes (MDS)). However, repeated blood transfusions can cause a build-up of excess iron. This is because blood contains iron and your body does not have a natural way to remove the excess iron you get with your blood transfusions. In patients with non-transfusion-dependent thalassaemia syndromes, iron overload may also develop over time, mainly due to increased absorption of dietary iron in response to low blood cell counts. Over time, the excess iron can damage important organs such as the liver and heart. Medicines called iron chelators are used to remove the excess iron and reduce the risk of it causing organ damage. EXJADE is used to treat chronic iron overload caused by frequent blood transfusions in patients with beta thalassaemia major aged 6 years and older. EXJADE is also used to treat chronic iron overload when deferoxamine therapy is contraindicated or inadequate in patients with beta thalassaemia major with iron overload caused by infrequent blood transfusions, in patients with other types of anaemias, and in children aged 2 to 5 years. EXJADE is also used when deferoxamine therapy is contraindicated or inadequate to treat patients aged 10 years or older who have iron overload associated with their thalassaemia syndromes, but who are not transfusion dependent. 126 2. What you need to know before you take EXJADE Do not take EXJADE - if you are allergic to deferasirox or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor before taking EXJADE. If you think you may be allergic, ask your doctor for advice. - if you have moderate or severe kidney disease. - if you are currently taking any other iron chelator medicines. EXJADE is not recommended - if you are at an advanced stage of myelodysplastic syndrome (MDS; decreased production of blood cells by the bone marrow) or have advanced cancer. Warnings and precautions Talk to your doctor or pharmacist before taking EXJADE: - if you have a kidney or liver problem. - if you have a cardiac problem due to iron overload. - if you notice a marked decrease in your urine output (sign of kidney problem). - if you develop a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction, see also section 4 “Possible side effects”). - if you experience a combination of any of the following symptoms: rash, red skin, blistering of the lips, eyes or mouth, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes (signs of severe skin reaction, see also section 4 “Possible side effects”). - if you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems). - if you experience difficulty thinking, remembering information, or solving problems, being less alert or aware or feeling very sleepy with low energy (signs of a high level of ammonia in your blood, which may be associated with liver or renal problems, see also section 4 “Possible side effects”). - if you vomit blood and/or have black stools. - if you experience frequent abdominal pain, particularly after eating or taking EXJADE. - if you experience frequent heartburn. - if you have a low level of platelets or white blood cells in your blood test. - if you have blurred vision - if you have diarrhoea or vomiting. If any of these apply to you, tell your doctor straight away. Monitoring your EXJADE treatment You will have regular blood and urine tests during treatment. These will monitor the amount of iron in your body (blood level of ferritin) to see how well EXJADE is working. The tests will also monitor your kidney function (blood level of creatinine, presence of protein in the urine) and liver function (blood level of transaminases). Your doctor may require you to undergo a kidney biopsy, if he/she suspects significant kidney damage. You may also have MRI (magnetic resonance imaging) tests to determine the amount of iron in your liver. Your doctor will take these tests into consideration when deciding on the dose of EXJADE most suitable for you and will also use these tests to decide when you should stop taking EXJADE. Your eyesight and hearing will be tested each year during treatment as a precautionary measure. 127 Other medicines and EXJADE Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes in particular: - other iron chelators, which must not be taken with EXJADE, - antacids (medicines used to treat heartburn) containing aluminium, which should not be taken at the same time of day as EXJADE, - ciclosporin (used to prevent the body rejecting a transplanted organ or for other conditions, such as rheumatoid arthritis or atopic dermatitis), - simvastatin (used to lower cholesterol), - certain painkillers or anti-inflammatory medicines (e.g. aspirin, ibuprofen, corticosteroids), - oral bisphosphonates (used to treat osteoporosis), - anticoagulant medicines (used to prevent or treat blood clotting), - hormonal contraceptive agents (birth control medicines), - bepridil, ergotamine (used for heart problems and migraines), - repaglinide (used to treat diabetes), - rifampicin (used to treat tuberculosis), - phenytoin, phenobarbital, carbamazepine (used to treat epilepsy), - ritonavir (used in the treatment of HIV infection), - paclitaxel (used in cancer treatment), - theophylline (used to treat respiratory diseases such as asthma), - clozapine (used to treat psychiatric disorders such as schizophrenia), - tizanidine (used as a muscle relaxant), - cholestyramine (used to lower cholesterol levels in the blood), - busulfan (used as a treatment prior to transplantation in order to destroy the original bone marrow before the transplant). Additional tests may be required to monitor the blood levels of some of these medicines. Older people (age 65 years and over) EXJADE can be used by people aged 65 years and over at the same dose as for other adults. Elderly patients may experience more side effects (in particular diarrhoea) than younger patients. They should be monitored closely by their doctor for side effects that may require a dose adjustment. Children and adolescents EXJADE can be used in children and adolescents receiving regular blood transfusions aged 2 years and over and in children and adolescents not receiving regular blood transfusions aged 10 years and over. As the patient grows the doctor will adjust the dose. EXJADE is not recommended for children aged under 2 years. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. EXJADE is not recommended during pregnancy unless clearly necessary. If you are currently using an oral contraceptive or using a patch contraceptive to prevent pregnancy, you should use an additional or different type of contraception (e.g. condom), as EXJADE may reduce the effectiveness of oral and patch contraceptives. Breast-feeding is not recommended during treatment with EXJADE. Driving and using machines If you feel dizzy after taking EXJADE, do not drive or operate any tools or machines until you are feeling normal again. 128 3. How to take EXJADE Treatment with EXJADE will be overseen by a doctor who is experienced in the treatment of iron overload caused by blood transfusions. Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. How much EXJADE to take The dose of EXJADE is related to body weight for all patients. Your doctor will calculate the dose you need and tell you how many tablets to take each day.  The usual daily dose for EXJADE film-coated tablets at the start of the treatment for patients receiving regular blood transfusions is 14 mg per kilogram body weight. A higher or lower starting dose may be recommended by your doctor based on your individual treatment needs.  The usual daily dose for EXJADE film-coated tablets at the start of the treatment for patients not receiving regular blood transfusions is 7 mg per kilogram body weight.  Depending on how you respond to treatment, your doctor may later adjust your treatment to a higher or lower dose.  The maximum recommended daily dose for EXJADE film-coated tablets is:  28 mg per kilogram body weight for patients receiving regular blood transfusions,  14 mg per kilogram body weight for adult patients not receiving regular blood transfusions,  7 mg per kilogram body weight for children and adolescents not receiving regular blood transfusions. Deferasirox also comes as “dispersible” tablets. If you are switching from the dispersible tablets to these film-coated tablets, you will need an adjustment of the dose. When to take EXJADE  Take EXJADE once a day, every day, at about the same time each day with some water.  Take EXJADE film-coated tablets either on an empty stomach or with a light meal. Taking EXJADE at the same time each day will also help you remember when to take your tablets. For patients who are unable to swallow whole tablets, EXJADE film-coated tablets may be crushed and taken by sprinkling the full dose onto soft food such as yogurt or apple sauce (pureed apple). The food should be immediately and completely consumed. Do not store it for future use. How long to take EXJADE Continue taking EXJADE every day for as long as your doctor tells you. This is a long-term treatment, possibly lasting for months or years. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect (see also section 2: “Monitoring your EXJADE treatment”). If you have questions about how long to take EXJADE, talk to your doctor. If you take more EXJADE than you should If you have taken too much EXJADE, or if someone else accidentally takes your tablets, contact your doctor or hospital for advice straight away. Show the doctor the pack of tablets. Urgent medical treatment may be necessary. You may experience effects such as abdominal pain, diarrhoea, nausea and vomiting and kidney or liver problems that can be serious. If you forget to take EXJADE If you miss a dose, take it as soon as you remember on that day. Take your next dose as scheduled. Do not take a double dose on the next day to make up for the forgotten tablet(s). 129 If you stop taking EXJADE Do not stop taking EXJADE unless your doctor tells you to. If you stop taking it, the excess iron will no longer be removed from your body (see also above section “How long to take EXJADE”). 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of the side effects are mild to moderate and will generally disappear after a few days to a few weeks of treatment. Some side effects could be serious and need immediate medical attention. These side effects are uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people).  If you get a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction),  If you experience a combination of any of the following symptoms: rash, red skin, blistering of the lips, eyes or mouth, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes, (signs of severe skin reactions),  If you notice a marked decrease in your urine output (sign of kidney problem),  If you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems),  If you experience difficulty thinking, remembering information, or solving problems, being less alert or aware or feeling very sleepy with low energy (signs of a high level of ammonia in your blood, which may be associated with liver or renal problems and lead to a change in your brain function),  If you vomit blood and/or have black stools,  If you experience frequent abdominal pain, particularly after eating or taking EXJADE,  If you experience frequent heartburn,  If you experience partial loss of vision,  If you experience severe upper stomach pain (pancreatitis), stop taking this medicine and tell your doctor straight away. Some side effects could become serious. These side effects are uncommon.  If you get blurred or cloudy eyesight,  If you get reduced hearing, tell your doctor as soon as possible. Other side effects Very common (may affect more than 1 in 10 people)  Disturbance in kidney function tests. Common (may affect up to 1 in 10 people)  Gastrointestinal disorders, such as nausea, vomiting, diarrhoea, pain in the abdomen, bloating, constipation, indigestion  Rash  Headache  Disturbance in liver function tests  Itching  Disturbance in urine test (protein in the urine) If any of these affects you severely, tell your doctor. 130 Uncommon (may affect up to 1 in 100 people)  Dizziness  Fever  Sore throat  Swelling of arms or legs  Change in the colour of the skin  Anxiety  Sleep disorder  Tiredness If any of these affects you severely, tell your doctor. Frequency not known (cannot be estimated from the available data).  A decrease in the number of cells involved in blood clotting (thrombocytopenia), in the number of red blood cells (anaemia aggravated), in the number of white blood cells (neutropenia) or in the number of all kinds of blood cells (pancytopenia)  Hair loss  Kidney stones  Low urine output  Tear in stomach or intestine wall that can be painful and cause nausea  Severe upper stomach pain (pancreatitis)  Abnormal level of acid in blood Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store EXJADE  Keep this medicine out of the sight and reach of children.  Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP. The expiry date refers to the last day of that month.  Do not use any pack that is damaged or shows signs of tampering.  Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What EXJADE contains The active substance is deferasirox.  Each film-coated tablet of EXJADE 90 mg contains 90 mg deferasirox.  Each film-coated tablet of EXJADE 180 mg contains 180 mg deferasirox.  Each film-coated tablet of EXJADE 360 mg contains 360 mg deferasirox. The other ingredients are microcrystalline cellulose; crospovidone; povidone; magnesium stearate; colloidal anhydrous silica and poloxamer. The tablet coating material contains: hypromellose; titanium dioxide (E171); macrogol (4000); talc; indigo carmine aluminium lake (E132). http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 131 What EXJADE looks like and contents of the pack EXJADE is supplied as film-coated tablets. The film-coated tablets are ovaloid and biconvex.  EXJADE 90 mg film-coated tablets are light blue and stamped “90” on one side and “NVR” on the other.  EXJADE 180 mg film-coated tablets are medium blue and stamped “180” on one side and “NVR” on the other.  EXJADE 360 mg film-coated tablets are dark blue and stamped “360” on one side and “NVR” on the other. Each blister pack contains 30 or 90 film-coated tablets. The multipacks contain 300 (10 packs of 30) film-coated tablets. Not all pack sizes or strengths may be available in your country. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany Novartis Farmacéutica SA Ronda de Santa Maria 158 08210 Barberà del Vallès, Barcelona Spain For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva Novartis Pharma Services Inc. Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел.: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 26 37 82 555 132 Eesti Novartis Pharma Services Inc. Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA “Novartis Baltics” Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu http://www.ema.europa.eu/ 133 Package leaflet: Information for the user EXJADE 90 mg granules in sachet EXJADE 180 mg granules in sachet EXJADE 360 mg granules in sachet Deferasirox This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed only for you or your child. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What EXJADE is and what it is used for 2. What you need to know before you take EXJADE 3. How to take EXJADE 4. Possible side effects 5. How to store EXJADE 6. Contents of the pack and other information 1. What EXJADE is and what it is used for What EXJADE is EXJADE contains an active substance called deferasirox. It is an iron chelator which is a medicine used to remove the excess iron from the body (also called iron overload). It traps and removes excess iron which is then excreted mainly in the stools. What EXJADE is used for Repeated blood transfusions may be necessary in patients with various types of anaemia (for example thalassaemia, sickle cell disease or myelodysplastic syndromes (MDS)). However, repeated blood transfusions can cause a build-up of excess iron. This is because blood contains iron and your body does not have a natural way to remove the excess iron you get with your blood transfusions. In patients with non-transfusion-dependent thalassaemia syndromes, iron overload may also develop over time, mainly due to increased absorption of dietary iron in response to low blood cell counts. Over time, the excess iron can damage important organs such as the liver and heart. Medicines called iron chelators are used to remove the excess iron and reduce the risk of it causing organ damage. EXJADE is used to treat chronic iron overload caused by frequent blood transfusions in patients with beta thalassaemia major aged 6 years and older. EXJADE is also used to treat chronic iron overload when deferoxamine therapy is contraindicated or inadequate in patients with beta thalassaemia major with iron overload caused by infrequent blood transfusions, in patients with other types of anaemias, and in children aged 2 to 5 years. EXJADE is also used when deferoxamine therapy is contraindicated or inadequate to treat patients aged 10 years or older who have iron overload associated with their thalassaemia syndromes, but who are not transfusion dependent. 134 2. What you need to know before you take EXJADE Do not take EXJADE - if you are allergic to deferasirox or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor before taking EXJADE. If you think you may be allergic, ask your doctor for advice. - if you have moderate or severe kidney disease. - if you are currently taking any other iron chelator medicines. EXJADE is not recommended - if you are at an advanced stage of myelodysplastic syndrome (MDS; decreased production of blood cells by the bone marrow) or have advanced cancer. Warnings and precautions Talk to your doctor or pharmacist before taking EXJADE: - if you have a kidney or liver problem. - if you have a cardiac problem due to iron overload. - if you notice a marked decrease in your urine output (sign of kidney problem). - if you develop a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction, see also section 4 “Possible side effects”). - if you experience a combination of any of the following symptoms: rash, red skin, blistering of the lips, eyes or mouth, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes (signs of severe skin reaction, see also section 4 “Possible side effects”). - if you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems). - if you experience difficulty thinking, remembering information, or solving problems, being less alert or aware or feeling very sleepy with low energy (signs of a high level of ammonia in your blood, which may be associated with liver or renal problems, see also section 4 “Possible side effects”). - if you vomit blood and/or have black stools. - if you experience frequent abdominal pain, particularly after eating or taking EXJADE. - if you experience frequent heartburn. - if you have a low level of platelets or white blood cells in your blood test. - if you have blurred vision - if you have diarrhoea or vomiting. If any of these apply to you, tell your doctor straight away. Monitoring your EXJADE treatment You will have regular blood and urine tests during treatment. These will monitor the amount of iron in your body (blood level of ferritin) to see how well EXJADE is working. The tests will also monitor your kidney function (blood level of creatinine, presence of protein in the urine) and liver function (blood level of transaminases). Your doctor may require you to undergo a kidney biopsy, if he/she suspects significant kidney damage. You may also have MRI (magnetic resonance imaging) tests to determine the amount of iron in your liver. Your doctor will take these tests into consideration when deciding on the dose of EXJADE most suitable for you and will also use these tests to decide when you should stop taking EXJADE. Your eyesight and hearing will be tested each year during treatment as a precautionary measure. 135 Other medicines and EXJADE Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes in particular: - other iron chelators, which must not be taken with EXJADE, - antacids (medicines used to treat heartburn) containing aluminium, which should not be taken at the same time of day as EXJADE, - ciclosporin (used to prevent the body rejecting a transplanted organ or for other conditions, such as rheumatoid arthritis or atopic dermatitis), - simvastatin (used to lower cholesterol), - certain painkillers or anti-inflammatory medicines (e.g. aspirin, ibuprofen, corticosteroids), - oral bisphosphonates (used to treat osteoporosis), - anticoagulant medicines (used to prevent or treat blood clotting), - hormonal contraceptive agents (birth control medicines), - bepridil, ergotamine (used for heart problems and migraines), - repaglinide (used to treat diabetes), - rifampicin (used to treat tuberculosis), - phenytoin, phenobarbital, carbamazepine (used to treat epilepsy), - ritonavir (used in the treatment of HIV infection), - paclitaxel (used in cancer treatment), - theophylline (used to treat respiratory diseases such as asthma), - clozapine (used to treat psychiatric disorders such as schizophrenia), - tizanidine (used as a muscle relaxant), - cholestyramine (used to lower cholesterol levels in the blood), - busulfan (used as a treatment prior to transplantation in order to destroy the original bone marrow before the transplant). Additional tests may be required to monitor the blood levels of some of these medicines. Older people (age 65 years and over) EXJADE can be used by people aged 65 years and over at the same dose as for other adults. Elderly patients may experience more side effects (in particular diarrhoea) than younger patients. They should be monitored closely by their doctor for side effects that may require a dose adjustment. Children and adolescents EXJADE can be used in children and adolescents receiving regular blood transfusions aged 2 years and over and in children and adolescents not receiving regular blood transfusions aged 10 years and over. As the patient grows the doctor will adjust the dose. EXJADE is not recommended for children aged under 2 years. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. EXJADE is not recommended during pregnancy unless clearly necessary. If you are currently using an oral contraceptive or using a patch contraceptive to prevent pregnancy, you should use an additional or different type of contraception (e.g. condom), as EXJADE may reduce the effectiveness of oral and patch contraceptives. Breast-feeding is not recommended during treatment with EXJADE. Driving and using machines If you feel dizzy after taking EXJADE, do not drive or operate any tools or machines until you are feeling normal again. 136 3. How to take EXJADE Treatment with EXJADE will be overseen by a doctor who is experienced in the treatment of iron overload caused by blood transfusions. Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. How much EXJADE to take The dose of EXJADE is related to body weight for all patients. Your doctor will calculate the dose you need and tell you how many sachets to take each day.  The usual daily dose for EXJADE granules at the start of the treatment for patients receiving regular blood transfusions is 14 mg per kilogram body weight. A higher or lower starting dose may be recommended by your doctor based on your individual treatment needs.  The usual daily dose for EXJADE granules at the start of the treatment for patients not receiving regular blood transfusions is 7 mg per kilogram body weight.  Depending on how you respond to treatment, your doctor may later adjust your treatment to a higher or lower dose.  The maximum recommended daily dose for EXJADE granules:  28 mg per kilogram body weight for patients receiving regular blood transfusions,  14 mg per kilogram body weight for adult patients not receiving regular blood transfusions,  7 mg per kilogram body weight for children and adolescents not receiving regular blood transfusions. Deferasirox also comes as “dispersible” tablets. If you are switching from the dispersible tablets to these granules, you will need an adjustment of the dose. When to take EXJADE  Take EXJADE once a day, every day, at about the same time each day.  Take EXJADE granules either with or without a light meal. Taking EXJADE at the same time each day will also help you remember when to take your medicine. EXJADE granules should be taken by sprinkling the full dose onto soft food such as yogurt or apple sauce (pureed apple). The food should be immediately and completely consumed. Do not store it for future use. How long to take EXJADE Continue taking EXJADE every day for as long as your doctor tells you. This is a long-term treatment, possibly lasting for months or years. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect (see also section 2: “Monitoring your EXJADE treatment”). If you have questions about how long to take EXJADE, talk to your doctor. If you take more EXJADE than you should If you have taken too much EXJADE, or if someone else accidentally takes your granules, contact your doctor or hospital for advice straight away. Show the doctor the pack of granules. Urgent medical treatment may be necessary. You may experience effects such as abdominal pain, diarrhoea, nausea and vomiting and kidney or liver problems that can be serious. If you forget to take EXJADE If you miss a dose, take it as soon as you remember on that day. Take your next dose as scheduled. Do not take a double dose on the next day to make up for the forgotten granules. 137 If you stop taking EXJADE Do not stop taking EXJADE unless your doctor tells you to. If you stop taking it, the excess iron will no longer be removed from your body (see also above section “How long to take EXJADE”). 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of the side effects are mild to moderate and will generally disappear after a few days to a few weeks of treatment. Some side effects could be serious and need immediate medical attention. These side effects are uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people).  If you get a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction),  If you experience a combination of any of the following symptoms: rash, red skin, blistering of the lips, eyes or mouth, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes, (signs of severe skin reactions),  If you notice a marked decrease in your urine output (sign of kidney problem),  If you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems),  If you experience difficulty thinking, remembering information, or solving problems, being less alert or aware or feeling very sleepy with low energy (signs of a high level of ammonia in your blood, which may be associated with liver or renal problems and lead to a change in your brain function),  If you vomit blood and/or have black stools,  If you experience frequent abdominal pain, particularly after eating or taking EXJADE,  If you experience frequent heartburn,  If you experience partial loss of vision,  If you experience severe upper stomach pain (pancreatitis), stop taking this medicine and tell your doctor straight away. Some side effects could become serious. These side effects are uncommon.  If you get blurred or cloudy eyesight,  If you get reduced hearing, tell your doctor as soon as possible. Other side effects Very common (may affect more than 1 in 10 people)  Disturbance in kidney function tests. Common (may affect up to 1 in 10 people)  Gastrointestinal disorders, such as nausea, vomiting, diarrhoea, pain in the abdomen, bloating, constipation, indigestion  Rash  Headache  Disturbance in liver function tests  Itching  Disturbance in urine test (protein in the urine) If any of these affects you severely, tell your doctor. 138 Uncommon (may affect up to 1 in 100 people)  Dizziness  Fever  Sore throat  Swelling of arms or legs  Change in the colour of the skin  Anxiety  Sleep disorder  Tiredness If any of these affects you severely, tell your doctor. Frequency not known (cannot be estimated from the available data).  A decrease in the number of cells involved in blood clotting (thrombocytopenia), in the number of red blood cells (anaemia aggravated), in the number of white blood cells (neutropenia) or in the number of all kinds of blood cells (pancytopenia)  Hair loss  Kidney stones  Low urine output  Tear in stomach or intestine wall that can be painful and cause nausea  Severe upper stomach pain (pancreatitis)  Abnormal level of acid in blood Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store EXJADE  Keep this medicine out of the sight and reach of children.  Do not use this medicine after the expiry date which is stated on the sachet and the carton after EXP. The expiry date refers to the last day of that month.  Do not use any pack that is damaged or shows signs of tampering.  Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What EXJADE contains The active substance is deferasirox.  Each sachet of EXJADE 90 mg granules contains 90 mg deferasirox.  Each sachet of EXJADE 180 mg granules contains 180 mg deferasirox.  Each sachet of EXJADE 360 mg granules contains 360 mg deferasirox. The other ingredients are microcrystalline cellulose; crospovidone; povidone; magnesium stearate; colloidal anhydrous silica and poloxamer. What EXJADE looks like and contents of the pack EXJADE granules are supplied as white to almost white granules in sachets. Each pack contains 30 sachets. Not all strengths may be available in your country. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 139 Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva Novartis Pharma Services Inc. Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел.: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 26 37 82 555 Eesti Novartis Pharma Services Inc. Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 140 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA “Novartis Baltics” Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take exjade', 'Section_Content': 'do not take exjade - if you are allergic to deferasirox or any of the other ingredients of this medicine (listed in section 6). if this applies to you, tell your doctor before taking exjade. if you think you may be allergic, ask your doctor for advice. - if you have moderate or severe kidney disease. - if you are currently taking any other iron chelator medicines. exjade is not recommended - if you are at an advanced stage of myelodysplastic syndrome (mds; decreased production of blood cells by the bone marrow) or have advanced cancer. warnings and precautions talk to your doctor or pharmacist before taking exjade: - if you have a kidney or liver problem. - if you have a cardiac problem due to iron overload. - if you notice a marked decrease in your urine output (sign of kidney problem). - if you develop a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction, see also section 4 "possible side effects"). - if you experience a combination of any of the following symptoms: rash, red skin, blistering of the lips, eyes, or mouth, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes (signs of severe skin reaction, see also section 4 "possible side effects"). - if you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems). - if you experience difficulty thinking, remembering information, or solving problems, being less alert or aware or feeling very sleepy with low energy (signs of a high level of ammonia in your blood, which may be associated with liver or renal problems, see also section 4 "possible side effects"). - if you vomit blood and/or have black stools. - if you experience frequent abdominal pain, particularly after eating or taking exjade. - if you experience frequent heartburn. - if you have a low level of platelets or white blood cells in your blood test. - if you have blurred vision. - if you have diarrhoea or vomiting. if any of these apply to you, tell your doctor straight away. monitoring your exjade treatment you will have regular blood and urine tests during treatment. these will monitor the amount of iron in your body (blood level of ferritin) to see how well exjade is working. the tests will also monitor your kidney function (blood level of creatinine, presence of protein in the urine) and liver function (blood level of transaminases). your doctor may require you to undergo a kidney biopsy, if he/she suspects significant kidney damage. you may also have mri (magnetic resonance imaging) tests to determine the amount of iron in your liver. your doctor will take these tests into consideration when deciding on the dose of exjade most suitable for you and will also use these tests to decide when you should stop taking exjade. your eyesight and hearing will be tested each year during treatment as a precautionary measure. other medicines and exjade tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. this includes in particular: - other iron chelators, which must not be taken with exjade, - antacids (medicines used to treat heartburn) containing aluminium, which should not be taken at the same time of day as exjade, - ciclosporin (used to prevent the body rejecting a transplanted organ or for other conditions, such as rheumatoid arthritis or atopic dermatitis), - simvastatin (used to lower cholesterol), - certain painkillers or anti-inflammatory medicines (e.g. aspirin, ibuprofen, corticosteroids), - oral bisphosphonates (used to treat osteoporosis), - anticoagulant medicines (used to prevent or treat blood clotting), - hormonal contraceptive agents (birth control medicines), - bepridil, ergotamine (used for heart problems and migraines), - repaglinide (used to treat diabetes), - rifampicin (used to treat tuberculosis), - phenytoin, phenobarbital, carbamazepine (used to treat epilepsy), - ritonavir (used in the treatment of hiv infection), - paclitaxel (used in cancer treatment), - theophylline (used to treat respiratory diseases such as asthma), - clozapine (used to treat psychiatric disorders such as schizophrenia), - tizanidine (used as a muscle relaxant), - cholestyramine (used to lower cholesterol levels in the blood), - busulfan (used as a treatment prior to transplantation in order to destroy the original bone marrow before the transplant). additional tests may be required to monitor the blood levels of some of these medicines. older people (age 65 years and over) exjade can be used by people aged 65 years and over at the same dose as for other adults. elderly patients may experience more side effects (in particular diarrhoea) than younger patients. they should be monitored closely by their doctor for side effects that may require a dose adjustment. children and adolescents exjade can be used in children and adolescents receiving regular blood transfusions aged 2 years and over and in children and adolescents not receiving regular blood transfusions aged 10 years and over. as the patient grows the doctor will adjust the dose. exjade is not recommended for children aged under 2 years. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. exjade is not recommended during pregnancy unless clearly necessary. if you are currently using an oral contraceptive or using a patch contraceptive to prevent pregnancy, you should use an additional or different type of contraception (e.g. condom), as exjade may reduce the effectiveness of oral and patch contraceptives. breast-feeding is not recommended during treatment with exjade. driving and using machines if you feel dizzy after taking exjade, do not drive or operate any tools or 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{'Title': '3. how to take exjade', 'Section_Content': 'treatment with exjade will be overseen by a doctor who is experienced in the treatment of iron overload caused by blood transfusions. always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. how much exjade to take the dose of exjade is related to body weight for all patients. your doctor will calculate the dose you need and tell you how many tablets to take each day. the usual daily dose for exjade dispersible tablets at the start of the treatment for patients receiving regular blood transfusions is 20 mg per kilogram body weight. a higher or lower starting dose may be recommended by your doctor based on your individual treatment needs. the usual daily dose for exjade dispersible tablets at the start of the treatment for patients not receiving regular blood transfusions is 10 mg per kilogram body weight. depending on how you respond to treatment, your doctor may later adjust your treatment to a higher or lower dose. the maximum recommended daily dose for exjade dispersible tablets is 40 mg per kilogram body weight for patients receiving regular blood transfusions, 20 mg per kilogram body weight for adult patients not receiving regular blood transfusions and 10 mg per kilogram body weight for children and adolescents not receiving regular blood transfusions. deferasirox also comes as "film-coated" tablets and granules. if you are switching from the film-coated tablets or granules to these dispersible tablets, you will need an adjustment of the dose. when to take exjade take exjade once a day, every day, at about the same time each day. take the exjade dispersible tablets on an empty stomach. then wait at least 30 minutes before eating any food. taking exjade at the same time each day will also help you remember when to take your tablets. how to take exjade: drop the tablet(s) into a glass of water, or apple or orange juice (100 to 200 ml). stir until the tablet(s) dissolve completely. the liquid in the glass will look cloudy. drink everything in the glass. then add a little water or juice to what is left in the glass, swirl the liquid around and drink that too. do not dissolve the tablets in fizzy drinks or milk. do not chew, break or crush the tablets. do not swallow the tablets whole. how long to take exjade continue taking exjade every day for as long as your doctor tells you. this is a long-term treatment, possibly lasting for months or years. your doctor will regularly monitor your condition to check that the treatment is having the desired effect (see also section 2: "monitoring your exjade treatment"). if you have questions about how long to take exjade, talk to your doctor. if you take more exjade than you should if you have taken too much exjade, or if someone else accidentally takes your tablets, contact your doctor or hospital for advice straight away. show the doctor the pack of tablets. urgent medical treatment may be necessary. you may experience effects such as abdominal pain, diarrhoea, nausea and vomiting and kidney or liver problems that can be serious. if you forget to take exjade if you miss a dose, take it as soon as you remember on that day. take your next dose as scheduled. do not take a double dose on the next day to make up for the forgotten tablet(s). if you stop taking exjade do not stop taking exjade unless your doctor tells you to. if you stop taking it, the excess iron will no longer be removed from your body (see also above section "how long to take exjade").', 'Entity_Recognition': [{'Text': 'exjade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 9}, {'Id': 1, 'BeginOffset': 15, 'EndOffset': 21, 'Score': 0.9815438985824585, 'Text': 'exjade', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 28, 'BeginOffset': 90, 'EndOffset': 103, 'Score': 0.877109706401825, 'Text': 'iron 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. most of the side effects are mild to moderate and will generally disappear after a few days to a few weeks of treatment. some side effects could be serious and need immediate medical attention. these side effects are uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people). if you get a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction), if you experience a combination of any of the following symptoms: rash, red skin, blistering of the lips, eyes, or mouth, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes, (signs of severe skin reactions), if you notice a marked decrease in your urine output (sign of kidney problem), if you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems), if you experience difficulty thinking, remembering information, or solving problems, being less alert or aware or feeling very sleepy with low energy (signs of a high level of ammonia in your blood, which may be associated with liver or renal problems and lead to a change in your brain function), if you vomit blood and/or have black stools, if you experience frequent abdominal pain, particularly after eating or taking exjade, if you experience frequent heartburn, if you experience partial loss of vision, if you experience severe upper stomach pain (pancreatitis), stop taking this medicine and tell your doctor straight away. some side effects could become serious. these side effects are uncommon. if you get blurred or cloudy eyesight, if you get reduced hearing, tell your doctor as soon as possible. other side effects very common (may affect more than 1 in 10 people) disturbance in kidney function tests. common (may affect up to 1 in 10 people) gastrointestinal disorders, such as nausea, vomiting, diarrhoea, pain in the abdomen, bloating, constipation, indigestion rash headache disturbance in liver function tests itching disturbance in urine test (protein in the urine) if any of these affects you severely, tell your doctor. uncommon (may affect up to 1 in 100 people) dizziness fever sore throat swelling of arms or legs change in the colour of the skin anxiety sleep disorder tiredness if any of these affects you severely, tell your doctor. frequency not known (cannot be estimated from the available data). a decrease in the number of cells involved in blood clotting (thrombocytopenia), in the number of red blood cells (anaemia aggravated), in the number of white blood cells (neutropenia) or in the number of all kinds of blood cells (pancytopenia) hair loss kidney stones low urine output tear in stomach or intestine wall that can be painful and cause nausea severe upper stomach pain (pancreatitis) abnormal level of acid in blood reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'exjade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 21, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9665244817733765, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7329886555671692}]}, {'Id': 22, 'BeginOffset': 104, 'EndOffset': 116, 'Score': 0.8761621713638306, 'Text': 'side effects', 'Category': 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{'Title': '5. how to store exjade', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and the carton after exp. the expiry date refers to the last day of that month. store in the original package in order to protect from moisture. do not use any pack that is damaged or shows signs of tampering. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what exjade contains the active substance is deferasirox. each dispersible tablet of exjade 125 mg contains 125 mg deferasirox. each dispersible tablet of exjade 250 mg contains 250 mg deferasirox. each dispersible tablet of exjade 500 mg contains 500 mg deferasirox. the other ingredients are lactose monohydrate, crospovidone type a, povidone, sodium laurilsulfate, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate. what exjade looks like and contents of the pack exjade is supplied as dispersible tablets. the tablets are white to slightly yellow, round and flat. exjade 125 mg tablets are stamped "j 125" on one side and "nvr" on the other. exjade 250 mg tablets are stamped "j 250" on one side and "nvr" on the other. exjade 500 mg tablets are stamped "j 500" on one side and "nvr" on the other. exjade 125 mg, 250 mg and 500 mg dispersible tablets are available in unit packs containing 28, 84 or 252 dispersible tablets. exjade 500 mg dispersible tablets are also available in multipacks containing 294 (3 packs of 98) dispersible tablets. not all pack sizes or strengths may be available in your country.', 'Entity_Recognition': [{'Text': 'exjade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 11, 'Score': 0.9632551670074463, 'Text': 'exjade', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 45, 'EndOffset': 56, 'Score': 0.9940778017044067, 'Text': 'deferasirox', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.45653313398361206, 'RelationshipScore': 0.9825416803359985, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 63, 'EndOffset': 81, 'Text': 'dispersible tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.6842012405395508, 'RelationshipScore': 0.5001708269119263, 'RelationshipType': 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00D784D36A6F97276B4CACA1A67234D2

https://www.ema.europa.eu/documents/product-information/clopidogrel-apotex-epar-product-information_en.pdf

Clopidogrel Apotex

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Clopidogrel Apotex 75 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 75 mg of clopidogrel (as besilate). Excipients with a known effect: Each film-coated tablet contains 2.5 mg of lactose (as monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Pink, round, biconvex, film-coated tablets. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Secondary prevention of atherothrombotic events Clopidogrel is indicated in:  Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.  Adult patients suffering from acute coronary syndrome: - Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). - ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy. Prevention of atherothrombotic and thromboembolic events in atrial fibrillation - In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke. For further information please refer to section 5.1. 4.2 Posology and method of administration Posology  Adults and elderly 3 Clopidogrel should be given as a single daily dose of 75 mg. In patients suffering from acute coronary syndrome:  Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300-mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months (see section 5.1). - ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300-mg loading dose in combination with ASA and with or without thrombolytics. For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination of clopidogrel with ASA beyond four weeks has not been studied in this setting (see section 5.1). In patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg. ASA (75-100 mg daily) should be initiated and continued in combination with clopidogrel (see section 5.1). If a dose is missed: Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time. For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.  Paediatric population Clopidogrel should not be used in children because of efficacy concerns (see section 5.1).  Renal impairment Therapeutic experience is limited in patients with renal impairment (see section 4.4).  Hepatic impairment Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses (see section 4.4). Method of administration For oral use It may be given with or without food. 4.3 Contraindications  Hypersensitivity to the active substance or to any of the excipients listed in section 2 or section 6.1.  Severe hepatic impairment.  Active pathological bleeding such as peptic ulcer or intracranial haemorrhage. 4.4 Special warnings and precautions for use 4 Bleeding and haematological disorders Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or other medicinal products associated with bleeding risk such as pentoxifylline (see section 4.5). Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.5). If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician. Thrombotic Thrombocytopenic Purpura (TTP) Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. Acquired haemophilia Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued. Recent ischaemic stroke In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke. Cytochrome P450 2C19 (CYP2C19) Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Tests are available to identify a patient's CYP2C19 genotype. Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2). CYP2C8 substrates 5 Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinal products (see section 4.5). Cross-reactions among thienopyridines Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see section 4.8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised. Renal impairment Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients (see section 4.2). Hepatic impairment Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population (see section 4.2). Excipients Clopidogrel Apotex contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicinal products associated with bleeding risk should be undertaken with caution (see section 4.4). Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.4). Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4). Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). However, clopidogrel and ASA have been administered together for up to one year (see section 5.1). Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction 6 between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA (see section 4.8) NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution (see section 4.4). SSRIs: since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution. Other concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4 and 5.2). Medicinal products that are strong or moderate CYP2C19 inhibitors include for example omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz. Proton Pump Inhibitors (PPI): Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours between the administrations of the two drugs decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel. Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be discouraged (see section 4.4). Less pronounced reductions of metabolite exposure has been observed with pantoprazole or lansoprazole. The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole. There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers or antacids interfere with antiplatelet activity of clopidogrel. Boosted anti-retroviral therapy (ART): HIV patients treated with boosted anti-retroviral therapies (ART) are at high risk of vascular events. 7 A significantly reduced platelet inhibition has been shown in HIV patients treated with ritonavir-or cobicistat-boosted ART. Although the clinical relevance of these findings is uncertain, there have been spontaneous reports of HIV-infected patients treated with ritonavir boosted ART, who have experienced re-occlusive events after de-obstruction or have suffered thrombotic events under a clopidogrel loading treatment schedule. Average platelet inhibition can be decreased with concomitant use of clopidogrel and ritonavir. Therefore, concomitant use of clopidogrel with ART boosted therapies should be discouraged. Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co- administration of phenobarbital or oestrogen. The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption. Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely co-administered with clopidogrel. CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see section 4.4). Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions. As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists. 4.6 Fertility, pregnancy and lactation Pregnancy As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Breast-feeding 8 It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during treatment with Clopidogrel Apotex. Fertility Clopidogrel was not shown to alter fertility in animal studies. 4.7 Effects on ability to drive and use machines Clopidogrel has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Clopidogrel has been evaluated for safety in more than 44,000 patients who have participated in clinical studies, including over 12,000 patients treated for 1 year or more. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactions have been spontaneously reported. Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the first month of treatment. In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA. In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA. In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the placebo plus ASA group .The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy. In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups. In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo +ASA group), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA group and 0.7% in the placebo +ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups. Tabulated list of adverse reactions 9 Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness. System Organ Class Common Uncommon Rare Very rare, not known* Blood and the lymphatic system disorders Thrombocytopenia, leucopenia, eosinophilia Neutropenia, including severe neutropenia Thrombotic thrombocytopenic purpura (TTP) (see section 4.4), aplastic anaemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired haemophilia A, granulocytopenia, anaemia Cardiac disorders Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel* Immune system disorders Serum sickness, anaphylactoid reactions, cross reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel) (see section 4.4)*, insulin autoimmune syndrome, which can lead to severe hypoglycemia, particularly in patients with HLA DRA4 subtype (more frequent in the Japanese population)* 10 System Organ Class Common Uncommon Rare Very rare, not known* Psychiatric disorders Hallucinations, confusion Nervous system disorders Intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizziness Taste disturbances, ageusia Eye disorders Eye bleeding (conjunctival, ocular, retinal) Ear and labyrinth disorders Vertigo Vascular disorders Haematoma Serious haemorrhage, haemorrhage of operative wound, vasculitis, hypotension Respiratory, thoracic and mediastinal disorders Epistaxis Respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia Gastrointestinal disorders Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia Gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence Retroperitoneal haemorrhage Gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis Hepato-biliary disorders Acute liver failure, hepatitis, abnormal liver function test 11 System Organ Class Common Uncommon Rare Very rare, not known* Skin and subcutaneous tissue disorders Bruising Rash, pruritus, skin bleeding (purpura) Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme, acute generalised exanthematous pustulosis (AGEP)), angioedema, drug- induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), rash erythematous or exfoliative, urticaria, eczema, lichen planus Reproductive systems and breast disorders Gyanecomastia Musculoskeletal, connective tissue and bone disorders Musculo-skeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgia Renal and urinary disorders Haematuria Glomerulonephritis, blood creatinine increased General disorders and administration site conditions Bleeding at puncture site Fever Investigations Bleeding time prolonged, neutrophil count decreased, platelet count decreased * Information related to clopidogrel with frequency “not known”. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose 12 Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC Code: B01AC-04. Mechanism of action Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition. Pharmacodynamic effects Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued. Clinical efficacy and safety The safety and efficacy of clopidogrel have been evaluated in 5 double-blind studies involving over 88,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY, COMMIT and ACTIVE-A studies comparing clopidogrel to placebo, both medicinal products given in combination with ASA and other standard therapy. Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of the patients received ASA for the first few days following the acute myocardial infarction. 13 Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA (relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every 1,000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6.0%). In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the benefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = -4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients over 75 years was less than that observed in patients 75 years. Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real, or a result of chance. Acute coronary syndrome The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA (75- 325 mg once daily) and other standard therapies. Patients were treated for up to one year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in more than 90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy. The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)). New cardiovascular events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage persisted (see section 4.4). The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy (RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%, 28.3%). The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel-treated group. 14 This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated group]. There was no observed effect on the rate of rehospitalisation for unstable angina. The results obtained in populations with different characteristics (e.g. unstable angina or non-Q-wave MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with the results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the total CURE population) who underwent stent placement (Stent-CURE), the data showed that clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the second co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this subset are in line with the overall trial results. The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of ASA (75-325 mg once daily). In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT. The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population included 19.7% women and 29.2% patients ≥ 65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7% ACE inhibitors and 63% statins. Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36 % odds reduction in favor of clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients’ age and gender, infarct location, and type of fibrinolytic or heparin used. The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co- primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The population included 27.8% women, 58.4% patients ≥ 60 years (26% ≥ 70 years) and 54.5% patients who received fibrinolytics. Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours. 15 De-escalation of P2Y12 Inhibitor Agents inAcute Coronary Syndrome Switching from a more potent P2Y12 receptor inhibitor to clopidogrel in association with aspirin after acute phase in Acute Coronary Syndrome (ACS) has been evaluated in two randomized investigator- sponsored studies (ISS) –TOPIC and TROPICAL-ACS – with clinical outcome data. The clinical benefit provided by the more potent P2Y12 inhibitors, ticagrelor and prasugrel, in their pivotal studies is related to a significant reduction in recurrent ischaemic events (including acute and subacute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Although the ischaemic benefit was consistent throughout the first year, greater reduction in ischaemic recurrence after ACS was observed during the initial days following the treatment initiation. In contrast, post-hoc analyses demonstrated statistically significant increases in the bleeding risk with the more potent P2Y12 inhibitors, occurring predominantly during the maintenance phase, after the first month post-ACS. TOPIC and TROPICAL-ACS were designed to study how to mitigate the bleeding events while maintaining efficacy. TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome) This randomized, open-label trial included ACS patients requiring percutaneous coronary intervention (PCI). Patients on aspirin and a more potent P2Y12 blocker and without adverse event at one month were assigned to switch to fixed-dose aspirin plus clopidogrel (de-escalated dual antiplatelet therapy (DAPT)) or continuation of their drug regimen (unchanged DAPT). Overall, 645 of 646 patients with ST-elevation-MI (STEMI) or non-ST-elevation-MI (NSTEMI) or unstable angina were analyzed (de-escalated DAPT (n=322); unchanged DAPT (n=323)). Follow-up at one year was performed for 316 patients (98.1%) in the de-escalated DAPT group and 318 patients (98.5%) in the unchanged DAPT group. The median follow-up for both groups was 359 days. The characteristics of the studied cohort were similar in the 2 groups. The primary outcome, a composite of cardiovascular death, stroke, urgent revascularization, and BARC (Bleeding Academic Research Consortium) bleeding ≥2 at 1 year post ACS, occurred in 43 patients (13.4%) in the de-escalated DAPT group and in 85 patients (26.3%) in the unchanged DAPT group (p<0.01). This statistically significant difference was mainly driven by fewer bleeding events, with no difference reported in ischaemic endpoints (p=0.36), while BARC ≥2 bleeding occurred less frequently in the de-escalated DAPT group (4.0%) versus 14.9% in the unchanged DAPT group (p<0.01). Bleeding events defined as all BARC occurred in 30 patients (9.3%) in the de-escalated DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01). TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes) This randomized, open-label trial included 2,610 biomarker-positive ACS patients after successful PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/d (Days 0-14) (n=1306), or prasugrel 5 or 10 mg/d (Days 0-7) then de-escalated to clopidogrel 75 mg/d (Days 8-14) (n=1304), in combination with ASA (<100 mg/day). At Day 14, platelet function testing (PFT) was performed. The prasugrel-only patients were continued on prasugrel for 11.5 months. The de-escalated patients underwent high platelet reactivity (HPR) testing. If HPR≥46 units, the patients were escalated back to prasugrel 5 or 10 mg/d for 11.5 months; if HPR<46 units, the patients continued on clopidogrel 75 mg/d for 11.5 months. Therefore, the guided de-escalation arm had patients on either prasugrel (40%) or clopidogrel (60%). All patients were continued on aspirin and were followed for one year. The primary endpoint (the combined incidence of CV death, MI, stroke and BARC bleeding grade ≥2 16 at 12 months) was met showing non-inferiority. Ninety five patients (7%) in the guided de-escalation group and 118 patients (9%) in the control group (p non-inferiority=0.0004) had an event. The guided de-escalation did not result in an increased combined risk of ischemic events (2.5% in the deescalation group vs 3.2% in the control group; p non-inferiority=0.0115), nor in the key secondary endpoint of BARC bleeding ≥2 ((5%) in the de-escalation group versus 6% in the control group (p=0.23)). The cumulative incidence of all bleeding events (BARC class 1 to 5) was 9% (114 events) in the guided de-escalation group versus 11% (137 events) in the control group (p=0.14). Atrial fibrillation The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (such as warfarin). The ACTIVE-A study included patients who could not receive VKA therapy because they were unable or unwilling to receive the treatment. The ACTIVE-W study demonstrated that anticoagulant treatment with vitamin K antagonists was more effective than with clopidogrel and ASA. The ACTIVE-A study (N=7,554) was a multicenter, randomized, double-blind, placebo-controlled study which compared clopidogrel 75 mg/day + ASA (N=3,772) to placebo + ASA (N=3,782). The recommended dose for ASA was 75 to 100 mg/day. Patients were treated for up to 5 years. Patients randomized in the ACTIVE program were those presenting with documented AF, i.e., either permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of the following risk factors: age 75 years or age 55 to 74 years and either diabetes mellitus requiring drug therapy, or documented previous MI or documented coronary artery disease; treated for systemic hypertension; prior stroke, transient ischaemic attack (TIA), or non-CNS systemic embolus; left ventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheral vascular disease. The mean CHADS2 score was 2.0 (range 0-6). The major exclusion criteria for patients were documented peptic ulcer disease within the previous 6 months; prior intracerebral hemorrhage; significant thrombocytopenia (platelet count < 50 x 109/l); requirement for clopidogrel or oral anticoagulants (OAC); or intolerance to any of the two compounds. Seventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA due to physician assessment, inability to comply with INR (international normalised ratio) monitoring, predisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the physician’s decision was based on the patient’s unwillingness to take VKA. The patient population included 41.8 % women. The mean age was 71 years, 41.6% of patients were ≥75 years. A total of 23.0% of patients received anti-arrhythmics, 52.1% beta-blockers, 54.6% ACE inhibitors, and 25.4% statins. The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%; 95% CI of 2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving placebo + ASA (relative risk reduction, 28.4%; 95% CI, 16.8% to 38.3%; p=0.00001). Paediatric population 17 In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis (PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and infants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition of 49.3% (5 µM ADP-induced platelet aggregation) which was comparable to that of adults taking Clopidogrel 75 mg/day. In a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with concomitant background therapy up to the time of second stage surgery. The mean time between shunt palliation and first administration of study medicinal product was 20 days. Approximately 88% of patients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference between groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related intervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%] for the clopidogrel group and 90 [20.5%] for the placebo group) (see section 4.2). Bleeding was the most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was no significant difference in the bleeding rate between groups. In the long-term safety follow-up of this study, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 months of age. No new safety concerns were noted during this long-term follow-up. The CLARINET and the PICOLO trials were conducted using a constituted solution of clopidogrel. In a relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent and slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the authorised tablet. 5.2 Pharmacokinetic properties Absorption After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Distribution Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration range. Biotransformation Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2 CYP2B6 and CYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation. The Cmax of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose as it is after four days of 75-mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. 18 Elimination Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite was 8 hours after single and repeated administration. Pharmacogenetics CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, *6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as defined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient’s CYP2C19 genotype. A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of 39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the 300 mg/75 mg regimen,and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials. Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers. The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomised, controlled trials. There have been a number of retrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), TRITON-TIMI 38 (n=1477), and ACTIVE-A (n=601), as well as a number of published cohort studies. In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers. 19 In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers. In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status. None of these analyses were adequately sized to detect differences in outcome in poor metabolisers. Special populations The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations. Renal impairment After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients. Hepatic impairment After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups. Race The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events. 5.3 Preclinical safety data During non-clinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the therapeutic dose. At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of clopidogrel was also reported in rat and baboon. There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day). Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies,and showed no genotoxic activity. Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be excluded. 20 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Core: Hydroxypropylcellulose (E463) Mannitol (E421) Crospovidone (type A) Citric acid, monohydrate Macrogol 6000 Microcrystalline cellulose Stearic acid Talc Coating Film: Hypromellose (E464) Lactose monohydrate Triacetin (E1518) Titanium dioxide (E171) Red iron oxide (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf-life 3 years. 6.4 Special precautions for storage In PVC/PE/PVDC/aluminium blisters, store below 25°C. In all aluminium blisters, this medicinal product does not require any special storage conditions. 6.5 Nature and content of container Blisters of white PVC/PE/PVDC-aluminium foil or PA/ALL/PVC-aluminium foil. Packs of 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Apotex Europe B.V. Archimedesweg 2 2333 CN , Leiden 21 The Netherlands 8. MARKETING AUTHORISATION NUMBERS EU/1/09/568/001 Cartons of 7 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/002 Cartons of 14 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/003 Cartons of 28 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/004 Cartons of 30 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/005 Cartons of 50 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/006 Cartons of 56 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/007 Cartons of 84 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/008 Cartons of 90 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/009 Cartons of 100 film-coated tablets in PVC/PE/PVDC/Alu blisters EU/1/09/568/010 Cartons of 7 film-coated tablets in PA/ALL/PVDC/Alu blisters EU/1/09/568/011 Cartons of 14 film-coated tablets in PA/ALL/PVDC /Alu blisters EU/1/09/568/012 Cartons of 28 film-coated tablets in PA/ALL/PVDC /Alu blisters EU/1/09/568/013 Cartons of 30 film-coated tablets in PA/ALL/PVDC /Alu blisters EU/1/09/568/014 Cartons of 50 film-coated tablets in PA/ALL/PVDC /Alu blisters EU/1/09/568/015 Cartons of 56 film-coated tablets in PA/ALL/PVDC /Alu blisters EU/1/09/568/016 Cartons of 84 film-coated tablets in PA/ALL/PVDC /Alu blisters EU/1/09/568/017 Cartons of 90 film-coated tablets in PA/ALL/PVDC /Alu blisters EU/1/09/568/018 Cartons of 100 film-coated tablets in PA/ALL/PVDC /Alu blisters 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 16.10.2009 Date of latest renewal: 18.09.2014 10. DATE OF REVISION OF THE TEXT 27 .09.2019 Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/ 22 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTION REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 23 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Pharmathen S.A. 6, Dervenakion 15351 Pallini Attiki Greece Pharmathen International S.A Industrial Park Sapes Rodopi Prefecture, Block No 5 Rodopi 69300 Greece Apotex Nederland B.V. Archimedesweg 2 2333 CN Leiden The Netherlands The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web- portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan(RMP) Not applicable. 24 ANNEX III LABELLING AND PACKAGE LEAFLET 25 A. LABELLING 26 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON for blisters of 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT Clopidogrel Apotex 75 mg film-coated tablets clopidogrel 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 75 mg of clopidogrel (as besilate). 3. LIST OF EXCIPIENTS It also contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 7 film-coated tablets 14 film-coated tablets 28 film-coated tablets 30 film-coated tablets 50 film-coated tablets 56 film-coated tablets 84 film-coated tablets 90 film-coated tablets 100 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 27 EXP 9. SPECIAL STORAGE CONDITIONS Store below 25°C (for PVC/PE/PVDC/aluminium blisters) 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Apotex Europe B.V. Archimedesweg 2 2333 CN , Leiden The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/568/001-018 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Clopidogrel Apotex 75 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 28 PC: SN: NN: 29 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS containing 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT Clopidogrel Apotex 75 mg film-coated tablets clopidogrel 2. NAME OF THE MARKETING AUTHORISATION HOLDER Apotex Europe B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 30 B. PACKAGE LEAFLET 31 Package leaflet: Information for the user Clopidogrel Apotex 75 mg film-coated tablets clopidogrel Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or your pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you have any side effects, including any side effects not listed in this leaflet, talk to your doctor or pharmacist. See section 4. What is in this leaflet: 1. What Clopidogrel Apotex is and what it is used for 2. What you need to know before you take Clopidogrel Apotex 3. How to take Clopidogrel Apotex 4. Possible side effects 5 How to store Clopidogrel Apotex 6. Contents of the pack and other information 1. What Clopidogrel Apotex is and what it is used for Clopidogrel Apotex contains clopidogrel and belongs to a group of medicines called antiplatelet medicinal products. Platelets are very small structures in the blood which clump together during blood clotting. By preventing this clumping, antiplatelet medicinal products reduce the chances of blood clots forming (a process called thrombosis). Clopidogrel Apotex is taken by adults to prevent blood clots (thrombi) forming in hardened blood vessels (arteries), a process known as atherothrombosis, which can lead to atherothrombotic events (such as stroke, heart attack, or death). You have been prescribed Clopidogrel Apotex to help prevent blood clots and reduce the risk of these severe events because: - You have a condition of hardening of arteries (also known as atherosclerosis), and - You have previously experienced a heart attack, stroke or have a condition known as peripheral arterial disease, or - You have experienced a severe type of chest pain known as ‘unstable angina’ or ‘myocardial infarction’ (heart attack). For the treatment of this condition your doctor may have placed a stent in the blocked or narrowed artery to restore effective blood flow. You should also be given acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever as well as to prevent blood clotting) by your doctor. - You have an irregular heartbeat, a condition called ‘atrial fibrillation’, and you cannot take medicines known as ‘oral anticoagulants’ (vitamin K antagonists) which prevent new clots from forming and prevent existing clots from growing. You should have been told that ‘oral anticoagulants’ are more effective than acetylsalicylic acid or the combined use of Clopidogrel and acetylsalicylic acid for this condition. Your doctor should have prescribed Clopidogrel plus acetylsalicylic acid if you cannot take ‘oral anticoagulants’ and you do not have a risk of major bleeding. 32 2. What you need to know before you take Clopidogrel Apotex Do not take Clopidogrel Apotex:  If you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of this medicine (listed in section 6).  If you have a medical condition that is currently causing bleeding such as a stomach ulcer or bleeding within the brain.  If you suffer from severe liver disease. If you think any of these apply to you, or if you are in any doubt at all, consult your doctor before taking Clopidogrel Apotex Warnings and precautions If any of the situations mentioned below apply to you, you should tell your doctor before taking Clopidogrel Apotex:  if you have a risk of bleeding such as - a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer). - a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, organs or joints of your body). - a recent serious injury. - a recent surgery (including dental). - a planned surgery (including dental) in the next seven days.  if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the last seven days.  if you have kidney or liver disease.  if you have had an allergy or reaction to any medicine used to treat your disease. While you are taking Clopidogrel Apotex:  You should tell your doctor if a surgery (including dental) is planned.  You should also tell your doctor immediately if you develop a medical condition (also known as Thrombotic Thrombocytopenic Purpura or TTP) that includes fever and bruising under the skin that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice) (see section 4 ‘Possible side effects’).  If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to the way your medicine works as it prevents the ability of blood clots to form. For minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 4 ‘Possible side effects’).  Your doctor may order blood tests. Children and adolescents Do not give this medicine to children because it does not work. Other medicines and Clopidogrel Apotex Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. Some other medicines may influence the use of Clopidogrel Apotex or vice versa. You should specifically tell your doctor if you take - medicines that may increase your risk of bleeding such as: 33 o oral anticoagulants, medicines used to reduce blood clotting, o a non-steroidal anti-inflammatory medicine, usually used to treat painful and/or inflammatory conditions of muscle or joints, o heparin or any other injectable medicine used to reduce blood clotting, o ticlopidine, other antiplatelet agent, o a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or fluvoxamine), medicines usually used to treat depression, - omeprazole or esomeprazole, medicines to treat upset stomach, - fluconazole or voriconazole, medicines to treat fungal infections, - efavirenz, or other anti-retroviral medicines (used to treat HIV infections), - carbamazepine, a medicine to treat some forms of epilepsy, - moclobemide, medicine to treat depression. - repaglinide, medicine to treat diabetes, - paclitaxel, medicine to treat cancer. - opioids: while you are treated with clopidogrel, you should inform your doctor before being prescribed any opioid (used to treat severe pain). If you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed Clopidogrel Apotex in combination with acetylsalicylic acid, a substance present in many medicines used to relieve pain and lower fever. An occasional use of acetylsalicylic acid (no more than 1,000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other circumstances should be discussed with your doctor. Clopidogrel Apotex with food and drink Clopidogrel Apotex may be taken with or without food. Pregnancy and breast-feeding It is preferable not to take this medicine during pregnancy. If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist before taking Clopidogrel Apotex. If you become pregnant while taking Clopidogrel Apotex, consult your doctor immediately as it is recommended not to take clopidogrel while you are pregnant. You should not breast-feed while taking this medicine. If you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Clopidogrel Apotex is unlikely to affect your ability to drive or to use machines. Clopidogrel Apotex contains lactose: If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicine. 3. How to take Clopidogrel Apotex Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. 34 The recommended dose, including for patients with a condition called ‘atrial fibrillation’ (an irregular heartbeat), is one 75 mg tablet of Clopidegrel Apotex per day to be taken orally with or without food, and at the same time each day. If you have experienced severe chest pain (unstable angina or heart attack), your doctor may give you 300 mg of Clopidogrel Apotex (4 tablets of 75 mg) once at the start of treatment. Then, the recommended dose is one 75-mg tablet of Clopidogrel Apotex per day as described above. You should take Clopidogrel Apotex for as long as your doctor continues to prescribe it. If you take more Clopidogrel Apotex than you should Contact your doctor or the nearest hospital emergency department because of the increased risk of bleeding. If you forget to take Clopidogrel Apotex If you forget to take a dose of Clopidogrel Apotex, but remember within 12 hours of your usual time, take your tablet straightaway and then take your next tablet at the usual time. If you forget for more than 12 hours, simply take the next single dose at the usual time. Do not take a double dose to make up for a forgotten tablet. If you stop taking Clopidogrel Apotex Do not stop the treatment unless your doctor tells you so. Contact your doctor or pharmacist before stopping. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Contact your doctor immediately if you experience: - fever, signs of infection or extreme tiredness. These may be due to rare decrease of some blood cells. - signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not associated with bleeding which appears under the skin as red pinpoint dots and/or confusion (see section 2 ‘Warnings and precautions’). - swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. These may be the signs of an allergic reaction. The most common side effect reported with Clopidogrel Apotex is bleeding. Bleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or bruising under the skin), nose bleed, blood in the urine. In a small number of cases, bleeding in the eye, inside the head, the lung or the joints has also been reported. If you experience prolonged bleeding when taking Clopidogrel Apotex If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to the way your medicine works as it prevents the ability of blood clots to form. For minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 2 ‘Warnings and precautions’). Other side effects include: 35 Common side effects (may affect up to 1 in 10 people: Diarrhoea, abdominal pain, indigestion or heartburn. Uncommon side effects (may affect up to 1 in 100 people): Headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of tingling and numbness. Rare side effect (may affect up to 1 in 1000 people): Vertigo, enlarged breasts in males. Very rare side effects (may affect up to 1 in 10,000 people): Jaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes associated with cough; generalised allergic reactions (for example, overall sensation of heat with sudden general discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy; sore mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; changes in taste or loss of taste of food. Side effects with frequency not known (frequency cannot be estimated from the available data): Hypersensitivity reactions with chest or abdominal pain, persistent low blood sugar symptoms. In addition, your doctor may identify changes in your blood or urine test results. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Clopidogrel Apotex Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the blister, after EXP. The expiry date refers to the last day of that month. Refer to the storage conditions on the carton. If Clopidogrel Apotex is supplied in PVC/PE/PVDC/aluminium blisters, store below 25°C. If Clopidogrel Apotex is supplied in all aluminium blisters, it does not require any special storage conditions. Do not use this medicine if you notice any visible sign of deterioration. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6 Contents of the pack and other information What Clopidogrel Apotex contains The active substance is clopidogrel. Each tablet contains 75 mg of clopidogrel (as besilate). 36 The other ingredients are (see section 2 ‘Clopidogrel Apotex contains lactose’): - Tablet core: hydroxypropylcellulose (E463), mannitol (E421), crospovidone (type A), citric acid monohydrate, microcrystalline cellulose, macrogol 6000, stearic acid, talc - Tablet coating: lactose monohydrate (milk sugar), hypromellose (E464), triacetin (E1518), red iron oxide (E172) and titanium dioxide (E171), What Clopidogrel Apotex looks like and contents of the pack Clopidogrel Apotex film-coated tablets are pink, round and biconvex. They are supplied in PVC/PE/PVDC/Alu blisters or in PA/ALL/PVC-Alu blisters packed in cartons containing 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturers: Marketing Authorisation Holder: Apotex Europe B.V. Archimedesweg 2 2333 CN, Leiden The Netherlands Manufacturers: Pharmathen S.A., 6 Dervenakion 15351 Pallini Attiki Greece Or Pharmathen International S.A Industrial Park Sapes Rodopi Prefecture, Block No 5 Rodopi 69300 Greece Or Apotex Nederland B.V. Archimedesweg 2 2333 CN Leiden The Netherlands For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien NV Apotex SA Tél/Tel:+32 475.35.40. Luxembourg/Luxemburg NV Apotex SA Tel: +32 475.35.40 България Apotex Europe B.V. Tel: +31 71. 52.43.100 Magyarország Apotex Europe B.V. Tel: +31 71. 52.43.100 37 Česká republika Apotex (ČR) s.r.o. Tel:+ 420 234.705.700 Malta Apotex Europe B.V. Tel: +31 71. 52.43.100 Danmark Apotex Europe B.V. Tlf: +31 71. 52.43.100 Nederland Apotex Nederland B.V. Tel:+31 71. 52.43.100 Deutschland Apotex Europe B.V. Tel: +31 71. 52.43.100 Norge Apotex Europe B.V. Tlf: +31 71. 52.43.100 Eesti Apotex Europe B.V. Tel+31 71. 52.43.100 Österreich Apotex Europe B.V. Tel: +31 71. 52.43.100 Ελλάδα Apotex Europe B.V. Τηλ: +31 71. 52.43.100 Polska Apotex Polska Sp. z o.o. Polsce Tel:+48 22.311.20.00 España APOTEX ESPAÑA S.L. Tel:+34 91.486.15.65 Portugal Apotex Europe B.V. Tel: +31 71. 52.43.100 France NV APOTEX SA Tel:+32 475.35.40 România Apotex Europe B.V. Tel: +31 71. 52.43.100 Ireland Apotex Europe B.V. Tel+31 71. 52.43.100 Slovenija Apotex Europe B.V. Tel: +31 71. 52.43.100 Ísland Apotex Europe B.V. Sími: +31 71. 52.43.100 Slovenská republika Apotex Europe B.V. Tel: +31 71. 52.43.100 Italia Apotex Europe B.V. Tel: +31 71. 52.43.100 Suomi/Finland Apotex Europe B.V. Puh/Tel: +31 71. 52.43.100 Κύπρος Apotex Europe B.V. Τηλ: +31 71. 52.43.100 Sverige Apotex Europe B.V. Tel: +31 71. 52.43.100 Latvija Apotex Europe B.V. Tel: +31 71. 52.43.100 United Kingdom Apotex Europe B.V. Tel: +31 71. 52.43.100 Lietuva Apotex Europe B.V. 38 Tel: ++31 71. 52.43.100 This leaflet was last revised in {MM/YYYY} . Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take clopidogrel apotex', 'Section_Content': "do not take clopidogrel apotex: if you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of this medicine (listed in section 6). if you have a medical condition that is currently causing bleeding such as a stomach ulcer or bleeding within the brain. if you suffer from severe liver disease. if you think any of these apply to you, or if you are in any doubt at all, consult your doctor before taking clopidogrel apotex warnings and precautions if any of the situations mentioned below apply to you, you should tell your doctor before taking clopidogrel apotex: if you have a risk of bleeding such as - a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer). - a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, organs or joints of your body). - a recent serious injury. - a recent surgery (including dental). - a planned surgery (including dental) in the next seven days. if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the last seven days. if you have kidney or liver disease. if you have had an allergy or reaction to any medicine used to treat your disease. while you are taking clopidogrel apotex: you should tell your doctor if a surgery (including dental) is planned. you should also tell your doctor immediately if you develop a medical condition (also known as thrombotic thrombocytopenic purpura or ttp) that includes fever and bruising under the skin that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice) (see section 4 'possible side effects'). if you cut or injure yourself, it may take longer than usual for bleeding to stop. this is linked to the way your medicine works as it prevents the ability of blood clots to form. for minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. however, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 4 'possible side effects'). your doctor may order blood tests. children and adolescents do not give this medicine to children because it does not work. other medicines and clopidogrel apotex tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. some other medicines may influence the use of clopidogrel apotex or vice versa. you should specifically tell your doctor if you take - medicines that may increase your risk of bleeding such as: 33 o oral anticoagulants, medicines used to reduce blood clotting, o a non-steroidal anti-inflammatory medicine, usually used to treat painful and/or inflammatory conditions of muscle or joints, o heparin or any other injectable medicine used to reduce blood clotting, o ticlopidine, other antiplatelet agent, o a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or fluvoxamine), medicines usually used to treat depression, - omeprazole or esomeprazole, medicines to treat upset stomach, - fluconazole or voriconazole, medicines to treat fungal infections, - efavirenz, or other anti-retroviral medicines (used to treat hiv infections), - carbamazepine, a medicine to treat some forms of epilepsy, - moclobemide, medicine to treat depression. - repaglinide, medicine to treat diabetes, - paclitaxel, medicine to treat cancer. - opioids: while you are treated with clopidogrel, you should inform your doctor before being prescribed any opioid (used to treat severe pain). if you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed clopidogrel apotex in combination with acetylsalicylic acid, a substance present in many medicines used to relieve pain and lower fever. an occasional use of acetylsalicylic acid (no more than 1,000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other circumstances should be discussed with your doctor. clopidogrel apotex with food and drink clopidogrel apotex may be taken with or without food. pregnancy and breast-feeding it is preferable not to take this medicine during pregnancy. if you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist before taking clopidogrel apotex. if you become pregnant while taking clopidogrel apotex, consult your doctor immediately as it is recommended not to take clopidogrel while you are pregnant. you should not breast-feed while taking this medicine. if you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. ask your doctor or pharmacist for advice before taking any medicine. driving and using machines clopidogrel apotex is unlikely to affect your ability to drive or to use machines. clopidogrel apotex contains lactose: if you 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{'Title': '3. how to take clopidogrel apotex', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose, including for patients with a condition called 'atrial fibrillation' (an irregular heartbeat), is one 75 mg tablet of clopidegrel apotex per day to be taken orally with or without food, and at the same time each day. if you have experienced severe chest pain (unstable angina or heart attack), your doctor may give you 300 mg of clopidogrel apotex (4 tablets of 75 mg) once at the start of treatment. then, the recommended dose is one 75-mg tablet of clopidogrel apotex per day as described above. you should take clopidogrel apotex for as long as your doctor continues to prescribe it. if you take more clopidogrel apotex than you should contact your doctor or the nearest hospital emergency department because of the increased risk of bleeding. if you forget to take clopidogrel apotex if you forget to take a dose of clopidogrel apotex, but remember within 12 hours of your usual time, take your tablet straightaway and then take your next tablet at the usual time. if you forget for more than 12 hours, simply take the next single dose at the usual time. do not take a double dose to make up for a forgotten tablet. if you stop taking clopidogrel apotex do not stop the treatment unless your doctor tells you so. contact your doctor or pharmacist before stopping. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.", 'Entity_Recognition': [{'Text': 'clopidogrel apotex', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 'a condition', 'Type': 'PROBLEM', 'BeginOffset': 185, 'EndOffset': 196}, {'Text': "'atrial fibrillation", 'Type': 'PROBLEM', 'BeginOffset': 204, 'EndOffset': 224}, {'Text': 'an irregular heartbeat', 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. contact your doctor immediately if you experience: - fever, signs of infection or extreme tiredness. these may be due to rare decrease of some blood cells. - signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not associated with bleeding which appears under the skin as red pinpoint dots and/or confusion (see section 2 'warnings and precautions'). - swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. these may be the signs of an allergic reaction. the most common side effect reported with clopidogrel apotex is bleeding. bleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or bruising under the skin), nose bleed, blood in the urine. in a small number of cases, bleeding in the eye, inside the head, the lung or the joints has also been reported. if you experience prolonged bleeding when taking clopidogrel apotex if you cut or injure yourself, it may take longer than usual for bleeding to stop. this is linked to the way your medicine works as it prevents the ability of blood clots to form. for minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. however, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 2 'warnings and precautions'). other side effects include: 35 common side effects (may affect up to 1 in 10 people: diarrhoea, abdominal pain, indigestion or heartburn. uncommon side effects (may affect up to 1 in 100 people): headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of tingling and numbness. rare side effect (may affect up to 1 in 1000 people): vertigo, enlarged breasts in males. very rare side effects (may affect up to 1 in 10,000 people): jaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes associated with cough; generalised allergic reactions (for example, overall sensation of heat with sudden general discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy; sore mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; changes in taste or loss of taste of food. side effects with frequency not known (frequency cannot be estimated from the available data): hypersensitivity reactions with chest or abdominal pain, persistent low blood sugar symptoms. in addition, your doctor may identify changes in your blood or urine test results. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting 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0.9501580595970154}]}, {'Id': 99, 'BeginOffset': 2073, 'EndOffset': 2103, 'Score': 0.407398521900177, 'Text': 'generalised allergic reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.938666820526123}]}, {'Id': 100, 'BeginOffset': 2126, 'EndOffset': 2143, 'Score': 0.7065852880477905, 'Text': 'sensation of heat', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8236172795295715}]}, {'Text': 'sudden general discomfort', 'Type': 'PROBLEM', 'BeginOffset': 2149, 'EndOffset': 2174}, {'Id': 102, 'BeginOffset': 2181, 'EndOffset': 2189, 'Score': 0.893211841583252, 'Text': 'fainting', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.888922393321991}]}, {'Text': 'swelling in the mouth', 'Type': 'PROBLEM', 'BeginOffset': 2192, 'EndOffset': 2213}, {'Text': 'blisters of the skin', 'Type': 'PROBLEM', 'BeginOffset': 2215, 'EndOffset': 2235}, {'Id': 105, 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0.9764161705970764}]}, {'Id': 110, 'BeginOffset': 2315, 'EndOffset': 2329, 'Score': 0.9967560172080994, 'Text': 'hallucinations', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9670820236206055}]}, {'Id': 111, 'BeginOffset': 2331, 'EndOffset': 2341, 'Score': 0.8902590274810791, 'Text': 'joint pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9578453898429871}]}, {'Id': 112, 'BeginOffset': 2343, 'EndOffset': 2356, 'Score': 0.9575396180152893, 'Text': 'muscular pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9412511587142944}]}, {'Id': 113, 'BeginOffset': 2358, 'EndOffset': 2374, 'Score': 0.9819995164871216, 'Text': 'changes in taste', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5012502670288086}]}, {'Id': 114, 'BeginOffset': 2378, 'EndOffset': 2399, 'Score': 0.964347243309021, 'Text': 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{'Title': '5 how to store clopidogrel apotex', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and on the blister, after exp. the expiry date refers to the last day of that month. refer to the storage conditions on the carton. if clopidogrel apotex is supplied in pvc/pe/pvdc/aluminium blisters, store below 25. if clopidogrel apotex is supplied in all aluminium blisters, it does not require any special storage conditions. do not use this medicine if you notice any visible sign of deterioration. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'clopidogrel apotex', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'clopidogrel apotex', 'Type': 'TREATMENT', 'BeginOffset': 271, 'EndOffset': 289}, {'Text': 'pe', 'Type': 'PROBLEM', 'BeginOffset': 309, 'EndOffset': 311}, {'Text': 'pvdc', 'Type': 'PROBLEM', 'BeginOffset': 312, 'EndOffset': 316}, {'Text': 'aluminium blisters', 'Type': 'PROBLEM', 'BeginOffset': 317, 'EndOffset': 335}, {'Text': '25.', 'Type': 'NUMBER', 'BeginOffset': 349, 'EndOffset': 352}, {'Text': 'clopidogrel apotex', 'Type': 'TREATMENT', 'BeginOffset': 356, 'EndOffset': 374}, {'Text': 'all aluminium blisters', 'Type': 'PROBLEM', 'BeginOffset': 390, 'EndOffset': 412}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 477, 'EndOffset': 490}, {'Text': 'deterioration', 'Type': 'PROBLEM', 'BeginOffset': 525, 'EndOffset': 538}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 674, 'EndOffset': 688}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what clopidogrel apotex contains the active substance is clopidogrel. each tablet contains 75 mg of clopidogrel (as besilate). the other ingredients are (see section 2 'clopidogrel apotex contains lactose'): - tablet core: hydroxypropylcellulose (e463), mannitol (e421), crospovidone (type a), citric acid monohydrate, microcrystalline cellulose, macrogol 6000, stearic acid, talc - tablet coating: lactose monohydrate (milk sugar), hypromellose (e464), triacetin (e1518), red iron oxide (e172) and titanium dioxide (e171), what clopidogrel apotex looks like and contents of the pack clopidogrel apotex film-coated tablets are pink, round and biconvex. they are supplied in pvc/pe/pvdc/alu blisters or in pa/all/pvc-alu blisters packed in cartons containing 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets. not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'clopidogrel apotex', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'what clopidogrel apotex', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 23}, {'Id': 1, 'BeginOffset': 57, 'EndOffset': 68, 'Score': 0.9985051155090332, 'Text': 'clopidogrel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.87066251039505, 'RelationshipScore': 0.9815234541893005, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 75, 'EndOffset': 81, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 91, 'EndOffset': 93}, {'Id': 4, 'BeginOffset': 100, 'EndOffset': 111, 'Score': 0.9986864924430847, 'Text': 'clopidogrel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.87066251039505, 'RelationshipScore': 0.5758596062660217, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 75, 'EndOffset': 81, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9853834509849548, 'RelationshipScore': 0.9994741082191467, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 91, 'EndOffset': 96, 'Text': '75 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 116, 'EndOffset': 124, 'Score': 0.33372193574905396, 'Text': 'besilate', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 166, 'EndOffset': 167}, {'Text': "clopidogrel apotex contains lactose'", 'Type': 'TREATMENT', 'BeginOffset': 169, 'EndOffset': 205}, {'Id': 7, 'BeginOffset': 223, 'EndOffset': 245, 'Score': 0.8499834537506104, 'Text': 'hydroxypropylcellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 254, 'EndOffset': 262, 'Score': 0.7731724381446838, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 271, 'EndOffset': 283, 'Score': 0.9944281578063965, 'Text': 'crospovidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 294, 'EndOffset': 317, 'Score': 0.9967346787452698, 'Text': 'citric acid monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 319, 'EndOffset': 345, 'Score': 0.997564435005188, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 347, 'EndOffset': 374, 'Score': 0.6280324459075928, 'Text': 'macrogol 6000, stearic acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '6000', 'Type': 'NUMBER', 'BeginOffset': 356, 'EndOffset': 360}, {'Id': 13, 'BeginOffset': 376, 'EndOffset': 418, 'Score': 0.20871149003505707, 'Text': 'talc - tablet coating: lactose monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'hypromellose (e', 'Type': 'TREATMENT', 'BeginOffset': 433, 'EndOffset': 448}, {'Id': 16, 'BeginOffset': 454, 'EndOffset': 463, 'Score': 0.913203239440918, 'Text': 'triacetin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 473, 'EndOffset': 487, 'Score': 0.9810834527015686, 'Text': 'red iron oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 18, 'BeginOffset': 499, 'EndOffset': 515, 'Score': 0.9981327652931213, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'what clopidogrel apotex', 'Type': 'TREATMENT', 'BeginOffset': 524, 'EndOffset': 547}, {'Text': 'the pack clopidogrel apotex film', 'Type': 'TREATMENT', 'BeginOffset': 575, 'EndOffset': 607}, {'Id': 24, 'BeginOffset': 633, 'EndOffset': 638, 'Score': 0.3395266532897949, 'Text': 'round', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 23, 'BeginOffset': 643, 'EndOffset': 651, 'Score': 0.6780130863189697, 'Text': 'biconvex', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'pe', 'Type': 'PROBLEM', 'BeginOffset': 678, 'EndOffset': 680}, {'Text': 'pvdc', 'Type': 'PROBLEM', 'BeginOffset': 681, 'EndOffset': 685}, {'Text': 'alu blisters', 'Type': 'PROBLEM', 'BeginOffset': 686, 'EndOffset': 698}, {'Text': 'pa/all/pvc', 'Type': 'TREATMENT', 'BeginOffset': 705, 'EndOffset': 715}, {'Text': 'alu blisters', 'Type': 'PROBLEM', 'BeginOffset': 716, 'EndOffset': 728}, {'Text': '7', 'Type': 'NUMBER', 'BeginOffset': 758, 'EndOffset': 759}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 761, 'EndOffset': 763}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 765, 'EndOffset': 767}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 769, 'EndOffset': 771}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 773, 'EndOffset': 775}, {'Text': '56', 'Type': 'NUMBER', 'BeginOffset': 777, 'EndOffset': 779}, {'Text': '84', 'Type': 'NUMBER', 'BeginOffset': 781, 'EndOffset': 783}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 785, 'EndOffset': 787}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 791, 'EndOffset': 794}, {'Text': 'film', 'Type': 'TEST', 'BeginOffset': 795, 'EndOffset': 799}]}

04911FCEAF108BB5FFDE953E31D76C08

https://www.ema.europa.eu/documents/product-information/trazec-epar-product-information_en.pdf

Trazec

Me dic ina l p rod uc t n o l on ge r a uth ori se d 1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Me dic ina l p rod uc t n o l on ge r a uth ori se d 2 1. NAME OF THE MEDICINAL PRODUCT TRAZEC 60 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 60 mg nateglinide. Excipients: Lactose monohydrate: 141.5 mg per tablet. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet 60 mg pink, round, bevelled-edge tablets with “NVR” marked on one side and “TS” on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Nateglinide is indicated for combination therapy with metformin in type 2 diabetic patients inadequately controlled despite a maximally tolerated dose of metformin alone. 4.2 Posology and method of administration Nateglinide should be taken within 1 to 30 minutes before meals (usually breakfast, lunch and dinner). The dosage of nateglinide should be determined by the physician according to the patient’s requirements. The recommended starting dose is 60 mg three times daily before meals, particularly in patients who are near goal HbA1c. This may be increased to 120 mg three times daily. Dose adjustments should be based on periodic glycosylated haemoglobin (HbA1c) measurements. Since the primary therapeutic effect of Trazec is to reduce mealtime glucose, (a contributor to HbA1c), the therapeutic response to Trazec may also be monitored with 1–2 hour post-meal glucose. The recommended maximum daily dose is 180 mg three times daily to be taken before the three main meals. Specific patient groups Elderly The clinical experience in patients over 75 years of age is limited. Children and adolescents There are no data available on the use of nateglinide in patients under 18 years of age, and therefore its use in this age group is not recommended. Patients with hepatic impairment No dose adjustment is necessary for patients with mild to moderate hepatic impairment. As patients with severe liver disease were not studied, nateglinide is contraindicated in this group. Me dic ina l p rod uc t n o l on ge r a uth ori se d 3 Patients with renal impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Although there is a 49% decrease in Cmax of nateglinide in dialysis patients, the systemic availability and half-life in diabetic subjects with moderate to severe renal insufficiency (creatinine clearance 15–50 ml/min) was comparable between renal subjects requiring haemodialysis and healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax. Others In debilitated or malnourished patients the initial and maintenance dosage should be conservative and careful titration is required to avoid hypoglycaemic reactions. 4.3 Contraindications Trazec is contraindicated in patients with: • Hypersensitivity to the active substance or to any of the excipients • Type 1 diabetes (insulin-dependent diabetes mellitus, C-peptide negative) • Diabetic ketoacidosis, with or without coma • Pregnancy and breast-feeding (see section 4.6) • Severe hepatic impairment 4.4 Special warnings and precautions for use General Nateglinide should not be used in monotherapy. Like other insulin secretagogues, nateglinide is capable of producing hypoglycaemia. Hypoglycaemia has been observed in patients with type 2 diabetes on diet and exercise, and in those treated with oral antidiabetic agents (see section 4.8). Elderly, malnourished patients and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose- lowering effect of these treatments. The risk of hypoglycaemia in type 2 diabetic patients may be increased by strenuous physical exercise, or ingestion of alcohol. Symptoms of hypoglycaemia (unconfirmed by blood glucose levels) were observed in patients whose baseline HbA1c was close to the therapeutic target (HbA1c <7.5%). Combination with metformin is associated with an increased risk of hypoglycaemia compared to monotherapy. Hypoglycaemia may be difficult to recognise in subjects receiving beta blockers. When a patient stabilised on any oral hypoglycaemic agent is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue oral hypoglycaemic treatment and replace it with insulin on a temporary basis. Trazec contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, of the Lapp lactase deficiency or of glucose-galactose malabsorption should not take this medicine. Specific patient groups Nateglinide should be used with caution in patients with moderate hepatic impairment. No clinical studies have been conducted in patients with severe hepatic impairment or children and adolescents. Treatment is therefore not recommended in these patient groups. Me dic ina l p rod uc t n o l on ge r a uth ori se d 4 4.5 Interaction with other medicinal products and other forms of interaction A number of medicinal products influence glucose metabolism and possible interactions should therefore be taken into account by the physician: The following agents may enhance the hypoglycaemic effect of nateglinide: angiotensin-converting enzyme inhibitors (ACEI). The following agents may reduce the hypoglycaemic effect of nateglinide: diuretics, corticosteroids, and beta2 agonists. When these medicinal products are administered to or withdrawn from patients receiving nateglinide, the patient should be observed closely for changes in glycaemic control. Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly metabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent. In an interaction trial with sulfinpyrazone, a CYP2C9 inhibitor, a modest increase in nateglinide AUC (~28%) was observed in healthy volunteers, with no changes in the mean Cmax and elimination half-life. A more prolonged effect and possibly a risk of hypoglycaemia cannot be excluded in patients when nateglinide is co-administered with CYP2C9 inhibitors. Particular caution is recommended when nateglinide is co-administered with other more potent inhibitors of CYP2C9, e.g. fluconazole or gemfibrozil, or in patients known to be poor metabolisers for CYP2C9. Interaction studies with a 3A4 inhibitor have not been carried out in vivo. In vivo, nateglinide has no clinically relevant effect on the pharmacokinetics of medicinal products metabolised by CYP2C9 and CYP3A4. The pharmacokinetics of warfarin (a substrate for CYP3A4 and CYP2C9), diclofenac (a substrate for CYP2C9), and digoxin were unaffected by coadministration with nateglinide. Conversely, these medicinal products had no effect on the pharmacokinetics of nateglinide. Thus, no dosage adjustment is required for digoxin, warfarin or other drugs that are CYP2C9 or CYP3A4 substrates upon coadministration with Trazec. Similarly, there was no clinically significant pharmacokinetic interaction of Trazec with other oral antidiabetic agents such as metformin or glibenclamide. Nateglinide has shown a low potential for protein displacement in in vitro studies. 4.6 Pregnancy and lactation Studies in animals have shown developmental toxicity (see section 5.3). There is no experience in pregnant women, therefore the safety of Trazec in pregnant women cannot be assessed. Trazec, like other oral antidiabetic agents, is not recommended for use in pregnancy. Nateglinide is excreted in the milk following a peroral dose to lactating rats. Although it is not known whether nateglinide is excreted in human milk, the potential for hypoglycaemia in breast-fed infants may exist and therefore nateglinide should not be used in lactating women. 4.7 Effects on ability to drive and use machines Patients should be advised to take precautions to avoid hypoglycaemia whilst driving or operating machinery. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances. Me dic ina l p rod uc t n o l on ge r a uth ori se d 5 4.8 Undesirable effects Based on the experience with nateglinide and with other hypoglycaemic agents, the following adverse reactions have been seen. Frequencies are defined as: common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000). Hypoglycaemia As with other antidiabetic agents, symptoms suggestive of hypoglycaemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness. These were generally mild in nature and easily handled by intake of carbohydrates when necessary. In completed clinical trials, symptoms of hypoglycaemia were reported in 10.4% with nateglinide monotherapy, 14.5% with nateglinide+metformin combination, 6.9% with metformin alone, 19.8% with glibenclamide alone, and 4.1% with placebo. Immune system disorders Rare: Hypersensitivity reactions such as rash, itching and urticaria. Metabolism and nutrition disorders Common: Symptoms suggestive of hypoglycaemia. Gatrointestinal disorders Common: Abdominal pain, diarrhoea, dyspepsia, nausea. Uncommon: Vomiting. Hepatobiliary disorders Rare: Elevations in liver enzymes. Other events Other adverse events observed in clinical studies were of a similar incidence in Trazec-treated and placebo-treated patients. Post-marketing data revealed very rare cases of erythema multiforme. 4.9 Overdose In a clinical study in patients, Trazec was administered in increasing doses up to 720 mg a day for 7 days and was well tolerated. There is no experience of an overdose of Trazec in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect, with the development of hypoglycaemic symptoms. Hypoglycaemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycaemic reactions with coma, seizure or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein-bound, dialysis is not an efficient means of removing it from the blood. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: D-phenylalanine derivative, ATC code: A10 BX 03 Nateglinide is an amino acid (phenylalanine) derivative, which is chemically and pharmacologically distinct from other antidiabetic agents. Nateglinide is a rapid, short-acting oral insulin secretagogue. Its effect is dependent on functioning beta cells in the pancreas islets. Early insulin secretion is a mechanism for the maintenance of normal glycaemic control. Nateglinide, Me dic ina l p rod uc t n o l on ge r a uth ori se d 6 when taken before a meal, restores early or first phase insulin secretion, which is lost in patients with type 2 diabetes, resulting in a reduction in post-meal glucose and HbA1c. Nateglinide closes ATP-dependent potassium channels in the beta-cell membrane with characteristics that distinguish it from other sulphonylurea receptor ligands. This depolarises the beta cell and leads to an opening of the calcium channels. The resulting calcium influx enhances insulin secretion. Electrophysiological studies demonstrate that nateglinide has 45–300-fold selectivity for pancreatic beta cell versus cardiovascular K+ATP channels. In type 2 diabetic patients, the insulinotropic response to a meal occurs within the first 15 minutes following an oral dose of nateglinide. This results in a blood-glucose-lowering effect throughout the meal period. Insulin levels return to baseline within 3 to 4 hours, reducing post-meal hyperinsulinaemia. Nateglinide-induced insulin secretion by pancreatic beta cells is glucose-sensitive, such that less insulin is secreted as glucose levels fall. Conversely, the coadministration of food or a glucose infusion results in an enhancement of insulin secretion. In combination with metformin, which mainly affected fasting plasma glucose, the effect of nateglinide on HbA1c was additive compared to either agent alone. Nateglinide efficacy was inferior to that of metformin in monotherapy (decrease in HbA1c (%) with metformin 500 mg three times daily monotherapy: –1.23 [95% CI: –1.48; –0.99] and with nateglinide 120 mg three times daily monotherapy –0.90 [95% CI: –1.14; –0.66]). The efficacy of nateglinide in combination with metformin has been compared to the combination of gliclazide plus metformin in a 6-month randomised, double-blind trial in 262 patients using a superiority design. The decrease from baseline in HbA1c was –0.41% in the nateglinide plus metformin group and –0.57% in the gliclazide plus metformin group (difference 0.17%, [95% CI –0.03, 0.36]). Both treatments were well tolerated. An outcome study has not been conducted with nateglinide, therefore the long-term benefits associated with improved glycaemic control have not been demonstrated. 5.2 Pharmacokinetic properties Absorption and bioavailability Nateglinide is rapidly absorbed following oral administration of Trazec tablets prior to a meal, with mean peak drug concentration generally occurring in less than 1 hour. Nateglinide is rapidly and almost completely (≥ 90%) absorbed from an oral solution. Absolute oral bioavailability is estimated to be 72%. In type 2 diabetic patients given Trazec over the dose range 60 to 240 mg before three meals per day for one week, nateglinide showed linear pharmacokinetics for both AUC and Cmax, and tmax was independent of dose. Distribution The steady-state volume of distribution of nateglinide based on intravenous data is estimated to be approximately 10 litres. In vitro studies show that nateglinide is extensively bound (97–99%) to serum proteins, mainly serum albumin and to a lesser extent alpha1-acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1–10 μg Trazec/ml. Metabolism Nateglinide is extensively metabolised. The main metabolites found in humans result from hydroxylation of the isopropyl side-chain, either on the methine carbon, or one of the methyl groups; activity of the main metabolites is about 5–6 and 3 times less potent than nateglinide, respectively. Minor metabolites identified were a diol, an isopropene and acyl glucuronide(s) of nateglinide; only the isopropene minor metabolite possesses activity, which is almost as potent as nateglinide. Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly Me dic ina l p rod uc t n o l on ge r a uth ori se d 7 metabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent. Excretion Nateglinide and its metabolites are rapidly and completely eliminated. Most of the [14C] nateglinide is excreted in the urine (83%), with an additional 10% eliminated in the faeces. Approximately 75% of the administered [14C] nateglinide is recovered in the urine within six hours post-dose. Approximately 6–16% of the administered dose was excreted in the urine as unchanged drug. Plasma concentrations decline rapidly and the elimination half-life of nateglinide typically averaged 1.5 hours in all studies of Trazec in volunteers and type 2 diabetic patients. Consistent with its short elimination half-life, there is no apparent accumulation of nateglinide upon multiple dosing with up to 240 mg three times daily. Food effect When given post-prandially, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterised by a decrease in Cmax and a delay in time to peak plasma concentration (tmax). It is recommended that Trazec be administered prior to meals. It is usually taken immediately (1 minute) before a meal but may be taken up to 30 minutes before meals. Sub-populations Elderly: Age did not influence the pharmacokinetic properties of nateglinide. Hepatic impairment: The systemic availability and half-life of nateglinide in non-diabetic subjects with mild to moderate hepatic impairment did not differ to a clinically significant degree from those in healthy subjects. Renal impairment: The systemic availability and half-life of nateglinide in diabetic patients with mild, moderate (creatinine clearance 31–50 ml/min) and severe (creatinine clearance 15–30 ml/min) renal impairment (not undergoing dialysis) did not differ to a clinically significant degree from those in healthy subjects. There is a 49% decrease in Cmax of nateglinide in dialysis-dependent diabetic patients. The systemic availability and half-life in dialysis-dependent diabetic patients was comparable with healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax. Gender: No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. 5.3 Preclinical safety data Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to fertility and post-natal development. Nateglinide was not teratogenic in rats. In rabbits, at maternally toxic doses a higher incidence of foetuses with no gallbladder was observed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Cellulose, microcrystalline Povidone Croscarmellose sodium Magnesium stearate Red iron oxide (E172) Hypromellose Titanium dioxide (E171) Talc Macrogol Silica, colloidal anhydrous Me dic ina l p rod uc t n o l on ge r a uth ori se d 8 6.2 Incompatibilities Not applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 30°C. Store in the original package. 6.5 Nature and contents of container Blisters: PVC/PE/PVDC moulded foil with aluminium lidding foil. Packs contain 12, 60, 84, 120 and 360 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) EU/1/01/175/001 EU/1/01/175/004-007 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 03.04.2001 Date of first renewal: 03.04.2006 10. DATE OF REVISION OF THE TEXT Me dic ina l p rod uc t n o l on ge r a uth ori se d 9 1. NAME OF THE MEDICINAL PRODUCT TRAZEC 120 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 120 mg nateglinide. Excipients: Lactose monohydrate: 283 mg per tablet For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet 120 mg yellow, ovaloid tablets with “NVR” marked on one side and “TSL” on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Nateglinide is indicated for combination therapy with metformin in type 2 diabetic patients inadequately controlled despite a maximally tolerated dose of metformin alone. 4.2 Posology and method of administration Nateglinide should be taken within 1 to 30 minutes before meals (usually breakfast, lunch and dinner). The dosage of nateglinide should be determined by the physician according to the patient’s requirements. The recommended starting dose is 60 mg three times daily before meals, particularly in patients who are near goal HbA1c. This may be increased to 120 mg three times daily. Dose adjustments should be based on periodic glycosylated haemoglobin (HbA1c) measurements. Since the primary therapeutic effect of Trazec is to reduce mealtime glucose, (a contributor to HbA1c), the therapeutic response to Trazec may also be monitored with 1–2 hour post-meal glucose. The recommended maximum daily dose is 180 mg three times daily to be taken before the three main meals. Specific patient groups Elderly The clinical experience in patients over 75 years of age is limited. Children and adolescents There are no data available on the use of nateglinide in patients under 18 years of age, and therefore its use in this age group is not recommended. Patients with hepatic impairment No dose adjustment is necessary for patients with mild to moderate hepatic impairment. As patients with severe liver disease were not studied, nateglinide is contraindicated in this group. Me dic ina l p rod uc t n o l on ge r a uth ori se d 10 Patients with renal impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Although there is a 49% decrease in Cmax of nateglinide in dialysis patients, the systemic availability and half-life in diabetic subjects with moderate to severe renal insufficiency (creatinine clearance 15–50 ml/min) was comparable between renal subjects requiring haemodialysis and healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax. Others In debilitated or malnourished patients the initial and maintenance dosage should be conservative and careful titration is required to avoid hypoglycaemic reactions. 4.3 Contraindications Trazec is contraindicated in patients with: • Hypersensitivity to the active substance or to any of the excipients • Type 1 diabetes (insulin-dependent diabetes mellitus, C-peptide negative) • Diabetic ketoacidosis, with or without coma • Pregnancy and breast-feeding (see section 4.6) • Severe hepatic impairment 4.4 Special warnings and precautions for use General Nateglinide should not be used in monotherapy. Like other insulin secretagogues, nateglinide is capable of producing hypoglycaemia. Hypoglycaemia has been observed in patients with type 2 diabetes on diet and exercise, and in those treated with oral antidiabetic agents (see section 4.8). Elderly, malnourished patients and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose- lowering effect of these treatments. The risk of hypoglycaemia in type 2 diabetic patients may be increased by strenuous physical exercise, or ingestion of alcohol. Symptoms of hypoglycaemia (unconfirmed by blood glucose levels) were observed in patients whose baseline HbA1c was close to the therapeutic target (HbA1C <7.5%). Combination with metformin is associated with an increased risk of hypoglycaemia compared to monotherapy. Hypoglycaemia may be difficult to recognise in subjects receiving beta blockers. When a patient stabilised on any oral hypoglycaemic agent is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue oral hypoglycaemic treatment and replace it with insulin on a temporary basis. Trazec contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, of the Lapp lactase deficiency or of glucose-galactose malabsorption should not take this medicine. Specific patient groups Nateglinide should be used with caution in patients with moderate hepatic impairment. No clinical studies have been conducted in patients with severe hepatic impairment or children and adolescents. Treatment is therefore not recommended in these patient groups. Me dic ina l p rod uc t n o l on ge r a uth ori se d 11 4.5 Interaction with other medicinal products and other forms of interaction A number of medicinal products influence glucose metabolism and possible interactions should therefore be taken into account by the physician: The following agents may enhance the hypoglycaemic effect of nateglinide: angiotensin-converting enzyme inhibitors (ACEI). The following agents may reduce the hypoglycaemic effect of nateglinide: diuretics, corticosteroids, and beta2 agonists. When these medicinal products are administered to or withdrawn from patients receiving nateglinide, the patient should be observed closely for changes in glycaemic control. Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly metabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent. In an interaction trial with sulfinpyrazone, a CYP2C9 inhibitor, a modest increase in nateglinide AUC (~28%) was observed in healthy volunteers, with no changes in the mean Cmax and elimination half-life. A more prolonged effect and possibly a risk of hypoglycaemia cannot be excluded in patients when nateglinide is co-administered with CYP2C9 inhibitors. Particular caution is recommended when nateglinide is co-administered with other more potent inhibitors of CYP2C9, e.g. fluconazole or gemfibrozil, or in patients known to be poor metabolisers for CYP2C9. Interaction studies with a 3A4 inhibitor have not been carried out in vivo. In vivo, nateglinide has no clinically relevant effect on the pharmacokinetics of medicinal products metabolised by CYP2C9 and CYP3A4. The pharmacokinetics of warfarin (a substrate for CYP3A4 and CYP2C9), diclofenac (a substrate for CYP2C9), and digoxin were unaffected by coadministration with nateglinide. Conversely, these medicinal products had no effect on the pharmacokinetics of nateglinide. Thus, no dosage adjustment is required for digoxin, warfarin or other drugs that are CYP2C9 or CYP3A4 substrates upon coadministration with Trazec. Similarly, there was no clinically significant pharmacokinetic interaction of Trazec with other oral antidiabetic agents such as metformin or glibenclamide. Nateglinide has shown a low potential for protein displacement in in vitro studies. 4.6 Pregnancy and lactation Studies in animals have shown developmental toxicity (see section 5.3). There is no experience in pregnant women, therefore the safety of Trazec in pregnant women cannot be assessed. Trazec, like other oral antidiabetic agents, is not recommended for use in pregnancy. Nateglinide is excreted in the milk following a peroral dose to lactating rats. Although it is not known whether nateglinide is excreted in human milk, the potential for hypoglycaemia in breast-fed infants may exist and therefore nateglinide should not be used in lactating women. 4.7 Effects on ability to drive and use machines Patients should be advised to take precautions to avoid hypoglycaemia whilst driving or operating machinery. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances. Me dic ina l p rod uc t n o l on ge r a uth ori se d 12 4.8 Undesirable effects Based on the experience with nateglinide and with other hypoglycaemic agents, the following adverse reactions have been seen. Frequencies are defined as: common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000). Hypoglycaemia As with other antidiabetic agents, symptoms suggestive of hypoglycaemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness. These were generally mild in nature and easily handled by intake of carbohydrates when necessary. In completed clinical trials, symptoms of hypoglycaemia were reported in 10.4% with nateglinide monotherapy, 14.5% with nateglinide+metformin combination, 6.9% with metformin alone, 19.8% with glibenclamide alone, and 4.1% with placebo. Immune system disorders Rare: Hypersensitivity reactions such as rash, itching and urticaria. Metabolism and nutrition disorders Common: Symptoms suggestive of hypoglycaemia. Gatrointestinal disorders Common: Abdominal pain, diarrhoea, dyspepsia, nausea. Uncommon: Vomiting. Hepatobiliary disorders Rare: Elevations in liver enzymes. Other events Other adverse events observed in clinical studies were of a similar incidence in Trazec-treated and placebo-treated patients. Post-marketing data revealed very rare cases of erythema multiforme. 4.9 Overdose In a clinical study in patients, Trazec was administered in increasing doses up to 720 mg a day for 7 days and was well tolerated. There is no experience of an overdose of Trazec in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect, with the development of hypoglycaemic symptoms. Hypoglycaemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycaemic reactions with coma, seizure or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein-bound, dialysis is not an efficient means of removing it from the blood. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: D-phenylalanine derivative, ATC code: A10 BX 03 Nateglinide is an amino acid (phenylalanine) derivative, which is chemically and pharmacologically distinct from other antidiabetic agents. Nateglinide is a rapid, short-acting oral insulin secretagogue. Its effect is dependent on functioning beta cells in the pancreas islets. Early insulin secretion is a mechanism for the maintenance of normal glycaemic control. Nateglinide, Me dic ina l p rod uc t n o l on ge r a uth ori se d 13 when taken before a meal, restores early or first phase insulin secretion, which is lost in patients with type 2 diabetes, resulting in a reduction in post-meal glucose and HbA1c. Nateglinide closes ATP-dependent potassium channels in the beta-cell membrane with characteristics that distinguish it from other sulphonylurea receptor ligands. This depolarises the beta cell and leads to an opening of the calcium channels. The resulting calcium influx enhances insulin secretion. Electrophysiological studies demonstrate that nateglinide has 45–300-fold selectivity for pancreatic beta cell versus cardiovascular K+ATP channels. In type 2 diabetic patients, the insulinotropic response to a meal occurs within the first 15 minutes following an oral dose of nateglinide. This results in a blood-glucose-lowering effect throughout the meal period. Insulin levels return to baseline within 3 to 4 hours, reducing post-meal hyperinsulinaemia. Nateglinide-induced insulin secretion by pancreatic beta cells is glucose-sensitive, such that less insulin is secreted as glucose levels fall. Conversely, the coadministration of food or a glucose infusion results in an enhancement of insulin secretion. In combination with metformin, which mainly affected fasting plasma glucose, the effect of nateglinide on HbA1c was additive compared to either agent alone. Nateglinide efficacy was inferior to that of metformin in monotherapy (decrease in HbA1c (%) with metformin 500 mg three times daily monotherapy: –1.23 [95% CI: –1.48; –0.99] and with nateglinide 120 mg three times daily monotherapy –0.90 [95% CI: –1.14; –0.66]). The efficacy of nateglinide in combination with metformin has been compared to the combination of gliclazide plus metformin in a 6-month randomised, double-blind trial in 262 patients using a superiority design. The decrease from baseline in HbA1c was –0.41% in the nateglinide plus metformin group and –0.57% in the gliclazide plus metformin group (difference 0.17%, [95% CI –0.03, 0.36]). Both treatments were well tolerated. An outcome study has not been conducted with nateglinide, therefore the long-term benefits associated with improved glycaemic control have not been demonstrated. 5.2 Pharmacokinetic properties Absorption and bioavailability Nateglinide is rapidly absorbed following oral administration of Trazec tablets prior to a meal, with mean peak drug concentration generally occurring in less than 1 hour. Nateglinide is rapidly and almost completely (≥ 90%) absorbed from an oral solution. Absolute oral bioavailability is estimated to be 72%. In type 2 diabetic patients given Trazec over the dose range 60 to 240 mg before three meals per day for one week, nateglinide showed linear pharmacokinetics for both AUC and Cmax, and tmax was independent of dose. Distribution The steady-state volume of distribution of nateglinide based on intravenous data is estimated to be approximately 10 litres. In vitro studies show that nateglinide is extensively bound (97–99%) to serum proteins, mainly serum albumin and to a lesser extent alpha1-acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1–10 μg Trazec/ml. Metabolism Nateglinide is extensively metabolised. The main metabolites found in humans result from hydroxylation of the isopropyl side-chain, either on the methine carbon, or one of the methyl groups; activity of the main metabolites is about 5–6 and 3 times less potent than nateglinide, respectively. Minor metabolites identified were a diol, an isopropene and acyl glucuronide(s) of nateglinide; only the isopropene minor metabolite possesses activity, which is almost as potent as nateglinide. Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly Me dic ina l p rod uc t n o l on ge r a uth ori se d 14 metabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent. Excretion Nateglinide and its metabolites are rapidly and completely eliminated. Most of the [14C] nateglinide is excreted in the urine (83%), with an additional 10% eliminated in the faeces. Approximately 75% of the administered [14C] nateglinide is recovered in the urine within six hours post-dose. Approximately 6–16% of the administered dose was excreted in the urine as unchanged drug. Plasma concentrations decline rapidly and the elimination half-life of nateglinide typically averaged 1.5 hours in all studies of Trazec in volunteers and type 2 diabetic patients. Consistent with its short elimination half-life, there is no apparent accumulation of nateglinide upon multiple dosing with up to 240 mg three times daily. Food effect When given post-prandially, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterised by a decrease in Cmax and a delay in time to peak plasma concentration (tmax). It is recommended that Trazec be administered prior to meals. It is usually taken immediately (1 minute) before a meal but may be taken up to 30 minutes before meals. Sub-populations Elderly: Age did not influence the pharmacokinetic properties of nateglinide. Hepatic impairment: The systemic availability and half-life of nateglinide in non-diabetic subjects with mild to moderate hepatic impairment did not differ to a clinically significant degree from those in healthy subjects. Renal impairment: The systemic availability and half-life of nateglinide in diabetic patients with mild, moderate (creatinine clearance 31–50 ml/min) and severe (creatinine clearance 15–30 ml/min) renal impairment (not undergoing dialysis) did not differ to a clinically significant degree from those in healthy subjects. There is a 49% decrease in Cmax of nateglinide in dialysis-dependent diabetic patients. The systemic availability and half-life in dialysis-dependent diabetic patients was comparable with healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax. Gender: No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. 5.3 Preclinical safety data Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to fertility and post-natal development. Nateglinide was not teratogenic in rats. In rabbits, at maternally toxic doses a higher incidence of foetuses with no gallbladder was observed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Cellulose, microcrystalline Povidone Croscarmellose sodium Magnesium stearate Yellow iron oxide (E172) Hypromellose Titanium dioxide (E171) Talc Macrogol Me dic ina l p rod uc t n o l on ge r a uth ori se d 15 Silica, colloidal anhydrous 6.2 Incompatibilities Not applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 30°C. Store in the original package. 6.5 Nature and contents of container Blisters: PVC/PE/PVDC moulded foil with aluminium lidding foil. Packs contain 12, 60, 84, 120 and 360 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) EU/1/01/175/008 EU/1/01/175/011-014 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 03.04.2001 Date of first renewal: 03.04.2006 10. DATE OF REVISION OF THE TEXT Me dic ina l p rod uc t n o l on ge r a uth ori se d 16 1. NAME OF THE MEDICINAL PRODUCT TRAZEC 180 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 180 mg nateglinide. Excipients: Lactose monohydrate: 214 mg per tablet For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet 180 mg red, ovaloid tablets with “NVR” marked on one side and “TSX” on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Nateglinide is indicated for combination therapy with metformin in type 2 diabetic patients inadequately controlled despite a maximally tolerated dose of metformin alone. 4.2 Posology and method of administration Nateglinide should be taken within 1 to 30 minutes before meals (usually breakfast, lunch and dinner). The dosage of nateglinide should be determined by the physician according to the patient’s requirements. The recommended starting dose is 60 mg three times daily before meals, particularly in patients who are near goal HbA1c. This may be increased to 120 mg three times daily. Dose adjustments should be based on periodic glycosylated haemoglobin (HbA1c) measurements. Since the primary therapeutic effect of Trazec is to reduce mealtime glucose, (a contributor to HbA1c), the therapeutic response to Trazec may also be monitored with 1–2 hour post-meal glucose. The recommended maximum daily dose is 180 mg three times daily to be taken before the three main meals. Specific patient groups Elderly The clinical experience in patients over 75 years of age is limited. Children and adolescents There are no data available on the use of nateglinide in patients under 18 years of age, and therefore its use in this age group is not recommended. Patients with hepatic impairment No dose adjustment is necessary for patients with mild to moderate hepatic impairment. As patients with severe liver disease were not studied, nateglinide is contraindicated in this group. Me dic ina l p rod uc t n o l on ge r a uth ori se d 17 Patients with renal impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Although there is a 49% decrease in Cmax of nateglinide in dialysis patients, the systemic availability and half-life in diabetic subjects with moderate to severe renal insufficiency (creatinine clearance 15–50 ml/min) was comparable between renal subjects requiring haemodialysis and healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax. Others In debilitated or malnourished patients the initial and maintenance dosage should be conservative and careful titration is required to avoid hypoglycaemic reactions. 4.3 Contraindications Trazec is contraindicated in patients with: • Hypersensitivity to the active substance or to any of the excipients • Type 1 diabetes (insulin-dependent diabetes mellitus, C-peptide negative) • Diabetic ketoacidosis, with or without coma • Pregnancy and breast-feeding (see section 4.6) • Severe hepatic impairment 4.4 Special warnings and precautions for use General Nateglinide should not be used in monotherapy. Like other insulin secretagogues, nateglinide is capable of producing hypoglycaemia. Hypoglycaemia has been observed in patients with type 2 diabetes on diet and exercise, and in those treated with oral antidiabetic agents (see section 4.8). Elderly, malnourished patients and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose- lowering effect of these treatments. The risk of hypoglycaemia in type 2 diabetic patients may be increased by strenuous physical exercise, or ingestion of alcohol. Symptoms of hypoglycaemia (unconfirmed by blood glucose levels) were observed in patients whose baseline HbA1c was close to the therapeutic target (HbA1C <7.5%). Combination with metformin is associated with an increased risk of hypoglycaemia compared to monotherapy. Hypoglycaemia may be difficult to recognise in subjects receiving beta blockers. When a patient stabilised on any oral hypoglycaemic agent is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue oral hypoglycaemic treatment and replace it with insulin on a temporary basis. Trazec contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, of the Lapp lactase deficiency or of glucose-galactose malabsorption should not take this medicine. Specific patient groups Nateglinide should be used with caution in patients with moderate hepatic impairment. No clinical studies have been conducted in patients with severe hepatic impairment or children and adolescents. Treatment is therefore not recommended in these patient groups. Me dic ina l p rod uc t n o l on ge r a uth ori se d 18 4.5 Interaction with other medicinal products and other forms of interaction A number of medicinal products influence glucose metabolism and possible interactions should therefore be taken into account by the physician: The following agents may enhance the hypoglycaemic effect of nateglinide: angiotensin-converting enzyme inhibitors (ACEI). The following agents may reduce the hypoglycaemic effect of nateglinide: diuretics, corticosteroids, and beta2 agonists. When these medicinal products are administered to or withdrawn from patients receiving nateglinide, the patient should be observed closely for changes in glycaemic control. Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly metabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent. In an interaction trial with sulfinpyrazone, a CYP2C9 inhibitor, a modest increase in nateglinide AUC (~28%) was observed in healthy volunteers, with no changes in the mean Cmax and elimination half-life. A more prolonged effect and possibly a risk of hypoglycaemia cannot be excluded in patients when nateglinide is co-administered with CYP2C9 inhibitors. Particular caution is recommended when nateglinide is co-administered with other more potent inhibitors of CYP2C9, e.g. fluconazole or gemfibrozil, or in patients known to be poor metabolisers for CYP2C9. Interaction studies with a 3A4 inhibitor have not been carried out in vivo. In vivo, nateglinide has no clinically relevant effect on the pharmacokinetics of medicinal products metabolised by CYP2C9 and CYP3A4. The pharmacokinetics of warfarin (a substrate for CYP3A4 and CYP2C9), diclofenac (a substrate for CYP2C9), and digoxin were unaffected by coadministration with nateglinide. Conversely, these medicinal products had no effect on the pharmacokinetics of nateglinide. Thus, no dosage adjustment is required for digoxin, warfarin or other drugs that are CYP2C9 or CYP3A4 substrates upon coadministration with Trazec. Similarly, there was no clinically significant pharmacokinetic interaction of Trazec with other oral antidiabetic agents such as metformin or glibenclamide. Nateglinide has shown a low potential for protein displacement in in vitro studies. 4.6 Pregnancy and lactation Studies in animals have shown developmental toxicity (see section 5.3). There is no experience in pregnant women, therefore the safety of Trazec in pregnant women cannot be assessed. Trazec, like other oral antidiabetic agents, is not recommended for use in pregnancy. Nateglinide is excreted in the milk following a peroral dose to lactating rats. Although it is not known whether nateglinide is excreted in human milk, the potential for hypoglycaemia in breast-fed infants may exist and therefore nateglinide should not be used in lactating women. 4.7 Effects on ability to drive and use machines Patients should be advised to take precautions to avoid hypoglycaemia whilst driving or operating machinery. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances. Me dic ina l p rod uc t n o l on ge r a uth ori se d 19 4.8 Undesirable effects Based on the experience with nateglinide and with other hypoglycaemic agents, the following adverse reactions have been seen. Frequencies are defined as: common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000). Hypoglycaemia As with other antidiabetic agents, symptoms suggestive of hypoglycaemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness. These were generally mild in nature and easily handled by intake of carbohydrates when necessary. In completed clinical trials, symptoms of hypoglycaemia were reported in 10.4% with nateglinide monotherapy, 14.5% with nateglinide+metformin combination, 6.9% with metformin alone, 19.8% with glibenclamide alone, and 4.1% with placebo. Immune system disorders Rare: Hypersensitivity reactions such as rash, itching and urticaria. Metabolism and nutrition disorders Common: Symptoms suggestive of hypoglycaemia. Gatrointestinal disorders Common: Abdominal pain, diarrhoea, dyspepsia, nausea. Uncommon: Vomiting. Hepatobiliary disorders Rare: Elevations in liver enzymes. Other events Other adverse events observed in clinical studies were of a similar incidence in Trazec-treated and placebo-treated patients. Post-marketing data revealed very rare cases of erythema multiforme. 4.9 Overdose In a clinical study in patients, Trazec was administered in increasing doses up to 720 mg a day for 7 days and was well tolerated. There is no experience of an overdose of Trazec in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect, with the development of hypoglycaemic symptoms. Hypoglycaemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycaemic reactions with coma, seizure or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein-bound, dialysis is not an efficient means of removing it from the blood. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: D-phenylalanine derivative, ATC code: A10 BX 03 Nateglinide is an amino acid (phenylalanine) derivative, which is chemically and pharmacologically distinct from other antidiabetic agents. Nateglinide is a rapid, short-acting oral insulin secretagogue. Its effect is dependent on functioning beta cells in the pancreas islets. Early insulin secretion is a mechanism for the maintenance of normal glycaemic control. Nateglinide, Me dic ina l p rod uc t n o l on ge r a uth ori se d 20 when taken before a meal, restores early or first phase insulin secretion, which is lost in patients with type 2 diabetes, resulting in a reduction in post-meal glucose and HbA1c. Nateglinide closes ATP-dependent potassium channels in the beta-cell membrane with characteristics that distinguish it from other sulphonylurea receptor ligands. This depolarises the beta cell and leads to an opening of the calcium channels. The resulting calcium influx enhances insulin secretion. Electrophysiological studies demonstrate that nateglinide has 45–300-fold selectivity for pancreatic beta cell versus cardiovascular K+ATP channels. In type 2 diabetic patients, the insulinotropic response to a meal occurs within the first 15 minutes following an oral dose of nateglinide. This results in a blood-glucose-lowering effect throughout the meal period. Insulin levels return to baseline within 3 to 4 hours, reducing post-meal hyperinsulinaemia. Nateglinide-induced insulin secretion by pancreatic beta cells is glucose-sensitive, such that less insulin is secreted as glucose levels fall. Conversely, the coadministration of food or a glucose infusion results in an enhancement of insulin secretion. In combination with metformin, which mainly affected fasting plasma glucose, the effect of nateglinide on HbA1c was additive compared to either agent alone. Nateglinide efficacy was inferior to that of metformin in monotherapy (decrease in HbA1c (%) with metformin 500 mg three times daily monotherapy: –1.23 [95% CI: –1.48; –0.99] and with nateglinide 120 mg three times daily monotherapy –0.90 [95% CI: –1.14; –0.66]). The efficacy of nateglinide in combination with metformin has been compared to the combination of gliclazide plus metformin in a 6-month randomised, double-blind trial in 262 patients using a superiority design. The decrease from baseline in HbA1c was –0.41% in the nateglinide plus metformin group and –0.57% in the gliclazide plus metformin group (difference 0.17%, [95% CI –0.03, 0.36]). Both treatments were well tolerated. An outcome study has not been conducted with nateglinide, therefore the long-term benefits associated with improved glycaemic control have not been demonstrated. 5.2 Pharmacokinetic properties Absorption and bioavailability Nateglinide is rapidly absorbed following oral administration of Trazec tablets prior to a meal, with mean peak drug concentration generally occurring in less than 1 hour. Nateglinide is rapidly and almost completely (≥ 90%) absorbed from an oral solution. Absolute oral bioavailability is estimated to be 72%. In type 2 diabetic patients given Trazec over the dose range 60 to 240 mg before three meals per day for one week, nateglinide showed linear pharmacokinetics for both AUC and Cmax, and tmax was independent of dose. Distribution The steady-state volume of distribution of nateglinide based on intravenous data is estimated to be approximately 10 litres. In vitro studies show that nateglinide is extensively bound (97–99%) to serum proteins, mainly serum albumin and to a lesser extent alpha1-acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1–10 μg Trazec/ml. Metabolism Nateglinide is extensively metabolised. The main metabolites found in humans result from hydroxylation of the isopropyl side-chain, either on the methine carbon, or one of the methyl groups; activity of the main metabolites is about 5–6 and 3 times less potent than nateglinide, respectively. Minor metabolites identified were a diol, an isopropene and acyl glucuronide(s) of nateglinide; only the isopropene minor metabolite possesses activity, which is almost as potent as nateglinide. Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly Me dic ina l p rod uc t n o l on ge r a uth ori se d 21 metabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent. Excretion Nateglinide and its metabolites are rapidly and completely eliminated. Most of the [14C] nateglinide is excreted in the urine (83%), with an additional 10% eliminated in the faeces. Approximately 75% of the administered [14C] nateglinide is recovered in the urine within six hours post-dose. Approximately 6–16% of the administered dose was excreted in the urine as unchanged drug. Plasma concentrations decline rapidly and the elimination half-life of nateglinide typically averaged 1.5 hours in all studies of Trazec in volunteers and type 2 diabetic patients. Consistent with its short elimination half-life, there is no apparent accumulation of nateglinide upon multiple dosing with up to 240 mg three times daily. Food effect When given post-prandially, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterised by a decrease in Cmax and a delay in time to peak plasma concentration (tmax). It is recommended that Trazec be administered prior to meals. It is usually taken immediately (1 minute) before a meal but may be taken up to 30 minutes before meals. Sub-populations Elderly: Age did not influence the pharmacokinetic properties of nateglinide. Hepatic impairment: The systemic availability and half-life of nateglinide in non-diabetic subjects with mild to moderate hepatic impairment did not differ to a clinically significant degree from those in healthy subjects. Renal impairment: The systemic availability and half-life of nateglinide in diabetic patients with mild, moderate (creatinine clearance 31–50 ml/min) and severe (creatinine clearance 15–30 ml/min) renal impairment (not undergoing dialysis) did not differ to a clinically significant degree from those in healthy subjects. There is a 49% decrease in Cmax of nateglinide in dialysis-dependent diabetic patients. The systemic availability and half-life in dialysis-dependent diabetic patients was comparable with healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax. Gender: No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. 5.3 Preclinical safety data Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to fertility and post-natal development. Nateglinide was not teratogenic in rats. In rabbits, at maternally toxic doses a higher incidence of foetuses with no gallbladder was observed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Cellulose, microcrystalline Povidone Croscarmellose sodium Magnesium stearate Red iron oxide (E172) Hypromellose Titanium dioxide (E171) Talc Macrogol Me dic ina l p rod uc t n o l on ge r a uth ori se d 22 Silica, colloidal anhydrous 6.2 Incompatibilities Not applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 30°C. Store in the original package. 6.5 Nature and contents of container Blisters: PVC/PE/PVDC moulded foil with aluminium lidding foil. Packs contain 12, 60, 84, 120 and 360 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) EU/1/01/175/015 EU/1/01/175/018-021 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 03.04.2001 Date of first renewal: 03.04.2006 10. DATE OF REVISION OF THE TEXT Me dic ina l p rod uc t n o l on ge r a uth ori se d 23 ANNEX II A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION Me dic ina l p rod uc t n o l on ge r a uth ori se d 24 A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Novartis Farma S.p.A. Via Provinciale Schito, 131 I-80058 Torre Annunziata - Napoli Italy B. CONDITIONS OF THE MARKETING AUTHORISATION • CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER Medicinal product subject to medical prescription • CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Not applicable. Me dic ina l p rod uc t n o l on ge r a uth ori se d 25 ANNEX III LABELLING AND PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 26 A. LABELLING Me dic ina l p rod uc t n o l on ge r a uth ori se d 27 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Trazec 60 mg film-coated tablets Nateglinide 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 film-coated tablet contains 60 mg nateglinide. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. 4. PHARMACEUTICAL FORM AND CONTENTS 12 film-coated tablets 60 film-coated tablets 84 film-coated tablets 120 film-coated tablets 360 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. Store in the original package. Me dic ina l p rod uc t n o l on ge r a uth ori se d 28 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/1/01/175/001 12 film-coated tablets EU/1/01/175/004 60 film-coated tablets EU/1/01/175/005 84 film-coated tablets EU/1/01/175/006 120 film-coated tablets EU/1/01/175/007 360 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Trazec 60 mg Me dic ina l p rod uc t n o l on ge r a uth ori se d 29 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Trazec 60 mg tablets Nateglinide 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 30 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Trazec 120 mg film-coated tablets Nateglinide 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 film-coated tablet contains 120 mg nateglinide. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. 4. PHARMACEUTICAL FORM AND CONTENTS 12 film-coated tablets 60 film-coated tablets 84 film-coated tablets 120 film-coated tablets 360 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. Store in the original package. Me dic ina l p rod uc t n o l on ge r a uth ori se d 31 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/1/01/175/008 12 film-coated tablets EU/1/01/175/011 60 film-coated tablets EU/1/01/175/012 84 film-coated tablets EU/1/01/175/013 120 film-coated tablets EU/1/01/175/014 360 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Trazec 120 mg Me dic ina l p rod uc t n o l on ge r a uth ori se d 32 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Trazec 120 mg tablets Nateglinide 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 33 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Trazec 180 mg film-coated tablets Nateglinide 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 film-coated tablet contains 180 mg nateglinide. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. 4. PHARMACEUTICAL FORM AND CONTENTS 12 film-coated tablets 60 film-coated tablets 84 film-coated tablets 120 film-coated tablets 360 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. Store in the original package. Me dic ina l p rod uc t n o l on ge r a uth ori se d 34 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/1/01/175/015 12 film-coated tablets EU/1/01/175/018 60 film-coated tablets EU/1/01/175/019 84 film-coated tablets EU/1/01/175/020 120 film-coated tablets EU/1/01/175/021 360 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Trazec 180 mg Me dic ina l p rod uc t n o l on ge r a uth ori se d 35 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Trazec 180 mg tablets Nateglinide 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 36 B. PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 37 PACKAGE LEAFLET: INFORMATION FOR THE USER Trazec 60 mgfilm-coated tablets Trazec 120 mg film-coated tablets Trazec 180 mg film-coated tablets Nateglinide Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Trazec is and what it is used for 2. Before you take Trazec 3. How to take Trazec 4. Possible side effects 5. How to store Trazec 6. Further information 1. WHAT TRAZEC IS AND WHAT IT IS USED FOR Trazec is a medicine to lower blood sugar (glucose), which is taken by mouth (these medicines are also known as oral anti-diabetics). It is used by people with type 2 diabetes. (This kind of diabetes is also called non-insulin-dependent diabetes mellitus.) Insulin is a substance produced by a body organ called the pancreas. It helps to decrease blood sugar levels, especially after meals. In patients with type 2 diabetes, the body may not start producing insulin quickly enough after meals. Trazec works by stimulating the pancreas to produce insulin more quickly. This helps to keep the blood sugar controlled after meals. Your doctor will prescribe Trazec together with another oral anti-diabetic containing metformin. Trazec tablets start to act quickly after you take them and are eliminated from the body rapidly. 2. BEFORE YOU TAKE TRAZEC Follow all instructions given to you by your doctor and pharmacist carefully, even if they are different from what is in this leaflet. Do not take Trazec - if you are allergic (hypersensitive) to nateglinide or any of the other ingredients of Trazec. - if you have type 1 diabetes (i.e. your body does not produce any insulin). - if you know that you have a severe liver problem. - if you are pregnant or planning to become pregnant. - if you are breast-feeding. Talk to your doctor if you have any further questions or you think that any of these may apply to you. Me dic ina l p rod uc t n o l on ge r a uth ori se d 38 Take special care with Trazec People with diabetes sometimes get symptoms of low blood sugar (also called hypoglycaemia). Medicines, including Trazec, may also produce symptoms of low blood sugar. If you get any of these symptoms – feeling dizzy, light-headed, hungry, shaky or any of the other signs in section 4, “Possible side effects” – eat or drink something containing sugar. Some people are more likely to get symptoms of low blood sugar than others. Take care - if you are over 65 years of age. - if you are undernourished. - if you have another medical condition that may cause low blood sugar (e.g. an under-active pituitary or adrenal gland). If any of these apply to you, monitor your blood sugar levels more carefully. Talk to your doctor - if you know that you have a liver problem. - if you have a severe kidney problem. - if you have problems of drug metabolism. - if you are due to have an operation. - if you have suffered a fever, an accident or an infection. Your treatment may need to be adjusted. Taking other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. The amount of Trazec that you need may change if you take other medicines as these may cause your blood sugar levels to go up or down. It is especially important that you tell your doctor or pharmacist if you are taking: - Beta blockers or angiotensin-converting enzyme inhibitors (used, for example, to treat high blood pressure and certain heart conditions). - Diuretics (used in the treatment of high blood pressure). - Corticosteroids such as prednisone and cortisone (used to treat inflammatory disorders). - Inhibitors of drug metabolism such as fluconazole (used to treat fungal infection), gemfibrozil (used to treat dyslipidaemia) or sulfinpyrazone (used to treat chronic gout). Your doctor may adjust the dose of these medicines. Food, drink and exercise Take Trazec before meals (see section 3, “How to take Trazec”). Its effect may be delayed if it is taken during or after meals. Even though you are taking medicines for your diabetes, it is important to keep following the diet and/or exercise your doctor has recommended for you. Watch carefully for signs of low blood sugar, especially - if you have exercised more strenuously than usual. - if you have drunk alcohol. Alcohol may upset the control of your blood sugar so you are advised to talk to your doctor about drinking alcohol while taking Trazec. If you do get symptoms of low blood sugar, eat or drink something containing sugar and talk to your doctor. Trazec and older people Trazec can be used by people over 65 years of age. Take special care to avoid low blood sugar. Me dic ina l p rod uc t n o l on ge r a uth ori se d 39 Trazec and children and adolescents Trazec is not recommended for children and adolescents (under 18 years of age) because its effects in this age group have not been studied. Pregnancy and breast-feeding Do not take Trazec if you are pregnant or planning to become pregnant. See your doctor as soon as possible if you become pregnant during treatment. Do not breast-feed during treatment with Trazec. Ask your doctor or pharmacist for advice before taking any medicine while you are pregnant or breast- feeding. Driving and using machines You are advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important if you have reduced or absent awareness of the warning signs of hypoglycaemia or if you have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances. Important information about some of the ingredients of Trazec Trazec tablets contain lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. 3. HOW TO TAKE TRAZEC Always take Trazec exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. When to take Trazec Take Trazec before the three main meals, usually: - 1 dose before breakfast - 1 dose before lunch - 1 dose before dinner It is best to take it right before a main meal but you can take it up to 30 minutes before. Do not take it if you are not going to eat a main meal. If you miss a meal, skip that dose of Trazec and wait until your next meal. How much to take Take Trazec as your doctor told you to. Your doctor will determine the dosage you require. The usual dose of Trazec to start with is 60 mg before the three main meals. In some cases your doctor may prescribe higher doses. The recommended maximum daily dose is 180 mg three times daily to be taken before the three main meals. Swallow the tablets whole with a glass of water before the meal. How long to take Trazec Take Trazec daily until your doctor tells you to stop. If you take more Trazec than you should If you have accidentally taken too many tablets, talk to a doctor straight away. If you experience symptoms of low blood sugar – if you feel dizzy, light-headed, hungry, shaky, or any of the other signs in section 4, “Possible side effects” – eat or drink something containing sugar. Me dic ina l p rod uc t n o l on ge r a uth ori se d 40 If you feel as if you are about to have a severe hypoglycaemic attack (which may lead to loss of consciousness or seizure), call for urgent medical help – or make sure that someone else does this for you. If you forget to take Trazec If you forget to take a tablet simply take the next one before your next meal. Do not take a double dose of Trazec to make up for the one that you missed. 4. POSSIBLE SIDE EFFECTS Like all medicines, Trazec can cause side effects, although not everybody gets them. The side effects caused by Trazec are usually mild to moderate. The most common side effects are symptoms of low blood sugar (hypoglycaemia), which are usually mild. These include - sweating, - dizziness, - shaking, - weakness, - hunger, - feeling your heart beating fast, - tiredness, - feeling sick (nausea). They can also be caused by lack of food or too high a dose of any anti-diabetic medicine you are taking. If you do get symptoms of low blood sugar, eat or drink something containing sugar. Abdominal pain, indigestion, diarrhoea, nausea and vomiting have been reported. Rare effects are mild abnormalities in liver function tests and allergic (hypersensitivity) reactions such as rash and itching. A very rare effect is skin rash with blisters affecting the lips, eyes, mouth, sometimes with headache, fever and/or diarrhoea. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE TRAZEC Keep out of the reach and sight of children. Store in the original package. Do not use Trazec after the expiry date stated on the carton after EXP. The expiry date refers to the last day of that month. Do not use any Trazec pack that is damaged or shows signs of tampering. Do not store above 30°C. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. Me dic ina l p rod uc t n o l on ge r a uth ori se d 41 6. FURTHER INFORMATION What Trazec contains - The active substance is nateglinide. - The other ingredients are lactose monohydrate; cellulose, microcrystalline; povidone; croscarmellose sodium; magnesium stearate and silica, colloidal anhydrous. - The tablet coating contains hypromellose; titanium dioxide (E171); talc; macrogol and red (60 and 180 mg tablets) or yellow (120 mg tablets) iron oxide (E172). What Trazec looks like and contents of the pack Trazec 60 mg film-coated tablets are pink, round tablets with “NVR” marked on one side and “TS” on the other. Trazec 120 mg film-coated tablets are yellow, ovaloid tablets with “NVR” marked on one side and “TSL” on the other. Trazec 180 mg film-coated tablets are red, ovaloid tablets with “NVR” marked on one side and “TSX” on the other. Each blister pack contains 12, 60, 84, 120 or 360 tablets. Not all pack sizes or tablet strengths may be available in your country. Marketing Authorisation Holder Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom Manufacturer Novartis Farma S.p.A. Via Provinciale Schito, 131 I-80058 Torre Annunziata - Napoli Italy For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Luxembourg/Luxemburg Novartis Pharma GmbH Tél/Tel: +49 911 273 0 България Novartis Pharma Services Inc. Тел.: +359 2 489 98 28 Magyarország Novartis Hungária Kft. Pharma Tel.: +36 1 457 65 00 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Malta Novartis Pharma Services Inc. Tel: +356 2298 3217 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Nederland Novartis Pharma B.V. Tel: +31 26 37 82 111 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Me dic ina l p rod uc t n o l on ge r a uth ori se d 42 Eesti Novartis Pharma Services Inc. Tel: +372 60 62 400 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 550 8888 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 România Novartis Pharma Services Inc. Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 77 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 9 61 33 22 11 Κύπρος Δημητριάδης και Παπαέλληνας Λτδ Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija Novartis Pharma Services Inc. Tel: +371 7 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 Lietuva Novartis Pharma Services Inc. Tel: +370 5 269 16 50 This leaflet was last approved in SUMMARY OF PRODUCT CHARACTERISTICS MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE CONDITIONS OF THE MARKETING AUTHORISATION LABELLING PACKAGE LEAFLET

{'Title': '1. what trazec is and what it is used for', 'Section_Content': 'trazec is a medicine to lower blood sugar (glucose), which is taken by mouth (these medicines are also known as oral anti-diabetics). it is used by people with type 2 diabetes. (this kind of diabetes is also called non-insulin-dependent diabetes mellitus.) insulin is a substance produced by a body organ called the pancreas. it helps to decrease blood sugar levels, especially after meals. in patients with type 2 diabetes, the body may not start producing insulin quickly enough after meals. trazec works by stimulating the pancreas to produce insulin more quickly. this helps to keep the blood sugar controlled after meals. your doctor will prescribe trazec together with another oral anti-diabetic containing metformin. trazec tablets start to act quickly after you take them and are eliminated from the body rapidly.', 'Entity_Recognition': [{'Text': 'trazec', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a medicine', 'Type': 'TREATMENT', 'BeginOffset': 10, 'EndOffset': 20}, {'Id': 0, 'BeginOffset': 71, 'EndOffset': 76, 'Score': 0.3341602683067322, 'Text': 'mouth', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'these medicines', 'Type': 'TREATMENT', 'BeginOffset': 78, 'EndOffset': 93}, {'Id': 16, 'BeginOffset': 112, 'EndOffset': 131, 'Score': 0.5494529008865356, 'Text': 'oral anti-diabetics', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 160, 'EndOffset': 175, 'Score': 0.43868306279182434, 'Text': 'type 2 diabetes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9612381458282471}]}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 165, 'EndOffset': 166}, {'Id': 13, 'BeginOffset': 191, 'EndOffset': 199, 'Score': 0.977110743522644, 'Text': 'diabetes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9431222081184387}]}, {'Id': 14, 'BeginOffset': 215, 'EndOffset': 254, 'Score': 0.6286898851394653, 'Text': 'non-insulin-dependent diabetes mellitus', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9771479368209839}]}, {'Id': 4, 'BeginOffset': 257, 'EndOffset': 264, 'Score': 0.8608843088150024, 'Text': 'insulin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 316, 'EndOffset': 324, 'Score': 0.8570722341537476, 'Text': 'pancreas', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'blood sugar levels', 'Type': 'TEST', 'BeginOffset': 347, 'EndOffset': 365}, {'Id': 15, 'BeginOffset': 408, 'EndOffset': 423, 'Score': 0.3906492292881012, 'Text': 'type 2 diabetes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9553783535957336}]}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 413, 'EndOffset': 414}, {'Id': 5, 'BeginOffset': 458, 'EndOffset': 465, 'Score': 0.9773377180099487, 'Text': 'insulin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'trazec', 'Type': 'TREATMENT', 'BeginOffset': 494, 'EndOffset': 500}, {'Id': 2, 'BeginOffset': 526, 'EndOffset': 534, 'Score': 0.680372416973114, 'Text': 'pancreas', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 6, 'BeginOffset': 546, 'EndOffset': 553, 'Score': 0.6460414528846741, 'Text': 'insulin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the blood sugar', 'Type': 'TEST', 'BeginOffset': 587, 'EndOffset': 602}, {'Text': 'trazec', 'Type': 'TREATMENT', 'BeginOffset': 654, 'EndOffset': 660}, {'Text': 'another oral anti-diabetic containing metformin', 'Type': 'TREATMENT', 'BeginOffset': 675, 'EndOffset': 722}, {'Text': 'trazec tablets', 'Type': 'TREATMENT', 'BeginOffset': 724, 'EndOffset': 738}, {'Id': 3, 'BeginOffset': 808, 'EndOffset': 812, 'Score': 0.6702772378921509, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}]}

{'Title': '2. before you take trazec', 'Section_Content': 'follow all instructions given to you by your doctor and pharmacist carefully, even if they are different from what is in this leaflet. do not take trazec - if you are allergic (hypersensitive) to nateglinide or any of the other ingredients of trazec. - if you have type 1 diabetes (i.e. your body does not produce any insulin). - if you know that you have a severe liver problem. - if you are pregnant or planning to become pregnant. - if you are breast-feeding. talk to your doctor if you have any further questions or you think that any of these may apply to you. take special care with trazec people with diabetes sometimes get symptoms of low blood sugar (also called hypoglycaemia). medicines, including trazec, may also produce symptoms of low blood sugar. if you get any of these symptoms feeling dizzy, light-headed, hungry, shaky or any of the other signs in section 4, "possible side effects" eat or drink something containing sugar. some people are more likely to get symptoms of low blood sugar than others. take care - if you are over 65 years of age. - if you are undernourished. - if you have another medical condition that may cause low blood sugar (e.g. an under-active pituitary or adrenal gland). if any of these apply to you, monitor your blood sugar levels more carefully. talk to your doctor - if you know that you have a liver problem. - if you have a severe kidney problem. - if you have problems of drug metabolism. - if you are due to have an operation. - if you have suffered a fever, an accident or an infection. your treatment may need to be adjusted. taking other medicines please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. the amount of trazec that you need may change if you take other medicines as these may cause your blood sugar levels to go up or down. it is especially important that you tell your doctor or pharmacist if you are taking: - beta blockers or angiotensin-converting enzyme inhibitors (used, for example, to treat high blood pressure and certain heart conditions). - diuretics (used in the treatment of high blood pressure). - corticosteroids such as prednisone and cortisone (used to treat inflammatory disorders). - inhibitors of drug metabolism such as fluconazole (used to treat fungal infection), gemfibrozil (used to treat dyslipidaemia) or sulfinpyrazone (used to treat chronic gout). your doctor may adjust the dose of these medicines. food, drink and exercise take trazec before meals (see section 3, "how to take trazec"). its effect may be delayed if it is taken during or after meals. even though you are taking medicines for your diabetes, it is important to keep following the diet and/or exercise your doctor has recommended for you. watch carefully for signs of low blood sugar, especially - if you have exercised more strenuously than usual. - if you have drunk alcohol. alcohol may upset the control of your blood sugar so you are advised to talk to your doctor about drinking alcohol while taking trazec. if you do get symptoms of low blood sugar, eat or drink something containing sugar and talk to your doctor. trazec and older people trazec can be used by people over 65 years of age. take special care to avoid low blood sugar. trazec and children and adolescents trazec is not recommended for children and adolescents (under 18 years of age) because its effects in this age group have not been studied. pregnancy and breast-feeding do not take trazec if you are pregnant or planning to become pregnant. see your doctor as soon as possible if you become pregnant during treatment. do not breast-feed during treatment with trazec. ask your doctor or pharmacist for advice before taking any medicine while you are pregnant or breast- feeding. driving and using machines you are advised to take precautions to avoid hypoglycaemia whilst driving. this is particularly important if you have reduced or absent awareness of the warning signs of hypoglycaemia or if you have frequent episodes of hypoglycaemia. the advisability of driving should be considered in these circumstances. important information about some of the ingredients of trazec trazec tablets contain lactose monohydrate. if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.', 'Entity_Recognition': [{'Text': 'trazec', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 147, 'EndOffset': 153, 'Score': 0.24744601547718048, 'Text': 'trazec', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 167, 'EndOffset': 175}, {'Id': 9, 'BeginOffset': 177, 'EndOffset': 191, 'Score': 0.7305088639259338, 'Text': 'hypersensitive', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 5, 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{'Title': '3. how to take trazec', 'Section_Content': 'always take trazec exactly as your doctor has told you. you should check with your doctor or pharmacist if you are not sure. when to take trazec take trazec before the three main meals, usually: - 1 dose before breakfast - 1 dose before lunch - 1 dose before dinner it is best to take it right before a main meal but you can take it up to 30 minutes before. do not take it if you are not going to eat a main meal. if you miss a meal, skip that dose of trazec and wait until your next meal. how much to take take trazec as your doctor told you to. your doctor will determine the dosage you require. the usual dose of trazec to start with is 60 mg before the three main meals. in some cases your doctor may prescribe higher doses. the recommended maximum daily dose is 180 mg three times daily to be taken before the three main meals. swallow the tablets whole with a glass of water before the meal. how long to take trazec take trazec daily until your doctor tells you to stop. if you take more trazec than you should if you have accidentally taken too many tablets, talk to a doctor straight away. if you experience symptoms of low blood sugar if you feel dizzy, light-headed, hungry, shaky, or any of the other signs in section 4, "possible side effects" eat or drink something containing sugar. if you feel as if you are about to have a severe hypoglycaemic attack (which may lead to loss of consciousness or seizure), call for urgent medical help or make sure that someone else does this for you. if you forget to take trazec if you forget to take a tablet simply take the next one before your next meal. do not take a double dose of trazec to make up for the one that you missed.', 'Entity_Recognition': [{'Text': 'trazec', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 138, 'EndOffset': 144, 'Score': 0.7459972500801086, 'Text': 'trazec', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, trazec can cause side effects, although not everybody gets them. the side effects caused by trazec are usually mild to moderate. the most common side effects are symptoms of low blood sugar (hypoglycaemia), which are usually mild. these include - sweating, - dizziness, - shaking, - weakness, - hunger, - feeling your heart beating fast, - tiredness, - feeling sick (nausea). they can also be caused by lack of food or too high a dose of any anti-diabetic medicine you are taking. if you do get symptoms of low blood sugar, eat or drink something containing sugar. abdominal pain, indigestion, diarrhoea, nausea and vomiting have been reported. rare effects are mild abnormalities in liver function tests and allergic (hypersensitivity) reactions such as rash and itching. a very rare effect is skin rash with blisters affecting the lips, eyes, mouth, sometimes with headache, fever and/or diarrhoea. if any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'trazec', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Id': 6, 'BeginOffset': 20, 'EndOffset': 26, 'Score': 0.34380587935447693, 'Text': 'trazec', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 37, 'EndOffset': 49, 'Score': 0.9592241644859314, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6216953992843628}]}, {'Id': 9, 'BeginOffset': 89, 'EndOffset': 101, 'Score': 0.8712767362594604, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6483694911003113}]}, {'Id': 10, 'BeginOffset': 165, 'EndOffset': 177, 'Score': 0.8579558730125427, 'Text': 'side effects', 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{'Title': '5. how to store trazec', 'Section_Content': 'keep out of the reach and sight of children. store in the original package. do not use trazec after the expiry date stated on the carton after exp. the expiry date refers to the last day of that month. do not use any trazec pack that is damaged or shows signs of tampering. do not store above 30. medicines should not be disposed of via wastewater or household waste. ask your pharmacist how to dispose of medicines no longer required. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'trazec', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'trazec', 'Type': 'TREATMENT', 'BeginOffset': 87, 'EndOffset': 93}, {'Text': 'any trazec pack', 'Type': 'TREATMENT', 'BeginOffset': 213, 'EndOffset': 228}, {'Text': 'tampering', 'Type': 'PROBLEM', 'BeginOffset': 263, 'EndOffset': 272}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 293, 'EndOffset': 296}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 297, 'EndOffset': 306}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 406, 'EndOffset': 415}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 436, 'EndOffset': 450}]}

{'Title': '6. further information', 'Section_Content': 'what trazec contains - the active substance is nateglinide. - the other ingredients are lactose monohydrate; cellulose, microcrystalline; povidone; croscarmellose sodium; magnesium stearate and silica, colloidal anhydrous. - the tablet coating contains hypromellose; titanium dioxide (e171); talc; macrogol and red (60 and 180 mg tablets) or yellow (120 mg tablets) iron oxide (e172). what trazec looks like and contents of the pack trazec 60 mg film-coated tablets are pink, round tablets with "nvr" marked on one side and "ts" on the other. trazec 120 mg film-coated tablets are yellow, ovaloid tablets with "nvr" marked on one side and "tsl" on the other. trazec 180 mg film-coated tablets are red, ovaloid tablets with "nvr" marked on one side and "tsx" on the other. each blister pack contains 12, 60, 84, 120 or 360 tablets. not all pack sizes or tablet strengths may be available in your country.', 'Entity_Recognition': [{'Text': 'trazec', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 47, 'EndOffset': 58, 'Score': 0.9892093539237976, 'Text': 'nateglinide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 88, 'EndOffset': 107, 'Score': 0.4224409759044647, 'Text': 'lactose monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 109, 'EndOffset': 118, 'Score': 0.8071549534797668, 'Text': 'cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 120, 'EndOffset': 136, 'Score': 0.9959204196929932, 'Text': 'microcrystalline', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 138, 'EndOffset': 146, 'Score': 0.8927015066146851, 'Text': 'povidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 148, 'EndOffset': 169, 'Score': 0.9933910369873047, 'Text': 'croscarmellose sodium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'magnesium stearate and silica, colloidal anhydrous', 'Type': 'TREATMENT', 'BeginOffset': 171, 'EndOffset': 221}, {'Text': 'the tablet coating', 'Type': 'TREATMENT', 'BeginOffset': 225, 'EndOffset': 243}, {'Text': 'hypromellose; titanium dioxide', 'Type': 'TREATMENT', 'BeginOffset': 253, 'EndOffset': 283}, {'Text': 'talc', 'Type': 'TREATMENT', 'BeginOffset': 292, 'EndOffset': 296}, {'Id': 12, 'BeginOffset': 298, 'EndOffset': 306, 'Score': 0.8475673794746399, 'Text': 'macrogol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.991327702999115, 'RelationshipScore': 0.9693326950073242, 'RelationshipType': 'FORM', 'Id': 17, 'BeginOffset': 357, 'EndOffset': 364, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 13, 'BeginOffset': 311, 'EndOffset': 314, 'Score': 0.35369107127189636, 'Text': 'red', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.5449653267860413, 'RelationshipScore': 0.9999746084213257, 'RelationshipType': 'DOSAGE', 'Id': 14, 'BeginOffset': 316, 'EndOffset': 329, 'Text': '60 and 180 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9817762970924377, 'RelationshipScore': 0.9989271759986877, 'RelationshipType': 'FORM', 'Id': 15, 'BeginOffset': 330, 'EndOffset': 337, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8975921273231506, 'RelationshipScore': 0.9999886751174927, 'RelationshipType': 'DOSAGE', 'Id': 16, 'BeginOffset': 350, 'EndOffset': 356, 'Text': '120 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.991327702999115, 'RelationshipScore': 0.9992936849594116, 'RelationshipType': 'FORM', 'Id': 17, 'BeginOffset': 357, 'EndOffset': 364, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 316, 'EndOffset': 318}, {'Text': '180', 'Type': 'NUMBER', 'BeginOffset': 323, 'EndOffset': 326}, {'Text': '120', 'Type': 'NUMBER', 'BeginOffset': 350, 'EndOffset': 353}, {'Id': 18, 'BeginOffset': 366, 'EndOffset': 376, 'Score': 0.9966734647750854, 'Text': 'iron oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.9817762970924377, 'RelationshipScore': 0.7351542115211487, 'RelationshipType': 'FORM', 'Id': 15, 'BeginOffset': 330, 'EndOffset': 337, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8975921273231506, 'RelationshipScore': 0.6089541912078857, 'RelationshipType': 'DOSAGE', 'Id': 16, 'BeginOffset': 350, 'EndOffset': 356, 'Text': '120 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.991327702999115, 'RelationshipScore': 0.9876587986946106, 'RelationshipType': 'FORM', 'Id': 17, 'BeginOffset': 357, 'EndOffset': 364, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the pack trazec', 'Type': 'TREATMENT', 'BeginOffset': 424, 'EndOffset': 439}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 440, 'EndOffset': 442}, {'Text': 'nvr', 'Type': 'PROBLEM', 'BeginOffset': 496, 'EndOffset': 499}, {'Id': 24, 'BeginOffset': 543, 'EndOffset': 549, 'Score': 0.8059282898902893, 'Text': 'trazec', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.7471734881401062, 'RelationshipScore': 0.9967551827430725, 'RelationshipType': 'STRENGTH', 'Id': 25, 'BeginOffset': 550, 'EndOffset': 556, 'Text': '120 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7125019431114197, 'RelationshipScore': 0.9975103139877319, 'RelationshipType': 'FORM', 'Id': 26, 'BeginOffset': 557, 'EndOffset': 561, 'Text': 'film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.5926035046577454, 'RelationshipScore': 0.9994533658027649, 'RelationshipType': 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0.9984511137008667, 'RelationshipType': 'FORM', 'Id': 32, 'BeginOffset': 673, 'EndOffset': 677, 'Text': 'film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.5818553566932678, 'RelationshipScore': 0.9983629584312439, 'RelationshipType': 'FORM', 'Id': 33, 'BeginOffset': 678, 'EndOffset': 692, 'Text': 'coated tablets', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9798243045806885, 'RelationshipScore': 0.7425345182418823, 'RelationshipType': 'FORM', 'Id': 35, 'BeginOffset': 710, 'EndOffset': 717, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '180', 'Type': 'NUMBER', 'BeginOffset': 666, 'EndOffset': 669}, {'Text': 'film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 673, 'EndOffset': 692}, {'Text': 'red', 'Type': 'PROBLEM', 'BeginOffset': 697, 'EndOffset': 700}, {'Text': 'ovaloid tablets', 'Type': 'TREATMENT', 'BeginOffset': 702, 'EndOffset': 717}, {'Text': 'nvr', 'Type': 'PROBLEM', 'BeginOffset': 724, 'EndOffset': 727}, {'Text': 'each blister pack', 'Type': 'TREATMENT', 'BeginOffset': 772, 'EndOffset': 789}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 799, 'EndOffset': 801}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 803, 'EndOffset': 805}, {'Text': '84', 'Type': 'NUMBER', 'BeginOffset': 807, 'EndOffset': 809}, {'Text': '120', 'Type': 'NUMBER', 'BeginOffset': 811, 'EndOffset': 814}, {'Text': '360', 'Type': 'NUMBER', 'BeginOffset': 818, 'EndOffset': 821}]}

7DA87D77F9783DA205FA5997A6611135

https://www.ema.europa.eu/documents/product-information/vantobra-epar-product-information_en.pdf

Vantobra

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Me dic ina l p rod uc t n o l on ge r a uth ori se d 2 1. NAME OF THE MEDICINAL PRODUCT Vantobra 170 mg nebuliser solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each single-dose ampoule of 1.7 ml contains 170 mg tobramycin. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Nebuliser solution. A clear to slightly yellow solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Vantobra is indicated for the management of chronic pulmonary infection due to Pseudomonas aeruginosa in patients aged 6 years and older with cystic fibrosis (CF). Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Posology The dose of Vantobra is the same for all patients within the approved age range, regardless of age or weight. The recommended dose is one ampoule (170 mg/1.7 ml) administered twice daily (i.e. total daily dose is 2 ampoules) for 28 days. The dose interval should be as close as possible to 12 hours and not less than 6 hours. Vantobra is taken in alternating cycles of 28 days. A cycle of 28 days of active therapy (on-treatment period) and 28 days of rest from treatment (off-treatment period) should be maintained. Missed doses In case of a missed dose with at least 6 hours remaining until the next dose, the patient should inhale the dose as soon as possible. If less than 6 hours remain to the next planned dose, the patient should wait for the next dose and not inhale more to make up for the missed dose. Duration of treatment Treatment should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the treatment taking into account that long-term safety data are not available for Vantobra. If clinical deterioration of pulmonary status is evident, additional or alternative anti-pseudomonal therapy should be considered. See also information on clinical benefit and tolerability in sections 4.4, 4.8 and 5.1. Special populations Elderly patients (≥65 years) There are insufficient data in this population to support a recommendation for or against dose adjustment. Me dic ina l p rod uc t n o l on ge r a uth ori se d 3 Renal impairment There are no data in this population to support a recommendation for or against dose adjustment with Vantobra. Please also refer to nephrotoxicity information in section 4.4 and excretion information in section 5.2. Hepatic impairment No studies have been performed on patients with hepatic impairment. As tobramycin is not metabolised, an effect of hepatic impairment on the exposure to tobramycin is not expected. Patients after organ transplantation Adequate data do not exist for the use of inhaled tobramycin in patients after organ transplantation. No recommendation for or against dose adjustment can be made for patients after organ transplantation. Paediatric population There is no relevant use of Vantobra in children below 6 years of age. Method of administration Inhalation use. Vantobra is administered by inhalation using the Tolero nebuliser handset provided in the pack. For detailed instructions on use see section 6.6. Vantobra must not be administered by any other route or using any other device than the one provided in the pack. The use of an alternative untested nebuliser system may alter the pulmonary deposition of the active substance. And this in turn may alter efficacy and safety of the product. Where patients are receiving several inhaled medicinal products and chest physiotherapy, it is recommended that Vantobra is used last. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Ototoxicity Ototoxicity, manifested as both auditory toxicity (hearing loss) and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. Auditory toxicity, as measured by complaints of hearing loss or by audiometric evaluations, was observed with parenteral aminoglycosides and may be considered also for the inhalation route of administration. In open label studies and post-marketing experience, some patients with a history of prolonged previous or concomitant use of intravenous aminoglycosides have experienced hearing loss. Physicians should consider the potential for aminoglycosides to cause vestibular and cochlear toxicity and carry out appropriate assessments of auditory function during Vantobra therapy. In patients with a predisposing risk due to previous prolonged systemic aminoglycoside therapy it may be necessary to consider audiological assessment before initiating Vantobra therapy. If a patient reports tinnitus or hearing loss during aminoglycoside therapy, the physician should consider referring them for audiological assessment. Me dic ina l p rod uc t n o l on ge r a uth ori se d 4 Nephrotoxicity Nephrotoxicity has been associated with parenteral aminoglycoside therapy. There was no evidence of nephrotoxicity during clinical trials with inhaled tobramycin and Vantobra. Caution should be exercised when prescribing Vantobra to patients with known or suspected renal dysfunction. According to current clinical practice baseline renal function should be assessed. Urea and creatinine levels should be reassessed after every 6 complete cycles of Vantobra therapy (180 days of nebulised aminoglycoside therapy). Monitoring of serum tobramycin concentrations Patients with known or suspected auditory or renal dysfunction should be monitored for serum tobramycin concentrations. If oto- or nephrotoxicity occurs in a patient receiving Vantobra, tobramycin therapy should be discontinued until serum concentration falls below 2 µg/ml. Serum concentrations greater than 12 µg/ml are associated with tobramycin toxicity and treatment should be discontinued if concentrations exceed this level. The serum concentration of tobramycin should only be monitored using validated methods. Finger prick blood sampling is not recommended due to the risk of contamination of the sample. Bronchospasm Bronchospasm can occur with inhalation of medicinal products and has been reported with the use of nebulised tobramycin. Bronchospasm should be treated as medically appropriate. The first dose of Vantobra should be used under supervision of a physician, after taking a bronchodilator if this is part of the current regimen for the patient. FEV1 should be measured before and after nebulisation. If there is evidence of therapy-induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of Vantobra outweighs the risks to the patient. If an allergic response is suspected, Vantobra should be discontinued. Neuromuscular disorders Vantobra should be used with great caution in patients with neuromuscular disorders such as Parkinsonism or other conditions characterized by myasthenia, including myasthenia gravis, as aminoglycosides may aggravate muscle weakness due to a potential curare-like effect on neuromuscular function. Haemoptysis Inhalation of nebulised tobramycin solutions may induce a cough reflex. The treatment with Vantobra in patients with active, severe haemoptysis should be initiated only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage. Development of resistance The development of antibiotic-resistant P. aeruginosa and superinfection with other pathogens represent potential risks associated with antibiotic therapy. Development of resistance during inhaled tobramycin therapy could limit treatment options during acute exacerbations; this should be monitored. Other precautions Patients receiving concomitant parenteral aminoglycoside therapy (or any medicine affecting renal excretion, such as diuretics) should be monitored as clinically appropriate taking into account the risk of cumulative toxicity. This includes monitoring of serum concentrations of tobramycin. Safety and efficacy have not been studied in patients colonised with Burkholderia cepacia. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Based on the interaction profile for tobramycin following intravenous and aerosolised administration, concurrent and/or sequential use of Vantobra is not recommended with other medicinal products with nephrotoxic or ototoxic potential, such as: Me dic ina l p rod uc t n o l on ge r a uth ori se d 5 - amphotericin B, cefalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity); - platinum compounds (risk of increased nephrotoxicity and ototoxicity); Concurrent use of Vantobra with diuretic compounds (such as ethacrynic acid, furosemide, urea or mannitol) is not recommended. Such compounds can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue (see section 4.4). Other medicinal products that have been reported to increase the potential toxicity of parenterally administered aminoglycosides include: - anticholinesterases, botulinum toxin (neuromuscular effects). In clinical studies patients using inhaled tobramycin continued to take dornase alfa, bronchodilators, inhaled corticosteroids and macrolides. No evidence of drug interactions with these medicines was identified. 4.6 Fertility, pregnancy and lactation Pregnancy There are limited data from the parenteral use of tobramycin in pregnant women. There are no adequate data from the use of tobramycin administered by inhalation in pregnant women. Animal studies do not indicate a teratogenic effect of tobramycin (see section 5.3). However, aminoglycosides can cause foetal harm (e.g., congenital deafness and nephrotoxicity) when high systemic concentrations are achieved in a pregnant woman. Systemic exposure following inhalation of Vantobra is very low (see section 5.2). If Vantobra is used during pregnancy, or if the patient becomes pregnant while taking Vantobra, she should be informed of the potential hazard to the foetus. Vantobra should not be used during pregnancy unless the benefits to the mother outweigh the risks to the foetus or baby. Breast-feeding Tobramycin is excreted in human breast milk after systemic administration. The amount of tobramycin excreted in human breast milk after administration by inhalation is not known, though it is estimated to be very low considering the low systemic exposure. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate breast-feeding or discontinue treatment with Vantobra, taking into account the importance of the treatment to the mother. Fertility No effect on male or female fertility was observed in animal studies after subcutaneous administration (see section 5.3). 4.7 Effects on ability to drive and use machines Vantobra has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile In controlled clinical trials with Vantobra the most frequent adverse reactions in cystic fibrosis patients with P. aeruginosa infection were cough and dysphonia. Clinical experience with tobramycin nebuliser solutions reports dysphonia and tinnitus in patients treated with tobramycin. The episodes of tinnitus were transient and resolved without discontinuation of tobramycin therapy. Me dic ina l p rod uc t n o l on ge r a uth ori se d 6 Occasionally, patients with a history of prolonged previous or concomitant use of intravenous aminoglycosides may experience hearing loss. Parenteral aminoglycosides have been associated with hypersensitivity, ototoxicity and nephrotoxicity (see section 4.4). Long-term safety data are not available for Vantobra (see also section 5.1). Tabulated list of adverse reactions Adverse drug reactions reported for tobramycin nebuliser solution are listed in Table 1. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category is provided using the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000). Table 1 Adverse reactions System Organ Class Frequency category Adverse Reactions Infections and infestations Rare Laryngitis Very rare Fungal infection Oral candidiasis Blood and lymphatic system disorders Very rare Lymphadenopathy Immune system disorders Very rare Hypersensitivity Metabolism and nutrition disorders Rare Anorexia Nervous system disorders Rare Dizziness Aphonia Headache Very rare Somnolence Ear and labyrinth disorders Rare Hearing loss Tinnitus Very rare Ear pain Ear disorder Vascular disorders Rare Haemoptysis Epistaxis Respiratory, thoracic and mediastinal disorders Uncommon Dyspnoea Dysphonia Pharyngitis Cough Rare Asthma Lung disorder Chest discomfort Productive cough Rhinitis Bronchospasm Very rare Hypoxia Hyperventilation Me dic ina l p rod uc t n o l on ge r a uth ori se d 7 Sinusitis Gastrointestinal disorders Rare Vomiting Mouth ulceration Nausea Dysgeusia Very rare Diarrhoea Abdominal pain Skin and subcutaneous tissue disorders Rare Rash Very rare Urticaria Pruritus Musculoskeletal and connective tissue disorders Very rare Back pain General disorders and administration site conditions Rare Asthenia Pyrexia Pain Chest pain Very rare Malaise Investigations Rare Pulmonary function test decreased Paediatric population There was no difference in the safety profile between pediatric and adult patient population treated with Vantobra. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Administration by inhalation results in low systemic bioavailability of tobramycin. Symptoms of aerosol overdose may include severe hoarseness. In the event of accidental ingestion of Vantobra, toxicity is unlikely as tobramycin is poorly absorbed from an intact gastrointestinal tract. In the event of inadvertent administration of Vantobra by the intravenous route, signs and symptoms of parenteral tobramycin overdose may occur, including dizziness, tinnitus, vertigo, loss of hearing acuity, respiratory distress and/or neuromuscular blockage and renal impairment. Acute toxicity should be treated with immediate withdrawal of Vantobra and baseline tests of renal function should be undertaken. Assessment of tobramycin serum concentrations may be helpful in monitoring overdose. In the case of any overdose, the possibility of drug interactions with alterations in the elimination of Vantobra or other medicinal products should be considered. 5. PHARMACOLOGICAL PROPERTIES Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 8 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antibacterials for systemic use, Aminoglycoside antibacterials. ATC code: J01GB01 Mechanism of action Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. It acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope and eventual cell death. It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations. Breakpoints Established susceptibility breakpoints for parenteral administration of tobramycin are inappropriate in the aerosolised administration of the medicinal product. Sputum of cystic fibrosis patients exhibits an inhibitory action on the local biological activity of nebulised aminoglycosides. This necessitates sputum concentrations following treatment with aerosolised tobramycin to be ten to twentyfive-fold above the Minimum Inhibitory Concentration (MIC) for both P. aeruginosa growth suppression and control of bactericidal activity. In controlled clinical trials, 97% of patients receiving tobramycin nebuliser solution achieved sputum concentrations 10-fold of the highest P. aeruginosa MIC cultured from the patient and 95% of patients receiving tobramycin nebuliser solution achieved 25-fold of the highest MIC. Susceptibility In the absence of conventional susceptibility breakpoints for the nebulised route of administration, caution must be exercised in defining organisms as susceptible or insusceptible to nebulised tobramycin. In clinical studies with TOBI, most patients with P. aeruginosa isolates with tobramycin MICs < 128 µg/ml at baseline showed improved lung function following treatment with TOBI. Patients with a P. aeruginosa isolate with MIC 128 µg/ml at baseline are less likely to show a clinical response. However, seven of 13 patients (54%) in the placebo-controlled trials who acquired isolates with MICs of 128 µg/ml while using TOBI had improvement in pulmonary function. Based upon in-vitro data and/or clinical trial experience, the organisms associated with pulmonary infections in CF may be expected to respond to Vantobra therapy as follows: Susceptible Pseudomonas aeruginosa Haemophilus influenzae Staphylococcus aureus Insusceptible Burkholderia cepacia Stenotrophomonas maltophilia Alcaligenes xylosoxidans Treatment with the 28-days on and 28-days off dose regimen in clinical studies showed a small but clear increase in tobramycin, amikacin and gentamicin MICs for P. aeruginosa isolates tested. Each additional 6 months of treatment resulted in incremental increases similar in magnitude to that observed in the 6 months of controlled studies. The most prevalent aminoglycoside resistance mechanism seen in P. aeruginosa isolated from chronically infected CF patients is impermeability, defined by a general lack of susceptibility to all aminoglycosides. P. aeruginosa isolated from CF patients has also been shown to exhibit adaptive aminoglycoside resistance that is characterised by a reversion to susceptibility when the antibiotic is removed. Other information There is no evidence that patients treated with up to 18 months with tobramycin nebuliser solution were at a greater risk for acquiring B. cepacia, S. maltophilia or A. xylosoxidans, than would be expected in untreated patients. Aspergillus species were more frequently recovered from the sputum of treated patients; however, Me dic ina l p rod uc t n o l on ge r a uth ori se d 9 clinical sequelae such as Allergic Bronchopulmonary Aspergillosis (ABPA) were reported rarely and with similar frequency as in the control group. Aerosol characteristics Table 2: Comparative performance data for the clinical test and reference batches: Vantobra /Tolero nebuliser handset1, and TOBI/PARI LC PLUS2. Performance parameter/ Drug/Device combination* Vantobra/Tolero TOBI/PARI LC PLUS Total Drug Delivered [mg±SD] 96 ± 4.4 101 ± 8.5 Fine Particle Mass < 5 µm [mg±SD] 72 ± 6.5 65 ± 7.1 Drug Delivery Rate [mg/min] 27 ± 5.0 7 ± 0.9 Mass Median Aerodynamic Diameter [µm ± SD] 3.8 ± 0.3 3.6 ± 0.4 Geometric Standard Deviation ±SD 1.5 ± 0.0 2.3 ± 0.2 Nebulisation Time [min] 3.9 ± 0.6 15.3 ± 0.6 *Results from breath simulation and cascade impactor measurements. 1 connected with an eBase controller or eFlow rapid controller 2 connected with a PARI Boy SX compressor The drug delivery rate of Vantobra with the Tolero nebuliser is independent of the breathing pattern applied i.e. adult or child in contrast to the PARI LC PLUS nebuliser. Clinical efficacy and safety Limited data from one controlled clinical study over one treatment cycle indicate that the improvement in lung function was maintained above baseline during the 28-day off-treatment period. As a result of study 12012.101, lung function improvement FEV1% predicted relative to baseline increased by 8.2 ± 9.4% under Vantobra and by 4.8 ± 9.6% under the reference therapy in the first treatment cycle showing non-inferior (p=0.0005) efficacy. CFU reduction as an indicator for suppression of P. aeruginosa was comparable for Vantobra and the reference product. 5.2 Pharmacokinetic properties Absorption and distribution The systemic exposure to tobramycin after inhalation of Vantobra is expected to emerge primarily from the inhaled portion of the medicinal product as tobramycin is not absorbed to any appreciable extent when administered via the oral route. Inhalation of nebulised tobramycin produces high sputum concentrations and low plasma levels. For comparative aerosol data please refer to Table 2 in section 5.1 At the end of a 4-weeks dosing cycle of Vantobra (170 mg/1.7 ml twice daily) in cystic fibrosis patients, maximum tobramycin plasma concentrations (Cmax) of 1.27 ± 0.81 µg/ml were reached at approximately one hour after inhalation. Sputum concentrations were higher and more variable with Cmax of 1,951 + 2,187 µg/g. After administering a single dose of Vantobra 170 mg to healthy volunteers Cmax of 1.1 + 0.4 µg/ml were reached after a tmax of approximately 4 hours. Distribution Less than 10% of tobramycin is bound to plasma proteins. Biotransformation Tobramycin is not metabolised and is primarily excreted unchanged in the urine. Elimination Me dic ina l p rod uc t n o l on ge r a uth ori se d 10 The elimination of tobramycin administered by the inhalation route has not been studied. Following intravenous administration, systemically absorbed tobramycin is eliminated by glomerular filtration. The elimination half-life of tobramycin from serum is approximately 2 hours. Unabsorbed tobramycin following administration by inhalation is probably eliminated primarily in expectorated sputum. 5.3 Preclinical safety data Non-clinical data reveal that the main hazard for humans, based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development, consists of renal toxicity and ototoxicity. In repeated dose toxicity studies it has been shown that target organs of toxicity are the kidneys and vestibular/cochlear functions. In general, toxicity is seen at higher systemic tobramycin levels than are achievable by inhalation of the recommended clinical dose. No reproduction toxicology studies have been conducted with tobramycin administered by inhalation. Subcutaneous administration at doses of 100 mg/kg/day in rats and the maximum tolerated dose of 20 mg/kg/day in rabbits during organogenesis was not teratogenic. Teratogenicity could not be assessed at higher parenteral doses in rabbits as they induced maternal toxicity and abortion. Based on available data from animals a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded. Tobramycin did not impair fertility in male or female rats at subcutaneous doses up to 100 mg/kg/day. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Calcium chloride Magnesium sulphate Sulphuric acid (for pH adjustment) Sodium hydroxide (for pH adjustment) Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products in the nebuliser. 6.3 Shelf life 3 years The contents of a single-dose ampoule should be used immediately after opening (see section 6.6). Stability after opening of the pouch: 4 weeks when stored below 25 °C 6.4 Special precautions for storage Store in a refrigerator (2 °C – 8 °C). For storage conditions after first opening of the medicinal product, see section 6.3. 6.5 Nature and contents of container Me dic ina l p rod uc t n o l on ge r a uth ori se d 11 Vantobra is supplied in polyethylene (PE) ampoules that are packed in sealed aluminium foil pouches (8 ampoules per pouch). Outer carton contains: • One carton with the medicinal product: 56 ampoules with nebuliser solution in 7 pouches. • One carton with the Tolero nebuliser handset. 6.6 Special precautions for disposal and other handling The contents of one ampoule should be emptied into the medication reservoir of the Tolero nebuliser handset and administered by inhalation until no medicine is left in the reservoir. The Tolero nebuliser handset can be operated either with an eBase controller or with the eFlow rapid control unit. The performance parameters from in vitro aerosol characterisation studies are identical for the two controllers and are shown in section 5.1, Table 2. • Nebulisation should take place in a well ventilated room. • The nebuliser handset must be kept horizontally during operation. • The patient should sit in an upright position during inhalation. Inhalation should be performed by applying a normal breathing pattern without interruption. • The Tolero nebuliser handset must be cleaned and disinfected as described in the instructions for use of the device. Vantobra is a clear to slightly yellow solution, but some variability in colour may be observed, which does not indicate loss of activity if the product is stored as recommended. Vantobra solution is a sterile, aqueous preparation for single use only. As it is preservative-free, the contents of the whole ampoule should be used immediately after opening and any unused solution should be discarded. Opened ampoule should never be stored for re-use. Use a new Tolero nebuliser handset for each treatment cycle (28 days on-treatment) as provided with the medicine. Any unused medicinal product or waste material should be disposed off in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER PARI Pharma GmbH Moosstrasse 3 D-82319 Starnberg Germany Tel.: +49 (0) 89 – 74 28 46 - 10 Fax: +49 (0) 89 – 74 28 46 - 30 E-Mail: info@paripharma.com 8. MARKETING AUTHORISATION NUMBER(S) EU/1/14/932/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 18 March 2015 Me dic ina l p rod uc t n o l on ge r a uth ori se d 12 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 13 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Me dic ina l p rod uc t n o l on ge r a uth ori se d 14 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release PARI Pharma GmbH Lochhamer Schlag 21 82166 Graefelfing GERMANY B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal products subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 12 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. Me dic ina l p rod uc t n o l on ge r a uth ori se d 15 ANNEX III LABELLING AND PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 16 A. LABELLING Me dic ina l p rod uc t n o l on ge r a uth ori se d 17 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Vantobra 170 mg nebuliser solution Tobramycin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ampoule of 1.7 ml contains 170 mg tobramycin. 3. LIST OF EXCIPIENTS Excipients: sodium chloride, calcium chloride, magnesium sulphate, water for injections, sulphuric acid and sodium hydroxide for pH adjustment. 4. PHARMACEUTICAL FORM AND CONTENTS Package contains • One carton with: 56 ampoules with nebuliser solution in 7 pouches. • One carton with a Tolero nebuliser handset. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read both the package leaflet of Vantobra and the Instructions for Use of the Tolero nebuliser handset before use. Inhalation use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Me dic ina l p rod uc t n o l on ge r a uth ori se d 18 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER PARI Pharma GmbH Moosstrasse 3 D-82319 Starnberg Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/932/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Vantobra 170 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER _ HUMAN READABLE DATA PC: {number} SN: {number} NN: {number} Me dic ina l p rod uc t n o l on ge r a uth ori se d 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON CONTAINING THE MEDICINE 1. NAME OF THE MEDICINAL PRODUCT Vantobra 170 mg nebuliser solution Tobramycin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ampoule of 1.7 ml contains 170 mg tobramycin. 3. LIST OF EXCIPIENTS Excipients: sodium chloride, calcium chloride, magnesium sulphate, water for injections, sulphuric acid and sodium hydroxide for pH adjustment. 4. PHARMACEUTICAL FORM AND CONTENTS Package contains 56 ampoules with nebuliser solution in 7 pouches. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read both the package leaflet of Vantobra and the Instructions for Use of the Tolero nebuliser handset before use. Inhalation use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Me dic ina l p rod uc t n o l on ge r a uth ori se d 20 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER PARI Pharma GmbH Moosstrasse 3 D-82319 Starnberg Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/932/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Vantobra 170 mg Me dic ina l p rod uc t n o l on ge r a uth ori se d 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING POUCH 1. NAME OF THE MEDICINAL PRODUCT Vantobra 170 mg nebuliser solution Tobramycin 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ampoule of 1.7 ml contains 170 mg tobramycin. 3. LIST OF EXCIPIENTS Excipients: sodium chloride, calcium chloride, magnesium sulphate, water for injections, sulphuric acid and sodium hydroxide for pH adjustment. 4. PHARMACEUTICAL FORM AND CONTENTS Contains 8 ampoules. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read both the package leaflet of Vantobra and the Instructions for Use of the Tolero nebuliser handset before use. Inhalation use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Me dic ina l p rod uc t n o l on ge r a uth ori se d 22 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER PARI Pharma GmbH Moosstrasse 3 D-82319 Starnberg Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/932/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Me dic ina l p rod uc t n o l on ge r a uth ori se d 23 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS AMPOULE 1. NAME OF THE MEDICINAL PRODUCT Vantobra 170 mg nebuliser solution Tobramycin Inhalation use 2. NAME OF THE MARKETING AUTHORISATION HOLDER PARI Pharma GmbH 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 24 B. PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 25 Package leaflet: Information for the patient Vantobra 170 mg nebuliser solution Tobramycin Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Vantobra is and what it is used for 2. What you need to know before you use Vantobra 3. How to use Vantobra 4. Possible side effects 5. How to store Vantobra 6. Contents of the pack and other information 1. What Vantobra is and what it is used for What Vantobra is Vantobra contains an antibiotic medicine called tobramycin. It belongs to a class of antibiotic medicines called aminoglycosides. What Vantobra is used for Vantobra is used in patients with cystic fibrosis aged 6 years and older to treat lung infections caused by bacteria named Pseudomonas aeruginosa. Pseudomonas aeruginosa is a bacterium that frequently infects the lungs of cystic fibrosis patients at some time during their lives. If the infection is not properly treated, it continues to damage the lungs, causing further problems with breathing. How Vantobra works When you inhale Vantobra, the antibiotic can enter directly into your lungs to fight the bacteria causing the infection. It works by disrupting the production of proteins that the bacteria need to build their cell walls. This damages the bacteria and eventually kills them. 2. What you need to know before you use Vantobra Do not use Vantobra: • if you are allergic (hypersensitive) to tobramycin, to any type of aminoglycoside antibiotics, or to any of the other ingredients of Vantobra (listed in section 6). If this applies to you, tell your doctor before using Vantobra. Warnings and precautions Talk to your doctor if you have ever had any of the following conditions: • hearing problems (including noises in your ears and dizziness); • kidney problems; Me dic ina l p rod uc t n o l on ge r a uth ori se d 26 • chest tightness; • blood in your sputum (the substance you cough up); • muscle weakness that lasts or becomes worse over time, a symptom mostly related to conditions such as myasthenia (muscle weakness) or Parkinson’s disease. If any of these apply to you, tell your doctor before using Vantobra. If you have problems with your hearing or kidney function, your doctor may take blood samples to monitor the amount of Vantobra in your system. Inhaling medicines can cause chest tightness due to narrowing of the airways, and this can happen with Vantobra. Your doctor may ask you to use other appropriate medicines to widen the airways before using Vantobra. Strains of Pseudomonas can become resistant to treatment with an antibiotic over time. This means that Vantobra may not work as well as it should over time. Talk to your doctor if you are concerned about this. If you are also taking tobramycin or another aminoglycoside antibiotic by injection, it may increase the risk of side effects and your doctor will monitor for these as appropriate. Children The medicine is not intended for use in children under 6 years of age. Other medicines and Vantobra Tell your doctor or a pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. You should not take the following medicines while you are using Vantobra: • furosemide, a diuretic (“water tablet”); • other medicines with diuretic potential such as urea or mannitol; • other medicines which may harm your kidneys or hearing: o amphotericin B, cefalotin, polymyxins (used to treat microbial infections), ciclosporin, tacrolimus (used to reduce the activity of immune system). These medicines may harm the kidneys; o platinum compounds such as carboplatin and cisplatin (used to treat some forms of cancer). These medicines may harm the kidneys or hearing. The following medicines can increase the risks of harmful effects occurring if they are given to you while you also take tobramycin or another aminoglycoside antibiotic given by injection: • anticholinesterases such as neostigmine and pyridostigmine (used to treat muscle weakness), or botulinum toxin. These medicines may cause muscle weakness to appear or become worse. If you are taking one or more of the above medicines, talk to your doctor before you use Vantobra. You should not mix or dilute Vantobra with any other medicine in your Tolero nebuliser handset which is provided together with Vantobra. If you are taking several different treatments for cystic fibrosis, you should take them in the following order: 1. Bronchodilator therapy, such as salbutamol 2. Chest physiotherapy 3. Other inhaled medicines 4. Vantobra Please check this order with your doctor as well. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine. Me dic ina l p rod uc t n o l on ge r a uth ori se d 27 It is not known whether inhaling this medicine while you are pregnant causes side effects. When they are given by injection, tobramycin and other aminoglycoside antibiotics can cause harm to an unborn child, such as deafness and kidney problems. If you are breast feeding, you should talk to your doctor before using this medicine. Driving and using machines Vantobra is not expected to affect your ability to drive or use machines. 3. How to use Vantobra Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. The recommended dose is two ampoules each day (one in the morning and one in the evening) for 28 days. • The dose is the same for all persons aged 6 years and older. • Inhale by mouth the full content of one ampoule in the morning, and one ampoule in the evening using the Tolero nebuliser handset. • It is best to have an interval as close as possible to 12 hours between doses, but this interval must be at least 6 hours. • After you have used your medicine for 28 days, you then have a 28-day break, during which you do not inhale any Vantobra. You then start another course after the break (as illustrated). • It is important that you keep using the medicine twice each day during your 28 days on treatment, and that you keep to the 28-day on / 28-day off cycle. ON Vantobra OFF Vantobra Use Vantobra twice a day for 28 days Do not use any Vantobra for the next 28 days Repeat cycle Continue using Vantobra on this cyclical basis for as long as your doctor tells you. If you have questions about how long to use Vantobra, talk to your doctor or pharmacist. Preparing Vantobra for inhalation • Use Vantobra only with the Tolero nebuliser handset shown in the picture below to make sure you inhale the correct dose. Do not use the Tolero nebuliser handset for any other medicine. • Read the Instructions for Use provided with the handset device before use. • Make sure you have an eFlowrapid or eBase controller to connect the Tolero nebuliser handset. The respective controller can be prescribed by your physician or purchased separately. Me dic ina l p rod uc t n o l on ge r a uth ori se d 28 • Wash your hands thoroughly with soap and water. • Remove one ampoule of Vantobra from the aluminium foil pouch just before inhalation. • Keep the rest of the medicine refrigerated in the original carton. • Lay out all the pieces of your Tolero nebuliser handset on a clean, dry paper or cloth towel. Make sure the nebuliser handset is on a flat, stable surface. • Assemble the Tolero nebuliser handset as illustrated in the Instructions for Use of the handset device. • Hold the ampoule upright and tap lightly before twisting off the head part to avoid spilling. Empty the contents of one ampoule into the medication reservoir of the nebuliser handset. • Begin your treatment sitting in an upright position, in a well ventilated room. Hold the nebuliser handset horizontally and breath normally through your mouth. Avoid breathing through your nose. Continue to inhale and exhale comfortably until the treatment is finished. When all of the medicine has been delivered, you will hear the “treatment complete” tone. • If you need to interrupt your treatment for any reason, press and hold the On/Off button for one full second. To re-start the treatment, press and hold the On/Off button again for one full second to resume treatment. • The Tolero nebuliser handset must be cleaned and disinfected as described in the instructions for use of the device. • Use a new Tolero nebuliser handset for each treatment cycle (28 days on-treatment) as provided with the medicine. Do not use an alternative untested nebuliser system because it may alter the amount of medicine reaching the lungs. This in turn may alter how well the medicine works and its safety. If you use more Vantobra than you should If you inhale too much Vantobra you may get a very hoarse voice. Tell your doctor as soon as possible. If Vantobra is swallowed, it is unlikely to cause severe problems as tobramycin is poorly absorbed from the stomach, but you should still tell your doctor as soon as possible. If you forget to use Vantobra If you forget to use Vantobra and there are at least 6 hours to your next dose, use your dose as soon as you can. Otherwise, wait for your next dose. Do not use a double dose to make up for a forgotten dose. If you stop using Vantobra Do not stop using Vantobra unless your doctor tells you to do so, as your lung infection may not be controlled sufficiently and may become worse. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some side effects can be serious • chest tightness with difficulty in breathing (rare, affecting up to 1 in 1,000 people) • allergic reactions including hives and itching (very rare, affecting up to 1 in 10,000 people). If you experience any of these, stop using Vantobra and tell your doctor straight away. People with cystic fibrosis have many symptoms of the disease. These may still occur while using Vantobra, but should not be as frequent or worse than before. If your underlying lung disease seems to become worse while you are using Vantobra, tell your doctor straight away. Me dic ina l p rod uc t n o l on ge r a uth ori se d 29 Other side effects may include: Uncommon (may affect up to 1 in 100 people) • shortness of breath • voice alteration (hoarseness) • increased cough • sore throat Rare (may affect up to 1 in 1,000 people) • laryngitis (inflammation of the voice box that can cause voice alteration, sore throat and difficulty swallowing) • Loss of voice • headache, weakness • nosebleed, runny nose • ringing in the ears (normally transient), hearing loss, dizziness • coughing up blood, producing more sputum than normally, chest discomfort, asthma, fever • taste disturbances, feeling sick (nausea), mouth ulcers, being sick (vomiting), loss of appetite • rash • chest pain or general pain • worsening of lung function test results Very rare (may affect up to 1 in 10,000 people) • fungal infections of the mouth or throat, such as thrush • swelling of lymph glands • sleepiness • ear pain, ear problems • hyperventilating, low oxygen levels in your blood, sinusitis • diarrhoea, pain in and around the stomach • red pustules, papules on the skin • nettle rush, itching • back pain • generally feeling unwell Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Vantobra Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the ampoule or the pouch or carton after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C - 8°C). If you don’t have a refrigerator available (such as when you are transporting your medicine) you can store the carton with the medicine (pouches opened or unopened) below 25°C for up to 4 weeks. If the product has been stored at room temperature for longer than 4 weeks, it has to be disposed according to local requirements. Do not use this medicine if you notice that it has become cloudy, or if there are particles in the solution. Never store an opened ampoule. Once opened an ampoule should be used immediately, and any remaining product should be discarded. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 30 Do not throw away any medicines via household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Vantobra contains - The active substance is tobramycin. One ampoule contains 170 mg of tobramycin as a single dose. - The other ingredient(s) (excipient(s)) are: sodium chloride, calcium chloride, magnesium sulphate, water for injections, sulphuric acid and sodium hydroxide for pH adjustment. What Vantobra looks like and contents of the pack Vantobra nebuliser solution is provided in a ready-to-use ampoule. Vantobra is a clear to slightly yellow coloured solution which can vary to a darker yellow. This does not change how Vantobra works provided that the storage instructions have been followed. Ampoules are packed in pouches, one pouch contains 8 ampoules which correspond with 4 days of treatment. Vantobra is available together with a Tolero nebuliser handset. It is supplied in a carton that contains two inner cartons, one with the medicine (56 ampoules with nebuliser solution in 7 pouches), and one with the nebuliser handset. A package is sufficient for one treatment cycle of 28 days. Marketing Authorisation Holder and Manufacturer PARI Pharma GmbH Moosstrasse 3 D-82319 Starnberg Germany Tel.: +49 (0) 89 – 74 28 46 - 10 Fax: +49 (0) 89 – 74 28 46 30 E-Mail: info@paripharma.com This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what vantobra is and what it is used for', 'Section_Content': 'what vantobra is vantobra contains an antibiotic medicine called tobramycin. it belongs to a class of antibiotic medicines called aminoglycosides. what vantobra is used for vantobra is used in patients with cystic fibrosis aged 6 years and older to treat lung infections caused by bacteria named pseudomonas aeruginosa. pseudomonas aeruginosa is a bacterium that frequently infects the lungs of cystic fibrosis patients at some time during their lives. if the infection is not properly treated, it continues to damage the lungs, causing further problems with breathing. how vantobra works when you inhale vantobra, the antibiotic can enter directly into your lungs to fight the bacteria causing the infection. it works by disrupting the production of proteins that the bacteria need to build their cell walls. this damages the bacteria and eventually kills them.', 'Entity_Recognition': [{'Text': 'vantobra', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'vantobra', 'Type': 'TREATMENT', 'BeginOffset': 17, 'EndOffset': 25}, {'Text': 'an antibiotic medicine', 'Type': 'TREATMENT', 'BeginOffset': 35, 'EndOffset': 57}, {'Id': 4, 'BeginOffset': 65, 'EndOffset': 75, 'Score': 0.9596350193023682, 'Text': 'tobramycin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 102, 'EndOffset': 122, 'Score': 0.7470440864562988, 'Text': 'antibiotic medicines', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'aminoglycosides', 'Type': 'TREATMENT', 'BeginOffset': 130, 'EndOffset': 145}, {'Text': 'what vantobra', 'Type': 'TREATMENT', 'BeginOffset': 147, 'EndOffset': 160}, {'Text': 'vantobra', 'Type': 'TREATMENT', 'BeginOffset': 173, 'EndOffset': 181}, {'Id': 5, 'BeginOffset': 207, 'EndOffset': 222, 'Score': 0.6835870742797852, 'Text': 'cystic fibrosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9518685340881348}]}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 228, 'EndOffset': 229}, {'Id': 6, 'BeginOffset': 255, 'EndOffset': 270, 'Score': 0.8361319303512573, 'Text': 'lung infections', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9726239442825317}]}, {'Text': 'bacteria named pseudomonas aeruginosa', 'Type': 'PROBLEM', 'BeginOffset': 281, 'EndOffset': 318}, {'Id': 9, 'BeginOffset': 320, 'EndOffset': 342, 'Score': 0.9105793237686157, 'Text': 'pseudomonas aeruginosa', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8993708491325378}]}, {'Text': 'a bacterium', 'Type': 'PROBLEM', 'BeginOffset': 346, 'EndOffset': 357}, {'Id': 1, 'BeginOffset': 386, 'EndOffset': 391, 'Score': 0.9407488107681274, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 10, 'BeginOffset': 395, 'EndOffset': 410, 'Score': 0.8030456304550171, 'Text': 'cystic fibrosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9619303345680237}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9407488107681274, 'RelationshipScore': 0.9816402792930603, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 386, 'EndOffset': 391, 'Text': 'lungs', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the infection', 'Type': 'PROBLEM', 'BeginOffset': 456, 'EndOffset': 469}, {'Id': 12, 'BeginOffset': 511, 'EndOffset': 517, 'Score': 0.39825427532196045, 'Text': 'damage', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9921621680259705, 'RelationshipScore': 0.9711672067642212, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 2, 'BeginOffset': 522, 'EndOffset': 527, 'Text': 'lungs', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 2, 'BeginOffset': 522, 'EndOffset': 527, 'Score': 0.9921621680259705, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'further problems with breathing', 'Type': 'PROBLEM', 'BeginOffset': 537, 'EndOffset': 568}, {'Text': 'vantobra', 'Type': 'TREATMENT', 'BeginOffset': 605, 'EndOffset': 613}, {'Text': 'the antibiotic', 'Type': 'TREATMENT', 'BeginOffset': 615, 'EndOffset': 629}, {'Id': 3, 'BeginOffset': 659, 'EndOffset': 664, 'Score': 0.9503494501113892, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the bacteria', 'Type': 'PROBLEM', 'BeginOffset': 674, 'EndOffset': 686}, {'Text': 'the infection', 'Type': 'PROBLEM', 'BeginOffset': 695, 'EndOffset': 708}, {'Text': 'the bacteria', 'Type': 'PROBLEM', 'BeginOffset': 765, 'EndOffset': 777}, {'Text': 'this damages the bacteria', 'Type': 'PROBLEM', 'BeginOffset': 810, 'EndOffset': 835}]}

{'Title': '2. what you need to know before you use vantobra', 'Section_Content': 'do not use vantobra: if you are allergic (hypersensitive) to tobramycin, to any type of aminoglycoside antibiotics, or to any of the other ingredients of vantobra (listed in section 6). if this applies to you, tell your doctor before using vantobra. warnings and precautions talk to your doctor if you have ever had any of the following conditions: hearing problems (including noises in your ears and dizziness); kidney problems; 26 chest tightness; blood in your sputum (the substance you cough up); muscle weakness that lasts or becomes worse over time, a symptom mostly related to conditions such as myasthenia (muscle weakness) or parkinson\'s disease. if any of these apply to you, tell your doctor before using vantobra. if you have problems with your hearing or kidney function, your doctor may take blood samples to monitor the amount of vantobra in your system. inhaling medicines can cause chest tightness due to narrowing of the airways, and this can happen with vantobra. your doctor may ask you to use other appropriate medicines to widen the airways before using vantobra. strains of pseudomonas can become resistant to treatment with an antibiotic over time. this means that vantobra may not work as well as it should over time. talk to your doctor if you are concerned about this. if you are also taking tobramycin or another aminoglycoside antibiotic by injection, it may increase the risk of side effects and your doctor will monitor for these as appropriate. children the medicine is not intended for use in children under 6 years of age. other medicines and vantobra tell your doctor or a pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. you should not take the following medicines while you are using vantobra: furosemide, a diuretic ("water tablet"); other medicines with diuretic potential such as urea or mannitol; other medicines which may harm your kidneys or hearing: o amphotericin b, cefalotin, polymyxins (used to treat microbial infections), ciclosporin, tacrolimus (used to reduce the activity of immune system). these medicines may harm the kidneys; o platinum compounds such as carboplatin and cisplatin (used to treat some forms of cancer). these medicines may harm the kidneys or hearing. the following medicines can increase the risks of harmful effects occurring if they are given to you while you also take tobramycin or another aminoglycoside antibiotic given by injection: anticholinesterases such as neostigmine and pyridostigmine (used to treat muscle weakness), or botulinum toxin. these medicines may cause muscle weakness to appear or become worse. if you are taking one or more of the above medicines, talk to your doctor before you use vantobra. you should not mix or dilute vantobra with any other medicine in your tolero nebuliser handset which is provided together with vantobra. if you are taking several different treatments for cystic fibrosis, you should take them in the following order: 1. bronchodilator therapy, such as salbutamol 2. chest physiotherapy 3. other inhaled medicines 4. vantobra please check this order with your doctor as well. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine. it is not known whether inhaling this medicine while you are pregnant causes side effects. when they are given by injection, tobramycin and other aminoglycoside antibiotics can cause harm to an unborn child, such as deafness and kidney problems. if you are breast feeding, you should talk to your doctor before using this medicine. driving and using machines vantobra is not expected to affect your ability to drive or use machines.', 'Entity_Recognition': [{'Text': 'vantobra', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 8, 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{'Title': '3. how to use vantobra', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. the recommended dose is two ampoules each day (one in the morning and one in the evening) for 28 days. the dose is the same for all persons aged 6 years and older. inhale by mouth the full content of one ampoule in the morning, and one ampoule in the evening using the tolero nebuliser handset. it is best to have an interval as close as possible to 12 hours between doses, but this interval must be at least 6 hours. after you have used your medicine for 28 days, you then have a 28-day break, during which you do not inhale any vantobra. you then start another course after the break (as illustrated). it is important that you keep using the medicine twice each day during your 28 days on treatment, and that you keep to the 28-day on / 28-day off cycle. on vantobra off vantobra use vantobra twice a day for 28 days do not use any vantobra for the next 28 days repeat cycle continue using vantobra on this cyclical basis for as long as your doctor tells you. if you have questions about how long to use vantobra, talk to your doctor or pharmacist. preparing vantobra for inhalation use vantobra only with the tolero nebuliser handset shown in the picture below to make sure you inhale the correct dose. do not use the tolero nebuliser handset for any other medicine. read the instructions for use provided with the handset device before use. make sure you have an eflowrapid or ebase controller to connect the tolero nebuliser handset. the respective controller can be prescribed by your physician or purchased separately. wash your hands thoroughly with soap and water. remove one ampoule of vantobra from the aluminium foil pouch just before inhalation. keep the rest of the medicine refrigerated in the original carton. lay out all the pieces of your tolero nebuliser handset on a clean, dry paper or cloth towel. make sure the nebuliser handset is on a flat, stable surface. assemble the tolero nebuliser handset as illustrated in the instructions for use of the handset device. hold the ampoule upright and tap lightly before twisting off the head part to avoid spilling. empty the contents of one ampoule into the medication reservoir of the nebuliser handset. begin your treatment sitting in an upright position, in a well ventilated room. hold the nebuliser handset horizontally and breath normally through your mouth. avoid breathing through your nose. continue to inhale and exhale comfortably until the treatment is finished. when all of the medicine has been delivered, you will hear the "treatment complete" tone. if you need to interrupt your treatment for any reason, press and hold the on/off button for one full second. to re-start the treatment, press and hold the on/off button again for one full second to resume treatment. the tolero nebuliser handset must be cleaned and disinfected as described in the instructions for use of the device. use a new tolero nebuliser handset for each treatment cycle (28 days on-treatment) as provided with the medicine. do not use an alternative untested nebuliser system because it may alter the amount of medicine reaching the lungs. this in turn may alter how well the medicine works and its safety. if you use more vantobra than you should if you inhale too much vantobra you may get a very hoarse voice. tell your doctor as soon as possible. if vantobra is swallowed, it is unlikely to cause severe problems as tobramycin is poorly absorbed from the stomach, but you should still tell your doctor as soon as possible. if you forget to use vantobra if you forget to use vantobra and there are at least 6 hours to your next dose, use your dose as soon as you can. otherwise, wait for your next dose. do not use a double dose to make up for a forgotten dose. if you stop using vantobra do not stop using vantobra unless your doctor tells you to do so, as your lung 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects can be serious chest tightness with difficulty in breathing (rare, affecting up to 1 in 1,000 people) allergic reactions including hives and itching (very rare, affecting up to 1 in 10,000 people). if you experience any of these, stop using vantobra and tell your doctor straight away. people with cystic fibrosis have many symptoms of the disease. these may still occur while using vantobra, but should not be as frequent or worse than before. if your underlying lung disease seems to become worse while you are using vantobra, tell your doctor straight away. other side effects may include: uncommon (may affect up to 1 in 100 people) shortness of breath voice alteration (hoarseness) increased cough sore throat rare (may affect up to 1 in 1,000 people) laryngitis (inflammation of the voice box that can cause voice alteration, sore throat and difficulty swallowing) loss of voice headache, weakness nosebleed, runny nose ringing in the ears (normally transient), hearing loss, dizziness coughing up blood, producing more sputum than normally, chest discomfort, asthma, fever taste disturbances, feeling sick (nausea), mouth ulcers, being sick (vomiting), loss of appetite rash chest pain or general pain worsening of lung function test results very rare (may affect up to 1 in 10,000 people) fungal infections of the mouth or throat, such as thrush swelling of lymph glands sleepiness ear pain, ear problems hyperventilating, low oxygen levels in your blood, sinusitis diarrhoea, pain in and around the stomach red pustules, papules on the skin nettle rush, itching back pain generally feeling unwell reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting 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0.5204566121101379, 'Text': 'mouth ulcers', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9748295545578003}]}, {'Text': 'being sick (vomiting', 'Type': 'PROBLEM', 'BeginOffset': 1247, 'EndOffset': 1267}, {'Id': 64, 'BeginOffset': 1270, 'EndOffset': 1286, 'Score': 0.9801182746887207, 'Text': 'loss of appetite', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9703860282897949}]}, {'Text': 'rash chest pain', 'Type': 'PROBLEM', 'BeginOffset': 1287, 'EndOffset': 1302}, {'Id': 67, 'BeginOffset': 1306, 'EndOffset': 1318, 'Score': 0.5868603587150574, 'Text': 'general pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9647315144538879}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9885404706001282, 'RelationshipScore': 0.4217788577079773, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 9, 'BeginOffset': 1332, 'EndOffset': 1336, 'Text': 'lung', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 89, 'BeginOffset': 1332, 'EndOffset': 1350, 'Score': 0.5148541927337646, 'Text': 'lung function test', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1387, 'EndOffset': 1388}, {'Text': '10,000', 'Type': 'NUMBER', 'BeginOffset': 1392, 'EndOffset': 1398}, {'Text': 'fungal infections of the mouth or throat', 'Type': 'PROBLEM', 'BeginOffset': 1407, 'EndOffset': 1447}, {'Text': 'thrush swelling of lymph glands', 'Type': 'PROBLEM', 'BeginOffset': 1457, 'EndOffset': 1488}, {'Text': 'sleepiness ear pain', 'Type': 'PROBLEM', 'BeginOffset': 1489, 'EndOffset': 1508}, {'Id': 73, 'BeginOffset': 1510, 'EndOffset': 1539, 'Score': 0.8772513270378113, 'Text': 'ear problems hyperventilating', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9531996846199036}]}, {'Id': 74, 'BeginOffset': 1541, 'EndOffset': 1572, 'Score': 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{'Title': '5. how to store vantobra', 'Section_Content': "keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the ampoule or the pouch or carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 - 8). if you don't have a refrigerator available (such as when you are transporting your medicine) you can store the carton with the medicine (pouches opened or unopened) below 25 for up to 4 weeks. if the product has been stored at room temperature for longer than 4 weeks, it has to be disposed according to local requirements. do not use this medicine if you notice that it has become cloudy, or if there are particles in the solution. never store an opened ampoule. once opened an ampoule should be used immediately, and any remaining product should be discarded. do not throw away any medicines via household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.", 'Entity_Recognition': [{'Text': 'vantobra', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 381, 'EndOffset': 393}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 429, 'EndOffset': 431}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 442, 'EndOffset': 443}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 518, 'EndOffset': 519}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 593, 'EndOffset': 606}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 640, 'EndOffset': 646}, {'Text': 'an ampoule', 'Type': 'TREATMENT', 'BeginOffset': 734, 'EndOffset': 744}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 940, 'EndOffset': 954}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what vantobra contains - the active substance is tobramycin. one ampoule contains 170 mg of tobramycin as a single dose. - the other ingredient(s) (excipient(s)) are: sodium chloride, calcium chloride, magnesium sulphate, water for injections, sulphuric acid and sodium hydroxide for ph adjustment. what vantobra looks like and contents of the pack vantobra nebuliser solution is provided in a ready-to-use ampoule. vantobra is a clear to slightly yellow coloured solution which can vary to a darker yellow. this does not change how vantobra works provided that the storage instructions have been followed. ampoules are packed in pouches, one pouch contains 8 ampoules which correspond with 4 days of treatment. vantobra is available together with a tolero nebuliser handset. it is supplied in a carton that contains two inner cartons, one with the medicine (56 ampoules with nebuliser solution in 7 pouches), and one with the nebuliser handset. a package is sufficient for one treatment cycle of 28 days.', 'Entity_Recognition': [{'Text': 'vantobra', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 49, 'EndOffset': 59, 'Score': 0.9951481223106384, 'Text': 'tobramycin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.849319338798523, 'RelationshipScore': 0.9999924898147583, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 61, 'EndOffset': 72, 'Text': 'one ampoule', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '170', 'Type': 'NUMBER', 'BeginOffset': 82, 'EndOffset': 85}, {'Id': 3, 'BeginOffset': 92, 'EndOffset': 102, 'Score': 0.9950653910636902, 'Text': 'tobramycin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.971961498260498, 'RelationshipScore': 0.9985989928245544, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 82, 'EndOffset': 88, 'Text': '170 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 4, 'BeginOffset': 167, 'EndOffset': 182, 'Score': 0.999663233757019, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.7787878513336182, 'RelationshipScore': 0.9921724796295166, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 7, 'BeginOffset': 232, 'EndOffset': 242, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 184, 'EndOffset': 200, 'Score': 0.9995430707931519, 'Text': 'calcium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 202, 'EndOffset': 220, 'Score': 0.993919849395752, 'Text': 'magnesium sulphate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.7787878513336182, 'RelationshipScore': 0.6801309585571289, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 7, 'BeginOffset': 232, 'EndOffset': 242, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'water', 'Type': 'TREATMENT', 'BeginOffset': 222, 'EndOffset': 227}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 232, 'EndOffset': 242}, {'Id': 8, 'BeginOffset': 244, 'EndOffset': 258, 'Score': 0.9845208525657654, 'Text': 'sulphuric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.7787878513336182, 'RelationshipScore': 0.5714930891990662, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 7, 'BeginOffset': 232, 'EndOffset': 242, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 9, 'BeginOffset': 263, 'EndOffset': 279, 'Score': 0.9991497993469238, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ph adjustment', 'Type': 'TREATMENT', 'BeginOffset': 284, 'EndOffset': 297}, {'Text': 'the pack vantobra nebuliser solution', 'Type': 'TREATMENT', 'BeginOffset': 340, 'EndOffset': 376}, {'Text': 'ampoule', 'Type': 'TREATMENT', 'BeginOffset': 407, 'EndOffset': 414}, {'Text': 'vantobra', 'Type': 'TREATMENT', 'BeginOffset': 416, 'EndOffset': 424}, {'Text': 'slightly yellow coloured solution', 'Type': 'PROBLEM', 'BeginOffset': 439, 'EndOffset': 472}, {'Text': 'ampoules', 'Type': 'TREATMENT', 'BeginOffset': 607, 'EndOffset': 615}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 658, 'EndOffset': 659}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 691, 'EndOffset': 692}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 701, 'EndOffset': 710}, {'Id': 10, 'BeginOffset': 712, 'EndOffset': 720, 'Score': 0.1941479593515396, 'Text': 'vantobra', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a tolero nebuliser handset', 'Type': 'TREATMENT', 'BeginOffset': 748, 'EndOffset': 774}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 845, 'EndOffset': 857}, {'Id': 11, 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3F2DC70FD05CC06A9B2BB6AEA533A253

https://www.ema.europa.eu/documents/product-information/bosulif-epar-product-information_en.pdf

Bosulif

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Bosulif 100 mg film-coated tablets Bosulif 400 mg film-coated tablets Bosulif 500 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Bosulif 100 mg film-coated tablets Each film-coated tablet contains 100 mg bosutinib (as monohydrate). Bosulif 400 mg film-coated tablets Each film-coated tablet contains 400 mg bosutinib (as monohydrate). Bosulif 500 mg film-coated tablets Each film-coated tablet contains 500 mg bosutinib (as monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Bosulif 100 mg film-coated tablets Yellow oval (width: 5.6 mm; length: 10.7 mm) biconvex, film-coated tablet debossed with “Pfizer” on one side and “100” on the other side. Bosulif 400 mg film-coated tablets Orange oval (width: 8.8 mm; length: 16.9 mm) biconvex, film-coated tablet debossed with “Pfizer” on one side and “400” on the other side. Bosulif 500 mg film-coated tablets Red oval (width: 9.5 mm; length: 18.3 mm) biconvex, film-coated tablet debossed with “Pfizer” on one side and “500”on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Bosulif is indicated for the treatment of adult patients with: • newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML). • CP, accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one or more tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. 3 4.2 Posology and method of administration Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with CML. Posology Newly-diagnosed CP Ph+ CML The recommended dose is 400 mg bosutinib once daily. CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy The recommended dose is 500 mg bosutinib once daily. In clinical trials for both indications, treatment with bosutinib continued until disease progression or intolerance to therapy. Dose adjustments In the Phase 1/2 clinical study in patients with CML who were resistant or intolerant to prior therapy, dose escalations from 500 mg to 600 mg once daily with food were allowed in patients who failed to demonstrate complete haematological response (CHR) by Week 8 or complete cytogenetic response (CCyR) by Week 12 and did not have Grade 3 or higher adverse events possibly-related to the investigational product. Whereas, in the Phase 3 study in patients with newly-diagnosed CP CML treated with bosutinib 400 mg, dose escalations by 100 mg increments to a maximum of 600 mg once daily with food were permitted if the patient failed to demonstrate breakpoint cluster region-Abelson (BCR-ABL) transcripts ≤ 10% at Month 3, did not have a Grade 3 or 4 adverse reaction at the time of escalation, and all Grade 2 non-haematological toxicities were resolved to at least Grade 1. In the Phase 1/2 clinical study in patients with CML who were resistant or intolerant to prior therapy who started treatment at ≤ 500 mg, 93 (93/558; 16.7%) patients had dose escalations to 600 mg daily. In the Phase 3 study in patients with newly-diagnosed CP CML who started bosutinib treatment at 400 mg, a total of 46 patients (17.2%) received dose escalations to 500 mg. In addition, 5.6% of patients in the bosutinib treatment group had further dose escalations to 600 mg. Doses greater than 600 mg/day have not been studied and, therefore, should not be given. Dose adjustments for adverse reactions Non-haematological adverse reactions If clinically significant moderate or severe non-haematological toxicity develops, bosutinib should be interrupted, and may be resumed at a dose reduced by 100 mg taken once daily after the toxicity has resolved. If clinically appropriate, re-escalation to the dose prior to the dose reduction taken once daily should be considered (see section 4.4). Doses less than 300 mg/day have been used in patients; however, efficacy has not been established. Elevated liver transaminases: If elevations in liver transaminases > 5 × institutional upper limit of normal (ULN) occur, bosutinib should be interrupted until recovery to ≤ 2.5 × ULN and may be resumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation of bosutinib should be considered. If transaminase elevations ≥ 3 × ULN occur concurrently with 4 bilirubin elevations > 2 × ULN and alkaline phosphatase < 2 × ULN, bosutinib should be discontinued (see section 4.4). Diarrhoea: For NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade 3-4 diarrhoea, bosutinib should be interrupted and may be resumed at 400 mg once daily upon recovery to grade ≤ 1 (see section 4.4). Haematological adverse reactions Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia as described in Table 1: Table 1 – Dose adjustments for neutropenia and thrombocytopenia ANCa < 1.0 × 109/L and/or Platelets < 50 × 109/L Hold bosutinib until ANC  1.0 × 109/L and platelets  50 × 109/L. Resume treatment with bosutinib at the same dose if recovery occurs within 2 weeks. If blood counts remain low for > 2 weeks, upon recovery reduce dose by 100 mg and resume treatment. If cytopoenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment. Doses less than 300 mg/day have been used; however, efficacy has not been established. a ANC = absolute neutrophil count Special populations Elderly patients (≥ 65 years) No specific dose recommendation is necessary in the elderly. Since there is limited information in the elderly, caution should be exercised in these patients. Renal impairment Patients with serum creatinine > 1.5×ULN were excluded from CML studies. Increasing exposure (area under curve [AUC]) in patients with moderate and severe renal impairment during studies was observed. Newly-diagnosed CP Ph+ CML In patients with moderate renal impairment (creatinine clearance [CLCr] 30 to 50 mL/min, estimated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg daily with food (see sections 4.4 and 5.2). In patients with severe renal impairment (CLCr < 30 mL/min, estimated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 200 mg daily with food (see sections 4.4 and 5.2). Dose escalation to 400 mg once daily with food for patients with moderate renal impairment or to 300 mg once daily for patients with severe renal impairment may be considered if they do not experience severe or persistent moderate adverse reactions and if they do not achieve an adequate haematological, cytogenetic, or molecular response. 5 CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy In patients with moderate renal impairment (CLCr 30 to 50 mL/min, calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 400 mg daily (see sections 4.4 and 5.2). In patients with severe renal impairment (CLCr < 30 mL/min, calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg daily (see sections 4.4 and 5.2). Dose escalation to 500 mg once daily for patients with moderate renal impairment or to 400 mg once daily in patients with severe renal impairment may be considered in those who did not experience severe or persistent moderate adverse reactions, and if they do not achieve an adequate haematological, cytogenetic, or molecular response. Cardiac disorders In clinical studies, patients with uncontrolled or significant cardiac disease (e.g., recent myocardial infarction, congestive heart failure or unstable angina) were excluded. Caution should be exercised in patients with relevant cardiac disorders (see section 4.4). Recent or ongoing clinically significant gastrointestinal disorder In clinical studies, patients with recent or ongoing clinically significant gastrointestinal disorder (e.g., severe vomiting and/or diarrhoea) were excluded. Caution should be exercised in patients with recent or ongoing clinically significant gastrointestinal disorder (see section 4.4). Paediatric population The safety and efficacy of bosutinib in children and adolescents less than 18 years of age have not been established. No data are available. Method of administration Bosulif should be taken orally once daily with food (see section 5.2). If a dose is missed by more than 12 hours, the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hepatic impairment (see sections 5.1 and 5.2). 4.4 Special warnings and precautions for use Liver function abnormalities Treatment with bosutinib is associated with elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). Transaminase elevations generally occurred early in the course of treatment (of the patients who experienced transaminase elevations of any grade, > 80% experienced their first event within the first 3 months). Patients receiving bosutinib should have liver function tests prior to treatment initiation and monthly for the first 3 months of treatment, and as clinically indicated. Patients with transaminase elevations should be managed by withholding bosutinib temporarily (with consideration given to dose reduction after recovery to Grade 1 or baseline), and/or discontinuation of bosutinib. Elevations of transaminases, particularly in the setting of concomitant increases in bilirubin, may be an early indication of drug-induced liver injury and these patients should be managed appropriately (see sections 4.2 and 4.8). 6 Diarrhoea and vomiting Treatment with bosutinib is associated with diarrhoea and vomiting; therefore, patients with recent or ongoing clinically significant gastrointestinal disorder should use this medicinal product with caution and only after a careful benefit-risk assessment as respective patients were excluded from the clinical studies. Patients with diarrhoea and vomiting should be managed using standard-of-care treatment, including an antidiarrhoeal or antiemetic medicinal product and/or fluid replacement. In addition, diarrhoea and vomiting can also be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8). The antiemetic agent, domperidone, has the potential to increase QT interval (QTc) prolongation and to induce “torsade de pointes”- arrhythmias; therefore, co-administration with domperidone should be avoided. It should only be used, if other medicinal products are not efficacious. In these situations an individual benefit-risk assessment is mandatory and patients should be monitored for occurrence of QTc prolongation. Myelosuppression Treatment with bosutinib is associated with myelosuppression, defined as anaemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month and then monthly thereafter, or as clinically indicated. Myelosuppression should/can be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8). Fluid retention Treatment with bosutinib may be associated with fluid retention including pericardial effusion, pleural effusion, pulmonary oedema and/or peripheral oedema. Patients should be monitored and managed using standard-of-care treatment. In addition, fluid retention can also be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8). Serum lipase Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, bosutinib should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis (see section 4.2). Infections Bosutinib may predispose patients to bacterial, fungal, viral, or protozoan infections. Proarrhythmic potential Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. Bosutinib should be administered with caution to patients who have a history of or predisposition for QTc prolongation, who have uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, or who are taking medicinal products that are known to prolong the QTc (e.g., anti-arrhythmic medicinal products and other substances that may prolong QTc [see section 4.5]). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. Monitoring for an effect on the QTc is advisable and a baseline electrocardiogram (ECG) is recommended prior to initiating therapy with bosutinib and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to bosutinib administration and should be monitored periodically during therapy. Renal impairment Treatment with bosutinib may result in a clinically significant decline in renal function in CML patients. A decline over time in estimated glomerular filtration rate (eGFR) has been observed in patients treated with bosutinib in clinical studies. In patients with newly-diagnosed CP CML treated 7 with 400 mg, the median decline from baseline in eGFR was 4.9 ml/min/1.73 m2 at 3 months, 9.2 ml/min/1.73 m2 at 6 months and 11.1 ml/min/1.73 m2 at 12 months. Treatment-naïve CML patients treated with 500 mg showed a median eGFR decline of 5.1 ml/min/1.73 m2 at 3 months, of 9.2 ml/min/1.73 m2 at 12 months and of up to 16.3 ml/min/1.73 m2 until 5 years follow-up for patients on treatment. Pretreated and advanced stage CML patients on 500 mg showed a median eGFR decline of 5.3 ml/min/1.73 m2 at 3 months, of 7.6 ml/min/1.73 m2 at 12 months and of up to 10.9 ml/min/1.73 m2 in up to 4 years on treatment. It is important that renal function is assessed prior to treatment initiation and closely monitored during therapy with bosutinib, with particular attention in those patients who have pre-existing renal compromise or in those patients exhibiting risk factors for renal dysfunction, including concomitant use of medicinal products with potential for nephrotoxicity, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs). In a renal impairment study, bosutinib exposures were increased in subjects with moderately and severely impaired renal function. Dose reduction is recommended for patients with moderate or severe renal impairment (see sections 4.2 and 5.2). Patients with serum creatinine > 1.5 × ULN were excluded from the CML studies. Based on a population pharmacokinetic analysis increasing exposure (AUC) in patients with moderate and severe renal impairment at initiation of treatment during studies was observed (see sections 4.2 and 5.2). Clinical data are very limited (n = 3) for CML patients with moderate renal impairment receiving an escalated dose of 600 mg bosutinib. Severe skin reactions Bosutinib can induce severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Bosutinib should be permanently discontinued in patients who experience a severe skin reaction during treatment. Tumour lysis syndrome Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of bosutinib (see section 4.8). Hepatitis B reactivation Reactivation of hepatitis B (HBV) in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with bosutinib. Experts in liver disease and in the treatment of HBV should be consulted before treatment is initiated in patients with positive HBV serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with bosutinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8). Cytochrome P-450 (CYP)3A inhibitors The concomitant use of bosutinib with strong or moderate CYP3A inhibitors should be avoided, as an increase in bosutinib plasma concentration will occur (see section 4.5). Selection of an alternate concomitant medicinal product with no or minimal CYP3A inhibition potential, if possible, is recommended. If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, an interruption of bosutinib therapy or a dose reduction in bosutinib should be considered. 8 CYP3A inducers The concomitant use of bosutinib with strong or moderate CYP3A inducers should be avoided as a decrease in bosutinib plasma concentration will occur (see section 4.5). Food effect Grapefruit products, including grapefruit juice and other foods that are known to inhibit CYP3A should be avoided (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction Effects of other medicinal products on bosutinib CYP3A inhibitors The concomitant use of bosutinib with strong CYP3A inhibitors (including, but not limited to itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, nefazodone, mibefradil, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, boceprevir, telaprevir, grapefruit products including grapefruit juice) or moderate CYP3A inhibitors (including, but not limited to fluconazole, ciprofloxacin, erythromycin, diltiazem, verapamil, amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir, aprepitant, crizotinib, imatinib) should be avoided, as an increase in bosutinib plasma concentration will occur. Caution should be exercised if mild CYP3A inhibitors are used concomitantly with bosutinib. Selection of an alternate concomitant medicinal product with no or minimal CYP3A enzyme inhibition potential, if possible, is recommended. If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, an interruption of bosutinib therapy or a dose reduction in bosutinib should be considered. In a study of 24 healthy subjects in whom 5 daily doses of 400 mg ketoconazole (a strong CYP3A inhibitor) were co-administered with a single dose of 100 mg bosutinib under fasting conditions, ketoconazole increased bosutinib Cmax by 5.2-fold, and bosutinib AUC in plasma by 8.6-fold, as compared with administration of bosutinib alone. In a study of 20 healthy subjects, in whom a single dose of 125 mg aprepitant (a moderate CYP3A inhibitor) was co-administered with a single dose of 500 mg bosutinib under fed conditions, aprepitant increased bosutinib Cmax by 1.5-fold, and bosutinib AUC in plasma by 2.0-fold, as compared with administration of bosutinib alone. CYP3A inducers The concomitant use of bosutinib with strong CYP3A inducers (including, but not limited to carbamazepine, phenytoin, rifampicin, St. John’s Wort), or moderate CYP3A inducers (including, but not limited to bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided, as a decrease in bosutinib plasma concentration will occur. Based on the large reduction in bosutinib exposure that occurred when bosutinib was co-administered with rifampicin, increasing the dose of bosutinib when co-administering with strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure. Caution is warranted if mild CYP3A inducers are used concomitantly with bosutinib. Following concomitant administration of a single dose bosutinib with 6 daily doses of 600 mg rifampicin, in 24 healthy subjects in fed state bosutinib exposure (Cmax and AUC in plasma) decreased to 14% and 6%, respectively, of the values when bosutinib 500 mg was administered alone. 9 Proton pump inhibitors (PPIs) Caution should be exercised when administering bosutinib concomitantly with PPIs. Short-acting antacids should be considered as an alternative to PPIs and administration times of bosutinib and antacids should be separated (i.e. take bosutinib in the morning and antacids in the evening) whenever possible. Bosutinib displays pH-dependent aqueous solubility in vitro. When a single oral dose of bosutinib (400 mg) was co-administered with multiple-oral doses of lansoprazole (60 mg) in a study of 24 healthy fasting subjects, bosutinib Cmax and AUC decreased to 54% and 74%, respectively, of the values seen when bosutinib (400 mg) was given alone. Effects of bosutinib on other medicinal products In a study of 27 healthy subjects, in whom a single dose of 500 mg bosutinib was co-administered with a single dose of 150 mg dabigatran etexilate mesylate (a P-glycoprotein [P-gp] substrate) under fed conditions, bosutinib did not increase Cmax or AUC of dabigatran in plasma, as compared with administration of dabigatran etexilate mesylate alone. The study results indicate that bosutinib does not exhibit clinically relevant P-gp inhibitory effects. An in vitro study indicates that drug-drug interactions are unlikely to occur at therapeutic doses as a result of induction by bosutinib on the metabolism of medicinal products that are substrates for CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. In vitro studies indicate that clinical drug-drug interactions are unlikely to occur at therapeutic doses as a result of inhibition by bosutinib on the metabolism of medicinal products that are substrates for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. In vitro studies indicate that bosutinib has a low potential to inhibit breast cancer resistance protein (BCRP, systemically), organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2 at clinically relevant concentrations, but may have the potential to inhibit BCRP in the gastrointestinal tract and OCT1. Anti-arrhythmic medicinal products and other substances that may prolong QT Bosutinib should be used with caution in patients who have or may develop prolongation of QT, including those patients taking anti-arrhythmic medicinal products such as amiodarone, disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QT prolongation such as chloroquine, halofantrine, clarithromycin, domperidone, haloperidol, methadone, and moxifloxacin (see section 4.4). 4.6 Fertility, pregnancy and lactation Women of childbearing potential/Contraception Women of childbearing potential should be advised to use effective contraception during treatment with bosutinib and for at least 1 month after the last dose and to avoid becoming pregnant while receiving bosutinib. In addition, the patient should be advised that vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. Pregnancy There are limited amount of data in pregnant women from the use of bosutinib. Studies in animals have shown reproductive toxicity (see section 5.3). Bosutinib is not recommended for use during pregnancy, or in women of childbearing potential not using contraception. If bosutinib is used during pregnancy, or the patient becomes pregnant while taking bosutinib, she should be apprised of the potential hazard to the foetus. Breast-feeding It is unknown whether bosutinib and its metabolites are excreted in human milk. A study of [14C] radiolabelled bosutinib in rats demonstrated excretion of bosutinib-derived radioactivity in breast milk (see section 5.3). A potential risk to the breast-feeding infant cannot be excluded. 10 Breast-feeding should be discontinued during treatment with bosutinib. Fertility Based on non-clinical findings, bosutinib has the potential to impair reproductive function and fertility in humans (see section 5.3). Men being treated with bosutinib are advised to seek advice on conservation of sperm prior to treatment because of the possibility of decreased fertility due to therapy with bosutinib. 4.7 Effects on ability to drive and use machines Bosutinib has no or negligible influence on the ability to drive and use machines. However, if a patient taking bosutinib experiences dizziness, fatigue, visual impairment or other undesirable effects with a potential impact on the ability to drive or use machines safely, the patient should refrain from these activities for as long as the undesirable effects persist. 4.8 Undesirable effects Summary of safety profile A total of 1,272 leukaemia patients received at least 1 dose of single-agent bosutinib. The median duration of therapy was 13.8 months (range: 0.03 to 123.3 months). These patients were either newly diagnosed, with CP CML or were resistant or intolerant to prior therapy with chronic, accelerated, or blast phase CML or Ph+ acute lymphoblastic leukaemia (ALL). Of these patients, 268 (400 mg starting dose) and 248 (500 mg starting dose) are from the 2 Phase 3 studies in previously untreated CML patients, 570 and 63 are from 2 Phase 1/2 studies in previously treated Ph+ leukaemias, and 123 patients from a Phase 4 study in previously treated CML. The median duration of therapy was 14.1 months (range: 0.3 to 24.7 months), 61.6 months (0.03 to 99.6 months), 11.1 months (range: 0.03 to 123.3 months), 30.2 months (range: 0.3 to 85.6 months), and 5.7 months (range: 0.07 to 17.8 months), respectively. The safety analyses included data from an ongoing extension study. At least 1 adverse reaction of any toxicity grade was reported for 1,240 (97.5%) patients. The most frequent adverse reactions reported for  20% of patients were diarrhoea (78.1%), nausea (40.8%), thrombocytopenia (34.9%), abdominal pain (34.0%), vomiting (33.0%), rash (31.5%), anaemia (25.6%), pyrexia (21.8%), fatigue (21.4%), and ALT increased (25.0%). At least 1 Grade 3 or Grade 4 adverse reaction was reported for 814 (63.9%) patients. The Grade 3 or Grade 4 adverse reactions reported for  5% of patients were thrombocytopenia (20.3%), anaemia (10.2%), neutropenia (10.5%), ALT increased (12.7%), diarrhoea (9.6%), rash (5.0%), lipase increased (8.2%), and AST increased (5.8%). Tabulated list of adverse reactions The following adverse reactions were reported in patients in bosutinib clinical studies (Table 2). These represent an evaluation of the adverse reaction data from 1,272 patients with either newly-diagnosed CP CML or with chronic, accelerated, or blast phase CML resistant or intolerant to prior therapy or Ph+ ALL who have received at least 1 dose of single-agent bosutinib. These adverse reactions are presented by system organ class and frequency. Frequency categories are defined as: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 11 Table 2 - Adverse reactions for bosutinib Infections and infestations Very common Respiratory tract infection (including Lower respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection), Nasopharyngitis Common Pneumonia (including Atypical pneumonia), Influenza, Bronchitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Tumour lysis syndrome** Blood and lymphatic system disorders Very common Thrombocytopenia (including Platelet count decreased), Neutropenia (including Neutrophil count decreased), Anaemia (including haemoglobin decreased) Common Leukopenia (including White blood cell count decreased) Uncommon Febrile neutropenia, Granulocytopenia Immune system disorders Uncommon Anaphylactic shock, Hypersensitivity Metabolism and nutrition disorders Very common Decreased appetite Common Dehydration, Hyperkalaemia, Hypophosphataemia Nervous system disorders Very common Headache Common Dizziness, Dysgeusia Ear and labyrinth disorders Common Tinnitus Cardiac disorders Common Pericardial effusion, Electrocardiogram QTc prolonged (including Long QTc syndrome) Uncommon Pericarditis Vascular disorders Common Hypertension (including Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertensive crisis) Respiratory, thoracic and mediastinal disorders Very common Dyspnoea, Cough Common Pleural effusion Uncommon Pulmonary hypertension, Respiratory failure, Acute pulmonary oedema Gastrointestinal disorders Very common Diarrhoea, Vomiting, Nausea, Abdominal pain (including Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain) Common Gastritis, Gastrointestinal haemorrhage (including Anal haemorrhage, Gastric haemorrhage, Intestinal haemorrhage, Lower gastrointestinal haemorrhage, Rectal haemorrhage) Uncommon Pancreatitis (including Pancreatitis acute) Hepatobiliary disorders Very common Alanine aminotransferase increased, Aspartate aminotransferase increased Common Hepatotoxicity (including Hepatitis, Hepatitis toxic, Liver disorder), Hepatic function abnormal (including Liver function test abnormal, Liver function test increased, Transaminases increased), Blood bilirubin increased (including Hyperbilirubinaemia), Gamma-glutamyltransferase increased Uncommon Liver injury (including Drug-induced liver injury) Skin and subcutaneous tissue disorders Very common Rash (including Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic) 12 Common Urticaria, Acne, Pruritus Uncommon Exfoliative rash, Drug eruption Rare Erythema multiforme Unknown Stevens-Johnson Syndrome**, Toxic epidermal necrolysis** Musculoskeletal and connective tissue disorders Very common Arthralgia, Back pain Common Myalgia Renal and urinary disorders Common Acute kidney injury, Renal failure, Renal impairment General disorders and administration site conditions Very common Pyrexia, Asthenia, Oedema (including Face oedema, Localised oedema, Oedema peripheral), Fatigue (including Malaise) Common Chest pain (including Chest discomfort), Pain Investigations Very common Lipase increased (including Hyperlipasaemia) Common Blood creatinine increased, Amylase increased, Blood creatine phosphokinase increased ** Adverse reaction identified post marketing. Description of selected adverse reactions The descriptions included below are based on the safety population of 1,272 patients who received at least 1 dose of bosutinib for either newly-diagnosed CP CML or were resistant or intolerant to prior therapy with CP, AP, or BP CML, or Ph+ ALL. Blood and lymphatic system disorders Of the 297 (23%) patients with reports of adverse reactions of anaemia, 3 patients discontinued bosutinib due to anaemia. In these patients, the maximum toxicity of Grade 1 or 2 was experienced in 174 (58%) patients, Grade 3 in 96 patients (32%), and Grade 4 in 27 (9%) patients. Among these patients, the median time to first event was 28 days (range: 1 to 2,633 days) and the median duration per event was 15 days (range: 1 to 1,529 days). Of the 197 (15%) patients with reports of adverse reactions of neutropenia, 15 patients discontinued bosutinib due to neutropenia. Maximum Grade 1 or 2 events were experienced by 63 (32%) patients. The maximum toxicity of Grade 3 neutropenia was experienced in 90 (46%) patients and of Grade 4 in 44 (22%) patients. The median time to first event was 59 days (range: 27 to 505 days), and the median duration per event was 15 days (range: 1 to 913 days). Of the 445 (35%) patients with reports of adverse reactions of thrombocytopenia, 41 (9%) patients discontinued treatment with bosutinib due to thrombocytopenia. Maximum Grade 1 or 2 events were experienced by 186 (42%) patients. The maximum toxicity of thrombocytopenia of Grade 3 was experienced in 161 (36%) patients and Grade 4 in 98 (22%) patients. Among patients with thrombocytopenia reactions, the median time to first event was 28 days (range: 1 to 1,688 days), and median duration per event was 15 days (range: 1 to 1,762 days). Hepatobiliary disorders Among patients with reports of adverse reactions of elevations in either ALT or AST (all grades), the median time of onset observed was 29 days with a range of onset 1 to 2,465 days for ALT and AST. The median duration of an event was 18 days (range: 1 to 775 days), and 15 days (range: 1 to 803 days) for ALT and AST, respectively. In the entire development program, concurrent elevation in transaminases ≥ 3 × ULN and bilirubin > 2 × ULN with alkaline phosphatase < 2 × ULN occurred without alternative causes in 1/1,611 (< 0.1%) subjects treated with bosutinib. This finding was in a study of bosutinib in combination with letrozole in a patient with metastatic breast cancer. 13 Hepatitis B reactivation Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4). Gastrointestinal disorders Of the 994 (78%) patients that experienced diarrhoea, 10 patients discontinued bosutinib due to this event. Concomitant medicinal products were given to treat diarrhoea in 662 (66%) patients. The maximum toxicity of diarrhoea was Grade 1 or 2 in 88% of patients, Grade 3 in 12% of patients; 1 patient (< 1%) experienced a Grade 4 event. Among patients with diarrhoea, the median time to first event was 2 days (range: 1 to 2,415 days) and the median duration of any grade of diarrhoea was 2 days (range: 1 to 2,511 days). Among the 994 patients with diarrhoea, 180 patients (18%) were managed with treatment interruption and of these 170 (94%) were rechallenged with bosutinib. Of those who were rechallenged, 167 (98%) did not have a subsequent event or did not discontinue bosutinib due to a subsequent event of diarrhoea. Cardiac disorders Four patients (0.3%) experienced QTcF interval prolongation (greater than 500 ms). Nine (0.8%) patients experienced QTcF increase from baseline exceeding 60 ms. Patients with uncontrolled or significant cardiovascular disease including QTc prolongation, at baseline, were not included in clinical studies (see sections 5.1 and 5.3). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience with bosutinib overdose in clinical studies was limited to isolated cases. Patients who take an overdose of bosutinib should be observed and given appropriate supportive treatment. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE14. Mechanism of action Bosutinib belongs to a pharmacological class of medicinal products known as kinase inhibitors. Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML. Modeling studies indicate that bosutinib binds the kinase domain of BCR-ABL. Bosutinib is also an inhibitor of Src family kinases including Src, Lyn and Hck. Bosutinib minimally inhibits platelet-derived growth factor (PDGF) receptor and c-Kit. In in vitro studies, bosutinib inhibits proliferation and survival of established CML cell lines, Ph+ ALL cell lines, and patient-derived primary primitive CML cells. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL expressed in murine myeloid cell lines. Bosutinib treatment reduced the size of CML tumours growing in nude mice and inhibited growth of murine myeloid tumours expressing imatinib-resistant forms of BCR-ABL. Bosutinib also inhibits receptor tyrosine 14 kinases c-Fms, EphA and B receptors, Trk family kinases, Axl family kinases, Tec family kinases, some members of the ErbB family, the non-receptor tyrosine kinase Csk, serine/threonine kinases of the Ste20 family, and 2 calmodulin-dependent protein kinases. Pharmacodynamic effects The effect of bosutinib 500 mg administration on corrected QTc was evaluated in a randomised, single-dose, double-blind (with respect to bosutinib), crossover, placebo- and open-label moxifloxacin-controlled study in healthy subjects. The data from this study indicate that bosutinib does not prolong the QTc in healthy subjects at the dose of 500 mg daily with food, and under conditions that give rise to supratherapeutic plasma concentrations. Following administration of a single oral dose of bosutinib 500 mg (therapeutic dose) and bosutinib 500 mg with ketoconazole 400 mg (to achieve supratherapeutic concentrations of bosutinib) in healthy subjects, the upper bound of the 1-sided 95% confidence interval (CI) around the mean change in QTc was less than 10 ms at all post-dose time points, and no adverse events suggestive of QTc prolongation were observed. In a study in liver impaired subjects, an increasing frequency of QTc prolongation > 450 ms with declining hepatic function was observed. In the Phase 1/2 clinical study in patients with previously treated Ph+ leukaemias, QTcF interval changes > 60 ms from baseline were observed in 6 (1.1%) of 562 patients. In the Phase 3 clinical study in patients with newly-diagnosed CP CML treated with bosutinib 400 mg, there were no patients in the bosutinib treatment group with an increase of > 60 ms from baseline when the QT interval was corrected using Fridericia’s formula (QTcF). In the Phase 3 clinical study in patients with newly diagnosed Ph+ CP CML treated with bosutinib 500 mg, QTcF interval changes > 60 ms from baseline were observed in 2 (0.8%) of 248 patients receiving bosutinib. A proarrhythmic potential of bosutinib cannot be ruled out. Clinical efficacy Clinical study in CP previously untreated CML Bosutinib 400 mg study A 2-arm, Phase 3, open-label, multicentre superiority trial was conducted to investigate the efficacy and safety of bosutinib 400 mg once daily alone compared with imatinib 400 mg once daily alone in adult patients with newly-diagnosed Ph+ CP CML. The trial randomised 536 patients (268 in each treatment group) with Ph+ or Ph- newly-diagnosed CP CML (intent-to-treat population [ITT]) including 487 patients with Ph+ CML harbouring b2a2 and/or b3a2 transcripts and baseline BCR-ABL copies > 0 (modified intent-to-treat [mITT] population). The primary efficacy endpoint was the proportion demonstrating a major molecular response (MMR) at 12 months (48 weeks) in the bosutinib treatment group compared with that in the imatinib treatment group in the mITT population. MMR was defined as ≤ 0.1% BCR-ABL/ABL ratio by international scale (corresponding to ≥ 3 log reduction from standardised baseline) with a minimum of 3,000 ABL transcripts as assessed by the central laboratory. The secondary efficacy endpoints included MMR by 18 months, duration of MMR, CCyR by 12 months, duration of CCyR, event-free survival (EFS), and overall survival (OS). Complete cytogenetic response by Month 12, a secondary endpoint, was defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥ 20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogenetic assessment was unavailable. The p-values for endpoints other than MMR at 12 months and CCyR by 12 months have not been adjusted for multiple comparisons. Baseline characteristics for the mITT population were well balanced between the 2 treatment groups with respect to age (median age was 52 years for the bosutinib group and 53 years for the imatinib group with 19.5% and 17.4% of patients 65 years of age or older, respectively); gender (women 42.3% and 44.0%, respectively); and race (Caucasian 77.6% and 77.2%, Asian 12.2% and 15 12.4%, Black or African American 4.1% and 4.1%, and Other 5.7% and 5.8%, respectively, and 1 unknown in each group). After a minimum of 12 months of follow-up in the mITT population, 77.6% of patients treated with bosutinib (N=241) and 72.4% of patients treated with imatinib (N=239) were still receiving first-line treatment. After a minimum of 12 months of follow-up in the mITT population, discontinuations due to disease progression to AP or BP CML for bosutinib-treated patients were 0.4% compared to 1.7% for imatinib-treated patients. Five bosutinib patients and 7 imatinib patients transformed to AP CML or BP CML. Discontinuations due to suboptimal response or treatment failure as assessed by the investigator occurred for 2.0% of patients in the bosutinib-treated group compared to 6.3% of patients in the imatinib-treated group. One patient on bosutinib and 7 patients on imatinib died while on study. The efficacy results are summarised in Table 3. Table 3 - Summary of MMR at Months 12 and 18 and CCyR by Month 12, by treatment group in the mITT population Response Bosutinib (N=246) Imatinib (N=241) 1-sided p-value Major molecular response (n, %) MMR at Month 12 (95% CI) MMR at Month 18 (95% CI) 116 (47.2)a (40.9,53.4) 140 (56.9) (50.7,63.1) 89 (36.9) (30.8,43.0) 115 (47.7) (41.4,54.0) 0.0100a 0.0208b Complete cytogenetic response by Month 12 (n, %) CCyR (95% CI) 190 (77.2)a (72.0,82.5) 160 (66.4) (60.4,72.4) 0.0037a Note: MMR was defined as ≤ 0.1% BCR-ABL/ABL ratio by international scale (corresponding to ≥ 3 log reduction from standardised baseline) with a minimum of 3,000 ABL transcripts assessed by the central laboratory. Complete cytogenetic response was defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥ 20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogenetic assessment was unavailable. Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; CCyR=complete cytogenetic response; mITT=modified intent-to-treat; MMR=major molecular response; N/n=number of patients; Ph+=Philadelphia chromosome-positive. a Statistically significant comparison at the pre-specified significance level; based on CMH test stratified by geographical region and Sokal score at randomisation. b Based on CMH test stratified by geographical region and Sokal score at randomisation. At Month 12, the MR4 rate (defined as ≤ 0.01% BCR-ABL [corresponding to ≥ 4 log reduction from standardised baseline] with a minimum of 9,800 ABL transcripts) was higher in the bosutinib treatment group compared to the imatinib treatment group in the mITT population (20.7% [95% CI: 15.7%, 25.8%] versus 12.0% [95% CI: 7.9%, 16.1%], respectively, 1-sided p-value=0.0052). At Months 3, 6, and 9, the proportion of patients with MMR was higher in the bosutinib treatment group compared to the imatinib treatment group (Table 4). 16 Table 4 - Comparison of MMR at Months 3, 6, and 9 by treatment in the mITT population Time Number (%) of subjects with MMR 1-sided p-valuea Bosutinib (N=246) Imatinib (N=241) Month 3 (95% CI) Month 6 (95% CI) Month 9 (95% CI) 10 (4.1) (1.6,6.5) 86 (35.0) (29.0,40.9) 104 (42.3) (36.1,48.4) 4 (1.7) (0.0,3.3) 44 (18.3) (13.4,23.1) 71 (29.5) (23.7,35.2) 0.0578 < 0.0001 0.0015 Note: Percentages were based on number of patients in each treatment group. MMR was defined as ≤ 0.1% BCR-ABL/ABL ratio on international scale (corresponding to ≥ 3 log reduction from standardised baseline) with a minimum of 3,000 ABL transcripts assessed by the central laboratory. Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; CML=chronic myelogenous leukaemia; mITT=modified intent-to-treat; MMR=major molecular response; Ph+=Philadelphia chromosome-positive. a p-value based on CMH test stratified by geographical region and Sokal score at randomisation. The cumulative incidence of MMR adjusting for competing risk of treatment discontinuation without MMR was higher in the bosutinib treatment group compared to the imatinib treatment group in the mITT population (45.1% [95% CI: 38.8%, 51.2%] versus 33.7% [95% CI: 27.8%, 39.6%] at Week 48; hazard ratio [HR] from a stratified proportional subdistributional hazards model: 1.35 [95% CI: 1.07, 1.70], 1-sided p-value = 0.0086). The median time to MMR for responders was 24.7 weeks versus 36.3 weeks for the bosutinib treatment and imatinib treatment groups, respectively, in the mITT population. The cumulative incidence of CCyR adjusted for the competing risk of treatment discontinuation without CCyR was higher in the bosutinib treatment group compared to the imatinib treatment group in the mITT population (79.1% [95% CI: 73.4%, 83.7%] versus 67.3% [95% CI: 60.9%, 72.8%] at Week 48; HR: 1.38, [95% CI: 1.13, 1.68]; 1-sided p-value=0.0003). The median time to CCyR (responders only) was 23.9 weeks in the bosutinib group compared to the 24.3 weeks imatinib group. The Kaplan-Meier estimates of OS at 48 weeks for bosutinib and imatinib patients in the mITT population were 99.6% (95% CI: 97.1%, 99.9%) and 97.9% (95% CI: 95.0%, 99.1%), respectively. No additional deaths or transformations occurred in the ITT population. Clinical study in imatinib-resistant or intolerant CML in CP, AP, and BP A single-arm, Phase 1/2 open-label, multicentre trial was conducted to evaluate the efficacy and safety of bosutinib 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic, accelerated, and blast phase disease previously treated with 1 prior TKI (imatinib) or more than 1 TKI (imatinib followed by dasatinib and/or nilotinib). There were 570 patients treated with bosutinib in this trial including CP CML patients previously treated with only 1 prior TKI (imatinib), CP CML patients previously treated with imatinib and at least 1 additional TKI (dasatinib and/or nilotinib), CML patients in accelerated or blast phase previously treated with at least 1 TKI (imatinib) and patients with Ph+ ALL previously treated with at least 1 TKI (imatinib). 17 The primary efficacy endpoint of the study was the major cytogenetic response (MCyR) rate at Week 24 in patients with imatinib-resistant CP CML previously treated with only 1 prior TKI (imatinib). Other efficacy endpoints include the cumulative MCyR rate, time to and duration of MCyR, and time to and duration of CHR, in patients with CP CML previously treated with only 1 prior TKI (imatinib). For patients previously treated with both imatinib and at least 1 additional TKI, the endpoints include the cumulative MCyR rate, time to and duration of MCyR, and time to and duration of CHR. For patients with AP and BP CML previously treated with at least 1 prior TKI (imatinib), the endpoints were cumulative overall haematological response (OHR) and time to and duration of OHR. Other efficacy endpoints include transformation to AP/BP, progression free survival and OS for all cohorts. CP The efficacy results for Ph+ CP CML patients previously treated with imatinib and at least 1 additional TKI (minimum follow-up 48 months, median treatment duration of 9 months and 24.4% still on-treatment at 48 months) and the results for Ph+ CP CML patients previously treated with only imatinib (minimum follow-up 60 months, median treatment duration of 26 months and 40.5% still on-treatment at 60 months) are presented in Table 5. AP and BP CML patients The efficacy results for AP (minimum follow-up 48 months, median treatment duration of 10 months and 17.7% still on-treatment at 48 months) and BP (minimum follow-up 48 months, median treatment duration of 2.8 months and 3.1% still on-treatment at 48 months) Ph+ CML patients are present in Table 5. Table 5 - Efficacy results in previously treated patients with chronic and advanced phase CML* Ph+ CP CML with prior imatinib treatment only Ph+ CP CML with prior treatment with imatinib and dasatinib or nilotinib Accelerated phase with prior treatment of at least imatinib Blast phase with prior treatment of at least imatinib Cumulative cytogenetic responsea MCyR, % (95% CI) CCyR, % (95% CI) N=262 59.5 (53.3,65.5) 49.6 (43.4,55.8) N=112 40.2(31.0,49.9) 32.1(23.6,41.6) N=72 40.3 (28.9,52.5) 30.6 (20.2,42.5) N=54 37.0 (24.3,51.3) 27.8 (16.5,41.6) Time to MCyR for responders onlyb, weeks (95% CI) 12.3 (12.1,12.7) 12.3 (12.0,14.1) 12.0 (11.9,12.1) 8.2 (4.3,12.0) Duration of MCyRb K-M at year 1/2, % (95% CI)c K-M at year 4/5, % (95% CI)c Median, weeks (95% CI) N=156 76.4 (68.5,82.5) 71.1 (62.6,78.0) N/R N=45 72.0 (55.1,83.4) 69.3 (52.3,81.3) N/R N=29 62.2 (41.1,77.6) 46.7 (27.1,64.1) 84.0 (24.0,N/E) N=20 21.2 (5.2,44.2) 21.2 (5.2,44.2) 29.1 (11.9,38.3) Cumulative haematological responsed Overall, % (95% CI) Major, % (95% CI) Complete, % (95% CI) N=283 N/A N/A 86.6 (82.0,90.3) N=117 N/A N/A 73.5 (64.5,81.2) N=72 56. 9 (44.7,68.6) 47.2 (35.3,59.3) 33.3 (22.7,45.4) N=60 28.3 (17.5,41.4) 18.3 (9.5,30.4) 16.7 (8.3,28.5) Time to OHR for responders only, weeks (95% CI) N/A N/A 12.0 (11.1,12.1) 8.9 (4.1,12.0) Duration of CHR/OHRe K-M at year 1/2, % (95% CI)c K-M at year 4/5, % (95% CI)c Median, weeks (95% CI) N=245 71.9 (65.1,77.6) 66.0 (58.8,72.3) N/R N=86 73.4 (61.7,82.1) 62.9 (50.1,73.3) N/R N=41 78.2 (59.4,89.0) 52.0 (32.3,68.5) 207.0 (63.1,N/E) N=17 28.4 (7.8,53.9) 19.0 (3.3,44.5) 32.0 (29.0,54.6) 18 Transformation to AP/BPf On--treatment transformation, n N=284 15 N=119 5 N=79 3 N/A Progression-free survivalf K-M at year 1/2, % (95% CI)c K-M at year 4/5, % (95% CI)c Median, months (95% CI) N=284 80.0 (73.9,84.8) 72.5 (65.6,78.2) N/R N=119 75.1 (64.6,82.9) 65.1 (53.1,74.8) N/R N=79 66.8 (53.4,77.1) 40.8 (26.6,54.5) 22.1 (14.6,N/E) N=64 16.1 (6.6,29.3) 8.0 (1.7,21.2) 4.4 (3.2,8.5) Overall survivalf K-M at year 1/2, % (95% CI)c K-M at year 4/5, % (95% CI)c Median, months (95% CI) N=284 91.2 (87.1,94.0) 83.1 (77.5,87.4) N/R N=119 91.3 (84.5,95.2) 77.0 (66.9,84.4) N/R N=79 78.1 (67.1,85.8) 58.4 (45.6,69.1) N/R N=64 42.1 (29.7,53.9) 20.1 (6.2,39.8) 10.9 (8.7,19.7) * For efficacy results in the subgroup of patients corresponding to the approved indication, see text above. Snapshot date: 02Oct2015 Cytogenetic Response criteria: Major Cytogenetic Response included Complete [0% Ph+ metaphases from bone marrow or < 1% positive cells from fluorescent in situ hybridisation (FISH)] or partial (1%-35%) cytogenetic responses. Cytogenetic responses were based on the percentage of Ph+ metaphases among ≥ 20 metaphase cells in each bone marrow sample. FISH analysis (≥ 200 cells) could be used for post-baseline cytogenetic assessments if ≥ 20 metaphases were not available. Overall haematological response (OHR)=major haematological response (complete haematological response + no evidence of leukaemia) or return to chronic phase (RCP). All responses were confirmed after 4 weeks. Complete haematological response (CHR for AP and BP CML: WBC less than or equal to institutional upper limit of normal (ULN), platelets greater than or equal to 100,000/mm3 and less than 450,000/mm3, absolute neutrophil count (ANC) greater than or equal to 1.0×109/L, no blasts or promyelocytes in peripheral blood, less than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral b lood, and no extramedullary involvement. No evidence of leukaemia (NEL): Meets all other criteria for CHR except may have thrombocytopenia (platelets greater than or equal to 20,000/mm3 and less than 100,000/mm3) and/or neutropenia (ANC greater than or equal to 0.5×109/L and less than 1.0×109/L). Return to chronic phase (RCP)=disappearance of features defining accelerated or blast phases but still in chronic phase. Abbreviations: AP=accelerated phase; BP=blast phase; Ph+=Philadelphia chromosome-positive; CP=chronic phase; CML=chronic myelogenous leukaemia; K-M=Kaplan-Meier; N/n=number of patients; N/A=not applicable; N/R=not reached as of minimum follow-up; N/E=not estimable; CI=confidence interval; MCyR=major cytogenetic response; CCyR=complete cytogenetic response; OHR=overall haematological response; CHR=complete haematological response. a Includes patients (N) with a valid baseline assessment. The analyses allow baseline responders who maintained response post-baseline to be responders. Minimum follow-up time (time from last patient first dose to data snapshot date) of 60 months for CP treated with imatinib only and, 48 months for CP treated with imatinib and at least 1 other TKI, AP and BP. b Includes patients (N) who attained or maintained MCyR. c Years 2 (Month 24) and 5 (60 months) for CP treated with imatinib only and Years 1 (Month 12) and 4 (48 months) for CP treated with imatinib and at least 1 other TKI, AP, and BP. d Sample size (N) includes patients with a valid baseline haematological ass essment. These analyses allow baseline responders who maintained response post-baseline to be responders. e Includes patients (N) who attained or maintained CHR for CP patients and OHR for AP and BP patients. f Including patients (N) who received at least 1 dose of bosutinib. Based on the limited clinical information from the Phase 1/2 study, some evidence of clinical activity was observed in patients with BCR-ABL mutations (see Table 6). 19 Table 6 - Response by baseline BCR-ABL mutation status in CP CML evaluable population: prior imatinib and dasatinib and/or nilotinib (third-line) BCR-ABL mutation status at baseline Incidence at baseline n (%)a MCyR attained or maintained Resp/Evalb (%) N=112 Mutation assessed 96 (100.0) 34/92 (37.0) No mutation 57 (59.4) 21/55 (38.2) At least 1 mutation 39 (40.6) 13/37 (35.1) Dasatinib resistant mutations 10 (10.4) 1/9 (11.1) E255K/V 2 (2.0) 0/2 F317L 8 (8.3) 1/7 (14.3) Nilotinib resistant mutationsc 13 (13.5) 8/13 (61.5) Y253H 6 (6.3) 5/6 (83.3) E255K/V 2 (2.0) 0/2 F359C/I/V 7 (7.3) 5/7 (71.4) Snapshot date: 02Oct2015 Note: Baseline mutations were identified before the patient's first dose of study drug. Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CP=chronic phase; CML=chronic myelogenous leukaemia; MCyR=major cytogenetic response; N/n=number of patients; Resp=responders; Eval=evaluable. a The percentage is based on number of patients with baseline mutation assessment. b The evaluable population includes patients who had a valid baseline disease assessment. c 2 patients had more than 1 mutation in this category. One patient with the E255V mutation previously treated with nilotinib achieved CHR as best response. In vitro testing indicated that bosutinib had limited activity against the T315I or the V299L mutation. Therefore, clinical activity in patients with these mutations is not expected. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Bosulif in one or more subsets of the paediatric population in CML (see section 4.2 for information on paediatric use). Conditional approval This medicinal product has been authorised under a so-called “conditional approval” scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary. 5.2 Pharmacokinetic properties Absorption Following administration of a single dose of bosutinib (500 mg) with food in healthy subjects, the absolute bioavailability was 34%. Absorption was relatively slow, with a median time-to-peak concentration (tmax) reached after 6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to 600 mg. Food increased bosutinib Cmax 1.8-fold and bosutinib AUC 1.7-fold compared to the fasting state. In CML patients at steady state, Cmax (geometric mean, coefficient of variation [CV]%) was 145 (14) ng/mL, and AUCss (geometric 20 mean, CV%) was 2,700 (16) ng•h/mL after daily administration of bosutinib at 400 mg with food. After 500 mg bosutinib daily with food, Cmax was 200 (6) ng/mL and AUCss was 3,640 (12) ng•h/mL. The solubility of bosutinib is pH-dependent and absorption is reduced when gastric pH is increased (see section 4.5). Distribution Following administration of a single intravenous dose of 120 mg bosutinib to healthy subjects, bosutinib had a mean (% coefficient of variation [CV]) volume of distribution of 2,331 (32) L, suggesting that bosutinib is extensively distributed to extra vascular tissue. Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent. Biotransformation In vitro and in vivo studies indicated that bosutinib (parent compound) undergoes predominantly hepatic metabolism in humans. Following administration of single or multiple doses of bosutinib (400 or 500 mg) to humans, the major circulating metabolites appeared to be oxydechlorinated (M2) and N-desmethylated (M5) bosutinib, with bosutinib N-oxide (M6) as a minor circulating metabolite. The systemic exposure of N-desmethylated metabolite was 25% of the parent compound, while the oxydechlorinated metabolite was 19% of the parent compound. All 3 metabolites exhibited activity that was  5% that of bosutinib in a Src-transformed fibroblast anchorage-independent proliferation assay. In faeces, bosutinib and N-desmethyl bosutinib were the major drug-related components. In vitro studies with human liver microsomes indicated that the major cytochrome P450 isozyme involved in the metabolism of bosutinib is CYP3A4 and drug interaction studies have shown that ketoconazole and rifampicin had marked effect on the pharmacokinetics of bosutinib (see section 4.5). No metabolism of bosutinib was observed with CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A5. Elimination In healthy subjects given a single intravenous dose of 120 mg bosutinib, the mean (%CV) terminal elimination half-life was 35.5 (24) hours, and the mean (%CV) clearance was 61.9 (26) L/h. In a mass-balance study with oral bosutinib, an average of 94.6% of the total dose was recovered in 9 days; faeces (91.3%) was the major route of excretion, with 3.29% of the dose recovered in urine. Seventy-five percent of the dose was recovered within 96 hours. Excretion of unchanged bosutinib in urine was low with approximately 1% of the dose in both healthy subjects and those with advanced malignant solid tumours. Special populations Hepatic impairment A 200 mg dose of bosutinib administered with food was evaluated in a cohort of 18 hepatically impaired subjects (Child-Pugh classes A, B, and C) and 9 matched healthy subjects. Cmax of bosutinib in plasma increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C; and bosutinib AUC in plasma increased 2.3-fold, 2-fold, and 1.9-fold, respectively. The t½ of bosutinib increased in hepatic impaired patients as compared to the healthy subjects. Renal impairment In a renal impairment study, a single dose of 200 mg bosutinib was administered with food to 26 subjects with mild, moderate, or severe renal impairment and to 8 matching healthy volunteers. Renal impairment was based on CLCr (calculated by the Cockcroft-Gault formula) of < 30 mL/min (severe renal impairment), 30  CLCr  50 mL/min (moderate renal impairment), or 50 < CLCr  80 mL/min (mild renal impairment). Subjects with moderate and severe renal impairment had an increase in AUC over healthy volunteers of 35% and 60%, respectively. Maximal exposure Cmax increased by 28% and 34% in the moderate and severe groups, respectively. 21 Bosutinib exposure was not increased in subjects with mild renal impairment. The elimination half-life of bosutinib in subjects with renal impairment was similar to that in healthy subjects. Dose adjustments for renal impairment were based on the results of this study, and the known linear pharmacokinetics of bosutinib in the dose range of 200 to 600 mg. Age, gender and race No formal studies have been performed to assess the effects of these demographic factors. Population pharmacokinetic analyses in patients with Ph+ leukaemia or malignant solid tumour indicate that there are no clinically relevant effects of age, gender, body weight, race. Paediatric population Bosulif has not yet been studied in children and adolescents less than 18 years of age. 5.3 Preclinical safety data Bosutinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity, and photoxicity studies. Safety pharmacology Bosutinib did not have effects on respiratory functions. In a study of the central nervous system (CNS), bosutinib treated rats displayed decreased pupil size and impaired gait. A no observed effect level (NOEL) for pupil size was not established, but the NOEL for impaired gait occurred at exposures approximately 11-times the human exposure resulting from the clinical dose of 400 mg and 8-times the human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax in the respective species). Bosutinib activity in vitro in hERG assays suggested a potential for prolongation of cardiac ventricular repolarisation (QTc). In an oral study of bosutinib in dogs, bosutinib did not produce changes in blood pressure, abnormal atrial or ventricular arrhythmias, or prolongation of the PR, QRS, or QTc of the ECG at exposures up to 3-times the human exposure resulting from the clinical dose of 400 mg and 2-times the human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax in the respective species). A delayed increase in heart rate was observed. In an intravenous study in dogs, transient increases in heart rate and decreases in blood pressure and minimal prolongation of the QTc (< 10 msec) were observed at exposures ranging from approximately 6-times to 20-times the human exposure resulting from the clinical dose of 400 mg and 4-times to 15-times the human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax in the respective species). The relationship between the observed effects and medicinal product treatment were inconclusive. Repeated-dose toxicity Repeated-dose toxicity studies in rats of up to 6 months in duration and in dogs up to 9 months in duration revealed the gastrointestinal system to be the primary target organ of toxicity of bosutinib. Clinical signs of toxicity included foecal changes and were associated with decreased food consumption and body weight loss which occasionally led to death or elective euthanasia. Histopathologically, luminal dilation, goblet cell hyperplasia, haemorrhage, erosion, and oedema of the intestinal tract, and sinus erythrocytosis and haemorrhage in the mesenteric lymph nodes, were observed. The liver was also identified as a target organ in rats. Toxicities were characterised by an increase in liver weights in correlation with hepatocellular hypertrophy which occurred in the absence of elevated liver enzymes or microscopic signs of hepatocellular cytotoxicity, and is of unknown relevance to humans. The exposure camparison across species indicates that exposures that did not elicit adverse events in the 6- and 9-month toxicity studies in rats and dogs, respectively, were similar to the human exposure resulting from a clinical dose of 400 mg or 500 mg (based on unbound AUC in the respective species). 22 Genotoxicity Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo systems with and without metabolic activation did not reveal any evidence for a mutagenic potential of bosutinib. Reproductive toxicity and development toxicity In a rat fertility study, fertility was slightly decreased in males. Females were observed with increased embryonic resorptions, and decreases in implantations and viable embryos. The dose at which no adverse reproductive effects were observed in males (30 mg/kg/day) and females (3 mg/kg/day) resulted in exposures equal to 0.6-times and 0.3-times, respectively, the human exposure resulting from the clinical dose of 400 mg, and 0.5-times and 0.2-times, respectively, the human exposure resulting from the clinical dose of 500 mg (based on unbound AUC in the respective species). An effect on male fertility cannot be excluded (see section 4.6). Foetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental transfer study in gravid Sprague-Dawley rats. In a rat pre- and postnatal development study, there were reduced number of pups born at ≥ 30 mg/kg/day, and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day. The dose at which no adverse development effects were observed (10 mg/kg/day) resulted in exposures equal to 1.3-times and 1.0-times human exposure resulting from the clinical dose of 400 mg and 500 mg, respectively (based on unbound AUC in the respective species). In a rabbit developmental toxicity study at the maternally toxic dose, there were foetal anomalies observed (fused sternebrae, and 2 foetuses had various visceral observations), and a slight decrease in foetal body weight. The exposure at the highest dose tested in rabbits (10 mg/kg/day) that did not result in adverse foetal effects was 0.9-times and 0.7-times the human exposure resulting from the clinical dose of 400 mg or 500 mg, respectively (based on unbound AUC in the respective species). Following a single oral (10 mg/kg) administration of [14C] radiolabelled bosutinib to lactating Sprague-Dawley rats, radioactivity was readily excreted into breast milk as early as 0.5 hr after dosing. Concentration of radioactivity in milk was up to 8-fold higher than in plasma. This allowed measurable concentrations of radioactivity to appear in the plasma of nursing pups. Carcinogenicity Bosutinib was not carcinogenic in the 2-year rat carcinogenicity study. Phototoxicity Bosutinib has demonstrated the ability to absorb light in the UV-B and UV-A range and is distributed into the skin and uveal tract of pigmented rats. However, bosutinib did not demonstrate a potential for phototoxicity of the skin or eyes in pigmented rats exposed to bosutinib in the presence of UV radiation at bosutinib exposures up to 3-times and 2-times the human exposure resulting from the clinical dose of 400 or 500 mg, respectively (based on unbound Cmax in the respective species). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Microcrystalline cellulose (E460) Croscarmellose sodium (E468) Poloxamer 188 Povidone (E1201) Magnesium stearate (E470b) 23 Film coating Bosulif 100 mg film-coated tablets Polyvinyl alcohol Titanium dioxide (E171) Macrogol 3350 Talc (E553b) Iron oxide yellow (E172) Bosulif 400 mg film-coated tablets Polyvinyl alcohol Titanium dioxide (E171) Macrogol 3350 Talc (E553b) Iron oxide yellow (E172) Iron oxide red (E172) Bosulif 500 mg film-coated tablets Polyvinyl alcohol Titanium dioxide (E171) Macrogol 3350 Talc (E553b) Iron oxide red (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container White opaque 3-ply PVC/Polychlorotrifluoroethene/PVC blister sealed with push-through foil backing containing either 14 or 15 tablets. Bosulif 100 mg film-coated tablets Each carton contains 28, 30 or 112 tablets. Bosulif 400 mg film-coated tablets Each carton contains 28 or 30 tablets. Bosulif 500 mg film-coated tablets Each carton contains 28 or 30 tablets. Not all pack sizes may be marketed. 24 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium 8. MARKETING AUTHORISATION NUMBER(S) Bosulif 100 mg film-coated tablets EU/1/13/818/001 EU/1/13/818/002 EU/1/13/818/005 Bosulif 400 mg film-coated tablets EU/1/13/818/006 EU/1/13/818/007 Bosulif 500 mg film-coated tablets EU/1/13/818/003 EU/1/13/818/004 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 27 March 2013 Date of latest renewal: 18 February 2019 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 25 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST- AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION 26 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Pfizer Manufacturing Deutschland GmbH Betriebsstӓtte Freiburg Mooswaldallee 1 79090 Freiburg Germany B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 27 E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: Description Due date To conduct a single-arm open-label, multi-centre efficacy and safety study of bosutinib in patients with Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML) previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. Final Clinical Study Report: 31 May 2022 28 ANNEX III LABELLING AND PACKAGE LEAFLET 29 A. LABELLING 30 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Bosulif 100 mg film-coated tablets bosutinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 100 mg bosutinib (as monohydrate). 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets. 30 film-coated tablets. 112 film-coated tablets. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 31 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Dispose unused medicinal product in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/818/001 (28 film-coated tablets) EU/1/13/818/002 (30 film-coated tablets) EU/1/13/818/005 (112 film-coated tablets) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Bosulif 100 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 32 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 33 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Bosulif 100 mg film-coated tablets bosutinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER Pfizer 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 34 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Bosulif 400 mg film-coated tablets bosutinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 400 mg bosutinib (as monohydrate). 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets. 30 film-coated tablets. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 35 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Dispose unused medicinal product in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/818/006 (28 film-coated tablets) EU/1/13/818/007 (30 film-coated tablets) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Bosulif 400 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 36 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Bosulif 400 mg film-coated tablets bosutinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER Pfizer 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 37 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Bosulif 500 mg film-coated tablets bosutinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 500 mg bosutinib (as monohydrate). 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 Film-coated tablets. 30 Film-coated tablets. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 38 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Dispose unused medicinal product in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/818/003 28 film-coated tablets EU/1/13/818/004 30 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Bosulif 500 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 39 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Bosulif 500 mg film-coated tablets bosutinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER Pfizer 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 40 B. PACKAGE LEAFLET 41 Package leaflet: Information for the user Bosulif 100 mg film-coated tablets Bosulif 400 mg film-coated tablets Bosulif 500 mg film-coated tablets bosutinib This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Bosulif is and what it is used for 2. What you need to know before you take Bosulif 3. How to take Bosulif 4. Possible side effects 5. How to store Bosulif 6. Content of the pack and other information 1. What Bosulif is and what it is used for Bosulif contains the active substance bosutinib. It is used to treat adult patients who have a type of leukaemia called Philadelphia chromosome-positive (Ph-positive) Chronic Myeloid Leukaemia (CML) and are newly-diagnosed or for whom previous medicines to treat CML have either not worked or are not suitable. Ph-positive CML is a cancer of the blood which makes the body produce too many of a specific type of white blood cell called granulocytes. If you have any questions about how Bosulif works or why this medicine has been prescribed for you, ask your doctor. 2. What do you need to know before you take take Bosulif Do not take Bosulif - if you are allergic to bosutinib or any of the other ingredients of this medicine (listed in section 6). - if your doctor has told you that your liver has been damaged and is not working normally. Warnings and precautions Talk to your doctor, pharmacist or nurse before taking Bosulif: 42 - if you have, or have had in the past, liver problems. Tell your doctor if you have a history of liver problems including hepatitis (liver infection or inflammation) of any kind, or a history of any of the following signs and symptoms of liver problems: itching, yellow eyes or skin, dark urine, and pain or discomfort in the right upper stomach area. Your doctor should do blood tests to check your liver function prior to your starting treatment with Bosulif and for the first 3 months of treatment with Bosulif, and as clinically indicated. - if you have diarrhoea and vomiting. Tell your doctor if you develop any of the following signs and symptoms: an increase in the number of stools (bowel movements) per day over normal, an increase in episodes of vomiting, blood in your vomit, stools (bowel movements) or urine, or have black stools (tarry black bowel movements). You should ask your doctor if use of your treatment for vomiting may result in a greater risk of heart arrhythmias. In particular, you should ask your doctor if you want to use a medicine containing domperidone for the treatment of nausea and/or vomiting. Treatment of nausea or vomiting with such medicines together with Bosulif may result in a greater risk of dangerous heart arrhythmias. - if you suffer from bleeding problems. Tell your doctor if you develop any of the following signs and symptoms such as abnormal bleeding or bruising without having an injury. - if you have an infection. Tell your doctor if you develop any of the following signs and symptoms such as fever, problems with urine such as burning on urination, a new cough, or a new sore throat. - if you have fluid retention. Tell your doctor if you develop any of the following signs and symptoms of fluid retention during Bosulif treatment such as swelling of the ankles, feet or legs; difficulty breathing chest pain or a cough (these may be signs of fluid retention in the lungs or chest). - if you have heart problems. Tell your doctor if you have a heart disorders, such as arrhythmias or an abnormal electrical signal called “prolongation of the QT interval”. This is always important, but especially if you are experiencing frequent or prolonged diarrhoea as described above. If you faint (loss of consciousness) or have an irregular heartbeat while taking Bosulif, tell your doctor immediately, as this may be a sign of a serious heart condition. - if you have been told that you have problems with your kidneys. Tell your doctor if you are urinating more frequently and producing larger amounts of urine with a pale colour or if you are urinating less frequently and producing smaller amounts of urine with a dark colour. Also tell your doctor if you are losing weight or have experienced swelling of your feet, ankles, legs, hands or face. - if you have ever had or might now have a hepatitis B infection. This is because Bosulif could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started. - if you have or have had pancreas problems. Tell your doctor if you develop abdominal pain or discomfort. - if you have any of these symptoms: serious skin rashes. Tell your doctor if you develop any of the following signs and symptoms of painful red or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous membrane (e.g., mouth and lips). 43 - if you notice any of these symptoms: pain in your side, blood in your urine or reduced amount of urine. When your disease is very severe, your body may not be able to clear all the waste products from the dying cancer cells. This is called tumour lysis syndrome and can cause kidney failure and heart problems within 48 hours of the first dose of Bosulif. Your doctor will be aware of this and may ensure you are adequately hydrated and give you other medicines to help prevent it. Children and adolescents Bosulif is not recommended for people whose age is under 18 years. This medicine has not been studied in children and adoloscents. Other medicines and Bosulif Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription, vitamins, and herbal medicines. Some medicines can affect the levels of Bosulif in your body. You should inform your doctor if you are taking medicines containing active substances such as those listed below: The following active substances may increase the risk of side effects with Bosulif: - ketoconazole, itraconazole, voriconazole, posaconazole and fluconazole, used to treat fungal infections. - clarithromycin, telithromycin, erythromycin, and ciprofloxacin, used to treat bacterial infections. - nefazodone, used to treat depression. - mibefradil, diltiazem and verapamil, used to lower blood pressure in people with high blood pressure. - ritonavir, lopinavir/ritonavir, indinavir, nelfinavir, saquinavir, atazanavir, amprenavir, fosamprenavir and darunavir, used to treat human immunodeficiency virus (HIV)/AIDS. - boceprevir and telaprevir, used to treat hepatitis C. - aprepitant, used to prevent and control nausea (feeling sick) and vomiting. - imatinib, used to treat a type of leukaemia. - crizotinib, used to treat a type of lung cancer called non-small cell lung cancer. The following active substances may reduce the effectiveness of Bosulif: - rifampicin, used to treat tuberculosis. - phenytoin and carbamazepine, used to treat epilepsy. - bosentan, used to lower high blood pressure in the lungs (pulmonary artery hypertension). - nafcillin, an antibiotic used to treat bacterial infections. - St. John’s Wort (a herbal preparation obtained without a prescription), used to treat depression. - efavirenz and etravirine, used to treat HIV infections/AIDS. - modafinil, used to treat certain types of sleep disorders. These medicines should be avoided during your treatment with Bosulif. If you are taking any of them, tell your doctor. Your doctor may change the dose of these medicines, change the dose of Bosulif, or switch you to a different medicine. The following active substances may affect the heart rhythm: - amiodarone, disopyramide, procainamide, quinidine and sotalol used to treat heart disorder. - chloroquine, halofantrine used to treat malaria. - clarithromycin and moxifloxacin antibiotics used to treat bacterial infections. - haloperidol, used to treat psychotic disease such as schizophrenia. - domperidone, used to treat nausea and vomiting or to stimulate breast milk production. - methadone, used to treat pain. 44 These medicines should be taken with caution during your treatment with Bosulif. If you are taking any of them, tell your doctor. The medicines listed here may not be the only ones that could interact with Bosulif. Bosulif with food and drink Do not take Bosulif with grapefruit or grapefruit juice, as it may increase the risk of side effects. Pregnancy, breast-feeding and fertility Bosulif is not to be used during pregnancy, unless clearly necessary, because Bosulif could harm an unborn baby. Ask your doctor for advice before taking Bosulif if you are pregnant or might become pregnant. Women taking Bosulif will be advised to use effective contraception during treatment and for at least 1 month after the last dose. Vomiting or diarrhoea may reduce the effectiveness of oral contraceptives. There is a risk that treatment with Bosulif will lead to decreased fertility and you may wish to seek advice about sperm storage before the treatment starts. If you are breast-feeding, tell your doctor. Do not breast-feed during treatment with Bosulif as it could harm your baby. Driving and using machines If you experience dizziness, have blurred vision or feel unusually tired, do not drive or operate machines until these side effects have gone away. 3. How to take Bosulif Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Bosulif will only be prescribed to you by a doctor with experience in medicines to treat leukaemia. Dose and method of administration The recommended dose is 400 mg once daily for patients with newly-diagnosed CML. The recommended dose is 500 mg once daily for patients whose previous medicines to treat CML have either not worked or are not suitable. In the event that you have moderate or severe kidney problems, your doctor will reduce your dose by 100 mg once daily for moderate kidney problems and by an additional 100 mg once daily for severe kidney problems. Your doctor may adjust the dose using the 100 mg tablets depending upon your medical conditions, upon your response to treatment and/or on any side effect you may experience. Take the tablet(s) in the morning with food. Swallow the tablet(s) whole with water. If you take more Bosulif than you should If you accidentally take too many Bosulif tablets or a higher dose than you need, contact a doctor for advice right away. If possible, show the doctor the pack, or this leaflet. You may require medical attention. 45 If you forget to take Bosulif If dose is missed by less than 12 hours, take your recommended dose. If a dose is missed by more than 12 hours, take your next dose at your regular time on the following day. Do not take a double dose to make up for the forgotten tablets. If you stop taking Bosulif Do not stop taking Bosulif unless your doctor tells you to do so. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor right away. If you have any further questions on the use of this medicine ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. You must immediately contact your doctor if you experience any of those serious side effects (see also section 2 “What you need to know before you take Bosulif”): Blood disorders. Tell your doctor right away if you have any of these symptoms: bleeding, fever or easy bruising (you might have blood or lymphatic system disorder). Liver disorders. Tell your doctor right away if you have any of these symptoms: itching, yellow eyes or skin, dark urine, and pain or discomfort in the right upper stomach area or fever. Stomach/intestinal disorders. Tell your doctor if you develop stomach pain, heartburn, diarrhoea, constipation, nausea and vomiting. Heart problems. Tell your doctor if you have a heart disorder, such as an abnormal electrical signal called “prolongation of the QT interval”, or if you faint (loss of consciousness) or have an irregular heart beat while taking Bosulif. Hepatitis B reactivation. Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a liver infection). Severe skin reactions. Tell your doctor right away if you have any of these symptoms: painful red or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous membrane (e.g. mouth and lips). Side effects with Bosulif may include: Very common side effects (may affect more than 1 in 10 people): - reduction in the number of platelets, red blood cells and/or neutrophils (type of white blood cells). - diarrhoea, vomiting, stomach pain, nausea. - fever, swelling of hands, feet or face, fatigue, weakness. - respiratory tract infection. - nasopharyngitis. - changes in blood test to determine if Bosulif is affecting your liver and/or pancreas. - decrease of appetite. - joint pain, back pain. - headache. - skin rash, which may be itchy and/or generalised. 46 - cough. - shortness of breath. Common side effects (may affect up to 1 in 10 people): - low white blood cells count (leukopenia). - stomach irritation (gastritis), bleeding from the stomach or intestine. - chest pain, pain. - toxic damage to the liver, abnormal hepatic function including liver disorder. - infection of the lung (pneumonia), influenza, bronchitis. - defect in cardiac rhythm that predisposes to fainting, dizziness and palpitation. - increase in blood pressure. - high level of potassium in the blood, low level of phosphorus in the blood, excessive loss of body fluid (dehydration). - pain in the muscles. - feeling of instability (dizziness), alteration of the sense of taste (dysgeusia). - acute kidney failure, kidney failure, kidney impairment. - fluid on the lungs (pleural effusion). - fluid around the heart (pericardial effusion). - ringing in the ears (tinnitus). - itching, urticaria (hives), acne. Uncommon side effects (may affect up to 1 in 100 people): - fever associated with low white blood cell count (febrile neutropenia). - acute inflammation of the pancreas (acute pancreatitis). - damage to the liver. - life-threatening allergic reaction (anaphylactic shock). - abnormal build-up of fluid in the lungs (acute pulmonary oedema). - respiratory failure. - allergic reaction. - abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension). - skin eruption. - inflammation of the sac-like covering of the heart (pericarditis). - a marked decrease in the number of granulocytes (a type of white blood cells). Rare side effects (may affect up to 1 in 1,000 people): - severe skin disorder (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) due to an allergic reaction, exfoliative (scaly, peeling) rash. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Bosulif - Keep this medicine out of the sight and reach of children. - Do not use this medicine after the expiry date which is stated on the blister foil and carton after “EXP”. The expiry date refers to the last day of that month. - This medicine does not require any special storage conditions. - Do not use this medicine if you notice that the pack is damaged or shows signs of tampering. 47 - Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Content of the pack and other information What Bosulif contains - The active substance is bosutinib. Bosulif film-coated tablets come in different strengths. Bosulif 100 mg: each film-coated tablet contains 100 mg bosutinib (as monohydrate). Bosulif 400 mg: each film-coated tablet contains 400 mg bosutinib (as monohydrate). Bosulif 500 mg: each film-coated tablet contains 500 mg bosutinib (as monohydrate). - The other ingredients are: microcrystalline cellulose (E460), croscarmellose sodium (E468), poloxamer 188, povidone (E1201) and magnesium stearate (E470b). The tablet film-coating contains polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc (E553b) and iron oxide yellow (E172, for Bosulif 100 mg and 400 mg) or iron oxide red (E172, for Bosulif 400 mg and 500 mg). What Bosulif looks like and contents of the pack Bosulif 100 mg film-coated tablets are yellow, oval biconvex, debossed with “Pfizer” on one side and “100” on the other side. Bosulif 100 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 28 or 30 film-coated tablets or 112 film-coated tablets. Bosulif 400 mg film-coated tablets are orange, oval biconvex, debossed with “Pfizer” on one side and “400” on the other side. Bosulif 400 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 28 or 30 film-coated tablets. Bosulif 500 mg film-coated tablets are red, oval biconvex, debossed with “Pfizer” on one side and “500” on the other side. Bosulif 500 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 28 or 30 film-coated tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles Belgium Manufacturer Pfizer Manufacturing Deutschland GmbH Betriebsstӓtte Freiburg Mooswaldallee 1 79090 Freiburg Germany 48 For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: Belgique / België /Belgien Pfizer S.A. / N.V. Tél/Tel: +32 (0)2 554 62 11 Lietuva Pfizer Luxembourg SARL filialas Lietuvoje Tel. + 370 52 51 4000 България Пфайзер Люксембург САРЛ, Клон България Тел.: +359 2 970 4333 Luxembourg/Luxemburg Pfizer S.A. Tél/Tel: +32 (0)2 554 62 11 Česká republika Pfizer PFE, spol. s r.o. Tel.: +420 283 004 111 Magyarország Pfizer Kft. Tel.: +36-1-488-37-00 Danmark Pfizer ApS Tlf: +45 44 20 11 00 Malta Vivian Corporation Ltd. Tel: +356 21344610 Deutschland Pfizer Pharma GmbH Tel: +49 (0)30 550055 51000 Nederland Pfizer BV Tel: +31 (0)10 406 43 01 Eesti Pfizer Luxembourg SARL Eesti filiaal Tel: +372 666 7500 Norge Pfizer Norge AS Tlf: +47 67 52 61 00 Ελλάδα Pfizer Ελλάς A.E. Τλ: +30 210 6785 800 Österreich Pfizer Corporation Austria Ges.m.b.H. Tel: +43 (0)1 521 15-0 España Pfizer, S.L. Tél: +34 91 490 99 00 Polska Pfizer Polska Sp. z o.o. Tel.:+48 22 335 61 00 France Pfizer Tél: +33 (0)1 58 07 34 40 Portugal Pfizer Biofarmacêutica, Sociedade Unipessoal Lda Tel: +351 21 423 5500 Hrvatska Pfizer Croatia d.o.o. Tel: + 385 1 3908 777 România Pfizer Romania S.R.L. Tel: +40 (0) 21 207 28 00 Ireland Pfizer Healthcare Ireland Tel: 1800 633 363 (toll free) +44 (0)1304 616161 Slovenija Pfizer Luxembourg SARL Pfizer, podružnica za svetovanje s področja farmacevtske dejavnosti, Ljubljana Tel.: + 386 (0)1 52 11 400 Ísland Icepharma hf. Sími: +354 540 8000 Slovenská republika Pfizer Luxembourg SARL, organizačná zložka Tel.: + 421 2 3355 5500 49 Italia Pfizer S.r.l. Tel: +39 06 33 18 21 Suomi/Finland Pfizer Oy Puh./Tel: +358 (0)9 43 00 40 Kύπρος Pfizer Ελλάς Α.Ε. (Cyprus Branch) Tηλ+357 22 817690 Sverige Pfizer Innovations AB Tel: +46 (0)8 550 520 00 Latvija Pfizer Luxembourg SARL filiāle Latvijā Tel.: + 371 670 35 775 United Kingdom Pfizer Limited Tel: +44 (0) 1304 616161 This leaflet was last revised in This medicine has been given “conditional approval”. This means that there is more evidence to come about this medicine. The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary. Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what bosulif is and what it is used for', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '2. what you need to know before you take bosulif', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '3. how to take bosulif', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. bosulif will only be prescribed to you by a doctor with experience in medicines to treat leukaemia. dose and method of administration the recommended dose is 400 mg once daily for patients with newly-diagnosed cml. the recommended dose is 500 mg once daily for patients whose previous medicines to treat cml have either not worked or are not suitable. in the event that you have moderate or severe kidney problems, your doctor will reduce your dose by 100 mg once daily for moderate kidney problems and by an additional 100 mg once daily for severe kidney problems. your doctor may adjust the dose using the 100 mg tablets depending upon your medical conditions, upon your response to treatment and/or on any side effect you may experience. take the tablet(s) in the morning with food. swallow the tablet(s) whole with water. if you take more bosulif than you should if you accidentally take too many bosulif tablets or a higher dose than you need, contact a doctor for advice right away. if possible, show the doctor the pack, or this leaflet. you may require medical attention. if you forget to take bosulif if dose is missed by less than 12 hours, take your recommended dose. if a dose is missed by more than 12 hours, take your next dose at your regular time on the following day. do not take a double dose to make up for the forgotten tablets. if you stop taking bosulif do not stop taking bosulif unless your doctor tells you to do so. if you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor right away. if you have any further questions on the use of this medicine ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'bosulif', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. you must immediately contact your doctor if you experience any of those serious side effects (see also section 2 "what you need to know before you take bosulif"): blood disorders. tell your doctor right away if you have any of these symptoms: bleeding, fever or easy bruising (you might have blood or lymphatic system disorder). liver disorders. tell your doctor right away if you have any of these symptoms: itching, yellow eyes or skin, dark urine, and pain or discomfort in the right upper stomach area or fever. stomach/intestinal disorders. tell your doctor if you develop stomach pain, heartburn, diarrhoea, constipation, nausea and vomiting. heart problems. tell your doctor if you have a heart disorder, such as an abnormal electrical signal called "prolongation of the qt interval", or if you faint (loss of consciousness) or have an irregular heart beat while taking bosulif. hepatitis b reactivation. recurrence (reactivation) of hepatitis b infection when you have had hepatitis b in the past (a liver infection). severe skin reactions. tell your doctor right away if you have any of these symptoms: painful red or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous membrane (e.g. mouth and lips). side effects with bosulif may include: very common side effects (may affect more than 1 in 10 people): - reduction in the number of platelets, red blood cells and/or neutrophils (type of white blood cells). - diarrhoea, vomiting, stomach pain, nausea. - fever, swelling of hands, feet or face, fatigue, weakness. - respiratory tract infection. - nasopharyngitis. - changes in blood test to determine if bosulif is affecting your liver and/or pancreas. - decrease of appetite. - joint pain, back pain. - headache. - skin rash, which may be itchy and/or generalised. - cough. - shortness of breath. common side effects (may affect up to 1 in 10 people): - low white blood cells count (leukopenia). - stomach irritation (gastritis), bleeding from the stomach or intestine. - chest pain, pain. - toxic damage to the liver, abnormal hepatic function including liver disorder. - infection of the lung (pneumonia), influenza, bronchitis. - defect in cardiac rhythm that predisposes to fainting, dizziness and palpitation. - increase in blood pressure. - high level of potassium in the blood, low level of phosphorus in the blood, excessive loss of body fluid (dehydration). - pain in the muscles. - feeling of instability (dizziness), alteration of the sense of taste (dysgeusia). - acute kidney failure, kidney failure, kidney impairment. - fluid on the lungs (pleural effusion). - fluid around the heart (pericardial effusion). - ringing in the ears (tinnitus). - itching, urticaria (hives), acne. uncommon side effects (may affect up to 1 in 100 people): - fever associated with low white blood cell count (febrile neutropenia). - acute inflammation of the pancreas (acute pancreatitis). - damage to the liver. - life-threatening allergic reaction (anaphylactic shock). - abnormal build-up of fluid in the lungs (acute pulmonary oedema). - respiratory failure. - allergic reaction. - abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension). - skin eruption. - inflammation of the sac-like covering of the heart (pericarditis). - a marked decrease in the number of granulocytes (a type of white blood cells). rare side effects (may affect up to 1 in 1,000 people): - severe skin disorder (erythema multiforme, stevens-johnson syndrome, toxic epidermal necrolysis) due to an allergic reaction, exfoliative (scaly, peeling) rash. reporting of side effects if you get any side effects, talk to your doctor or pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national 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0.9627512097358704}]}, {'Id': 77, 'BeginOffset': 1645, 'EndOffset': 1653, 'Score': 0.9967509508132935, 'Text': 'weakness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9299228191375732}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9975084066390991, 'RelationshipScore': 0.5925991535186768, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 17, 'BeginOffset': 1622, 'EndOffset': 1626, 'Text': 'feet', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9915169477462769, 'RelationshipScore': 0.6486301422119141, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 18, 'BeginOffset': 1630, 'EndOffset': 1634, 'Text': 'face', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 78, 'BeginOffset': 1657, 'EndOffset': 1684, 'Score': 0.8746203780174255, 'Text': 'respiratory tract infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4810953736305237}, {'Name': 'DIAGNOSIS', 'Score': 0.6979714632034302}]}, {'Id': 79, 'BeginOffset': 1688, 'EndOffset': 1703, 'Score': 0.6932225227355957, 'Text': 'nasopharyngitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.43179774284362793}]}, {'Id': 90, 'BeginOffset': 1718, 'EndOffset': 1728, 'Score': 0.696599543094635, 'Text': 'blood test', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 28, 'BeginOffset': 1745, 'EndOffset': 1752, 'Score': 0.46643492579460144, 'Text': 'bosulif', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'your liver and/or pancreas', 'Type': 'PROBLEM', 'BeginOffset': 1766, 'EndOffset': 1792}, {'Text': 'decrease of appetite', 'Type': 'PROBLEM', 'BeginOffset': 1796, 'EndOffset': 1816}, {'Id': 81, 'BeginOffset': 1820, 'EndOffset': 1830, 'Score': 0.7646681666374207, 'Text': 'joint pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8993699550628662}]}, {'Id': 82, 'BeginOffset': 1832, 'EndOffset': 1841, 'Score': 0.9744036793708801, 'Text': 'back pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.89686119556427}]}, {'Id': 83, 'BeginOffset': 1845, 'EndOffset': 1853, 'Score': 0.9933224320411682, 'Text': 'headache', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8575285077095032}]}, {'Id': 84, 'BeginOffset': 1857, 'EndOffset': 1866, 'Score': 0.8175912499427795, 'Text': 'skin rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8335695266723633}]}, {'Id': 85, 'BeginOffset': 1881, 'EndOffset': 1886, 'Score': 0.7417070865631104, 'Text': 'itchy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5034061670303345}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9935932755470276, 'RelationshipScore': 0.8820151686668396, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 24, 'BeginOffset': 1857, 'EndOffset': 1861, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 86, 'BeginOffset': 1894, 'EndOffset': 1905, 'Score': 0.9306968450546265, 'Text': 'generalised', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5481563806533813}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9935932755470276, 'RelationshipScore': 0.38606035709381104, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 24, 'BeginOffset': 1857, 'EndOffset': 1861, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 117, 'BeginOffset': 1909, 'EndOffset': 1914, 'Score': 0.9712004661560059, 'Text': 'cough', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.552535355091095}]}, {'Id': 118, 'BeginOffset': 1918, 'EndOffset': 1937, 'Score': 0.9807642698287964, 'Text': 'shortness of breath', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6986198425292969}]}, {'Text': 'common side effects', 'Type': 'PROBLEM', 'BeginOffset': 1939, 'EndOffset': 1958}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1977, 'EndOffset': 1978}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 1982, 'EndOffset': 1984}, {'Text': 'low white blood cells count', 'Type': 'PROBLEM', 'BeginOffset': 1996, 'EndOffset': 2023}, {'Id': 120, 'BeginOffset': 2025, 'EndOffset': 2035, 'Score': 0.955844521522522, 'Text': 'leukopenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8843690156936646}]}, {'Id': 121, 'BeginOffset': 2040, 'EndOffset': 2058, 'Score': 0.8169331550598145, 'Text': 'stomach irritation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4870939254760742}]}, {'Id': 122, 'BeginOffset': 2060, 'EndOffset': 2069, 'Score': 0.9255077838897705, 'Text': 'gastritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6809794902801514}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.895484983921051, 'RelationshipScore': 0.7767481207847595, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 94, 'BeginOffset': 2040, 'EndOffset': 2047, 'Text': 'stomach', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'bleeding from the stomach or intestine', 'Type': 'PROBLEM', 'BeginOffset': 2072, 'EndOffset': 2110}, {'Id': 124, 'BeginOffset': 2114, 'EndOffset': 2124, 'Score': 0.8643193244934082, 'Text': 'chest pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7194193601608276}]}, {'Id': 125, 'BeginOffset': 2126, 'EndOffset': 2130, 'Score': 0.9927977919578552, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6179397702217102}]}, {'Text': 'toxic damage to the liver', 'Type': 'PROBLEM', 'BeginOffset': 2134, 'EndOffset': 2159}, {'Id': 127, 'BeginOffset': 2161, 'EndOffset': 2186, 'Score': 0.5729413032531738, 'Text': 'abnormal hepatic function', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6791554689407349}]}, {'Id': 128, 'BeginOffset': 2197, 'EndOffset': 2211, 'Score': 0.9097950458526611, 'Text': 'liver disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9545009732246399}]}, {'Text': 'infection of the lung (pneumonia)', 'Type': 'PROBLEM', 'BeginOffset': 2215, 'EndOffset': 2248}, {'Id': 131, 'BeginOffset': 2250, 'EndOffset': 2259, 'Score': 0.7067969441413879, 'Text': 'influenza', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.41197502613067627}]}, {'Id': 132, 'BeginOffset': 2261, 'EndOffset': 2271, 'Score': 0.9937896132469177, 'Text': 'bronchitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.833735466003418}]}, {'Id': 133, 'BeginOffset': 2275, 'EndOffset': 2299, 'Score': 0.3967195451259613, 'Text': 'defect in cardiac rhythm', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 134, 'BeginOffset': 2320, 'EndOffset': 2328, 'Score': 0.9796941876411438, 'Text': 'fainting', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5448629856109619}]}, {'Id': 135, 'BeginOffset': 2330, 'EndOffset': 2339, 'Score': 0.995457649230957, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7683736085891724}]}, {'Id': 136, 'BeginOffset': 2344, 'EndOffset': 2355, 'Score': 0.948419988155365, 'Text': 'palpitation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7490226030349731}]}, {'Id': 137, 'BeginOffset': 2371, 'EndOffset': 2385, 'Score': 0.506620466709137, 'Text': 'blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SIGN', 'Score': 0.49241286516189575}, {'Name': 'SYMPTOM', 'Score': 0.6250687837600708}]}, {'Id': 138, 'BeginOffset': 2389, 'EndOffset': 2412, 'Score': 0.6451256275177002, 'Text': 'high level of potassium', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'the blood', 'Type': 'TEST', 'BeginOffset': 2416, 'EndOffset': 2425}, {'Text': 'low level of phosphorus in the blood', 'Type': 'PROBLEM', 'BeginOffset': 2427, 'EndOffset': 2463}, {'Text': 'excessive loss of body fluid (dehydration', 'Type': 'PROBLEM', 'BeginOffset': 2465, 'EndOffset': 2506}, {'Text': 'pain in the muscles', 'Type': 'PROBLEM', 'BeginOffset': 2511, 'EndOffset': 2530}, {'Id': 142, 'BeginOffset': 2534, 'EndOffset': 2556, 'Score': 0.4502660632133484, 'Text': 'feeling of instability', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8698862791061401}]}, {'Id': 143, 'BeginOffset': 2558, 'EndOffset': 2567, 'Score': 0.9918144345283508, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8593526482582092}]}, {'Id': 144, 'BeginOffset': 2570, 'EndOffset': 2602, 'Score': 0.4905133843421936, 'Text': 'alteration of the sense of taste', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7784870266914368}]}, {'Text': 'acute kidney failure', 'Type': 'PROBLEM', 'BeginOffset': 2618, 'EndOffset': 2638}, {'Id': 148, 'BeginOffset': 2640, 'EndOffset': 2654, 'Score': 0.9847079515457153, 'Text': 'kidney failure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9197259545326233}]}, {'Id': 149, 'BeginOffset': 2656, 'EndOffset': 2673, 'Score': 0.9824389219284058, 'Text': 'kidney impairment', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7234907150268555}]}, {'Text': 'fluid on the lungs (pleural effusion', 'Type': 'PROBLEM', 'BeginOffset': 2677, 'EndOffset': 2713}, {'Text': 'fluid around the heart (pericardial effusion', 'Type': 'PROBLEM', 'BeginOffset': 2718, 'EndOffset': 2762}, {'Text': 'ringing in the ears (tinnitus)', 'Type': 'PROBLEM', 'BeginOffset': 2767, 'EndOffset': 2797}, {'Id': 154, 'BeginOffset': 2801, 'EndOffset': 2808, 'Score': 0.9939633011817932, 'Text': 'itching', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5626202821731567}]}, {'Id': 155, 'BeginOffset': 2810, 'EndOffset': 2819, 'Score': 0.9929285645484924, 'Text': 'urticaria', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6708155870437622}]}, {'Id': 156, 'BeginOffset': 2821, 'EndOffset': 2826, 'Score': 0.9772182106971741, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7089556455612183}]}, {'Id': 157, 'BeginOffset': 2829, 'EndOffset': 2833, 'Score': 0.9950932264328003, 'Text': 'acne', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8318747282028198}]}, {'Text': 'uncommon side effects', 'Type': 'PROBLEM', 'BeginOffset': 2835, 'EndOffset': 2856}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 2875, 'EndOffset': 2876}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 2880, 'EndOffset': 2883}, {'Id': 159, 'BeginOffset': 2895, 'EndOffset': 2900, 'Score': 0.9072197079658508, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6100833415985107}]}, {'Text': 'low white blood cell count', 'Type': 'PROBLEM', 'BeginOffset': 2917, 'EndOffset': 2943}, {'Id': 161, 'BeginOffset': 2945, 'EndOffset': 2964, 'Score': 0.734660804271698, 'Text': 'febrile neutropenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8959422707557678}]}, {'Text': 'acute inflammation of the pancreas', 'Type': 'PROBLEM', 'BeginOffset': 2969, 'EndOffset': 3003}, {'Text': 'acute pancreatitis', 'Type': 'PROBLEM', 'BeginOffset': 3005, 'EndOffset': 3023}, {'Text': 'damage to the liver', 'Type': 'PROBLEM', 'BeginOffset': 3028, 'EndOffset': 3047}, {'Text': 'life-threatening allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 3051, 'EndOffset': 3085}, {'Id': 168, 'BeginOffset': 3087, 'EndOffset': 3105, 'Score': 0.9789213538169861, 'Text': 'anaphylactic shock', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9595962166786194}]}, {'Id': 169, 'BeginOffset': 3110, 'EndOffset': 3136, 'Score': 0.566875696182251, 'Text': 'abnormal build-up of fluid', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6657345294952393}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9941076040267944, 'RelationshipScore': 0.9994194507598877, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 111, 'BeginOffset': 3144, 'EndOffset': 3149, 'Text': 'lungs', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'acute pulmonary oedema', 'Type': 'PROBLEM', 'BeginOffset': 3151, 'EndOffset': 3173}, {'Id': 172, 'BeginOffset': 3178, 'EndOffset': 3197, 'Score': 0.9453654885292053, 'Text': 'respiratory failure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.936637818813324}]}, {'Id': 173, 'BeginOffset': 3201, 'EndOffset': 3218, 'Score': 0.9192508459091187, 'Text': 'allergic reaction', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8885170817375183}]}, {'Text': 'abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension', 'Type': 'PROBLEM', 'BeginOffset': 3222, 'EndOffset': 3305}, {'Id': 176, 'BeginOffset': 3310, 'EndOffset': 3323, 'Score': 0.7654966115951538, 'Text': 'skin eruption', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8234714269638062}]}, {'Id': 177, 'BeginOffset': 3327, 'EndOffset': 3339, 'Score': 0.9266983866691589, 'Text': 'inflammation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7714797854423523}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9840720295906067, 'RelationshipScore': 0.9871625304222107, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 115, 'BeginOffset': 3372, 'EndOffset': 3377, 'Text': 'heart', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the sac', 'Type': 'PROBLEM', 'BeginOffset': 3343, 'EndOffset': 3350}, {'Id': 115, 'BeginOffset': 3372, 'EndOffset': 3377, 'Score': 0.9840720295906067, 'Text': 'heart', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 178, 'BeginOffset': 3379, 'EndOffset': 3391, 'Score': 0.8326748609542847, 'Text': 'pericarditis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8322157859802246}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9840720295906067, 'RelationshipScore': 0.6875682473182678, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 115, 'BeginOffset': 3372, 'EndOffset': 3377, 'Text': 'heart', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'a marked decrease', 'Type': 'PROBLEM', 'BeginOffset': 3396, 'EndOffset': 3413}, {'Text': 'granulocytes', 'Type': 'PROBLEM', 'BeginOffset': 3431, 'EndOffset': 3443}, {'Text': 'white blood cells', 'Type': 'TEST', 'BeginOffset': 3455, 'EndOffset': 3472}, {'Text': 'rare side effects', 'Type': 'PROBLEM', 'BeginOffset': 3475, 'EndOffset': 3492}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 3511, 'EndOffset': 3512}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 3516, 'EndOffset': 3521}, {'Text': 'severe skin disorder', 'Type': 'PROBLEM', 'BeginOffset': 3533, 'EndOffset': 3553}, {'Id': 181, 'BeginOffset': 3555, 'EndOffset': 3574, 'Score': 0.9223973751068115, 'Text': 'erythema multiforme', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9641086459159851}]}, {'Id': 182, 'BeginOffset': 3576, 'EndOffset': 3600, 'Score': 0.9920502305030823, 'Text': 'stevens-johnson syndrome', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9757761359214783}]}, {'Id': 183, 'BeginOffset': 3602, 'EndOffset': 3628, 'Score': 0.8524797558784485, 'Text': 'toxic epidermal necrolysis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9349867701530457}]}, {'Text': 'an allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 3637, 'EndOffset': 3657}, {'Text': 'exfoliative (scaly, peeling) rash', 'Type': 'PROBLEM', 'BeginOffset': 3659, 'EndOffset': 3692}, {'Id': 189, 'BeginOffset': 3707, 'EndOffset': 3719, 'Score': 0.9193827509880066, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6264484524726868}]}, {'Id': 190, 'BeginOffset': 3735, 'EndOffset': 3747, 'Score': 0.9462183713912964, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6898719668388367}]}, {'Id': 200, 'BeginOffset': 3820, 'EndOffset': 3832, 'Score': 0.9395541548728943, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6297024488449097}]}, {'Id': 201, 'BeginOffset': 3881, 'EndOffset': 3893, 'Score': 0.8513447642326355, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6967006921768188}]}, {'Id': 202, 'BeginOffset': 3947, 'EndOffset': 3958, 'Score': 0.3730241656303406, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5900313854217529}, {'Name': 'DIAGNOSIS', 'Score': 0.40676820278167725}]}, {'Id': 203, 'BeginOffset': 3972, 'EndOffset': 3984, 'Score': 0.8541449308395386, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7275785207748413}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 4040, 'EndOffset': 4053}]}

{'Title': '5. how to store bosulif', 'Section_Content': '- keep this medicine out of the sight and reach of children. - do not use this medicine after the expiry date which is stated on the blister foil and carton after "exp". the expiry date refers to the last day of that month. - this medicine does not require any special storage conditions. - do not use this medicine if you notice that the pack is damaged or shows signs of tampering. - do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. content of the pack and other information', 'Section_Content': 'what bosulif contains - the active substance is bosutinib. bosulif film-coated tablets come in different strengths. bosulif 100 mg: each film-coated tablet contains 100 mg bosutinib (as monohydrate). bosulif 400 mg: each film-coated tablet contains 400 mg bosutinib (as monohydrate). bosulif 500 mg: each film-coated tablet contains 500 mg bosutinib (as monohydrate). - the other ingredients are: microcrystalline cellulose (e460), croscarmellose sodium (e468), poloxamer 188, povidone (e1201) and magnesium stearate (e470b). the tablet film-coating contains polyvinyl alcohol, titanium dioxide (e171), macrogol 3350, talc (e553b) and iron oxide yellow (e172, for bosulif 100 mg and 400 mg) or iron oxide red (e172, for bosulif 400 mg and 500 mg). what bosulif looks like and contents of the pack bosulif 100 mg film-coated tablets are yellow, oval biconvex, debossed with "pfizer" on one side and "100" on the other side. bosulif 100 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 28 or 30 film-coated tablets or 112 film-coated tablets. bosulif 400 mg film-coated tablets are orange, oval biconvex, debossed with "pfizer" on one side and "400" on the other side. bosulif 400 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 28 or 30 film-coated tablets. bosulif 500 mg film-coated tablets are red, oval biconvex, debossed with "pfizer" on one side and "500" on the other side. bosulif 500 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 28 or 30 film-coated tablets. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'bosulif', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 12, 'Score': 0.40831607580184937, 'Text': 'bosulif', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 48, 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'RelationshipScore': 0.99950110912323, 'RelationshipType': 'STRENGTH', 'Id': 12, 'BeginOffset': 208, 'EndOffset': 214, 'Text': '400 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.31094714999198914, 'RelationshipScore': 0.9999252557754517, 'RelationshipType': 'FORM', 'Id': 13, 'BeginOffset': 216, 'EndOffset': 225, 'Text': 'each film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.8067443370819092, 'RelationshipScore': 0.9999814033508301, 'RelationshipType': 'FORM', 'Id': 14, 'BeginOffset': 226, 'EndOffset': 239, 'Text': 'coated tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9850196838378906, 'RelationshipScore': 0.9798234701156616, 'RelationshipType': 'DOSAGE', 'Id': 15, 'BeginOffset': 249, 'EndOffset': 255, 'Text': '400 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '400', 'Type': 'NUMBER', 'BeginOffset': 208, 'EndOffset': 211}, {'Text': '400', 'Type': 'NUMBER', 'BeginOffset': 249, 'EndOffset': 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4102ED063BB0171B37B6BDF6463572DA

https://www.ema.europa.eu/documents/product-information/brilique-epar-product-information_en.pdf

Brilique

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Brilique 60 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 60 mg ticagrelor. Brilique contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium-free’. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Round, biconvex, pink tablets marked with ‘60’ above ‘T’ on one side and plain on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Brilique, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with - acute coronary syndromes (ACS) or - a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event (see sections 4.2 and 5.1). 4.2 Posology and method of administration Posology Patients taking Brilique should also take a daily low maintenance dose of ASA 75-150 mg, unless specifically contraindicated. Acute coronary syndromes Brilique treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily. Treatment with Brilique 90 mg twice daily is recommended for 12 months in ACS patients unless discontinuation is clinically indicated (see section 5.1). History of myocardial infarction Brilique 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event (see section 5.1). Treatment may be started without interruption as continuation therapy after the initial one-year treatment with Brilique 90 mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in ACS patients with a high risk of an atherothrombotic event. Treatment can also be initiated up to 2 years from the MI, or within one year after stopping previous ADP receptor inhibitor treatment. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment. 3 If a switch is needed, the first dose of Brilique should be administered 24 hours following the last dose of the other antiplatelet medication. Missed dose Lapses in therapy should also be avoided. A patient who misses a dose of Brilique should take only one tablet (their next dose) at its scheduled time. Special populations Elderly No dose adjustment is required in elderly (see section 5.2). Renal impairment No dose adjustment is necessary for patients with renal impairment (see section 5.2). Hepatic impairment Ticagrelor has not been studied in patients with severe hepatic impairment and its use in these patients is therefore contraindicated (see section 4.3). Only limited information is available in patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor should be used with caution (see sections 4.4 and 5.2). No dose adjustment is necessary for patients with mild hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of ticagrelor in children below the age of 18 years have not been established. No data are available. Method of administration For oral use. Brilique can be administered with or without food. For patients who are unable to swallow the tablet(s) whole, the tablets can be crushed to a fine powder and mixed in half a glass of water and drunk immediately. The glass should be rinsed with a further half glass of water and the contents drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture. 4.3 Contraindications  Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.8).  Active pathological bleeding.  History of intracranial haemorrhage (see section 4.8).  Severe hepatic impairment (see sections 4.2, 4.4 and 5.2).  Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor (see section 4.5). 4.4 Special warnings and precautions for use Bleeding risk The use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events (see sections 4.8 and 5.1). If clinically indicated, ticagrelor should be used with caution in the following patient groups: 4  Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding). The use of ticagrelor is contraindicated in patients with active pathological bleeding, in those with a history of intracranial haemorrhage, and in patients with severe hepatic impairment (see section 4.3).  Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing. Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of ticagrelor with desmopressin did not decrease template-bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events (see section 4.5). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may increase haemostasis. Ticagrelor may be resumed after the cause of bleeding has been identified and controlled. Surgery Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken. In PLATO patients undergoing coronary artery bypass grafting (CABG), ticagrelor had more bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery (see section 4.8). If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 5 days prior to surgery (see section 5.1). Patients with prior ischaemic stroke ACS patients with prior ischaemic stroke can be treated with ticagrelor for up to 12 months (PLATO study). In PEGASUS, patients with history of MI with prior ischaemic stroke were not included. Therefore, in the absence of data, treatment beyond one year is not recommended in these patients. Hepatic impairment Use of ticagrelor is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3). There is limited experience with ticagrelor in patients with moderate hepatic impairment, therefore, caution is advised in these patients (see sections 4.2 and 5.2). Patients at risk for bradycardic events Holter ECG monitoring has shown an increased frequency of mostly asymptomatic ventricular pauses during treatment with ticagrelor compared with clopidogrel. Patients with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope) have been excluded from the main studies evaluating the safety and efficacy of ticagrelor. Therefore, due to the limited clinical experience, ticagrelor should be used with caution in these patients (see section 5.1). In addition, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil and 4% digoxin) (see section 4.5). 5 During the Holter substudy in PLATO, more patients had ventricular pauses >3 seconds with ticagrelor than with clopidogrel during the acute phase of their ACS. The increase in Holter-detected ventricular pauses with ticagrelor was higher in patients with chronic heart failure (CHF) than in the overall study population during the acute phase of ACS, but not at one month with ticagrelor or compared to clopidogrel. There were no adverse clinical consequences associated with this imbalance (including syncope or pacemaker insertion) in this patient population (see section 5.1). Dyspnoea Dyspnoea was reported in patients treated with ticagrelor. Dyspnoea is usually mild to moderate in intensity and often resolves without need for treatment discontinuation. Patients with asthma/chronic obstructive pulmonary disease (COPD) may have an increased absolute risk of experiencing dyspnoea with ticagrelor. Ticagrelor should be used with caution in patients with history of asthma and/or COPD. The mechanism has not been elucidated. If a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with ticagrelor should be stopped. For further details see section 4.8. Creatinine elevations Creatinine levels may increase during treatment with ticagrelor. The mechanism has not been elucidated. Renal function should be checked according to routine medical practice. In patients with ACS, it is recommended that renal function is also checked one month after initiating the treatment with ticagrelor, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an angiotensin receptor blocker (ARB). Uric acid increase Hyperuricaemia may occur during treatment with ticagrelor (see section 4.8). Caution is advised in patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged. Thrombotic Thrombocytopenic Purpura (TTP) Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely with the use of ticagrelor. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. Interference with platelet function tests to diagnose heparin induced thrombocytopenia (HIT) In the heparin induced platelet activation (HIPA) test used to diagnose HIT, anti-platelet factor 4/heparin antibodies in patient serum activate platelets of healthy donors in the presence of heparin. False negative results in a platelet function test (to include, but may not be limited to the HIPA test) for HIT have been reported in patients administered ticagrelor. This is related to inhibition of the P2Y12-receptor on the healthy donor platelets in the test by ticagrelor in the patient’s sera/plasma. Information on concomitant treatment with ticagrelor is required for interpretation of HIT platelet function tests. In patients who have developed HIT, the benefit-risk of continued treatment with ticagrelor should be assessed, taking both the prothrombotic state of HIT and the increased risk of bleeding with concomitant anticoagulant and ticagrelor treatment into consideration. Other 6 Based on a relationship observed in PLATO between maintenance ASA dose and relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high maintenance dose ASA (>300 mg) is not recommended (see section 5.1). Premature discontinuation Premature discontinuation with any antiplatelet therapy, including Brilique, could result in an increased risk of cardiovascular (CV) death, MI or stroke due to the patient’s underlying disease. Therefore, premature discontinuation of treatment should be avoided. 4.5 Interaction with other medicinal products and other forms of interaction Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates. Effects of medicinal and other products on ticagrelor CYP3A4 inhibitors  Strong CYP3A4 inhibitors – Co-administration of ketoconazole with ticagrelor increased the ticagrelor Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) would be expected to have similar effects and therefore concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section 4.3).  Moderate CYP3A4 inhibitors – Co-administration of diltiazem with ticagrelor increased the ticagrelor Cmax by 69% and AUC to 2.7-fold and decreased the active metabolite Cmax by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to have a similar effect and can as well be co-administered with ticagrelor.  A 2-fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3x200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients. CYP3A inducers Co-administration of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax of the active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well. Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged. Cyclosporine (P-gp and CYP3A inhibitor) Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of cyclosporine. No data are available on concomitant use of ticagrelor with other active substances that also are potent P-gp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) that also may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution. 7 Others Clinical pharmacology interaction studies showed that co-administration of ticagrelor with heparin, enoxaparin and ASA or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or the active metabolite or on ADP-induced platelet aggregation compared with ticagrelor alone. If clinically indicated, medicinal products that alter haemostasis should be used with caution in combination with ticagrelor. A delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, has been observed in patients with ACS treated with morphine (35% reduction in ticagrelor exposure). This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced ticagrelor efficacy in patients co-administered ticagrelor and morphine. In patients with ACS, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered. Effects of ticagrelor on other medicinal products Medicinal products metabolised by CYP3A4  Simvastatin – Co-administration of ticagrelor with simvastatin increased simvastatin Cmax by 81% and AUC by 56% and increased simvastatin acid Cmax by 64% and AUC by 52% with some individual increases equal to 2- to 3-fold. Co-administration of ticagrelor with doses of simvastatin exceeding 40 mg daily could cause adverse reactions of simvastatin and should be weighed against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. Ticagrelor may have similar effect on lovastatin. The concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended.  Atorvastatin – Co-administration of atorvastatin and ticagrelor increased atorvastatin acid Cmax by 23% and AUC by 36%. Similar increases in AUC and Cmax were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.  A similar effect on other statins metabolised by CYP3A4 cannot be excluded. Patients in PLATO receiving ticagrelor took a variety of statins, with no concern of an association with statin safety among the 93% of the PLATO cohort taking these medicinal products. Ticagrelor is a mild CYP3A4 inhibitor. Co-administration of ticagrelor and CYP3A4 substrates with narrow therapeutic indices (i.e. cisapride or ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal products. P-gp substrates (including digoxin, cyclosporine) Concomitant administration of ticagrelor increased the digoxin Cmax by 75% and AUC by 28%. The mean trough digoxin levels were increased about 30% with ticagrelor co-administration with some individual maximum increases to 2-fold. In the presence of digoxin, the Cmax and AUC of ticagrelor and its active metabolite were not affected. Therefore, appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent medicinal products like digoxin concomitantly with ticagrelor. There was no effect of ticagrelor on cyclosporine blood levels. Effect of ticagrelor on other P-gp substrates has not been studied. Medicinal products metabolised by CYP2C9 Co-administration of ticagrelor with tolbutamide resulted in no change in the plasma levels of either medicinal product, which suggests that ticagrelor is not a CYP2C9 inhibitor and unlikely to alter the CYP2C9 mediated metabolism of medicinal products like warfarin and tolbutamide. 8 Oral contraceptives Co-administration of ticagrelor and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are co-administered with ticagrelor. Medicinal products known to induce bradycardia Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia (see section 4.4). However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil and 4% digoxin). Other concomitant therapy In clinical studies, ticagrelor was commonly administered with ASA, proton pump inhibitors, statins, beta-blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers as needed for concomitant conditions for long-term and also heparin, low molecular weight heparin and intravenous GpIIb/IIIa inhibitors for short durations (see section 5.1). No evidence of clinically significant adverse interactions with these medicinal products was observed. Co-administration of ticagrelor with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (aPTT), activated coagulation time (ACT) or factor Xa assays. However, due to potential pharmacodynamic interactions, caution should be exercised with the concomitant administration of ticagrelor with medicinal products known to alter haemostasis. Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and citalopram), caution is advised when administering SSRIs with ticagrelor as this may increase the risk of bleeding. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy. Pregnancy There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Ticagrelor is not recommended during pregnancy. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk (see section 5.3). A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Ticagrelor had no effect on male or female fertility in animals (see section 5.3). 4.7 Effects on ability to drive and use machines 9 Ticagrelor has no or negligible influence on the ability to drive and use machines. During treatment with ticagrelor, dizziness and confusion have been reported. Therefore, patients who experience these symptoms should be cautious while driving or using machines. 4.8 Undesirable effects Summary of the safety profile The safety profile of ticagrelor has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients (see section 5.1). In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea (see section 4.4). Tabulated list of adverse reactions The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 1). Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: Very common (≥1/10), common (≥1/100 to 1/10), uncommon (≥1/1,000 to 1/100), rare (≥1/10,000 to 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Table 1 – Adverse reactions by frequency and system organ class (SOC) SOC Very common Common Uncommon Not known Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumour bleedingsa Blood and lymphatic system disorders Blood disorder bleedingsb Thrombotic Thrombocytopenic Purpurac Immune system disorders Hypersensitivity including angioedemac Metabolism and nutrition disorders Hyperuricaemiad Gout/Gouty Arthritis Psychiatric disorders Confusion Nervous system disorders Dizziness, Syncope, Headache Intracranial haemorrhage 10 SOC Very common Common Uncommon Not known Eye disorders Eye haemorrhagee Ear and labyrinth disorders Vertigo Ear haemorrhage Vascular disorders Hypotension Respiratory, thoracic and mediastinal disorders Dyspnoea Respiratory system bleedingsf Gastrointestinal disorders Gastrointestinal haemorrhageg, Diarrhoea, Nausea, Dyspepsia, Constipation Retroperitoneal haemorrhage Skin and subcutaneous tissue disorders Subcutaneous or dermal bleedingh, Rash, Pruritus Musculoskeletal connective tissue and bone Muscular bleedingsi Renal and urinary disorders Urinary tract bleedingj Reproductive system and breast disorders Reproductive system bleedingsk Investigations Blood creatinine increasedd Injury, poisoning and procedural complications Post procedural haemorrhage, Traumatic bleedingsl a e.g. bleeding from bladder cancer, gastric cancer, colon cancer b e.g. increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis c Identified in post-marketing experience d Frequencies derived from lab observations (Uric acid increases to >upper limit of normal from baseline below or within reference range. Creatinine increases of >50% from baseline.) and not crude adverse event report frequency. e e.g. conjunctival, retinal, intraocular bleeding f e.g. epistaxis, haemoptysis g e.g. gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage h e.g. ecchymosis, skin haemorrhage, petechiae i e.g. haemarthrosis, muscle haemorrhage j e.g. haematuria, cystitis haemorrhagic k e.g. vaginal haemorrhage, haematospermia, postmenopausal haemorrhage l e.g. contusion, traumatic haematoma, traumatic haemorrhage 11 Description of selected adverse reactions Bleeding Bleeding findings in PLATO Overall outcome of bleeding rates in the PLATO study are shown in Table 2. Table 2 – Analysis of overall bleeding events, Kaplan-Meier estimates at 12 months (PLATO) Ticagrelor 90 mg twice daily N=9235 Clopidogrel N=9186 p-value* PLATO Total Major 11.6 11.2 0.4336 PLATO Major Fatal/Life-Threatening 5.8 5.8 0.6988 Non-CABG PLATO Major 4.5 3.8 0.0264 Non-Procedural PLATO Major 3.1 2.3 0.0058 PLATO Total Major + Minor 16.1 14.6 0.0084 Non-Procedural PLATO Major + Minor 5.9 4.3 0.0001 TIMI-defined Major 7.9 7.7 0.5669 TIMI-defined Major + Minor 11.4 10.9 0.3272 Bleeding category definitions: Major Fatal/Life-threatening Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused; or fatal; or intracranial; or intrapericardial with cardiac tamponade; or with hypovolaemic shock or severe hypotension requiring pressors or surgery. Major Other: Clinically apparent with 30-50 g/L decrease in haemoglobin or 2-3 red cell units transfused; or significantly disabling. Minor Bleed: Requires medical intervention to stop or treat bleeding. TIMI Major Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or intracranial haemorrhage. TIMI Minor Bleed: Clinically apparent with 30-50 g/L decrease in haemoglobin. *p-value calculated from Cox proportional hazards model with treatment group as the only explanatory variable. Ticagrelor and clopidogrel did not differ in rates of PLATO Major Fatal/Life-threatening bleeding, PLATO total Major bleeding, TIMI Major bleeding, or TIMI Minor bleeding (Table 2). However, more PLATO combined Major + Minor bleeding occurred with ticagrelor compared with clopidogrel. Few patients in PLATO had fatal bleeds: 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel (see section 4.4). Age, sex, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history, including a previous stroke or transient ischaemic attack, all did not predict either overall or non-procedural PLATO Major bleeding. Thus, no particular group was identified at risk for any subset of bleeding. CABG-related bleeding: In PLATO, 42% of the 1584 patients (12% of cohort) who underwent coronary artery bypass graft (CABG) surgery had a PLATO Major Fatal/Life-threatening bleeding with no difference between treatment groups. Fatal CABG bleeding occurred in 6 patients in each treatment group (see section 4.4). Non-CABG related bleeding and non-procedural related bleeding: Ticagrelor and clopidogrel did not differ in non-CABG PLATO-defined Major Fatal/Life- threatening bleeding, but PLATO-defined Total Major, TIMI Major, and TIMI Major + Minor bleeding were more common with ticagrelor. Similarly, when removing all procedure related bleeds, more bleeding occurred with ticagrelor than with clopidogrel (Table 2). Discontinuation of 12 treatment due to non-procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p<0.001). Intracranial bleeding: There were more intracranial non-procedural bleeds with ticagrelor (n=27 bleeds in 26 patients, 0.3%) than with clopidogrel (n=14 bleeds, 0.2%), of which 11 bleeds with ticagrelor and 1 with clopidogrel were fatal. There was no difference in overall fatal bleeds. Bleeding findings in PEGASUS Overall outcome of bleeding events in the PEGASUS study are shown in Table 3. Table 3 – Analysis of overall bleeding events, Kaplan-Meier estimates at 36 months (PEGASUS) Ticagrelor 60 mg twice daily + ASA N=6958 ASA alone N=6996 Safety Endpoints KM% Hazard Ratio (95% CI) KM% p-value TIMI-defined bleeding categories TIMI Major 2.3 2.32 (1.68, 3.21) 1.1 <0.0001 Fatal 0.3 1.00 (0.44, 2.27) 0.3 1.0000 ICH 0.6 1.33 (0.77, 2.31) 0.5 0.3130 Other TIMI Major 1.6 3.61 (2.31, 5.65) 0.5 <0.0001 TIMI Major or Minor 3.4 2.54 (1.93, 3.35) 1.4 <0.0001 TIMI Major or Minor or Requiring medical attention 16.6 2.64 (2.35, 2.97) 7.0 <0.0001 PLATO-defined bleeding categories PLATO Major 3.5 2.57 (1.95, 3.37) 1.4 <0.0001 Fatal/Life-threatening 2.4 2.38 (1.73, 3.26) 1.1 <0.0001 Other PLATO Major 1.1 3.37 (1.95, 5.83) 0.3 <0.0001 PLATO Major or Minor 15.2 2.71 (2.40, 3.08) 6.2 <0.0001 Bleeding category definitions: TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of haemorrhage associated with a drop in haemoglobin (Hgb) of ≥50 g/L, or when Hgb is not available, a fall in haematocrit (Hct) of 15%. Fatal: A bleeding event that directly led to death within 7 days. ICH: Intracranial haemorrhage. Other TIMI Major: Non-fatal non-ICH TIMI Major bleeding. TIMI Minor: Clinically apparent with 30-50 g/L decrease in haemoglobin. 13 TIMI Requiring medical attention: Requiring intervention, OR leading to hospitalisation, OR prompting evaluation. PLATO Major Fatal/life-threatening: Fatal bleeding, OR any intracranial bleeding, OR intrapericardial with cardiac tamponade, OR with hypovolaemic shock or severe hypotension requiring pressors/inotropes or surgery OR clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused. PLATO Major Other: Significantly disabling, OR clinically apparent with 30-50 g/L decrease in haemoglobin, OR 2-3 red cell units transfused. PLATO Minor: Requires medical intervention to stop or treat bleeding. In PEGASUS, TIMI Major bleeding for ticagrelor 60 mg twice daily was higher than for ASA alone. No increased bleeding risk was seen for fatal bleeding and only a minor increase was observed in intracranial haemorrhages, as compared to ASA therapy alone. There were few fatal bleeding events in the study, 11 (0.3%) for ticagrelor 60 mg and 12 (0.3%) for ASA therapy alone. The observed increased risk of TIMI Major bleeding with ticagrelor 60 mg was primarily due to a higher frequency of Other TIMI Major bleedings driven by events in the gastrointestinal SOC. Increased bleeding patterns similar to TIMI Major were seen for TIMI Major or Minor and PLATO Major and PLATO Major or Minor bleeding categories (see Table 3). Discontinuation of treatment due to bleeding was more common with ticagrelor 60 mg compared to ASA therapy alone (6.2% and 1.5%, respectively). The majority of these bleedings were of less severity (classified as TIMI Requiring medical attention), e.g. epistaxis, bruising and haematomas. The bleeding profile of ticagrelor 60 mg was consistent across multiple pre-defined subgroups (e.g. by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history) for TIMI Major, TIMI Major or Minor and PLATO Major bleeding events. Intracranial bleeding: Spontaneous ICHs were reported in similar rates for ticagrelor 60 mg and ASA therapy alone (n=13, 0.2% in both treatment groups). Traumatic and procedural ICHs showed a minor increase with ticagrelor 60 mg treatment, (n=15, 0.2%) compared with ASA therapy alone (n=10, 0.1%). There were 6 fatal ICHs with ticagrelor 60 mg and 5 fatal ICHs with ASA therapy alone. The incidence of intracranial bleeding was low in both treatment groups given the significant comorbidity and CV risk factors of the population under study. Dyspnoea Dyspnoea, a sensation of breathlessness, is reported by patients treated with ticagrelor. In PLATO, dyspnoea adverse events (AEs) (dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea), when combined, was reported by 13.8% of patients treated with ticagrelor and by 7.8% of patients treated with clopidogrel. In 2.2% of patients taking ticagrelor and by 0.6% taking clopidogrel investigators considered the dyspnoea causally related to treatment in the PLATO study and few were serious (0.14% ticagrelor; 0.02% clopidogrel), (see section 4.4). Most reported symptoms of dyspnoea were mild to moderate in intensity, and most were reported as a single episode early after starting treatment. Compared with clopidogrel, patients with asthma/COPD treated with ticagrelor may have an increased risk of experiencing non-serious dyspnoea (3.29% ticagrelor versus 0.53% clopidogrel) and serious dyspnoea (0.38% ticagrelor versus 0.00% clopidogrel). In absolute terms, this risk was higher than in the overall PLATO population. Ticagrelor should be used with caution in patients with history of asthma and/or COPD (see section 4.4). About 30% of episodes resolved within 7 days. PLATO included patients with baseline congestive heart failure, COPD or asthma; these patients, and the elderly, were more likely to report dyspnoea. For ticagrelor, 0.9% of patients discontinued study drug because of dyspnoea compared with 14 0.1% taking clopidogrel. The higher incidence of dyspnoea with ticagrelor is not associated with new or worsening heart or lung disease (see section 4.4). Ticagrelor does not affect tests of pulmonary function. In PEGASUS, dyspnoea was reported in 14.2% of patients taking ticagrelor 60 mg twice daily and in 5.5% of patients taking ASA alone. As in PLATO, most reported dyspnoea was mild to moderate in intensity (see section 4.4). Patients who reported dyspnoea tended to be older and more frequently had dyspnoea, COPD or asthma at baseline. Investigations Uric acid elevations: In PLATO, serum uric acid increased to more than upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. The corresponding numbers in PEGASUS were 9.1%, 8.8% and 5.5% for ticagrelor 90 mg, 60 mg and placebo, respectively. Mean serum uric acid increased approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel and after treatment was stopped, decreased to approximately 7% on ticagrelor but with no decrease observed for clopidogrel. In PEGASUS, a reversible increase in mean serum uric acid levels of 6.3% and 5.6% was found for ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In PLATO, the frequency of gouty arthritis was 0.2% for ticagrelor vs. 0.1% for clopidogrel. The corresponding numbers for gout/gouty arthritis in PEGASUS were 1.6%, 1.5% and 1.1% for ticagrelor 90 mg, 60 mg and placebo, respectively. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Ticagrelor is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in a single ascending dose study. Other clinically meaningful adverse reactions which may occur with overdose include dyspnoea and ventricular pauses (see section 4.8). In the event of an overdose, the above potential adverse reactions could occur and ECG monitoring should be considered. There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not dialysable (see section 5.2). Treatment of overdose should follow local standard medical practice. The expected effect of excessive ticagrelor dosing is prolonged duration of bleeding risk associated with platelet inhibition. Platelet transfusion is unlikely to be of clinical benefit in patients with bleeding (see section 4.4). If bleeding occurs other appropriate supportive measures should be taken. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC24 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 15 Mechanism of action Brilique contains ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct acting, selective and reversibly binding P2Y12 receptor antagonist that prevents ADP-mediated P2Y12 dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding but when bound to the P2Y12 receptor prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of CV events such as death, MI or stroke. Ticagrelor also increases local endogenous adenosine levels by inhibiting the equilibrative nucleoside transporter-1 (ENT-1). Ticagrelor has been documented to augment the following adenosine-induced effects in healthy subjects and in patients with ACS: vasodilation (measured by coronary blood flow increases in healthy volunteers and ACS patients; headache), inhibition of platelet function (in human whole blood in vitro) and dyspnoea. However, a link between the observed increases in adenosine and clinical outcomes (e.g. morbidity-mortality) has not been clearly elucidated. Pharmacodynamic effects Onset of action In patients with stable coronary artery disease (CAD) on ASA, ticagrelor demonstrates a rapid onset of pharmacological effect as demonstrated by a mean inhibition of platelet aggregation (IPA) for ticagrelor at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA effect of 89% by 2-4 hours post dose, and maintained between 2-8 hours. 90% of patients had final extent IPA>70% by 2 hours post dose. Offset of action If a CABG procedure is planned, ticagrelor bleeding risk is increased compared to clopidogrel when discontinued within less than 96 hours prior to procedure. Switching data Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute IPA increase of 26.4% and switching from ticagrelor to clopidogrel results in an absolute IPA decrease of 24.5%. Patients can be switched from clopidogrel to ticagrelor without any interruption of antiplatelet effect (see section 4.2). Clinical efficacy and safety The clinical evidence for the efficacy and safety of ticagrelor is derived from two phase 3 trials:  The PLATO [PLATelet Inhibition and Patient Outcomes] study, a comparison of ticagrelor to clopidogrel, both given in combination with ASA and other standard therapy.  The PEGASUS TIMI-54 [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients] study, a comparison of ticagrelor combined with ASA to ASA therapy alone. PLATO study (Acute Coronary Syndromes) The PLATO study included 18,624 patients who presented within 24 hours of onset of symptoms of unstable angina (UA), non ST elevation myocardial infarction (NSTEMI) or ST elevation myocardial infarction (STEMI), and were initially managed medically, or with percutaneous coronary intervention (PCI), or with CABG. 16 Clinical efficacy On a background of daily ASA, ticagrelor 90 mg twice daily showed superiority to 75 mg daily clopidogrel in preventing the composite endpoint of CV death, MI or stroke, with the difference driven by CV death and MI. Patients received a 300 mg loading dose of clopidogrel (600 mg possible if having PCI) or 180 mg of ticagrelor. The result appeared early (absolute risk reduction [ARR] 0.6% and relative risk reduction [RRR] of 12% at 30 days), with a constant treatment effect over the entire 12-month period, yielding ARR 1.9% per year with RRR of 16%. This suggests it is appropriate to treat patients with ticagrelor 90 mg twice daily for 12 months (see section 4.2). Treating 54 ACS patients with ticagrelor instead of clopidogrel will prevent 1 atherothrombotic event; treating 91 will prevent 1 CV death (see Figure 1 and Table 4). The treatment effect of ticagrelor over clopidogrel appears consistent across many subgroups, including weight; sex; medical history of diabetes mellitus, transient ischaemic attack or non-haemorrhagic stroke, or revascularisation; concomitant therapies including heparins, GpIIb/IIIa inhibitors and proton pump inhibitors (see section 4.5); final index event diagnosis (STEMI, NSTEMI or UA); and treatment pathway intended at randomisation (invasive or medical). A weakly significant treatment interaction was observed with region whereby the hazard ratio (HR) for the primary endpoint favours ticagrelor in the rest of world but favours clopidogrel in North America, which represented approximately 10% of the overall population studied (interaction p-value=0.045). Exploratory analyses suggest a possible association with ASA dose such that reduced efficacy was observed with ticagrelor with increasing ASA doses. Chronic daily ASA doses to accompany ticagrelor should be 75-150 mg (see sections 4.2 and 4.4). Figure 1 shows the estimate of the risk to the first occurrence of any event in the composite efficacy endpoint. 17 Figure 1 – Analysis of primary clinical composite endpoint of CV death, MI and stroke (PLATO) Ticagrelor reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI population (Table 4). Thus, Brilique 90 mg twice daily together with low-dose ASA can be used in patients with ACS (unstable angina, non-ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG). Table 4 - Analysis of primary and secondary efficacy endpoints (PLATO) Ticagrelor 90 mg twice daily (% patients with event) N=9333 Clopidogrel 75 mg once daily (% patients with event) N=9291 ARRa (%/yr) RRRa (%) (95% CI) p-value CV death, MI (excl. silent MI) or stroke 9.3 10.9 1.9 16 (8, 23) 0.0003 Invasive intent 8.5 10.0 1.7 16 (6, 25) 0.0025 Medical intent 11.3 13.2 2.3 15 (0.3, 27) 0.0444d CV death 3.8 4.8 1.1 21 (9, 31) 0.0013 MI (excl. silent MI)b 5.4 6.4 1.1 16 (5, 25) 0.0045 Stroke 1.3 1.1 -0.2 -17 (-52, 9) 0.2249 All-cause mortality, MI (excl. silent MI) or stroke 9.7 11.5 2.1 16 (8, 23) 0.0001 18 CV death, total MI, stroke, SRI, RI, TIA or other ATEc 13.8 15.7 2.1 12 (5, 19) 0.0006 All-cause mortality 4.3 5.4 1.4 22 (11, 31) 0.0003d Definite stent thrombosis 1.2 1.7 0.6 32 (8, 49) 0.0123d a ARR = absolute risk reduction; RRR = relative risk reduction = (1-Hazard ratio) x 100%. A negative RRR indicates a relative risk increase. b Excluding silent MI. c SRI = serious recurrent ischaemia; RI = recurrent ischaemia; TIA = transient ischaemic attack; ATE = arterial thrombotic event. Total MI includes silent MI, with date of event set to date when discovered. d Nominal significance value; all others are formally statistically significant by pre-defined hierarchical testing. PLATO genetic substudy CYP2C19 and ABCB1 genotyping of 10,285 patients in PLATO provided associations of genotype groups with PLATO outcomes. The superiority of ticagrelor over clopidogrel in reducing major CV events was not significantly affected by patient CYP2C19 or ABCB1 genotype. Similar to the overall PLATO study, total PLATO Major bleeding did not differ between ticagrelor and clopidogrel, regardless of CYP2C19 or ABCB1 genotype. Non-CABG PLATO Major bleeding was increased with ticagrelor compared clopidogrel in patients with one or more CYP2C19 loss of function alleles, but similar to clopidogrel in patients with no loss of function allele. Combined efficacy and safety composite A combined efficacy and safety composite (CV death, MI, stroke or PLATO-defined ‘Total Major’ bleeding) indicates that the benefit in efficacy of ticagrelor compared to clopidogrel is not offset by the major bleeding events (ARR 1.4%, RRR 8%, HR 0.92; p=0.0257) over 12 months after ACS. Clinical safety Holter substudy: To study the occurrence of ventricular pauses and other arrhythmic episodes during PLATO, investigators performed Holter monitoring in a subset of nearly 3000 patients, of whom approximately 2000 had recordings both in the acute phase of their ACS and after one month. The primary variable of interest was the occurrence of ventricular pauses ≥3 seconds. More patients had ventricular pauses with ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase; and 2.2% and 1.6%, respectively, after 1 month (see section 4.4). The increase in ventricular pauses in the acute phase of ACS was more pronounced in ticagrelor patients with history of CHF (9.2% versus 5.4% in patients without CHF history; for clopidogrel patients, 4.0% in those with versus 3.6% in those without CHF history). This imbalance did not occur at one month: 2.0% versus 2.1% for ticagrelor patients with and without CHF history, respectively; and 3.8% versus 1.4% with clopidogrel. There were no adverse clinical consequences associated with this imbalance (including pacemaker insertions) in this population of patients. PEGASUS study (History of Myocardial Infarction) The PEGASUS TIMI-54 study was a 21,162 patient, event-driven, randomised, double-blind, placebo-controlled, parallel group, international multicentre study to assess the prevention of atherothrombotic events with ticagrelor given at 2 doses (either 90 mg twice daily or 60 mg twice daily) combined with low dose ASA (75-150 mg), compared to ASA therapy alone in patients with history of MI and additional risk factors for atherothrombosis. Patients were eligible to participate if they were aged 50 years or over, with a history of MI (1 to 3 years prior to randomisation), and had at least one of the following risk factors for 19 atherothrombosis: age ≥65 years, diabetes mellitus requiring medication, a second prior MI, evidence of multivessel CAD or chronic non-end-stage renal dysfunction. Patients were ineligible if there was planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period; if they had a bleeding disorder or a history of an ischaemic stroke or intracranial bleeding, a central nervous system tumour or an intracranial vascular abnormality; if they had had gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days. Clinical efficacy Figure 2 - Analysis of primary clinical composite endpoint of CV death, MI and stroke (PEGASUS) Table 5 - Analysis of primary and secondary efficacy endpoints (PEGASUS) Ticagrelor 60 mg twice daily +ASA N = 7045 ASA alone N = 7067 p-value Characteristic Patients with events KM % HR (95% CI) Patients with events KM % Primary endpoint 20 Ticagrelor 60 mg twice daily +ASA N = 7045 ASA alone N = 7067 p-value Characteristic Patients with events KM % HR (95% CI) Patients with events KM % Composite of CV Death/MI/Stroke 487 (6.9%) 7.8% 0.84 (0.74, 0.95) 578 (8.2%) 9.0% 0.0043 (s) CV death 174 (2.5%) 2.9% 0.83 (0.68, 1.01) 210 (3.0%) 3.4% 0.0676 MI 285 (4.0%) 4.5% 0.84 (0.72, 0.98) 338 (4.8%) 5.2% 0.0314 Stroke 91 (1.3%) 1.5% 0.75 (0.57, 0.98) 122 (1.7%) 1.9% 0.0337 Secondary endpoint CV death 174 (2.5%) 2.9% 0.83 (0.68, 1.01) 210 (3.0%) 3.4% - All-cause mortality 289 (4.1%) 4.7% 0.89 (0.76, 1.04) 326 (4.6%) 5.2% - Hazard ratio and p-values are calculated separately for ticagrelor vs. ASA therapy alone from Cox proportional hazards model with treatment group as the only explanatory variable. KM percentage calculated at 36 months. Note: the number of first events for the components CV death, MI and stroke are the actual number of first events for each component and do not add up to the number of events in the composite endpoint (s) Indicates statistical significance. CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; KM = Kaplan-Meier; MI = Myocardial infarction; N = Number of patients. Both 60 mg twice daily and 90 mg twice daily regimens of ticagrelor in combination with ASA were superior to ASA alone in the prevention of atherothrombotic events (composite endpoint: CV death, MI and stroke), with a consistent treatment effect over the entire study period, yielding a 16% RRR and 1.27% ARR for ticagrelor 60 mg and a 15% RRR and 1.19% ARR for ticagrelor 90 mg. Although the efficacy profiles of 90 mg and 60 mg were similar, there is evidence that the lower dose has a better tolerability and safety profile in relation to risk of the bleeding and dyspnoea. Therefore, only Brilique 60 mg twice daily co-administered with ASA is recommended for the prevention atherothrombotic events (CV death, MI and stroke) in patients with a history of MI and a high risk of developing an atherothrombotic event. Relative to ASA alone, ticagrelor 60 mg twice daily significantly reduced the primary composite endpoint of CV death, MI and stroke. Each of the components contributed to the reduction in the primary composite endpoint (CV death 17% RRR, MI 16% RRR and stroke 25% RRR). The RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) was similar. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment. There was no evidence of benefit (no reduction in the primary composite endpoint of CV death, MI and stroke, but an increase in major bleeding) when ticagrelor 60 mg twice daily was introduced in 21 clinically stable patients >2 years from the MI, or more than one year after stopping previous ADP receptor inhibitor treatment (see also section 4.2). Clinical safety The rate of discontinuations with ticagrelor 60 mg due to bleeding and dyspnoea was higher in patients >75 years (42%) than in younger patients (range: 23-31%), with a difference versus placebo higher than 10% (42% vs. 29%) in patients >75 years. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Brilique in all subsets of the paediatric population in acute coronary syndromes (ACS) and history of myocardial infarction (MI) (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Ticagrelor demonstrates linear pharmacokinetics and exposure to ticagrelor and the active metabolite (AR-C124910XX) are approximately dose proportional up to 1260 mg. Absorption Absorption of ticagrelor is rapid with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with a median tmax of approximately 2.5 hours. Following an oral ticagrelor 90 mg single dose under fasted conditions in healthy subjects, Cmax is 529 ng/ml and AUC is 3451 ng*h/ml. The metabolite parent ratios are 0.28 for Cmax and 0.42 for AUC. The pharmacokinetics of ticagrelor and AR-C124910XX in patients with a history of MI were generally similar to that in the ACS population. Based on a population pharmacokinetic analysis of the PEGASUS study the median ticagrelor Cmax was 391 ng/ml and AUC was 3801 ng*h/ml at steady state for ticagrelor 60 mg. For ticagrelor 90 mg Cmax was 627 ng/ml and AUC was 6255 ng*h/ml at steady state. The mean absolute bioavailability of ticagrelor was estimated to be 36%. Ingestion of a high-fat meal resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite Cmax but had no effect on ticagrelor Cmax or the AUC of the active metabolite. These small changes are considered of minimal clinical significance; therefore, ticagrelor can be given with or without food. Ticagrelor as well as the active metabolite are P-gp substrates. Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, has a comparable bioavailability to whole tablets with regards to AUC and Cmax for ticagrelor and the active metabolite. Initial exposure (0.5 and 1 hour post-dose) from crushed ticagrelor tablets mixed in water was higher compared to whole tablets, with a generally identical concentration profile thereafter (2 to 48 hours). Distribution The steady state volume of distribution of ticagrelor is 87.5 l. Ticagrelor and the active metabolite is extensively bound to human plasma protein (>99.0%). Biotransformation CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. 22 The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor. Elimination The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabelled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the active metabolite is most likely via biliary secretion. The mean t1/2 was approximately 7 hours for ticagrelor and 8.5 hours for the active metabolite. Special populations Elderly Higher exposures to ticagrelor (approximately 25% for both Cmax and AUC) and the active metabolite were observed in elderly (≥75years) ACS patients compared to younger patients by the population pharmacokinetic analysis. These differences are not considered clinically significant (see section 4.2). Paediatric population Ticagrelor has not been evaluated in a paediatric population (see sections 4.2 and 5.1). Gender Higher exposures to ticagrelor and the active metabolite were observed in women compared to men. These differences are not considered clinically significant. Renal impairment Exposure to ticagrelor was approximately 20% lower and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment (creatinine clearance <30 ml/min) compared to subjects with normal renal function. In patients with end stage renal disease on haemodialysis AUC and Cmax of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately prior to dialysis (49% and 61%, respectively) showing that ticagrelor is not dialysable. Exposure of the active metabolite increased to a lesser extent (AUC 13-14% and Cmax 17-36%). The inhibition of platelet aggregation (IPA) effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to subjects with normal renal function (see section 4.2). Hepatic impairment Cmax and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to matched healthy subjects, respectively, however, the IPA effect of ticagrelor was similar between the two groups. No dose adjustment is needed for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with severe hepatic impairment and there is no pharmacokinetic information in patients with moderate hepatic impairment. In patients that had moderate or severe elevation in one or more liver function tests at baseline, ticagrelor plasma concentrations were on average similar or slightly higher as compared to those without baseline elevations. No dose adjustment is recommended in patients with moderate hepatic impairment (see sections 4.2 and 4.4). 23 Ethnicity Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Patients self-identified as black had an 18% lower bioavailability of ticagrelor compared to Caucasian patients, in clinical pharmacology studies, the exposure (Cmax and AUC) to ticagrelor in Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians. The exposure in patients self-identified as Hispanic or Latino was similar to that in Caucasians. 5.3 Preclinical safety data Preclinical data for ticagrelor and its major metabolite have not demonstrated unacceptable risk for adverse effects for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxic potential. Gastrointestinal irritation was observed in several animal species at clinical relevant exposure levels (see section 4.8). In female rats, ticagrelor at high dose showed an increased incidence of uterine tumours (adenocarcinomas) and an increased incidence of hepatic adenomas. The mechanism for uterine tumours is likely hormonal imbalance which can lead to tumours in rats. The mechanism for the hepatic adenomas is likely due to a rodent-specific enzyme induction in the liver. Thus, the carcinogenicity findings are considered unlikely to be relevant for humans. In rats, minor developmental anomalies were seen at a maternal toxic dose (safety margin of 5.1). In rabbits, a slight delay in hepatic maturity and skeletal development was seen in foetuses from dams at high dose without showing maternal toxicity (safety margin of 4.5). Studies in rats and rabbits have shown reproductive toxicity, with slightly reduced maternal body weight gain and reduced neonatal viability and birth weight, with delayed growth. Ticagrelor produced irregular cycles (mostly extended cycles) in female rats, but did not affect overall fertility in male and female rats. Pharmacokinetic studies performed with radiolabelled ticagrelor have shown that the parent compound and its metabolites are excreted in the milk of rats (see section 4.6). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Mannitol (E421) Calcium hydrogen phosphate dihydrate Magnesium stearate (E470b) Sodium starch glycolate type A Hydroxypropylcellulose (E463) Tablet coating Titanium dioxide (E171) Iron oxide black (E172) Iron oxide red (E172) Macrogol 400 Hypromellose (E464) 24 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container  PVC-PVDC/Al transparent blister (with sun/moon symbols) of 10 tablets; cartons of 60 tablets (6 blisters) and 180 tablets (18 blisters).  PVC-PVDC/Al transparent calendar blister (with sun/moon symbols) of 14 tablets; cartons of 14 tablets (1 blister), 56 tablets (4 blisters) and 168 tablets (12 blisters). Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 8. MARKETING AUTHORISATION NUMBER(S) EU/1/10/655/007-011 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 03 December 2010 Date of latest renewal: 17 July 2015 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 25 1. NAME OF THE MEDICINAL PRODUCT Brilique 90 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 90 mg ticagrelor. Brilique contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium-free’. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Round, biconvex, yellow tablets marked with ‘90’ above ‘T’ on one side and plain on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Brilique, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with - acute coronary syndromes (ACS) or - a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event (see sections 4.2 and 5.1). 4.2 Posology and method of administration Posology Patients taking Brilique should also take a daily low maintenance dose of ASA 75-150 mg, unless specifically contraindicated. Acute coronary syndromes Brilique treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.Treatment with Brilique 90 mg twice daily is recommended for 12 months in ACS patients unless discontinuation is clinically indicated (see section 5.1). History of myocardial infarction Brilique 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event (see section 5.1). Treatment may be started without interruption as continuation therapy after the initial one-year treatment with Brilique 90 mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in ACS patients with a high risk of an atherothrombotic event. Treatment can also be initiated up to 2 years from the MI, or within one year after stopping previous ADP receptor inhibitor treatment. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment. 26 If a switch is needed, the first dose of Brilique should be administered 24 hours following the last dose of the other antiplatelet medication. Missed dose Lapses in therapy should also be avoided. A patient who misses a dose of Brilique should take only one tablet (their next dose) at its scheduled time. Special populations Elderly No dose adjustment is required in elderly (see section 5.2). Renal impairment No dose adjustment is necessary for patients with renal impairment (see section 5.2). Hepatic impairment Ticagrelor has not been studied in patients with severe hepatic impairment and its use in these patients is therefore contraindicated (see section 4.3). Only limited information is available in patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor should be used with caution (see sections 4.4 and 5.2). No dose adjustment is necessary for patients with mild hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of ticagrelor in children below the age of 18 years have not been established. No data are available. Method of administration For oral use. Brilique can be administered with or without food. For patients who are unable to swallow the tablet(s) whole, the tablets can be crushed to a fine powder and mixed in half a glass of water and drunk immediately. The glass should be rinsed with a further half glass of water and the contents drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture. 4.3 Contraindications  Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.8).  Active pathological bleeding.  History of intracranial haemorrhage (see section 4.8).  Severe hepatic impairment (see sections 4.2, 4.4 and 5.2).  Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor (see section 4.5). 4.4 Special warnings and precautions for use Bleeding risk The use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events (see sections 4.8 and 5.1). If clinically indicated, ticagrelor should be used with caution in the following patient groups: 27  Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding). The use of ticagrelor is contraindicated in patients with active pathological bleeding, in those with a history of intracranial haemorrhage, and in patients with severe hepatic impairment (see section 4.3).  Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing. Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of ticagrelor with desmopressin did not decrease template-bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events (see section 4.5). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may increase haemostasis. Ticagrelor may be resumed after the cause of bleeding has been identified and controlled. Surgery Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken. In PLATO patients undergoing coronary artery bypass grafting (CABG), ticagrelor had more bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery (see section 4.8). If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 5 days prior to surgery (see section 5.1). Patients with prior ischaemic stroke ACS patients with prior ischaemic stroke can be treated with ticagrelor for up to 12 months (PLATO study). In PEGASUS, patients with history of MI with prior ischaemic stroke were not included. Therefore, in the absence of data, treatment beyond one year is not recommended in these patients. Hepatic impairment Use of ticagrelor is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3). There is limited experience with ticagrelor in patients with moderate hepatic impairment, therefore, caution is advised in these patients (see sections 4.2 and 5.2). Patients at risk for bradycardic events Holter ECG monitoring has shown an increased frequency of mostly asymptomatic ventricular pauses during treatment with ticagrelor compared with clopidogrel. Patients with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope) have been excluded from the main studies evaluating the safety and efficacy of ticagrelor. Therefore, due to the limited clinical experience, ticagrelor should be used with caution in these patients (see section 5.1). In addition, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil and 4% digoxin) (see section 4.5). 28 During the Holter substudy in PLATO, more patients had ventricular pauses >3 seconds with ticagrelor than with clopidogrel during the acute phase of their ACS. The increase in Holter-detected ventricular pauses with ticagrelor was higher in patients with chronic heart failure (CHF) than in the overall study population during the acute phase of ACS, but not at one month with ticagrelor or compared to clopidogrel. There were no adverse clinical consequences associated with this imbalance (including syncope or pacemaker insertion) in this patient population (see section 5.1). Dyspnoea Dyspnoea was reported in patients treated with ticagrelor. Dyspnoea is usually mild to moderate in intensity and often resolves without need for treatment discontinuation. Patients with asthma/chronic obstructive pulmonary disease (COPD) may have an increased absolute risk of experiencing dyspnoea with ticagrelor. Ticagrelor should be used with caution in patients with history of asthma and/or COPD. The mechanism has not been elucidated. If a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with ticagrelor should be stopped. For further details see section 4.8. Creatinine elevations Creatinine levels may increase during treatment with ticagrelor. The mechanism has not been elucidated. Renal function should be checked according to routine medical practice. In patients with ACS, it is recommended that renal function is also checked one month after initiating the treatment with ticagrelor, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an angiotensin receptor blocker (ARB). Uric acid increase Hyperuricaemia may occur during treatment with ticagrelor (see section 4.8). Caution is advised in patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged. Thrombotic Thrombocytopenic Purpura (TTP) Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely with the use of ticagrelor. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. Interference with platelet function tests to diagnose heparin induced thrombocytopenia (HIT) In the heparin induced platelet activation (HIPA) test used to diagnose HIT, anti-platelet factor 4/heparin antibodies in patient serum activate platelets of healthy donors in the presence of heparin. False negative results in a platelet function test (to include, but may not be limited to the HIPA test) for HIT have been reported in patients administered ticagrelor. This is related to inhibition of the P2Y12-receptor on the healthy donor platelets in the test by ticagrelor in the patient’s sera/plasma. Information on concomitant treatment with ticagrelor is required for interpretation of HIT platelet function tests. In patients who have developed HIT, the benefit-risk of continued treatment with ticagrelor should be assessed, taking both the prothrombotic state of HIT and the increased risk of bleeding with concomitant anticoagulant and ticagrelor treatment into consideration. Other 29 Based on a relationship observed in PLATO between maintenance ASA dose and relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high maintenance dose ASA (>300 mg) is not recommended (see section 5.1). Premature discontinuation Premature discontinuation with any antiplatelet therapy, including Brilique, could result in an increased risk of cardiovascular (CV) death, MI or stroke due to the patient’s underlying disease. Therefore, premature discontinuation of treatment should be avoided. 4.5 Interaction with other medicinal products and other forms of interaction Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates. Effects of medicinal and other products on ticagrelor CYP3A4 inhibitors  Strong CYP3A4 inhibitors – Co-administration of ketoconazole with ticagrelor increased the ticagrelor Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) would be expected to have similar effects and therefore concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section 4.3).  Moderate CYP3A4 inhibitors – Co-administration of diltiazem with ticagrelor increased the ticagrelor Cmax by 69% and AUC to 2.7-fold and decreased the active metabolite Cmax by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to have a similar effect and can as well be co-administered with ticagrelor.  A 2-fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3x200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients. CYP3A inducers Co-administration of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax of the active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well. Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged. Cyclosporine (P-gp and CYP3A inhibitor) Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of cyclosporine. No data are available on concomitant use of ticagrelor with other active substances that also are potent P-gp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) that also may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution. 30 Others Clinical pharmacology interaction studies showed that co-administration of ticagrelor with heparin, enoxaparin and ASA or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or the active metabolite or on ADP-induced platelet aggregation compared with ticagrelor alone. If clinically indicated, medicinal products that alter haemostasis should be used with caution in combination with ticagrelor. A delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, has been observed in patients with ACS treated with morphine (35% reduction in ticagrelor exposure). This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced ticagrelor efficacy in patients co-administered ticagrelor and morphine. In patients with ACS, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered. Effects of ticagrelor on other medicinal products Medicinal products metabolised by CYP3A4  Simvastatin – Co-administration of ticagrelor with simvastatin increased simvastatin Cmax by 81% and AUC by 56% and increased simvastatin acid Cmax by 64% and AUC by 52% with some individual increases equal to 2- to 3-fold. Co-administration of ticagrelor with doses of simvastatin exceeding 40 mg daily could cause adverse reactions of simvastatin and should be weighed against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. Ticagrelor may have similar effect on lovastatin. The concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended.  Atorvastatin – Co-administration of atorvastatin and ticagrelor increased atorvastatin acid Cmax by 23% and AUC by 36%. Similar increases in AUC and Cmax were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.  A similar effect on other statins metabolised by CYP3A4 cannot be excluded. Patients in PLATO receiving ticagrelor took a variety of statins, with no concern of an association with statin safety among the 93% of the PLATO cohort taking these medicinal products. Ticagrelor is a mild CYP3A4 inhibitor. Co-administration of ticagrelor and CYP3A4 substrates with narrow therapeutic indices (i.e. cisapride or ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal products. P-gp substrates (including digoxin, cyclosporine) Concomitant administration of ticagrelor increased the digoxin Cmax by 75% and AUC by 28%. The mean trough digoxin levels were increased about 30% with ticagrelor co-administration with some individual maximum increases to 2-fold. In the presence of digoxin, the Cmax and AUC of ticagrelor and its active metabolite were not affected. Therefore, appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent medicinal products like digoxin concomitantly with ticagrelor. There was no effect of ticagrelor on cyclosporine blood levels. Effect of ticagrelor on other P-gp substrates has not been studied. Medicinal products metabolised by CYP2C9 Co-administration of ticagrelor with tolbutamide resulted in no change in the plasma levels of either medicinal product, which suggests that ticagrelor is not a CYP2C9 inhibitor and unlikely to alter the CYP2C9 mediated metabolism of medicinal products like warfarin and tolbutamide. 31 Oral contraceptives Co-administration of ticagrelor and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are co-administered with ticagrelor. Medicinal products known to induce bradycardia Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia (see section 4.4). However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil and 4% digoxin). Other concomitant therapy In clinical studies, ticagrelor was commonly administered with ASA, proton pump inhibitors, statins, beta-blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers as needed for concomitant conditions for long-term and also heparin, low molecular weight heparin and intravenous GpIIb/IIIa inhibitors for short durations (see section 5.1). No evidence of clinically significant adverse interactions with these medicinal products was observed. Co-administration of ticagrelor with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (aPTT), activated coagulation time (ACT) or factor Xa assays. However, due to potential pharmacodynamic interactions, caution should be exercised with the concomitant administration of ticagrelor with medicinal products known to alter haemostasis. Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and citalopram), caution is advised when administering SSRIs with ticagrelor as this may increase the risk of bleeding. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy. Pregnancy There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Ticagrelor is not recommended during pregnancy. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk (see section 5.3). A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Ticagrelor had no effect on male or female fertility in animals (see section 5.3). 4.7 Effects on ability to drive and use machines 32 Ticagrelor has no or negligible influence on the ability to drive and use machines. During treatment with ticagrelor, dizziness and confusion have been reported. Therefore, patients who experience these symptoms should be cautious while driving or using machines. 4.8 Undesirable effects Summary of the safety profile The safety profile of ticagrelor has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients (see section 5.1). In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea (see section 4.4). Tabulated list of adverse reactions The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 1). Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: Very common (≥1/10), common (≥1/100 to 1/10), uncommon (≥1/1,000 to 1/100), rare (≥1/10,000 to 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Table 1 – Adverse reactions by frequency and system organ class (SOC) SOC Very common Common Uncommon Not known Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumour bleedingsa Blood and lymphatic system disorders Blood disorder bleedingsb Thrombotic Thrombocytopenic Purpurac Immune system disorders Hypersensitivity including angioedemac Metabolism and nutrition disorders Hyperuricaemiad Gout/Gouty Arthritis Psychiatric disorders Confusion Nervous system disorders Dizziness, Syncope, Headache Intracranial haemorrhage 33 SOC Very common Common Uncommon Not known Eye disorders Eye haemorrhagee Ear and labyrinth disorders Vertigo Ear haemorrhage Vascular disorders Hypotension Respiratory, thoracic and mediastinal disorders Dyspnoea Respiratory system bleedingsf Gastrointestinal disorders Gastrointestinal haemorrhageg, Diarrhoea, Nausea, Dyspepsia, Constipation Retroperitoneal haemorrhage Skin and subcutaneous tissue disorders Subcutaneous or dermal bleedingh, Rash, Pruritus Musculoskeletal connective tissue and bone Muscular bleedingsi Renal and urinary disorders Urinary tract bleedingj Reproductive system and breast disorders Reproductive system bleedingsk Investigations Blood creatinine increasedd Injury, poisoning and procedural complications Post procedural haemorrhage, Traumatic bleedingsl a e.g. bleeding from bladder cancer, gastric cancer, colon cancer b e.g. increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis c Identified in post-marketing experience d Frequencies derived from lab observations (Uric acid increases to >upper limit of normal from baseline below or within reference range. Creatinine increases of >50% from baseline.) and not crude adverse event report frequency. e e.g. conjunctival, retinal, intraocular bleeding f e.g. epistaxis, haemoptysis g e.g. gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage h e.g. ecchymosis, skin haemorrhage, petechiae i e.g. haemarthrosis, muscle haemorrhage j e.g. haematuria, cystitis haemorrhagic k e.g. vaginal haemorrhage, haematospermia, postmenopausal haemorrhage l e.g. contusion, traumatic haematoma, traumatic haemorrhage 34 Description of selected adverse reactions Bleeding Bleeding findings in PLATO Overall outcome of bleeding rates in the PLATO study are shown in Table 2. Table 2 – Analysis of overall bleeding events, Kaplan-Meier estimates at 12 months (PLATO) Ticagrelor 90 mg twice daily N=9235 Clopidogrel N=9186 p-value* PLATO Total Major 11.6 11.2 0.4336 PLATO Major Fatal/Life-Threatening 5.8 5.8 0.6988 Non-CABG PLATO Major 4.5 3.8 0.0264 Non-Procedural PLATO Major 3.1 2.3 0.0058 PLATO Total Major + Minor 16.1 14.6 0.0084 Non-Procedural PLATO Major + Minor 5.9 4.3 0.0001 TIMI-defined Major 7.9 7.7 0.5669 TIMI-defined Major + Minor 11.4 10.9 0.3272 Bleeding category definitions: Major Fatal/Life-threatening Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused; or fatal; or intracranial; or intrapericardial with cardiac tamponade; or with hypovolaemic shock or severe hypotension requiring pressors or surgery. Major Other: Clinically apparent with 30-50 g/L decrease in haemoglobin or 2-3 red cell units transfused; or significantly disabling. Minor Bleed: Requires medical intervention to stop or treat bleeding. TIMI Major Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or intracranial haemorrhage. TIMI Minor Bleed: Clinically apparent with 30-50 g/L decrease in haemoglobin. *p-value calculated from Cox proportional hazards model with treatment group as the only explanatory variable. Ticagrelor and clopidogrel did not differ in rates of PLATO Major Fatal/Life-threatening bleeding, PLATO total Major bleeding, TIMI Major bleeding, or TIMI Minor bleeding (Table 2). However, more PLATO combined Major + Minor bleeding occurred with ticagrelor compared with clopidogrel. Few patients in PLATO had fatal bleeds: 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel (see section 4.4). Age, sex, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history, including a previous stroke or transient ischaemic attack, all did not predict either overall or non-procedural PLATO Major bleeding. Thus, no particular group was identified at risk for any subset of bleeding. CABG-related bleeding: In PLATO, 42% of the 1584 patients (12% of cohort) who underwent coronary artery bypass graft (CABG) surgery had a PLATO Major Fatal/Life-threatening bleeding with no difference between treatment groups. Fatal CABG bleeding occurred in 6 patients in each treatment group (see section 4.4). Non-CABG related bleeding and non-procedural related bleeding: Ticagrelor and clopidogrel did not differ in non-CABG PLATO-defined Major Fatal/Life- threatening bleeding, but PLATO-defined Total Major, TIMI Major, and TIMI Major + Minor bleeding were more common with ticagrelor. Similarly, when removing all procedure related bleeds, more bleeding occurred with ticagrelor than with clopidogrel (Table 2). Discontinuation of 35 treatment due to non-procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p<0.001). Intracranial bleeding: There were more intracranial non-procedural bleeds with ticagrelor (n=27 bleeds in 26 patients, 0.3%) than with clopidogrel (n=14 bleeds, 0.2%), of which 11 bleeds with ticagrelor and 1 with clopidogrel were fatal. There was no difference in overall fatal bleeds. Bleeding findings in PEGASUS Overall outcome of bleeding events in the PEGASUS study are shown in Table 3. Table 3 – Analysis of overall bleeding events, Kaplan-Meier estimates at 36 months (PEGASUS) Ticagrelor 60 mg twice daily + ASA N=6958 ASA alone N=6996 Safety Endpoints KM% Hazard Ratio (95% CI) KM% p-value TIMI-defined bleeding categories TIMI Major 2.3 2.32 (1.68, 3.21) 1.1 <0.0001 Fatal 0.3 1.00 (0.44, 2.27) 0.3 1.0000 ICH 0.6 1.33 (0.77, 2.31) 0.5 0.3130 Other TIMI Major 1.6 3.61 (2.31, 5.65) 0.5 <0.0001 TIMI Major or Minor 3.4 2.54 (1.93, 3.35) 1.4 <0.0001 TIMI Major or Minor or Requiring medical attention 16.6 2.64 (2.35, 2.97) 7.0 <0.0001 PLATO-defined bleeding categories PLATO Major 3.5 2.57 (1.95, 3.37) 1.4 <0.0001 Fatal/Life-threatening 2.4 2.38 (1.73, 3.26) 1.1 <0.0001 Other PLATO Major 1.1 3.37 (1.95, 5.83) 0.3 <0.0001 PLATO Major or Minor 15.2 2.71 (2.40, 3.08) 6.2 <0.0001 Bleeding category definitions: TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of haemorrhage associated with a drop in haemoglobin (Hgb) of ≥50 g/L, or when Hgb is not available, a fall in haematocrit (Hct) of 15%. Fatal: A bleeding event that directly led to death within 7 days. ICH: Intracranial haemorrhage. Other TIMI Major: Non-fatal non-ICH TIMI Major bleeding. TIMI Minor: Clinically apparent with 30-50 g/L decrease in haemoglobin. 36 TIMI Requiring medical attention: Requiring intervention, OR leading to hospitalisation, OR prompting evaluation. PLATO Major Fatal/life-threatening: Fatal bleeding, OR any intracranial bleeding, OR intrapericardial with cardiac tamponade, OR with hypovolaemic shock or severe hypotension requiring pressors/inotropes or surgery OR clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused. PLATO Major Other: Significantly disabling, OR clinically apparent with 30-50 g/L decrease in haemoglobin, OR 2-3 red cell units transfused. PLATO Minor: Requires medical intervention to stop or treat bleeding. In PEGASUS, TIMI Major bleeding for ticagrelor 60 mg twice daily was higher than for ASA alone. No increased bleeding risk was seen for fatal bleeding and only a minor increase was observed in intracranial haemorrhages, as compared to ASA therapy alone. There were few fatal bleeding events in the study, 11 (0.3%) for ticagrelor 60 mg and 12 (0.3%) for ASA therapy alone. The observed increased risk of TIMI Major bleeding with ticagrelor 60 mg was primarily due to a higher frequency of Other TIMI Major bleedings driven by events in the gastrointestinal SOC. Increased bleeding patterns similar to TIMI Major were seen for TIMI Major or Minor and PLATO Major and PLATO Major or Minor bleeding categories (see Table 3). Discontinuation of treatment due to bleeding was more common with ticagrelor 60 mg compared to ASA therapy alone (6.2% and 1.5%, respectively). The majority of these bleedings were of less severity (classified as TIMI Requiring medical attention), e.g. epistaxis, bruising and haematomas. The bleeding profile of ticagrelor 60 mg was consistent across multiple pre-defined subgroups (e.g. by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history) for TIMI Major, TIMI Major or Minor and PLATO Major bleeding events. Intracranial bleeding: Spontaneous ICHs were reported in similar rates for ticagrelor 60 mg and ASA therapy alone (n=13, 0.2% in both treatment groups). Traumatic and procedural ICHs showed a minor increase with ticagrelor 60 mg treatment, (n=15, 0.2%) compared with ASA therapy alone (n=10, 0.1%). There were 6 fatal ICHs with ticagrelor 60 mg and 5 fatal ICHs with ASA therapy alone. The incidence of intracranial bleeding was low in both treatment groups given the significant comorbidity and CV risk factors of the population under study. Dyspnoea Dyspnoea, a sensation of breathlessness, is reported by patients treated with ticagrelor. In PLATO, dyspnoea adverse events (AEs) (dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea), when combined, was reported by 13.8% of patients treated with ticagrelor and by 7.8% of patients treated with clopidogrel. In 2.2% of patients taking ticagrelor and by 0.6% taking clopidogrel investigators considered the dyspnoea causally related to treatment in the PLATO study and few were serious (0.14% ticagrelor; 0.02% clopidogrel), (see section 4.4). Most reported symptoms of dyspnoea were mild to moderate in intensity, and most were reported as a single episode early after starting treatment. Compared with clopidogrel, patients with asthma/COPD treated with ticagrelor may have an increased risk of experiencing non-serious dyspnoea (3.29% ticagrelor versus 0.53% clopidogrel) and serious dyspnoea (0.38% ticagrelor versus 0.00% clopidogrel). In absolute terms, this risk was higher than in the overall PLATO population. Ticagrelor should be used with caution in patients with history of asthma and/or COPD (see section 4.4). About 30% of episodes resolved within 7 days. PLATO included patients with baseline congestive heart failure, COPD or asthma; these patients, and the elderly, were more likely to report dyspnoea. For ticagrelor, 0.9% of patients discontinued study drug because of dyspnoea compared with 37 0.1% taking clopidogrel. The higher incidence of dyspnoea with ticagrelor is not associated with new or worsening heart or lung disease (see section 4.4). Ticagrelor does not affect tests of pulmonary function. In PEGASUS, dyspnoea was reported in 14.2% of patients taking ticagrelor 60 mg twice daily and in 5.5% of patients taking ASA alone. As in PLATO, most reported dyspnoea was mild to moderate in intensity (see section 4.4). Patients who reported dyspnoea tended to be older and more frequently had dyspnoea, COPD or asthma at baseline. Investigations Uric acid elevations: In PLATO, serum uric acid increased to more than upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. The corresponding numbers in PEGASUS were 9.1%, 8.8% and 5.5% for ticagrelor 90 mg, 60 mg and placebo, respectively. Mean serum uric acid increased approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel and after treatment was stopped, decreased to approximately 7% on ticagrelor but with no decrease observed for clopidogrel. In PEGASUS, a reversible increase in mean serum uric acid levels of 6.3% and 5.6% was found for ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In PLATO, the frequency of gouty arthritis was 0.2% for ticagrelor vs. 0.1% for clopidogrel. The corresponding numbers for gout/gouty arthritis in PEGASUS were 1.6%, 1.5% and 1.1% for ticagrelor 90 mg, 60 mg and placebo, respectively. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Ticagrelor is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in a single ascending dose study. Other clinically meaningful adverse reactions which may occur with overdose include dyspnoea and ventricular pauses (see section 4.8). In the event of an overdose, the above potential adverse reactions could occur and ECG monitoring should be considered. There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not dialysable (see section 5.2). Treatment of overdose should follow local standard medical practice. The expected effect of excessive ticagrelor dosing is prolonged duration of bleeding risk associated with platelet inhibition. Platelet transfusion is unlikely to be of clinical benefit in patients with bleeding (see section 4.4). If bleeding occurs other appropriate supportive measures should be taken. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC24 Mechanism of action http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 38 Brilique contains ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct acting, selective and reversibly binding P2Y12 receptor antagonist that prevents ADP-mediated P2Y12 dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding but when bound to the P2Y12 receptor prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of CV events such as death, MI or stroke. Ticagrelor also increases local endogenous adenosine levels by inhibiting the equilibrative nucleoside transporter-1 (ENT-1). Ticagrelor has been documented to augment the following adenosine-induced effects in healthy subjects and in patients with ACS: vasodilation (measured by coronary blood flow increases in healthy volunteers and ACS patients; headache), inhibition of platelet function (in human whole blood in vitro) and dyspnoea. However, a link between the observed increases in adenosine and clinical outcomes (e.g. morbidity-mortality) has not been clearly elucidated. Pharmacodynamic effects Onset of action In patients with stable coronary artery disease (CAD) on ASA, ticagrelor demonstrates a rapid onset of pharmacological effect as demonstrated by a mean inhibition of platelet aggregation (IPA) for ticagrelor at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA effect of 89% by 2-4 hours post dose, and maintained between 2-8 hours. 90% of patients had final extent IPA>70% by 2 hours post dose. Offset of action If a CABG procedure is planned, ticagrelor bleeding risk is increased compared to clopidogrel when discontinued within less than 96 hours prior to procedure. Switching data Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute IPA increase of 26.4% and switching from ticagrelor to clopidogrel results in an absolute IPA decrease of 24.5%. Patients can be switched from clopidogrel to ticagrelor without any interruption of antiplatelet effect (see section 4.2). Clinical efficacy and safety The clinical evidence for the efficacy and safety of ticagrelor is derived from two phase 3 trials:  The PLATO [PLATelet Inhibition and Patient Outcomes] study, a comparison of ticagrelor to clopidogrel, both given in combination with ASA and other standard therapy.  The PEGASUS TIMI-54 [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients] study, a comparison of ticagrelor combined with ASA to ASA therapy alone. PLATO study (Acute Coronary Syndromes) The PLATO study included 18,624 patients who presented within 24 hours of onset of symptoms of unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI) or ST elevation myocardial infarction (STEMI), and were initially managed medically, or with percutaneous coronary intervention (PCI), or with CABG. Clinical efficacy 39 On a background of daily ASA, ticagrelor 90 mg twice daily showed superiority to 75 mg daily clopidogrel in preventing the composite endpoint of CV death, MI or stroke, with the difference driven by CV death and MI. Patients received a 300 mg loading dose of clopidogrel (600 mg possible if having PCI) or 180 mg of ticagrelor. The result appeared early (absolute risk reduction [ARR] 0.6% and relative risk reduction [RRR] of 12% at 30 days), with a constant treatment effect over the entire 12-month period, yielding ARR 1.9% per year with RRR of 16%. This suggests it is appropriate to treat patients with ticagrelor 90 mg twice daily for 12 months (see section 4.2). Treating 54 ACS patients with ticagrelor instead of clopidogrel will prevent 1 atherothrombotic event; treating 91 will prevent 1 CV death (see Figure 1 and Table 4). The treatment effect of ticagrelor over clopidogrel appears consistent across many subgroups, including weight; sex; medical history of diabetes mellitus, transient ischaemic attack or non-haemorrhagic stroke, or revascularisation; concomitant therapies including heparins, GpIIb/IIIa inhibitors and proton pump inhibitors (see section 4.5); final index event diagnosis (STEMI, NSTEMI or UA); and treatment pathway intended at randomisation (invasive or medical). A weakly significant treatment interaction was observed with region whereby the hazard ratio (HR) for the primary endpoint favours ticagrelor in the rest of world but favours clopidogrel in North America, which represented approximately 10% of the overall population studied (interaction p-value=0.045). Exploratory analyses suggest a possible association with ASA dose such that reduced efficacy was observed with ticagrelor with increasing ASA doses. Chronic daily ASA doses to accompany ticagrelor should be 75-150 mg (see sections 4.2 and 4.4). Figure 1 shows the estimate of the risk to the first occurrence of any event in the composite efficacy endpoint. 40 Figure 1 – Analysis of primary clinical composite endpoint of CV death, MI and stroke (PLATO) Ticagrelor reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI population (Table 4). Thus, Brilique 90 mg twice daily together with low-dose ASA can be used in patients with ACS (unstable angina, non-ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG). Table 4 - Analysis of primary and secondary efficacy endpoints (PLATO) Ticagrelor 90 mg twice daily (% patients with event) N=9333 Clopidogrel 75 mg once daily (% patients with event) N=9291 ARRa (%/yr) RRRa (%) (95% CI) p-value CV death, MI (excl. silent MI) or stroke 9.3 10.9 1.9 16 (8, 23) 0.0003 Invasive intent 8.5 10.0 1.7 16 (6, 25) 0.0025 Medical intent 11.3 13.2 2.3 15 (0.3, 27) 0.0444d CV death 3.8 4.8 1.1 21 (9, 31) 0.0013 MI (excl. silent MI)b 5.4 6.4 1.1 16 (5, 25) 0.0045 Stroke 1.3 1.1 -0.2 -17 (-52, 9) 0.2249 41 All-cause mortality, MI (excl. silent MI) or stroke 9.7 11.5 2.1 16 (8, 23) 0.0001 CV death, total MI, stroke, SRI, RI, TIA or other ATEc 13.8 15.7 2.1 12 (5, 19) 0.0006 All-cause mortality 4.3 5.4 1.4 22 (11, 31) 0.0003d Definite stent thrombosis 1.2 1.7 0.6 32 (8, 49) 0.0123d a ARR = absolute risk reduction; RRR = relative risk reduction = (1-Hazard ratio) x 100%. A negative RRR indicates a relative risk increase. b Excluding silent MI. c SRI = serious recurrent ischaemia; RI = recurrent ischaemia; TIA = transient ischaemic attack; ATE = arterial thrombotic event. Total MI includes silent MI, with date of event set to date when discovered. d Nominal significance value; all others are formally statistically significant by pre-defined hierarchical testing. PLATO genetic substudy CYP2C19 and ABCB1 genotyping of 10,285 patients in PLATO provided associations of genotype groups with PLATO outcomes. The superiority of ticagrelor over clopidogrel in reducing major CV events was not significantly affected by patient CYP2C19 or ABCB1 genotype. Similar to the overall PLATO study, total PLATO Major bleeding did not differ between ticagrelor and clopidogrel, regardless of CYP2C19 or ABCB1 genotype. Non-CABG PLATO Major bleeding was increased with ticagrelor compared clopidogrel in patients with one or more CYP2C19 loss of function alleles, but similar to clopidogrel in patients with no loss of function allele. Combined efficacy and safety composite A combined efficacy and safety composite (CV death, MI, stroke or PLATO-defined ‘Total Major’ bleeding) indicates that the benefit in efficacy of ticagrelor compared to clopidogrel is not offset by the major bleeding events (ARR 1.4%, RRR 8%, HR 0.92; p=0.0257) over 12 months after ACS. Clinical safety Holter substudy: To study the occurrence of ventricular pauses and other arrhythmic episodes during PLATO, investigators performed Holter monitoring in a subset of nearly 3000 patients, of whom approximately 2000 had recordings both in the acute phase of their ACS and after one month. The primary variable of interest was the occurrence of ventricular pauses ≥3 seconds. More patients had ventricular pauses with ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase; and 2.2% and 1.6%, respectively, after 1 month (see section 4.4). The increase in ventricular pauses in the acute phase of ACS was more pronounced in ticagrelor patients with history of CHF (9.2% versus 5.4% in patients without CHF history; for clopidogrel patients, 4.0% in those with versus 3.6% in those without CHF history). This imbalance did not occur at one month: 2.0% versus 2.1% for ticagrelor patients with and without CHF history, respectively; and 3.8% versus 1.4% with clopidogrel. There were no adverse clinical consequences associated with this imbalance (including pacemaker insertions) in this population of patients. PEGASUS study (History of Myocardial Infarction) The PEGASUS TIMI-54 study was a 21,162 patient, event-driven, randomised, double-blind, placebo-controlled, parallel group, international multicentre study to assess the prevention of atherothrombotic events with ticagrelor given at 2 doses (either 90 mg twice daily or 60 mg twice daily) combined with low dose ASA (75-150 mg), compared to ASA therapy alone in patients with history of MI and additional risk factors for atherothrombosis. 42 Patients were eligible to participate if they were aged 50 years or over, with a history of MI (1 to 3 years prior to randomisation), and had at least one of the following risk factors for atherothrombosis: age ≥65 years, diabetes mellitus requiring medication, a second prior MI, evidence of multivessel CAD or chronic non-end-stage renal dysfunction. Patients were ineligible if there was planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period; if they had a bleeding disorder or a history of an ischaemic stroke or intracranial bleeding, a central nervous system tumour or an intracranial vascular abnormality; if they had had gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days. Clinical efficacy Figure 2 - Analysis of primary clinical composite endpoint of CV death, MI and stroke (PEGASUS) Table 5 - Analysis of primary and secondary efficacy endpoints (PEGASUS) Ticagrelor 60 mg twice daily +ASA N = 7045 ASA alone N = 7067 p-value Characteristic Patients with events KM % HR (95% CI) Patients with events KM % Primary endpoint 43 Ticagrelor 60 mg twice daily +ASA N = 7045 ASA alone N = 7067 p-value Characteristic Patients with events KM % HR (95% CI) Patients with events KM % Composite of CV Death/MI/Stroke 487 (6.9%) 7.8% 0.84 (0.74, 0.95) 578 (8.2%) 9.0% 0.0043 (s) CV death 174 (2.5%) 2.9% 0.83 (0.68, 1.01) 210 (3.0%) 3.4% 0.0676 MI 285 (4.0%) 4.5% 0.84 (0.72, 0.98) 338 (4.8%) 5.2% 0.0314 Stroke 91 (1.3%) 1.5% 0.75 (0.57, 0.98) 122 (1.7%) 1.9% 0.0337 Secondary endpoint CV death 174 (2.5%) 2.9% 0.83 (0.68, 1.01) 210 (3.0%) 3.4% - All-cause mortality 289 (4.1%) 4.7% 0.89 (0.76, 1.04) 326 (4.6%) 5.2% - Hazard ratio and p-values are calculated separately for ticagrelor vs. ASA therapy alone from Cox proportional hazards model with treatment group as the only explanatory variable. KM percentage calculated at 36 months. Note: the number of first events for the components CV death, MI and stroke are the actual number of first events for each component and do not add up to the number of events in the composite endpoint (s) Indicates statistical significance. CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; KM = Kaplan-Meier; MI = Myocardial infarction; N = Number of patients. Both 60 mg twice daily and 90 mg twice daily regimens of ticagrelor in combination with ASA were superior to ASA alone in the prevention of atherothrombotic events (composite endpoint: CV death, MI and stroke), with a consistent treatment effect over the entire study period, yielding a 16% RRR and 1.27% ARR for ticagrelor 60 mg and a 15% RRR and 1.19% ARR for ticagrelor 90 mg. Although the efficacy profile of 90 mg and 60 mg were similar, there is evidence that the lower dose has a better tolerability and safety profile in relation to risk of the bleeding and dyspnoea. Therefore, only Brilique 60 mg twice daily co-administered with ASA is recommended for the prevention atherothrombotic events (CV death, MI and stroke) in patients with a history of MI and a high risk of developing an atherothrombotic event. Relative to ASA alone, ticagrelor 60 mg twice daily significantly reduced the primary composite endpoint of CV death, MI and stroke. Each of the components contributed to the reduction in the primary composite endpoint (CV death 17% RRR, MI 16% RRR and stroke 25% RRR). The RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) was similar. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment. There was no evidence of benefit (no reduction in the primary composite endpoint of CV death, MI and stroke, but an increase in major bleeding) when ticagrelor 60 mg twice daily was introduced in 44 clinically stable patients >2 years from the MI, or more than one year after stopping previous ADP receptor inhibitor treatment (see also section 4.2). Clinical safety The rate of discontinuations with ticagrelor 60 mg due to bleeding and dyspnoea was higher in patients >75 years (42%) than in younger patients (range: 23-31%), with a difference versus placebo higher than 10% (42% vs. 29%) in patients >75 years. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Brilique in all subsets of the paediatric population in acute coronary syndromes (ACS) and history of myocardial infarction (MI) (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Ticagrelor demonstrates linear pharmacokinetics and exposure to ticagrelor and the active metabolite (AR-C124910XX) are approximately dose proportional up to 1260 mg. Absorption Absorption of ticagrelor is rapid with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with a median tmax of approximately 2.5 hours. Following an oral ticagrelor 90 mg single dose under fasted conditions in healthy subjects, Cmax is 529 ng/ml and AUC is 3451 ng*h/ml. The metabolite parent ratios are 0.28 for Cmax and 0.42 for AUC. The pharmacokinetics of ticagrelor and AR-C124910XX in patients with a history of MI were generally similar to that in the ACS population. Based on a population pharmacokinetic analysis of the PEGASUS study the median ticagrelor Cmax was 391 ng/ml and AUC was 3801 ng*h/ml at steady state for ticagrelor 60 mg. For ticagrelor 90 mg Cmax was 627 ng/ml and AUC was 6255 ng*h/ml at steady state. The mean absolute bioavailability of ticagrelor was estimated to be 36%. Ingestion of a high-fat meal resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite Cmax but had no effect on ticagrelor Cmax or the AUC of the active metabolite. These small changes are considered of minimal clinical significance; therefore, ticagrelor can be given with or without food. Ticagrelor as well as the active metabolite are P-gp substrates. Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, has a comparable bioavailability to whole tablets with regards to AUC and Cmax for ticagrelor and the active metabolite. Initial exposure (0.5 and 1 hour post-dose) from crushed ticagrelor tablets mixed in water was higher compared to whole tablets, with a generally identical concentration profile thereafter (2 to 48 hours). Distribution The steady state volume of distribution of ticagrelor is 87.5 l. Ticagrelor and the active metabolite is extensively bound to human plasma protein (>99.0%). Biotransformation CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor. 45 Elimination The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabelled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the active metabolite is most likely via biliary secretion. The mean t1/2 was approximately 7 hours for ticagrelor and 8.5 hours for the active metabolite. Special populations Elderly Higher exposures to ticagrelor (approximately 25% for both Cmax and AUC) and the active metabolite were observed in elderly (≥75years) ACS patients compared to younger patients by the population pharmacokinetic analysis. These differences are not considered clinically significant (see section 4.2). Paediatric population Ticagrelor has not been evaluated in a paediatric population (see sections 4.2 and 5.1). Gender Higher exposures to ticagrelor and the active metabolite were observed in women compared to men. These differences are not considered clinically significant. Renal impairment Exposure to ticagrelor was approximately 20% lower and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment (creatinine clearance <30 ml/min) compared to subjects with normal renal function. In patients with end stage renal disease on haemodialysis AUC and Cmax of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately prior to dialysis (49% and 61%, respectively) showing that ticagrelor is not dialysable. Exposure of the active metabolite increased to a lesser extent (AUC 13-14% and Cmax 17-36%). The inhibition of platelet (IPA) effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to subjects with normal renal function (see section 4.2). Hepatic impairment Cmax and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to matched healthy subjects, respectively, however, the IPA effect of ticagrelor was similar between the two groups. No dose adjustment is needed for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with severe hepatic impairment and there is no pharmacokinetic information in patients with moderate hepatic impairment. In patients that had moderate or severe elevation in one or more liver function tests at baseline, ticagrelor plasma concentrations were on average similar or slightly higher as compared to those without baseline elevations. No dose adjustment is recommended in patients with moderate hepatic impairment (see sections 4.2 and 4.4). Ethnicity Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Patients self-identified as black had an 18% lower bioavailability of ticagrelor compared to Caucasian patients, in clinical pharmacology studies, the exposure (Cmax and AUC) to ticagrelor in 46 Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians. The exposure in patients self-identified as Hispanic or Latino was similar to that in Caucasians. 5.3 Preclinical safety data Preclinical data for ticagrelor and its major metabolite have not demonstrated unacceptable risk for adverse effects for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxic potential. Gastrointestinal irritation was observed in several animal species at clinical relevant exposure levels (see section 4.8). In female rats, ticagrelor at high dose showed an increased incidence of uterine tumours (adenocarcinomas) and an increased incidence of hepatic adenomas. The mechanism for uterine tumours is likely hormonal imbalance which can lead to tumours in rats. The mechanism for the hepatic adenomas is likely due to a rodent-specific enzyme induction in the liver. Thus, the carcinogenicity findings are considered unlikely to be relevant for humans. In rats, minor developmental anomalies were seen at a maternal toxic dose (safety margin of 5.1). In rabbits, a slight delay in hepatic maturity and skeletal development was seen in foetuses from dams at high dose without showing maternal toxicity (safety margin of 4.5). Studies in rats and rabbits have shown reproductive toxicity, with slightly reduced maternal body weight gain and reduced neonatal viability and birth weight, with delayed growth. Ticagrelor produced irregular cycles (mostly extended cycles) in female rats, but did not affect overall fertility in male and female rats. Pharmacokinetic studies performed with radiolabelled ticagrelor have shown that the parent compound and its metabolites are excreted in the milk of rats (see section 4.6). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Mannitol (E421) Calcium hydrogen phosphate dihydrate Magnesium stearate (E470b) Sodium starch glycolate type A Hydroxypropylcellulose (E463) Tablet coating Talc Titanium dioxide (E171) Iron oxide yellow (E172) Macrogol 400 Hypromellose (E464) 6.2 Incompatibilities Not applicable. 47 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container  PVC-PVDC/Al transparent blister (with sun/moon symbols) of 10 tablets; cartons of 60 tablets (6 blisters) and 180 tablets (18 blisters).  PVC-PVDC/Al transparent calendar blister (with sun/moon symbols) of 14 tablets; cartons of 14 tablets (1 blister), 56 tablets (4 blisters) and 168 tablets (12 blisters).  PVC-PVDC/Al perforated unit dose transparent blister of 10 tablets; cartons of 100x1 tablets (10 blisters). Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 8. MARKETING AUTHORISATION NUMBER(S) EU/1/10/655/001-006 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 03 December 2010 Date of latest renewal: 17 July 2015 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 48 1. NAME OF THE MEDICINAL PRODUCT Brilique 90 mg orodispersible tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each orodispersible tablet contains 90 mg ticagrelor. Brilique contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium-free’. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Orodispersible tablet. Round, flat, bevelled edged, white to pale pink, orodispersible tablets marked with ‘90’ above ‘TI’ on one side and plain on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Brilique, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with - acute coronary syndromes (ACS) or - a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event (see sections 4.2 and 5.1). 4.2 Posology and method of administration Posology Patients taking Brilique should also take a daily low maintenance dose of ASA 75-150 mg, unless specifically contraindicated. Acute coronary syndromes Brilique treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily. Treatment with Brilique 90 mg twice daily is recommended for 12 months in ACS patients unless discontinuation is clinically indicated (see section 5.1). History of myocardial infarction Brilique 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event (see section 5.1). Treatment may be started without interruption as continuation therapy after the initial one-year treatment with Brilique 90 mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in ACS patients with a high risk of an atherothrombotic event. Treatment can also be initiated up to 2 years from the MI, or within one year after stopping previous ADP receptor inhibitor treatment. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment. 49 If a switch is needed, the first dose of Brilique should be administered 24 hours following the last dose of the other antiplatelet medication. Missed dose Lapses in therapy should also be avoided. A patient who misses a dose of Brilique should take only one tablet (their next dose) at its scheduled time. Special populations Elderly No dose adjustment is required in elderly (see section 5.2). Renal impairment No dose adjustment is necessary for patients with renal impairment (see section 5.2). Hepatic impairment Ticagrelor has not been studied in patients with severe hepatic impairment and its use in these patients is therefore contraindicated (see section 4.3). Only limited information is available in patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor should be used with caution (see sections 4.4 and 5.2). No dose adjustment is necessary for patients with mild hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of ticagrelor in children below the age of 18 years have not been established. No data are available. Method of administration For oral use. Brilique can be administered with or without food. The orodispersible tablets may be used as an alternative to Brilique 90 mg film-coated tablets for patients who have difficulty swallowing the tablets whole or for whom there is a preference for orodispersible tablets. The tablet should be placed on the tongue, where it will rapidly disperse in saliva. It can then be swallowed with or without water (see section 5.2). The tablet can also be dispersed in water and administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture. A 60 mg orodispersible tablet is not available. 4.3 Contraindications  Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.8).  Active pathological bleeding.  History of intracranial haemorrhage (see section 4.8).  Severe hepatic impairment (see sections 4.2, 4.4 and 5.2).  Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor (see section 4.5). 50 4.4 Special warnings and precautions for use Bleeding risk The use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events (see sections 4.8 and 5.1). If clinically indicated, ticagrelor should be used with caution in the following patient groups:  Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding). The use of ticagrelor is contraindicated in patients with active pathological bleeding, in those with a history of intracranial haemorrhage, and in patients with severe hepatic impairment (see section 4.3).  Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing. Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of ticagrelor with desmopressin did not decrease template-bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events (see section 4.5). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may increase haemostasis. Ticagrelor may be resumed after the cause of bleeding has been identified and controlled. Surgery Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken. In PLATO patients undergoing coronary artery bypass grafting (CABG), ticagrelor had more bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery (see section 4.8). If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 5 days prior to surgery (see section 5.1). Patients with prior ischaemic stroke ACS patients with prior ischaemic stroke can be treated with ticagrelor for up to 12 months (PLATO study). In PEGASUS, patients with history of MI with prior ischaemic stroke were not included. Therefore, in the absence of data, treatment beyond one year is not recommended in these patients. Hepatic impairment Use of ticagrelor is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3). There is limited experience with ticagrelor in patients with moderate hepatic impairment, therefore, caution is advised in these patients (see sections 4.2 and 5.2). Patients at risk for bradycardic events Holter ECG monitoring has shown an increased frequency of mostly asymptomatic ventricular pauses during treatment with ticagrelor compared with clopidogrel. Patients with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope) have been excluded from the main studies evaluating the safety and efficacy of ticagrelor. Therefore, due to the limited clinical experience, ticagrelor should be used with caution in these patients (see section 5.1). 51 In addition, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil and 4% digoxin) (see section 4.5). During the Holter substudy in PLATO, more patients had ventricular pauses >3 seconds with ticagrelor than with clopidogrel during the acute phase of their ACS. The increase in Holter-detected ventricular pauses with ticagrelor was higher in patients with chronic heart failure (CHF) than in the overall study population during the acute phase of ACS, but not at one month with ticagrelor or compared to clopidogrel. There were no adverse clinical consequences associated with this imbalance (including syncope or pacemaker insertion) in this patient population (see section 5.1). Dyspnoea Dyspnoea was reported in patients treated with ticagrelor. Dyspnoea is usually mild to moderate in intensity and often resolves without need for treatment discontinuation. Patients with asthma/chronic obstructive pulmonary disease (COPD) may have an increased absolute risk of experiencing dyspnoea with ticagrelor. Ticagrelor should be used with caution in patients with history of asthma and/or COPD. The mechanism has not been elucidated. If a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with ticagrelor should be stopped. For further details see section 4.8. Creatinine elevations Creatinine levels may increase during treatment with ticagrelor. The mechanism has not been elucidated. Renal function should be checked according to routine medical practice. In patients with ACS, it is recommended that renal function is also checked one month after initiating the treatment with ticagrelor, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an angiotensin receptor blocker (ARB). Uric acid increase Hyperuricaemia may occur during treatment with ticagrelor (see section 4.8). Caution is advised in patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged. Thrombotic Thrombocytopenic Purpura (TTP) Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely with the use of ticagrelor. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. Interference with platelet function tests to diagnose heparin induced thrombocytopenia (HIT) In the heparin induced platelet activation (HIPA) test used to diagnose HIT, anti-platelet factor 4/heparin antibodies in patient serum activate platelets of healthy donors in the presence of heparin. False negative results in a platelet function test (to include, but may not be limited to the HIPA test) for HIT have been reported in patients administered ticagrelor. This is related to inhibition of the P2Y12-receptor on the healthy donor platelets in the test by ticagrelor in the patient’s sera/plasma. Information on concomitant treatment with ticagrelor is required for interpretation of HIT platelet function tests. 52 In patients who have developed HIT, the benefit-risk of continued treatment with ticagrelor should be assessed, taking both the prothrombotic state of HIT and the increased risk of bleeding with concomitant anticoagulant and ticagrelor treatment into consideration. Other Based on a relationship observed in PLATO between maintenance ASA dose and relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high maintenance dose ASA (>300 mg) is not recommended (see section 5.1). Premature discontinuation Premature discontinuation with any antiplatelet therapy, including Brilique, could result in an increased risk of cardiovascular (CV) death, MI or stroke due to the patient’s underlying disease. Therefore, premature discontinuation of treatment should be avoided. 4.5 Interaction with other medicinal products and other forms of interaction Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates. Effects of medicinal and other products on ticagrelor CYP3A4 inhibitors  Strong CYP3A4 inhibitors – Co-administration of ketoconazole with ticagrelor increased the ticagrelor Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) would be expected to have similar effects and therefore concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section 4.3).  Moderate CYP3A4 inhibitors – Co-administration of diltiazem with ticagrelor increased the ticagrelor Cmax by 69% and AUC to 2.7-fold and decreased the active metabolite Cmax by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to have a similar effect and can as well be co-administered with ticagrelor.  A 2-fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3x200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients. CYP3A inducers Co-administration of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax of the active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well. Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged. Cyclosporine (P-gp and CYP3A inhibitor) Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of cyclosporine. 53 No data are available on concomitant use of ticagrelor with other active substances that also are potent P-gp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) that also may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution. Others Clinical pharmacology interaction studies showed that co-administration of ticagrelor with heparin, enoxaparin and ASA or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or the active metabolite or on ADP-induced platelet aggregation compared with ticagrelor alone. If clinically indicated, medicinal products that alter haemostasis should be used with caution in combination with ticagrelor. A delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, has been observed in patients with ACS treated with morphine (35% reduction in ticagrelor exposure). This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced ticagrelor efficacy in patients co-administered ticagrelor and morphine. In patients with ACS, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered. Effects of ticagrelor on other medicinal products Medicinal products metabolised by CYP3A4  Simvastatin – Co-administration of ticagrelor with simvastatin increased simvastatin Cmax by 81% and AUC by 56% and increased simvastatin acid Cmax by 64% and AUC by 52% with some individual increases equal to 2- to 3-fold. Co-administration of ticagrelor with doses of simvastatin exceeding 40 mg daily could cause adverse reactions of simvastatin and should be weighed against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. Ticagrelor may have similar effect on lovastatin. The concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended.  Atorvastatin – Co-administration of atorvastatin and ticagrelor increased atorvastatin acid Cmax by 23% and AUC by 36%. Similar increases in AUC and Cmax were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.  A similar effect on other statins metabolised by CYP3A4 cannot be excluded. Patients in PLATO receiving ticagrelor took a variety of statins, with no concern of an association with statin safety among the 93% of the PLATO cohort taking these medicinal products. Ticagrelor is a mild CYP3A4 inhibitor. Co-administration of ticagrelor and CYP3A4 substrates with narrow therapeutic indices (i.e. cisapride or ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal products. P-gp substrates (including digoxin, cyclosporine) Concomitant administration of ticagrelor increased the digoxin Cmax by 75% and AUC by 28%. The mean trough digoxin levels were increased about 30% with ticagrelor co-administration with some individual maximum increases to 2-fold. In the presence of digoxin, the Cmax and AUC of ticagrelor and its active metabolite were not affected. Therefore, appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent medicinal products like digoxin concomitantly with ticagrelor. There was no effect of ticagrelor on cyclosporine blood levels. Effect of ticagrelor on other P-gp substrates has not been studied. 54 Medicinal products metabolised by CYP2C9 Co-administration of ticagrelor with tolbutamide resulted in no change in the plasma levels of either medicinal product, which suggests that ticagrelor is not a CYP2C9 inhibitor and unlikely to alter the CYP2C9 mediated metabolism of medicinal products like warfarin and tolbutamide. Oral contraceptives Co-administration of ticagrelor and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are co-administered with ticagrelor. Medicinal products known to induce bradycardia Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia (see section 4.4). However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil and 4% digoxin). Other concomitant therapy In clinical studies, ticagrelor was commonly administered with ASA, proton pump inhibitors, statins, beta-blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers as needed for concomitant conditions for long-term and also heparin, low molecular weight heparin and intravenous GpIIb/IIIa inhibitors for short durations (see section 5.1). No evidence of clinically significant adverse interactions with these medicinal products was observed. Co-administration of ticagrelor with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (aPTT), activated coagulation time (ACT) or factor Xa assays. However, due to potential pharmacodynamic interactions, caution should be exercised with the concomitant administration of ticagrelor with medicinal products known to alter haemostasis. Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and citalopram), caution is advised when administering SSRIs with ticagrelor as this may increase the risk of bleeding. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy. Pregnancy There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Ticagrelor is not recommended during pregnancy. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk (see section 5.3). A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. 55 Fertility Ticagrelor had no effect on male or female fertility in animals (see section 5.3). 4.7 Effects on ability to drive and use machines Ticagrelor has no or negligible influence on the ability to drive and use machines. During treatment with ticagrelor, dizziness and confusion have been reported. Therefore, patients who experience these symptoms should be cautious while driving or using machines. 4.8 Undesirable effects Summary of the safety profile The safety profile of ticagrelor has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients (see section 5.1). In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea (see section 4.4). Tabulated list of adverse reactions The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 1). Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: Very common (≥1/10), common (≥1/100 to 1/10), uncommon (≥1/1,000 to 1/100), rare (≥1/10,000 to 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Table 1 – Adverse reactions by frequency and system organ class (SOC) SOC Very common Common Uncommon Not known Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumour bleedingsa Blood and lymphatic system disorders Blood disorder bleedingsb Thrombotic Thrombocytopenic Purpurac Immune system disorders Hypersensitivity including angioedemac Metabolism and nutrition disorders Hyperuricaemiad Gout/Gouty Arthritis 56 SOC Very common Common Uncommon Not known Psychiatric disorders Confusion Nervous system disorders Dizziness, Syncope, Headache Intracranial haemorrhage Eye disorders Eye haemorrhagee Ear and labyrinth disorders Vertigo Ear haemorrhage Vascular disorders Hypotension Respiratory, thoracic and mediastinal disorders Dyspnoea Respiratory system bleedingsf Gastrointestinal disorders Gastrointestinal haemorrhageg, Diarrhoea, Nausea, Dyspepsia, Constipation Retroperitoneal haemorrhage Skin and subcutaneous tissue disorders Subcutaneous or dermal bleedingh, Rash, Pruritus Musculoskeletal connective tissue and bone Muscular bleedingsi Renal and urinary disorders Urinary tract bleedingj Reproductive system and breast disorders Reproductive system bleedingsk Investigations Blood creatinine increasedd Injury, poisoning and procedural complications Post procedural haemorrhage, Traumatic bleedingsl a e.g. bleeding from bladder cancer, gastric cancer, colon cancer b e.g. increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis c Identified in post-marketing experience d Frequencies derived from lab observations (Uric acid increases to >upper limit of normal from baseline below or within reference range. Creatinine increases of >50% from baseline.) and not crude adverse event report frequency. e e.g. conjunctival, retinal, intraocular bleeding f e.g. epistaxis, haemoptysis g e.g. gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage 57 h e.g. ecchymosis, skin haemorrhage, petechiae i e.g. haemarthrosis, muscle haemorrhage j e.g. haematuria, cystitis haemorrhagic k e.g. vaginal haemorrhage, haematospermia, postmenopausal haemorrhage l e.g. contusion, traumatic haematoma, traumatic haemorrhage Description of selected adverse reactions Bleeding Bleeding findings in PLATO Overall outcome of bleeding rates in the PLATO study are shown in Table 2. Table 2 – Analysis of overall bleeding events, Kaplan-Meier estimates at 12 months (PLATO) Ticagrelor 90 mg twice daily N=9235 Clopidogrel N=9186 p-value* PLATO Total Major 11.6 11.2 0.4336 PLATO Major Fatal/Life-Threatening 5.8 5.8 0.6988 Non-CABG PLATO Major 4.5 3.8 0.0264 Non-Procedural PLATO Major 3.1 2.3 0.0058 PLATO Total Major + Minor 16.1 14.6 0.0084 Non-Procedural PLATO Major + Minor 5.9 4.3 0.0001 TIMI-defined Major 7.9 7.7 0.5669 TIMI-defined Major + Minor 11.4 10.9 0.3272 Bleeding category definitions: Major Fatal/Life-threatening Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused; or fatal; or intracranial; or intrapericardial with cardiac tamponade; or with hypovolaemic shock or severe hypotension requiring pressors or surgery. Major Other: Clinically apparent with 30-50 g/L decrease in haemoglobin or 2-3 red cell units transfused; or significantly disabling. Minor Bleed: Requires medical intervention to stop or treat bleeding. TIMI Major Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or intracranial haemorrhage. TIMI Minor Bleed: Clinically apparent with 30-50 g/L decrease in haemoglobin. *p-value calculated from Cox proportional hazards model with treatment group as the only explanatory variable. Ticagrelor and clopidogrel did not differ in rates of PLATO Major Fatal/Life-threatening bleeding, PLATO total Major bleeding, TIMI Major bleeding, or TIMI Minor bleeding (Table 2). However, more PLATO combined Major + Minor bleeding occurred with ticagrelor compared with clopidogrel. Few patients in PLATO had fatal bleeds: 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel (see section 4.4). Age, sex, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history, including a previous stroke or transient ischaemic attack, all did not predict either overall or non-procedural PLATO Major bleeding. Thus, no particular group was identified at risk for any subset of bleeding. CABG-related bleeding: In PLATO, 42% of the 1584 patients (12% of cohort) who underwent coronary artery bypass graft (CABG) surgery had a PLATO Major Fatal/Life-threatening bleeding with no difference between treatment groups. Fatal CABG bleeding occurred in 6 patients in each treatment group (see section 4.4). Non-CABG related bleeding and non-procedural related bleeding: 58 Ticagrelor and clopidogrel did not differ in non-CABG PLATO-defined Major Fatal/Life- threatening bleeding, but PLATO-defined Total Major, TIMI Major, and TIMI Major + Minor bleeding were more common with ticagrelor. Similarly, when removing all procedure related bleeds, more bleeding occurred with ticagrelor than with clopidogrel (Table 2). Discontinuation of treatment due to non-procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p<0.001). Intracranial bleeding: There were more intracranial non-procedural bleeds with ticagrelor (n=27 bleeds in 26 patients, 0.3%) than with clopidogrel (n=14 bleeds, 0.2%), of which 11 bleeds with ticagrelor and 1 with clopidogrel were fatal. There was no difference in overall fatal bleeds. Bleeding findings in PEGASUS Overall outcome of bleeding events in the PEGASUS study are shown in Table 3. Table 3 – Analysis of overall bleeding events, Kaplan-Meier estimates at 36 months (PEGASUS) Ticagrelor 60 mg twice daily + ASA N=6958 ASA alone N=6996 Safety Endpoints KM% Hazard Ratio (95% CI) KM% p-value TIMI-defined bleeding categories TIMI Major 2.3 2.32 (1.68, 3.21) 1.1 <0.0001 Fatal 0.3 1.00 (0.44, 2.27) 0.3 1.0000 ICH 0.6 1.33 (0.77, 2.31) 0.5 0.3130 Other TIMI Major 1.6 3.61 (2.31, 5.65) 0.5 <0.0001 TIMI Major or Minor 3.4 2.54 (1.93, 3.35) 1.4 <0.0001 TIMI Major or Minor or Requiring medical attention 16.6 2.64 (2.35, 2.97) 7.0 <0.0001 PLATO-defined bleeding categories PLATO Major 3.5 2.57 (1.95, 3.37) 1.4 <0.0001 Fatal/Life-threatening 2.4 2.38 (1.73, 3.26) 1.1 <0.0001 Other PLATO Major 1.1 3.37 (1.95, 5.83) 0.3 <0.0001 PLATO Major or Minor 15.2 2.71 (2.40, 3.08) 6.2 <0.0001 Bleeding category definitions: TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of haemorrhage associated with a drop in haemoglobin (Hgb) of ≥50 g/L, or when Hgb is not available, a fall in haematocrit (Hct) of 15%. 59 Fatal: A bleeding event that directly led to death within 7 days. ICH: Intracranial haemorrhage. Other TIMI Major: Non-fatal non-ICH TIMI Major bleeding. TIMI Minor: Clinically apparent with 30-50 g/L decrease in haemoglobin. TIMI Requiring medical attention: Requiring intervention, OR leading to hospitalisation, OR prompting evaluation. PLATO Major Fatal/life-threatening: Fatal bleeding, OR any intracranial bleeding, OR intrapericardial with cardiac tamponade, OR with hypovolaemic shock or severe hypotension requiring pressors/inotropes or surgery OR clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused. PLATO Major Other: Significantly disabling, OR clinically apparent with 30-50 g/L decrease in haemoglobin, OR 2-3 red cell units transfused. PLATO Minor: Requires medical intervention to stop or treat bleeding. In PEGASUS, TIMI Major bleeding for ticagrelor 60 mg twice daily was higher than for ASA alone. No increased bleeding risk was seen for fatal bleeding and only a minor increase was observed in intracranial haemorrhages, as compared to ASA therapy alone. There were few fatal bleeding events in the study, 11 (0.3%) for ticagrelor 60 mg and 12 (0.3%) for ASA therapy alone. The observed increased risk of TIMI Major bleeding with ticagrelor 60 mg was primarily due to a higher frequency of Other TIMI Major bleedings driven by events in the gastrointestinal SOC. Increased bleeding patterns similar to TIMI Major were seen for TIMI Major or Minor and PLATO Major and PLATO Major or Minor bleeding categories (see Table 3). Discontinuation of treatment due to bleeding was more common with ticagrelor 60 mg compared to ASA therapy alone (6.2% and 1.5%, respectively). The majority of these bleedings were of less severity (classified as TIMI Requiring medical attention), e.g. epistaxis, bruising and haematomas. The bleeding profile of ticagrelor 60 mg was consistent across multiple pre-defined subgroups (e.g. by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history) for TIMI Major, TIMI Major or Minor and PLATO Major bleeding events. Intracranial bleeding: Spontaneous ICHs were reported in similar rates for ticagrelor 60 mg and ASA therapy alone (n=13, 0.2% in both treatment groups). Traumatic and procedural ICHs showed a minor increase with ticagrelor 60 mg treatment, (n=15, 0.2%) compared with ASA therapy alone (n=10, 0.1%). There were 6 fatal ICHs with ticagrelor 60 mg and 5 fatal ICHs with ASA therapy alone. The incidence of intracranial bleeding was low in both treatment groups given the significant comorbidity and CV risk factors of the population under study. Dyspnoea Dyspnoea, a sensation of breathlessness, is reported by patients treated with ticagrelor. In PLATO, dyspnoea adverse events (AEs) (dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea), when combined, was reported by 13.8% of patients treated with ticagrelor and by 7.8% of patients treated with clopidogrel. In 2.2% of patients taking ticagrelor and by 0.6% taking clopidogrel investigators considered the dyspnoea causally related to treatment in the PLATO study and few were serious (0.14% ticagrelor; 0.02% clopidogrel), (see section 4.4). Most reported symptoms of dyspnoea were mild to moderate in intensity, and most were reported as a single episode early after starting treatment. Compared with clopidogrel, patients with asthma/COPD treated with ticagrelor may have an increased risk of experiencing non-serious dyspnoea (3.29% ticagrelor versus 0.53% clopidogrel) and serious dyspnoea (0.38% ticagrelor versus 0.00% clopidogrel). In absolute terms, this risk was higher than in the overall PLATO population. Ticagrelor should be used with caution in patients with history of asthma and/or COPD (see section 4.4). 60 About 30% of episodes resolved within 7 days. PLATO included patients with baseline congestive heart failure, COPD or asthma; these patients, and the elderly, were more likely to report dyspnoea. For ticagrelor, 0.9% of patients discontinued study drug because of dyspnoea compared with 0.1% taking clopidogrel. The higher incidence of dyspnoea with ticagrelor is not associated with new or worsening heart or lung disease (see section 4.4). Ticagrelor does not affect tests of pulmonary function. In PEGASUS, dyspnoea was reported in 14.2% of patients taking ticagrelor 60 mg twice daily and in 5.5% of patients taking ASA alone. As in PLATO, most reported dyspnoea was mild to moderate in intensity (see section 4.4). Patients who reported dyspnoea tended to be older and more frequently had dyspnoea, COPD or asthma at baseline. Investigations Uric acid elevations: In PLATO, serum uric acid increased to more than upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. The corresponding numbers in PEGASUS were 9.1%, 8.8% and 5.5% for ticagrelor 90 mg, 60 mg and placebo, respectively. Mean serum uric acid increased approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel and after treatment was stopped, decreased to approximately 7% on ticagrelor but with no decrease observed for clopidogrel. In PEGASUS, a reversible increase in mean serum uric acid levels of 6.3% and 5.6% was found for ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In PLATO, the frequency of gouty arthritis was 0.2% for ticagrelor vs. 0.1% for clopidogrel. The corresponding numbers for gout/gouty arthritis in PEGASUS were 1.6%, 1.5% and 1.1% for ticagrelor 90 mg, 60 mg and placebo, respectively. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Ticagrelor is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in a single ascending dose study. Other clinically meaningful adverse reactions which may occur with overdose include dyspnoea and ventricular pauses (see section 4.8). In the event of an overdose, the above potential adverse reactions could occur and ECG monitoring should be considered. There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not dialysable (see section 5.2). Treatment of overdose should follow local standard medical practice. The expected effect of excessive ticagrelor dosing is prolonged duration of bleeding risk associated with platelet inhibition. Platelet transfusion is unlikely to be of clinical benefit in patients with bleeding (see section 4.4). If bleeding occurs other appropriate supportive measures should be taken. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 61 Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC24 Mechanism of action Brilique contains ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct acting, selective and reversibly binding P2Y12 receptor antagonist that prevents ADP-mediated P2Y12 dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding but when bound to the P2Y12 receptor prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of CV events such as death, MI or stroke. Ticagrelor also increases local endogenous adenosine levels by inhibiting the equilibrative nucleoside transporter-1 (ENT-1). Ticagrelor has been documented to augment the following adenosine-induced effects in healthy subjects and in patients with ACS: vasodilation (measured by coronary blood flow increases in healthy volunteers and ACS patients; headache), inhibition of platelet function (in human whole blood in vitro) and dyspnoea. However, a link between the observed increases in adenosine and clinical outcomes (e.g. morbidity-mortality) has not been clearly elucidated. Pharmacodynamic effects Onset of action In patients with stable coronary artery disease (CAD) on ASA, ticagrelor demonstrates a rapid onset of pharmacological effect as demonstrated by a mean inhibition of platelet aggregation (IPA) for ticagrelor at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA effect of 89% by 2-4 hours post dose, and maintained between 2-8 hours. 90% of patients had final extent IPA>70% by 2 hours post dose. Offset of action If a CABG procedure is planned, ticagrelor bleeding risk is increased compared to clopidogrel when discontinued within less than 96 hours prior to procedure. Switching data Switching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute IPA increase of 26.4% and switching from ticagrelor to clopidogrel results in an absolute IPA decrease of 24.5%. Patients can be switched from clopidogrel to ticagrelor without any interruption of antiplatelet effect (see section 4.2). Clinical efficacy and safety The clinical evidence for the efficacy and safety of ticagrelor is derived from two phase 3 trials:  The PLATO [PLATelet Inhibition and Patient Outcomes] study, a comparison of ticagrelor to clopidogrel, both given in combination with ASA and other standard therapy.  The PEGASUS TIMI-54 [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients] study, a comparison of ticagrelor combined with ASA to ASA therapy alone. PLATO study (Acute Coronary Syndromes) The PLATO study included 18,624 patients who presented within 24 hours of onset of symptoms of unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI) or ST elevation 62 myocardial infarction (STEMI), and were initially managed medically, or with percutaneous coronary intervention (PCI), or with CABG. Clinical efficacy On a background of daily ASA, ticagrelor 90 mg twice daily showed superiority to 75 mg daily clopidogrel in preventing the composite endpoint of CV death, MI or stroke, with the difference driven by CV death and MI. Patients received a 300 mg loading dose of clopidogrel (600 mg possible if having PCI) or 180 mg of ticagrelor. The result appeared early (absolute risk reduction [ARR] 0.6% and relative risk reduction [RRR] of 12% at 30 days), with a constant treatment effect over the entire 12-month period, yielding ARR 1.9% per year with RRR of 16%. This suggests it is appropriate to treat patients with ticagrelor 90 mg twice daily for 12 months (see section 4.2). Treating 54 ACS patients with ticagrelor instead of clopidogrel will prevent 1 atherothrombotic event; treating 91 will prevent 1 CV death (see Figure 1 and Table 4). The treatment effect of ticagrelor over clopidogrel appears consistent across many subgroups, including weight; sex; medical history of diabetes mellitus, transient ischaemic attack or non-haemorrhagic stroke, or revascularisation; concomitant therapies including heparins, GpIIb/IIIa inhibitors and proton pump inhibitors (see section 4.5); final index event diagnosis (STEMI, NSTEMI or UA); and treatment pathway intended at randomisation (invasive or medical). A weakly significant treatment interaction was observed with region whereby the hazard ratio (HR) for the primary endpoint favours ticagrelor in the rest of world but favours clopidogrel in North America, which represented approximately 10% of the overall population studied (interaction p-value=0.045). Exploratory analyses suggest a possible association with ASA dose such that reduced efficacy was observed with ticagrelor with increasing ASA doses. Chronic daily ASA doses to accompany ticagrelor should be 75-150 mg (see sections 4.2 and 4.4). Figure 1 shows the estimate of the risk to the first occurrence of any event in the composite efficacy endpoint. 63 Figure 1 – Analysis of primary clinical composite endpoint of CV death, MI and stroke (PLATO) Ticagrelor reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI population (Table 4). Thus, Brilique 90 mg twice daily together with low-dose ASA can be used in patients with ACS (unstable angina, non-ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG). Table 4 - Analysis of primary and secondary efficacy endpoints (PLATO) Ticagrelor 90 mg twice daily (% patients with event) N=9333 Clopidogrel 75 mg once daily (% patients with event) N=9291 ARRa (%/yr) RRRa (%) (95% CI) p-value CV death, MI (excl. silent MI) or stroke 9.3 10.9 1.9 16 (8, 23) 0.0003 Invasive intent 8.5 10.0 1.7 16 (6, 25) 0.0025 Medical intent 11.3 13.2 2.3 15 (0.3, 27) 0.0444d CV death 3.8 4.8 1.1 21 (9, 31) 0.0013 MI (excl. silent MI)b 5.4 6.4 1.1 16 (5, 25) 0.0045 Stroke 1.3 1.1 -0.2 -17 (-52, 9) 0.2249 All-cause mortality, MI (excl. silent MI) or stroke 9.7 11.5 2.1 16 (8, 23) 0.0001 64 CV death, total MI, stroke, SRI, RI, TIA or other ATEc 13.8 15.7 2.1 12 (5, 19) 0.0006 All-cause mortality 4.3 5.4 1.4 22 (11, 31) 0.0003d Definite stent thrombosis 1.2 1.7 0.6 32 (8, 49) 0.0123d a ARR = absolute risk reduction; RRR = relative risk reduction = (1-Hazard ratio) x 100%. A negative RRR indicates a relative risk increase. b Excluding silent MI. c SRI = serious recurrent ischaemia; RI = recurrent ischaemia; TIA = transient ischaemic attack; ATE = arterial thrombotic event. Total MI includes silent MI, with date of event set to date when discovered. d Nominal significance value; all others are formally statistically significant by pre-defined hierarchical testing. PLATO genetic substudy CYP2C19 and ABCB1 genotyping of 10,285 patients in PLATO provided associations of genotype groups with PLATO outcomes. The superiority of ticagrelor over clopidogrel in reducing major CV events was not significantly affected by patient CYP2C19 or ABCB1 genotype. Similar to the overall PLATO study, total PLATO Major bleeding did not differ between ticagrelor and clopidogrel, regardless of CYP2C19 or ABCB1 genotype. Non-CABG PLATO Major bleeding was increased with ticagrelor compared clopidogrel in patients with one or more CYP2C19 loss of function alleles, but similar to clopidogrel in patients with no loss of function allele. Combined efficacy and safety composite A combined efficacy and safety composite (CV death, MI, stroke, or PLATO-defined ‘Total Major’ bleeding) indicates that the benefit in efficacy of ticagrelor compared to clopidogrel is not offset by the major bleeding events (ARR 1.4%, RRR 8%, HR 0.92; p=0.0257) over 12 months after ACS. Clinical safety Holter substudy: To study the occurrence of ventricular pauses and other arrhythmic episodes during PLATO, investigators performed Holter monitoring in a subset of nearly 3000 patients, of whom approximately 2000 had recordings both in the acute phase of their ACS and after one month. The primary variable of interest was the occurrence of ventricular pauses ≥3 seconds. More patients had ventricular pauses with ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase; and 2.2% and 1.6%, respectively, after 1 month (see section 4.4). The increase in ventricular pauses in the acute phase of ACS was more pronounced in ticagrelor patients with history of CHF (9.2% versus 5.4% in patients without CHF history; for clopidogrel patients, 4.0% in those with versus 3.6% in those without CHF history). This imbalance did not occur at one month: 2.0% versus 2.1% for ticagrelor patients with and without CHF history, respectively; and 3.8% versus 1.4% with clopidogrel. There were no adverse clinical consequences associated with this imbalance (including pacemaker insertions) in this population of patients. PEGASUS study (History of Myocardial Infarction) The PEGASUS TIMI-54 study was a 21,162 patient, event-driven, randomised, double-blind, placebo-controlled, parallel group, international multicentre study to assess the prevention of atherothrombotic events with ticagrelor given at 2 doses (either 90 mg twice daily or 60 mg twice daily) combined with low dose ASA (75-150 mg), compared to ASA therapy alone in patients with history of MI and additional risk factors for atherothrombosis. 65 Patients were eligible to participate if they were aged 50 years or over, with a history of MI (1 to 3 years prior to randomisation), and had at least one of the following risk factors for atherothrombosis: age ≥65 years, diabetes mellitus requiring medication, a second prior MI, evidence of multivessel CAD or chronic non-end-stage renal dysfunction. Patients were ineligible if there was planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period; if they had a bleeding disorder or a history of an ischaemic stroke or intracranial bleeding, a central nervous system tumour or an intracranial vascular abnormality; if they had had gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days. Clinical efficacy Figure 2 - Analysis of primary clinical composite endpoint of CV death, MI and stroke (PEGASUS) Table 5 - Analysis of primary and secondary efficacy endpoints (PEGASUS) Ticagrelor 60 mg twice daily +ASA N = 7045 ASA alone N = 7067 p-value Characteristic Patients with events KM % HR (95% CI) Patients with events KM % Primary endpoint 66 Ticagrelor 60 mg twice daily +ASA N = 7045 ASA alone N = 7067 p-value Characteristic Patients with events KM % HR (95% CI) Patients with events KM % Composite of CV Death/MI/Stroke 487 (6.9%) 7.8% 0.84 (0.74, 0.95) 578 (8.2%) 9.0% 0.0043 (s) CV death 174 (2.5%) 2.9% 0.83 (0.68, 1.01) 210 (3.0%) 3.4% 0.0676 MI 285 (4.0%) 4.5% 0.84 (0.72, 0.98) 338 (4.8%) 5.2% 0.0314 Stroke 91 (1.3%) 1.5% 0.75 (0.57, 0.98) 122 (1.7%) 1.9% 0.0337 Secondary endpoint CV death 174 (2.5%) 2.9% 0.83 (0.68, 1.01) 210 (3.0%) 3.4% - All-cause mortality 289 (4.1%) 4.7% 0.89 (0.76, 1.04) 326 (4.6%) 5.2% - Hazard ratio and p-values are calculated separately for ticagrelor vs. ASA therapy alone from Cox proportional hazards model with treatment group as the only explanatory variable. KM percentage calculated at 36 months. Note: the number of first events for the components CV death, MI and stroke are the actual number of first events for each component and do not add up to the number of events in the composite endpoint (s) Indicates statistical significance. CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; KM = Kaplan-Meier; MI = Myocardial infarction; N = Number of patients. Both 60 mg twice daily and 90 mg twice daily regimens of ticagrelor in combination with ASA were superior to ASA alone in the prevention of atherothrombotic events (composite endpoint: CV death, MI and stroke), with a consistent treatment effect over the entire study period, yielding a 16% RRR and 1.27% ARR for ticagrelor 60 mg and a 15% RRR and 1.19% ARR for ticagrelor 90 mg. Although the efficacy profile of 90 mg and 60 mg were similar, there is evidence that the lower dose has a better tolerability and safety profile in relation to risk of the bleeding and dyspnoea. Therefore, only Brilique 60 mg twice daily co-administered with ASA is recommended for the prevention atherothrombotic events (CV death, MI and stroke) in patients with a history of MI and a high risk of developing an atherothrombotic event. Relative to ASA alone, ticagrelor 60 mg twice daily significantly reduced the primary composite endpoint of CV death, MI and stroke. Each of the components contributed to the reduction in the primary composite endpoint (CV death 17% RRR, MI 16% RRR and stroke 25% RRR). The RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) was similar. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment. There was no evidence of benefit (no reduction in the primary composite endpoint of CV death, MI and stroke, but an increase in major bleeding) when ticagrelor 60 mg twice daily was introduced in 67 clinically stable patients >2 years from the MI, or more than one year after stopping previous ADP receptor inhibitor treatment (see also section 4.2). Clinical safety The rate of discontinuations with ticagrelor 60 mg due to bleeding and dyspnoea was higher in patients >75 years (42%) than in younger patients (range: 23-31%), with a difference versus placebo higher than 10% (42% vs. 29%) in patients >75 years. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Brilique in all subsets of the paediatric population in acute coronary syndromes (ACS) and history of myocardial infarction (MI) (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Ticagrelor demonstrates linear pharmacokinetics and exposure to ticagrelor and the active metabolite (AR-C124910XX) are approximately dose proportional up to 1260 mg. Absorption Absorption of ticagrelor is rapid with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with a median tmax of approximately 2.5 hours. Following an oral ticagrelor 90 mg single dose under fasted conditions in healthy subjects, Cmax is 529 ng/ml and AUC is 3451 ng*h/ml. The metabolite parent ratios are 0.28 for Cmax and 0.42 for AUC. The pharmacokinetics of ticagrelor and AR-C124910XX in patients with a history of MI were generally similar to that in the ACS population. Based on a population pharmacokinetic analysis of the PEGASUS study the median ticagrelor Cmax was 391 ng/ml and AUC was 3801 ng*h/ml at steady state for ticagrelor 60 mg. For ticagrelor 90 mg Cmax was 627 ng/ml and AUC was 6255 ng*h/ml at steady state. The mean absolute bioavailability of ticagrelor was estimated to be 36%. Ingestion of a high-fat meal resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite Cmax but had no effect on ticagrelor Cmax or the AUC of the active metabolite. These small changes are considered of minimal clinical significance; therefore, ticagrelor can be given with or without food. Ticagrelor as well as the active metabolite are P-gp substrates. Ticagrelor orodispersible tablets, dispersed in saliva and swallowed without water or suspended in water and administered through a nasogastric tube into the stomach, were bioequivalent to film-coated whole tablets (AUC and Cmax within 80-125% for ticagrelor and the active metabolite). When the orodispersible tablet was dispersed in saliva and swallowed with water, ticagrelor AUC was similar, while Cmax was about 15% lower than for the film-coated tablet. The small difference in Cmax noted is unlikely to be of clinical relevance. Distribution The steady state volume of distribution of ticagrelor is 87.5 l. Ticagrelor and the active metabolite is extensively bound to human plasma protein (>99.0%). Biotransformation CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. 68 The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor. Elimination The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabelled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the active metabolite is most likely via biliary secretion. The mean t1/2 was approximately 7 hours for ticagrelor and 8.5 hours for the active metabolite. Special populations Elderly Higher exposures to ticagrelor (approximately 25% for both Cmax and AUC) and the active metabolite were observed in elderly (≥75 years) ACS patients compared to younger patients by the population pharmacokinetic analysis. These differences are not considered clinically significant (see section 4.2). Paediatric population Ticagrelor has not been evaluated in a paediatric population (see sections 4.2 and 5.1). Gender Higher exposures to ticagrelor and the active metabolite were observed in women compared to men. These differences are not considered clinically significant. Renal impairment Exposure to ticagrelor was approximately 20% lower and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment (creatinine clearance <30 ml/min) compared to subjects with normal renal function. In patients with end stage renal disease on haemodialysis AUC and Cmax of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately prior to dialysis (49% and 61%, respectively) showing that ticagrelor is not dialysable. Exposure of the active metabolite increased to a lesser extent (AUC 13-14% and Cmax 17-36%). The inhibition of platelet aggregation (IPA) effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to subjects with normal renal function (see section 4.2). Hepatic impairment Cmax and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to matched healthy subjects, respectively, however, the IPA effect of ticagrelor was similar between the two groups. No dose adjustment is needed for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with severe hepatic impairment and there is no pharmacokinetic information in patients with moderate hepatic impairment. In patients that had moderate or severe elevation in one or more liver function tests at baseline, ticagrelor plasma concentrations were on average similar or slightly higher as compared to those without baseline elevations. No dose adjustment is recommended in patients with moderate hepatic impairment (see sections 4.2 and 4.4). 69 Ethnicity Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Patients self-identified as black had an 18% lower bioavailability of ticagrelor compared to Caucasian patients, in clinical pharmacology studies, the exposure (Cmax and AUC) to ticagrelor in Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians. The exposure in patients self-identified as Hispanic or Latino was similar to that in Caucasians. 5.3 Preclinical safety data Preclinical data for ticagrelor and its major metabolite have not demonstrated unacceptable risk for adverse effects for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxic potential. Gastrointestinal irritation was observed in several animal species at clinical relevant exposure levels (see section 4.8). In female rats, ticagrelor at high dose showed an increased incidence of uterine tumours (adenocarcinomas) and an increased incidence of hepatic adenomas. The mechanism for uterine tumours is likely hormonal imbalance which can lead to tumours in rats. The mechanism for the hepatic adenomas is likely due to a rodent-specific enzyme induction in the liver. Thus, the carcinogenicity findings are considered unlikely to be relevant for humans. In rats, minor developmental anomalies were seen at a maternal toxic dose (safety margin of 5.1). In rabbits a slight delay in hepatic maturity and skeletal development was seen in foetuses from dams at high dose without showing maternal toxicity (safety margin of 4.5). Studies in rats and rabbits have shown reproductive toxicity, with slightly reduced maternal body weight gain and reduced neonatal viability and birth weight, with delayed growth. Ticagrelor produced irregular cycles (mostly extended cycles) in female rats, but did not affect overall fertility in male and female rats. Pharmacokinetic studies performed with radiolabelled ticagrelor have shown that the parent compound and its metabolites are excreted in the milk of rats (see section 4.6). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Mannitol (E421) Microcrystalline cellulose (E460) Crospovidone (E1202) Xylitol (E967) Anhydrous calcium hydrogen phosphate (E341) Sodium stearyl fumarate Hydroxypropylcellulose (E463) Colloidal anhydrous silica 6.2 Incompatibilities Not applicable. 70 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Al/Al perforated unit dose blister of 8 or 10 tablets; cartons of 10 x 1 tablets (1 blister), cartons of 56 x 1 tablets (7 blisters) and cartons of 60 x 1 tablets (6 blisters). Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 8. MARKETING AUTHORISATION NUMBER(S) EU/1/10/655/012-014 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 03 December 2010 Date of latest renewal: 17 July 2015 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 71 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 72 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release AstraZeneca AB Gärtunavägen SE-151 85 Södertälje Sweden AstraZeneca UK Limited Silk Road Business Park Macclesfield, Cheshire, SK10 2NA United Kingdom The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 73 ANNEX III LABELLING AND PACKAGE LEAFLET 74 A. LABELLING 75 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Brilique 60 mg film-coated tablets ticagrelor 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 60 mg ticagrelor 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 film-coated tablets 56 film-coated tablets 60 film-coated tablets 168 film-coated tablets 180 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 76 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/655/007 14 film-coated tablets EU/1/10/655/008 56 film-coated tablets EU/1/10/655/009 60 film-coated tablets EU/1/10/655/010 168 film-coated tablets EU/1/10/655/011 180 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE brilique 60 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 77 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 78 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Brilique 60 mg tablets ticagrelor 2. NAME OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Sun/Moon symbol 79 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS CALENDAR BLISTER 1. NAME OF THE MEDICINAL PRODUCT Brilique 60 mg tablets ticagrelor 2. NAME OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Mon Tue Wed Thu Fri Sat Sun Sun/Moon symbol 80 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Brilique 90 mg film-coated tablets ticagrelor 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 90 mg ticagrelor 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 film-coated tablets 56 film-coated tablets 60 film-coated tablets 100x1 film-coated tablets 168 film-coated tablets 180 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 81 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/655/001 60 film-coated tablets EU/1/10/655/002 180 film-coated tablets EU/1/10/655/003 14 film-coated tablets EU/1/10/655/004 56 film-coated tablets EU/1/10/655/005 168 film-coated tablets EU/1/10/655/006 100x1 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE brilique 90 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 82 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 83 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS PERFORATED UNIT DOSE BLISTER 1. NAME OF THE MEDICINAL PRODUCT Brilique 90 mg tablets ticagrelor 2. NAME OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 84 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Brilique 90 mg tablets ticagrelor 2. NAME OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Sun/Moon symbol 85 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS CALENDAR BLISTER 1. NAME OF THE MEDICINAL PRODUCT Brilique 90 mg tablets ticagrelor 2. NAME OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Mon Tue Wed Thu Fri Sat Sun Sun/Moon symbol 86 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Brilique 90 mg orodispersible tablets ticagrelor 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each orodispersible tablet contains 90 mg ticagrelor 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 10 x 1 orodispersible tablets 56 x 1 orodispersible tablets 60 x 1 orodispersible tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 87 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/655/012 10 x 1 orodispersible tablets EU/1/10/655/013 56 x 1 orodispersible tablets EU/1/10/655/014 60 x 1 orodispersible tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE brilique 90 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 88 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS PERFORATED UNIT DOSE BLISTER 1. NAME OF THE MEDICINAL PRODUCT Brilique 90 mg orodispersible tablets ticagrelor 2. NAME OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 89 B. PACKAGE LEAFLET 90 Package leaflet: Information for the user Brilique 60 mg film-coated tablets ticagrelor Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Brilique is and what it is used for 2. What you need to know before you take Brilique 3. How to take Brilique 4. Possible side effects 5. How to store Brilique 6. Contents of the pack and other information 1. What Brilique is and what it is used for What Brilique is Brilique contains an active substance called ticagrelor. This belongs to a group of medicines called antiplatelet medicines. What Brilique is used for Brilique in combination with acetylsalicylic acid (another antiplatelet agent) is to be used in adults only. You have been given this medicine because you have had:  a heart attack, over a year ago. It reduces the chances of you having another heart attack, stroke or dying from a disease related to your heart or blood vessels. How Brilique works Brilique affects cells called ‘platelets’ (also called thrombocytes). These very small blood cells help stop bleeding by clumping together to plug tiny holes in blood vessels that are cut or damaged. However, platelets can also form clots inside diseased blood vessels in the heart and brain. This can be very dangerous because:  the clot can cut off the blood supply completely; this can cause a heart attack (myocardial infarction) or stroke, or  the clot can partly block the blood vessels to the heart; this reduces the blood flow to the heart and can cause chest pain which comes and goes (called ‘unstable angina’). Brilique helps stop the clumping of platelets. This reduces the chance of a blood clot forming that can reduce blood flow. 91 2. What you need to know before you take Brilique Do not take Brilique if:  You are allergic to ticagrelor or any of the other ingredients of this medicine (listed in section 6).  You are bleeding now.  You have had a stroke caused by bleeding in the brain.  You have severe liver disease.  You are taking any of the following medicines: - ketoconazole (used to treat fungal infections) - clarithromycin (used to treat bacterial infections) - nefazodone (an antidepressant) - ritonavir and atazanavir (used to treat HIV infection and AIDS) Do not take Brilique if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine. Warnings and precautions Talk to your doctor or pharmacist before taking Brilique if:  You have an increased risk of bleeding because of: - a recent serious injury - recent surgery (including dental work, ask your dentist about this) - you have a condition that affects blood clotting - recent bleeding from your stomach or gut (such as a stomach ulcer or colon ‘polyps’)  You are due to have surgery (including dental work) at any time while taking Brilique. This is because of the increased risk of bleeding. Your doctor may want you to stop taking this medicine 5 days prior to surgery.  Your heart rate is abnormally low (usually lower than 60 beats per minute) and you do not already have in place a device that paces your heart (pacemaker).  You have asthma or other lung problems or breathing difficulties.  You have had any problems with your liver or have previously had any disease which may have affected your liver.  You have had a blood test that showed more than the usual amount of uric acid. If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking this medicine. If you are taking both Brilique and heparin:  Your doctor may require a sample of your blood for diagnostic tests if they suspect a rare platelet disorder caused by heparin. It is important that you inform your doctor that you are taking both Brilique and heparin, as Brilique may affect the diagnostic test. Children and adolescents Brilique is not recommended for children and adolescents under 18 years. Other medicines and Brilique Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because Brilique can affect the way some medicines work and some medicines can have an effect on Brilique. Tell your doctor or pharmacist if you are taking any of the following medicines:  more than 40 mg daily of either simvastatin or lovastatin (medicines used to treat high cholesterol)  rifampicin (an antibiotic)  phenytoin, carbamazepine and phenobarbital (used to control seizures) 92  digoxin (used to treat heart failure)  cyclosporine (used to lessen your body’s defenses)  quinidine and diltiazem (used to treat abnormal heart rhythms)  beta blockers and verapamil (used to treat high blood pressure)  morphine and other opioids (used to treat severe pain) In particular, tell your doctor or pharmacist if you are taking any of the following medicines that increase your risk of bleeding:  ‘oral anticoagulants’ often referred to as ‘blood thinners’ which include warfarin.  Non-Steroidal Anti-Inflammatory Drugs (abbreviated as NSAIDs) often taken as painkillers such as ibuprofen and naproxen.  Selective Serotonin Reuptake Inhibitors (abbreviated as SSRIs) taken as antidepressants such as paroxetine, sertraline and citalopram.  other medicines such as ketoconazole (used to treat fungal infections), clarithromycin (used to treat bacterial infections), nefazodone (an antidepressant), ritonavir and atazanavir (used to treat HIV infection and AIDS), cisapride (used to treat heartburn), ergot alkaloids (used to treat migraines and headaches). Also tell your doctor that because you are taking Brilique, you may have an increased risk of bleeding if your doctor gives you fibrinolytics, often called ‘clot dissolvers’, such as streptokinase or alteplase. Pregnancy and breast-feeding It is not recommended to use Brilique if you are pregnant or may become pregnant. Women should use appropriate contraceptive measures to avoid pregnancy while taking this medicine. Talk to your doctor before taking this medicine if you are breast-feeding. Your doctor will discuss with you the benefits and risks of taking Brilique during this time. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Driving and using machines Brilique is not likely to affect your ability to drive or use machines. If you feel dizzy or confused while taking this medicine, be careful while driving or using machines. Sodium content This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially ‘sodium-free’. 3. How to take Brilique Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. How much to take  The usual dose is one tablet of 60 mg twice a day. Continue taking Brilique as long as your doctor tells you.  Take this medicine around the same time every day (for example, one tablet in the morning and one in the evening). Taking Brilique with other medicines for blood clotting 93 Your doctor will usually also tell you to take acetylsalicylic acid. This is a substance present in many medicines used to prevent blood clotting. Your doctor will tell you how much to take (usually between 75-150 mg daily). How to take Brilique  You can take the tablet with or without food.  You can check when you last took a tablet of Brilique by looking on the blister. There is a sun (for the morning) and a moon (for the evening). This will tell you whether you have taken the dose. If you have trouble swallowing the tablet If you have trouble swallowing the tablet you can crush it and mix with water as follows:  Crush the tablet to a fine powder.  Pour the powder into half a glass of water.  Stir and drink immediately.  To make sure there is no medicine left, rinse the empty glass with another half a glass of water and drink it. If you are in the hospital you may be given this tablet mixed with some water and given through a tube via the nose (nasogastric tube). If you take more Brilique than you should If you take more Brilique than you should, talk to a doctor or go to hospital straight away. Take the medicine pack with you. You may be at increased risk of bleeding. If you forget to take Brilique  If you forget to take a dose, just take your next dose as normal.  Do not take a double dose (two doses at the same time) to make up for the forgotten dose. If you stop taking Brilique Do not stop taking Brilique without talking to your doctor. Take this medicine on a regular basis and for as long as your doctor keeps prescribing it. If you stop taking Brilique, it may increase your chances of having another heart attack or stroke or dying from a disease related to your heart or blood vessels. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may happen with this medicine: Brilique affects blood clotting, so most side effects are related to bleeding. Bleeding may occur in any part of the body. Some bleeding is common (like bruising and nosebleeds). Severe bleeding is uncommon but can be life threatening. See a doctor straight away if you notice any of the following – you may need urgent medical treatment:  Bleeding into the brain or inside the skull is an uncommon side effect, and may cause signs of a stroke such as: - sudden numbness or weakness of your arm, leg or face, especially if only on one side of the body - sudden confusion, difficulty speaking or understanding others - sudden difficulty in walking or loss of balance or co-ordination 94 - suddenly feeling dizzy or sudden severe headache with no known cause  Signs of bleeding such as: - bleeding that is severe or that you cannot control - unexpected bleeding or bleeding that lasts a long time - pink, red or brown urine - vomiting red blood or your vomit looks like ‘coffee grounds’ - red or black stools (look like tar) - coughing up or vomiting blood clots  Fainting (syncope) - a temporary loss of consciousness due to sudden drop in blood flow to the brain (common)  Signs of a blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP) such as: - fever and purplish spots (called purpura) on the skin or in the mouth, with or without yellowing of the skin or eyes (jaundice), unexplained extreme tiredness or confusion Discuss with your doctor if you notice any of the following:  Feeling short of breath - this is very common. It might be due to your heart disease or another cause, or it might be a side effect of Brilique. Brilique-related breathlessness is generally mild and characterised as a sudden, unexpected hunger for air usually occurring at rest and may appear in the first weeks of therapy and for many may disappear. If your feeling of shortness of breath gets worse or lasts a long time, tell your doctor. Your doctor will decide if it needs treatment or further investigations. Other possible side effects Very common (may affect more than 1 in 10 people)  High level of uric acid in your blood (as seen in tests)  Bleeding caused by blood disorders Common (may affect up to 1 in 10 people)  Bruising  Headache  Feeling dizzy or like the room is spinning  Diarrhoea or indigestion  Feeling sick (nausea)  Constipation  Rash  Itching  Severe pain and swelling in your joints – these are signs of gout  Feeling dizzy or light-headed, or having blurred vision – these are signs of low blood pressure  Nosebleed  Bleeding after surgery or from cuts (for example while shaving) and wounds more than is normal  Bleeding from your stomach lining (ulcer)  Bleeding gums Uncommon (may affect up to 1 in 100 people) 95  Allergic reaction – a rash, itching or a swollen face or swollen lips/tongue may be signs of an allergic reaction  Confusion  Visual problems caused by blood in your eye  Vaginal bleeding that is heavier, or happens at different times, than your normal period (menstrual) bleeding  Bleeding into your joints and muscles causing painful swelling  Blood in your ear  Internal bleeding, this may cause dizziness or light-headedness Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Brilique Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Brilique contains  The active substance is ticagrelor. Each film-coated tablet contains 60 mg of ticagrelor.  The other ingredients are: Tablet core: mannitol (E421), calcium hydrogen phosphate dihydrate, sodium starch glycolate type A, hydroxypropylcellulose (E463), magnesium stearate (E470b). Tablet film-coating: hypromellose (E464), titanium dioxide (E171), macrogol 400, iron oxide black (E172), iron oxide red (E172). What Brilique looks like and contents of the pack Film-coated tablet (tablet): The tablets are round, biconvex, pink, film-coated marked with a “60” above “T” on one side. Brilique is available in:  standard blisters (with sun/moon symbols) in cartons of 60 and 180 tablets  calendar blisters (with sun/moon symbols) in cartons of 14, 56 and 168 tablets Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: AstraZeneca AB SE-151 85 Södertälje http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 96 Sweden Manufacturer: AstraZeneca AB Gärtunavägen SE-151 85 Södertälje Sweden Manufacturer: AstraZeneca UK Limited Silk Road Business Park Macclesfield, Cheshire, SK10 2NA United Kingdom For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien AstraZeneca S.A./N.V. Tel: +32 2 370 48 11 Lietuva UAB AstraZeneca Lietuva Tel: +370 5 2660550 България АстраЗенека България ЕООД Teл.: +359 2 44 55 000 Luxembourg/Luxemburg AstraZeneca S.A./N.V. Tél/Tel: +32 2 370 48 11 Česká republika AstraZeneca Czech Republic s.r.o Tel: +420 222 807 111 Magyarország AstraZeneca Kft. Tel.: +36 1 883 6500 Danmark AstraZeneca A/S Tlf: +45 43 66 64 62 Malta Associated Drug Co. Ltd Tel: +356 2277 8000 Deutschland AstraZeneca GmbH Tel: +49 41 03 7080 Nederland AstraZeneca BV Tel: +31 79 363 2222 Eesti AstraZeneca Tel: +372 6549 600 Norge AstraZeneca AS Tlf: +47 21 00 64 00 Ελλάδα AstraZeneca A.E. Τηλ: +30 2 106871500 Österreich AstraZeneca Österreich GmbH Tel: +43 1 711 31 0 España AstraZeneca Farmacéutica Spain, S.A. Tel: +34 91 301 91 00 Polska AstraZeneca Pharma Poland Sp. z o.o. Tel.: +48 22 245 73 00 France AstraZeneca Tél: +33 1 41 29 40 00 Portugal AstraZeneca Produtos Farmacêuticos, Lda. Tel: +351 21 434 61 00 97 Hrvatska AstraZeneca d.o.o. Tel: +385 1 4628 000 România AstraZeneca Pharma SRL Tel: +40 21 317 60 41 Ireland AstraZeneca Pharmaceuticals (Ireland) DAC Tel: +353 1609 7100 Slovenija AstraZeneca UK Limited Tel: +386 1 51 35 600 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika AstraZeneca AB, o.z. Tel: +421 2 5737 7777 Italia AstraZeneca S.p.A. Tel: +39 02 9801 1 Suomi/Finland AstraZeneca Oy Puh/Tel: +358 10 23 010 Κύπρος Αλέκτωρ Φαρµακευτική Λτδ Τηλ: +357 22490305 Sverige AstraZeneca AB Tel: +46 8 553 26 000 Latvija SIA AstraZeneca Latvija Tel: +371 67377100 United Kingdom AstraZeneca UK Ltd Tel: +44 1582 836 836 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ 98 Package leaflet: Information for the user Brilique 90 mg film-coated tablets ticagrelor Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Brilique is and what it is used for 2. What you need to know before you take Brilique 3. How to take Brilique 4. Possible side effects 5. How to store Brilique 6. Contents of the pack and other information 1. What Brilique is and what it is used for What Brilique is Brilique contains an active substance called ticagrelor. This belongs to a group of medicines called antiplatelet medicines. What Brilique is used for Brilique in combination with acetylsalicylic acid (another antiplatelet agent) is to be used in adults only. You have been given this medicine because you have had:  a heart attack, or  unstable angina (angina or chest pain that is not well controlled). It reduces the chances of you having another heart attack, stroke or dying from a disease related to your heart or blood vessels. How Brilique works Brilique affects cells called ‘platelets’ (also called thrombocytes). These very small blood cells help stop bleeding by clumping together to plug tiny holes in blood vessels that are cut or damaged. However, platelets can also form clots inside diseased blood vessels in the heart and brain. This can be very dangerous because:  the clot can cut off the blood supply completely; this can cause a heart attack (myocardial infarction) or stroke, or  the clot can partly block the blood vessels to the heart; this reduces the blood flow to the heart and can cause chest pain which comes and goes (called ‘unstable angina’). Brilique helps stop the clumping of platelets. This reduces the chance of a blood clot forming that can reduce blood flow. 99 2. What you need to know before you take Brilique Do not take Brilique if:  You are allergic to ticagrelor or any of the other ingredients of this medicine (listed in section 6).  You are bleeding now.  You have had a stroke caused by bleeding in the brain.  You have severe liver disease.  You are taking any of the following medicines: - ketoconazole (used to treat fungal infections) - clarithromycin (used to treat bacterial infections) - nefazodone (an antidepressant) - ritonavir and atazanavir (used to treat HIV infection and AIDS) Do not take Brilique if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine. Warnings and precautions Talk to your doctor or pharmacist before taking Brilique if:  You have an increased risk of bleeding because of: - a recent serious injury - recent surgery (including dental work, ask your dentist about this) - you have a condition that affects blood clotting - recent bleeding from your stomach or gut (such as a stomach ulcer or colon ‘polyps’)  You are due to have surgery (including dental work) at any time while taking Brilique. This is because of the increased risk of bleeding. Your doctor may want you to stop taking this medicine 5 days prior to surgery.  Your heart rate is abnormally low (usually lower than 60 beats per minute) and you do not already have in place a device that paces your heart (pacemaker).  You have asthma or other lung problems or breathing difficulties.  You have had any problems with your liver or have previously had any disease which may have affected your liver.  You have had a blood test that showed more than the usual amount of uric acid. If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking this medicine. If you are taking both Brilique and heparin:  Your doctor may require a sample of your blood for diagnostic tests if they suspect a rare platelet disorder caused by heparin. It is important that you inform your doctor that you are taking both Brilique and heparin, as Brilique may affect the diagnostic test. Children and adolescents Brilique is not recommended for children and adolescents under 18 years. Other medicines and Brilique Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because Brilique can affect the way some medicines work and some medicines can have an effect on Brilique. Tell your doctor or pharmacist if you are taking any of the following medicines:  more than 40 mg daily of either simvastatin or lovastatin (medicines used to treat high cholesterol)  rifampicin (an antibiotic) 100  phenytoin, carbamazepine and phenobarbital (used to control seizures)  digoxin (used to treat heart failure)  cyclosporine (used to lessen your body’s defenses)  quinidine and diltiazem (used to treat abnormal heart rhythms)  beta blockers and verapamil (used to treat high blood pressure)  morphine and other opioids (used to treat severe pain) In particular, tell your doctor or pharmacist if you are taking any of the following medicines that increase your risk of bleeding:  ‘oral anticoagulants’ often referred to as ‘blood thinners’ which include warfarin.  Non-Steroidal Anti-Inflammatory Drugs (abbreviated as NSAIDs) often taken as painkillers such as ibuprofen and naproxen.  Selective Serotonin Reuptake Inhibitors (abbreviated as SSRIs) taken as antidepressants such as paroxetine, sertraline and citalopram.  other medicines such as ketoconazole (used to treat fungal infections), clarithromycin (used to treat bacterial infections), nefazodone (an antidepressant), ritonavir and atazanavir (used to treat HIV infection and AIDS), cisapride (used to treat heartburn), ergot alkaloids (used to treat migraines and headaches). Also tell your doctor that because you are taking Brilique, you may have an increased risk of bleeding if your doctor gives you fibrinolytics, often called ‘clot dissolvers’, such as streptokinase or alteplase. Pregnancy and breast-feeding It is not recommended to use Brilique if you are pregnant or may become pregnant. Women should use appropriate contraceptive measures to avoid pregnancy while taking this medicine. Talk to your doctor before taking this medicine if you are breast-feeding. Your doctor will discuss with you the benefits and risks of taking Brilique during this time. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Driving and using machines Brilique is not likely to affect your ability to drive or use machines. If you feel dizzy or confused while taking this medicine, be careful while driving or using machines. Sodium content This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially ‘sodium-free’. 3. How to take Brilique Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. How much to take  The starting dose is two tablets at the same time (loading dose of 180 mg). This dose will usually be given to you in the hospital.  After this starting dose, the usual dose is one tablet of 90 mg twice a day for up to 12 months unless your doctor tells you differently. 101  Take this medicine around the same time every day (for example, one tablet in the morning and one in the evening). Taking Brilique with other medicines for blood clotting Your doctor will usually also tell you to take acetylsalicylic acid. This is a substance present in many medicines used to prevent blood clotting. Your doctor will tell you how much to take (usually between 75-150 mg daily). How to take Brilique  You can take the tablet with or without food.  You can check when you last took a tablet of Brilique by looking on the blister. There is a sun (for the morning) and a moon (for the evening). This will tell you whether you have taken the dose. If you have trouble swallowing the tablet If you have trouble swallowing the tablet you can crush it and mix with water as follows:  Crush the tablet to a fine powder.  Pour the powder into half a glass of water.  Stir and drink immediately.  To make sure there is no medicine left, rinse the empty glass with another half a glass of water and drink it. If you are in the hospital you may be given this tablet mixed with some water and given through a tube via the nose (nasogastric tube). If you take more Brilique than you should If you take more Brilique than you should, talk to a doctor or go to hospital straight away. Take the medicine pack with you. You may be at increased risk of bleeding. If you forget to take Brilique  If you forget to take a dose, just take your next dose as normal.  Do not take a double dose (two doses at the same time) to make up for the forgotten dose. If you stop taking Brilique Do not stop taking Brilique without talking to your doctor. Take this medicine on a regular basis and for as long as your doctor keeps prescribing it. If you stop taking Brilique, it may increase your chances of having another heart attack or stroke or dying from a disease related to your heart or blood vessels. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may happen with this medicine: Brilique affects blood clotting, so most side effects are related to bleeding. Bleeding may occur in any part of the body. Some bleeding is common (like bruising and nosebleeds). Severe bleeding is uncommon but can be life threatening. See a doctor straight away if you notice any of the following – you may need urgent medical treatment: 102  Bleeding into the brain or inside the skull is an uncommon side effect, and may cause signs of a stroke such as: - sudden numbness or weakness of your arm, leg or face, especially if only on one side of the body - sudden confusion, difficulty speaking or understanding others - sudden difficulty in walking or loss of balance or co-ordination - suddenly feeling dizzy or sudden severe headache with no known cause  Signs of bleeding such as: - bleeding that is severe or that you cannot control - unexpected bleeding or bleeding that lasts a long time - pink, red or brown urine - vomiting red blood or your vomit looks like ‘coffee grounds’ - red or black stools (look like tar) - coughing up or vomiting blood clots  Fainting (syncope) - a temporary loss of consciousness due to sudden drop in blood flow to the brain (common)  Signs of a blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP) such as: - fever and purplish spots (called purpura) on the skin or in the mouth, with or without yellowing of the skin or eyes (jaundice), unexplained extreme tiredness or confusion Discuss with your doctor if you notice any of the following:  Feeling short of breath - this is very common. It might be due to your heart disease or another cause, or it might be a side effect of Brilique. Brilique-related breathlessness is generally mild and characterised as a sudden, unexpected hunger for air usually occurring at rest and may appear in the first weeks of therapy and for many may disappear. If your feeling of shortness of breath gets worse or lasts a long time, tell your doctor. Your doctor will decide if it needs treatment or further investigations. Other possible side effects Very common (may affect more than 1 in 10 people)  High level of uric acid in your blood (as seen in tests)  Bleeding caused by blood disorders Common (may affect up to 1 in 10 people)  Bruising  Headache  Feeling dizzy or like the room is spinning  Diarrhoea or indigestion  Feeling sick (nausea)  Constipation  Rash  Itching  Severe pain and swelling in your joints – these are signs of gout  Feeling dizzy or light-headed, or having blurred vision – these are signs of low blood pressure 103  Nosebleed  Bleeding after surgery or from cuts (for example while shaving) and wounds more than is normal  Bleeding from your stomach lining (ulcer)  Bleeding gums Uncommon (may affect up to 1 in 100 people)  Allergic reaction – a rash, itching or a swollen face or swollen lips/tongue may be signs of an allergic reaction  Confusion  Visual problems caused by blood in your eye  Vaginal bleeding that is heavier, or happens at different times, than your normal period (menstrual) bleeding  Bleeding into your joints and muscles causing painful swelling  Blood in your ear  Internal bleeding, this may cause dizziness or light-headedness Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Brilique Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Brilique contains  The active substance is ticagrelor. Each film-coated tablet contains 90 mg of ticagrelor.  The other ingredients are: Tablet core: mannitol (E421), calcium hydrogen phosphate dihydrate, sodium starch glycolate type A, hydroxypropylcellulose (E463), magnesium stearate (E470b). Tablet film-coating: hypromellose (E464), titanium dioxide (E171), talc, macrogol 400, iron oxide yellow (E172). What Brilique looks like and contents of the pack Film-coated tablet (tablet): The tablets are round, biconvex, yellow, film-coated marked with a “90” above “T” on one side. Brilique is available in:  standard blisters (with sun/moon symbols) in cartons of 60 and 180 tablets  calendar blisters (with sun/moon symbols) in cartons of 14, 56 and 168 tablets http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 104  perforated unit-dosed blisters in a carton of 100x1 tablets Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: AstraZeneca AB SE-151 85 Södertälje Sweden Manufacturer: AstraZeneca AB Gärtunavägen SE-151 85 Södertälje Sweden Manufacturer: AstraZeneca UK Limited Silk Road Business Park Macclesfield, Cheshire, SK10 2NA United Kingdom For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien AstraZeneca S.A./N.V. Tel: +32 2 370 48 11 Lietuva UAB AstraZeneca Lietuva Tel: +370 5 2660550 България АстраЗенека България ЕООД Teл.: +359 2 44 55 000 Luxembourg/Luxemburg AstraZeneca S.A./N.V. Tél/Tel: +32 2 370 48 11 Česká republika AstraZeneca Czech Republic s.r.o Tel: +420 222 807 111 Magyarország AstraZeneca Kft. Tel.: +36 1 883 6500 Danmark AstraZeneca A/S Tlf: +45 43 66 64 62 Malta Associated Drug Co. Ltd Tel: +356 2277 8000 Deutschland AstraZeneca GmbH Tel: +49 41 03 7080 Nederland AstraZeneca BV Tel: +31 79 363 2222 Eesti AstraZeneca Tel: +372 6549 600 Norge AstraZeneca AS Tlf: +47 21 00 64 00 Ελλάδα AstraZeneca A.E. Τηλ: +30 2 106871500 Österreich AstraZeneca Österreich GmbH Tel: +43 1 711 31 0 105 España AstraZeneca Farmacéutica Spain, S.A. Tel: +34 91 301 91 00 Polska AstraZeneca Pharma Poland Sp. z o.o. Tel.: +48 22 245 73 00 France AstraZeneca Tél: +33 1 41 29 40 00 Portugal AstraZeneca Produtos Farmacêuticos, Lda. Tel: +351 21 434 61 00 Hrvatska AstraZeneca d.o.o. Tel: +385 1 4628 000 România AstraZeneca Pharma SRL Tel: +40 21 317 60 41 Ireland AstraZeneca Pharmaceuticals (Ireland) DAC Tel: +353 1609 7100 Slovenija AstraZeneca UK Limited Tel: +386 1 51 35 600 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika AstraZeneca AB, o.z. Tel: +421 2 5737 7777 Italia AstraZeneca S.p.A. Tel: +39 02 9801 1 Suomi/Finland AstraZeneca Oy Puh/Tel: +358 10 23 010 Κύπρος Αλέκτωρ Φαρµακευτική Λτδ Τηλ: +357 22490305 Sverige AstraZeneca AB Tel: +46 8 553 26 000 Latvija SIA AstraZeneca Latvija Tel: +371 67377100 United Kingdom AstraZeneca UK Ltd Tel: +44 1582 836 836 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ 106 Package leaflet: Information for the user Brilique 90 mg orodispersible tablets ticagrelor Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Brilique is and what it is used for 2. What you need to know before you take Brilique 3. How to take Brilique 4. Possible side effects 5. How to store Brilique 6. Contents of the pack and other information 1. What Brilique is and what it is used for What Brilique is Brilique contains an active substance called ticagrelor. This belongs to a group of medicines called antiplatelet medicines. What Brilique is used for Brilique in combination with acetylsalicylic acid (another antiplatelet agent) is to be used in adults only. You have been given this medicine because you have had:  a heart attack, or  unstable angina (angina or chest pain that is not well controlled). It reduces the chances of you having another heart attack, stroke or dying from a disease related to your heart or blood vessels. How Brilique works Brilique affects cells called ‘platelets’ (also called thrombocytes). These very small blood cells help stop bleeding by clumping together to plug tiny holes in blood vessels that are cut or damaged. However, platelets can also form clots inside diseased blood vessels in the heart and brain. This can be very dangerous because:  the clot can cut off the blood supply completely; this can cause a heart attack (myocardial infarction) or stroke, or  the clot can partly block the blood vessels to the heart; this reduces the blood flow to the heart and can cause chest pain which comes and goes (called ‘unstable angina’). Brilique helps stop the clumping of platelets. This reduces the chance of a blood clot forming that can reduce blood flow. 107 2. What you need to know before you take Brilique Do not take Brilique if:  You are allergic to ticagrelor or any of the other ingredients of this medicine (listed in section 6).  You are bleeding now.  You have had a stroke caused by bleeding in the brain.  You have severe liver disease.  You are taking any of the following medicines: - ketoconazole (used to treat fungal infections) - clarithromycin (used to treat bacterial infections) - nefazodone (an antidepressant) - ritonavir and atazanavir (used to treat HIV infection and AIDS) Do not take Brilique if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine. Warnings and precautions Talk to your doctor or pharmacist before taking Brilique if:  You have an increased risk of bleeding because of: - a recent serious injury - recent surgery (including dental work, ask your dentist about this) - you have a condition that affects blood clotting - recent bleeding from your stomach or gut (such as a stomach ulcer or colon ‘polyps’)  You are due to have surgery (including dental work) at any time while taking Brilique. This is because of the increased risk of bleeding. Your doctor may want you to stop taking this medicine 5 days prior to surgery.  Your heart rate is abnormally low (usually lower than 60 beats per minute) and you do not already have in place a device that paces your heart (pacemaker).  You have asthma or other lung problems or breathing difficulties.  You have had any problems with your liver or have previously had any disease which may have affected your liver.  You have had a blood test that showed more than the usual amount of uric acid. If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking this medicine. If you are taking both Brilique and heparin:  Your doctor may require a sample of your blood for diagnostic tests if they suspect a rare platelet disorder caused by heparin. It is important that you inform your doctor that you are taking both Brilique and heparin, as Brilique may affect the diagnostic test. Children and adolescents Brilique is not recommended for children and adolescents under 18 years. Other medicines and Brilique Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because Brilique can affect the way some medicines work and some medicines can have an effect on Brilique. Tell your doctor or pharmacist if you are taking any of the following medicines:  more than 40 mg daily of either simvastatin or lovastatin (medicines used to treat high cholesterol)  rifampicin (an antibiotic) 108  phenytoin, carbamazepine and phenobarbital (used to control seizures)  digoxin (used to treat heart failure)  cyclosporine (used to lessen your body’s defenses)  quinidine and diltiazem (used to treat abnormal heart rhythms)  beta blockers and verapamil (used to treat high blood pressure)  morphine and other opioids (used to treat severe pain) In particular, tell your doctor or pharmacist if you are taking any of the following medicines that increase your risk of bleeding:  ‘oral anticoagulants’ often referred to as ‘blood thinners’ which include warfarin.  Non-Steroidal Anti-Inflammatory Drugs (abbreviated as NSAIDs) often taken as painkillers such as ibuprofen and naproxen.  Selective Serotonin Reuptake Inhibitors (abbreviated as SSRIs) taken as antidepressants such as paroxetine, sertraline and citalopram.  other medicines such as ketoconazole (used to treat fungal infections), clarithromycin (used to treat bacterial infections), nefazodone (an antidepressant), ritonavir and atazanavir (used to treat HIV infection and AIDS), cisapride (used to treat heartburn), ergot alkaloids (used to treat migraines and headaches). Also tell your doctor that because you are taking Brilique, you may have an increased risk of bleeding if your doctor gives you fibrinolytics, often called ‘clot dissolvers’, such as streptokinase or alteplase. Pregnancy and breast-feeding It is not recommended to use Brilique if you are pregnant or may become pregnant. Women should use appropriate contraceptive measures to avoid pregnancy while taking this medicine. Talk to your doctor before taking this medicine if you are breast-feeding. Your doctor will discuss with you the benefits and risks of taking Brilique during this time. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Driving and using machines Brilique is not likely to affect your ability to drive or use machines. If you feel dizzy or confused while taking this medicine, be careful while driving or using machines. Sodium content This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say that it is essentially ‘sodium-free’. 3. How to take Brilique Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. How much to take  The starting dose is two tablets at the same time (loading dose of 180 mg). This dose will usually be given to you in the hospital.  After this starting dose, the usual dose is one tablet of 90 mg twice a day for up to 12 months unless your doctor tells you differently. 109  Take this medicine around the same time every day (for example, one tablet in the morning and one in the evening). Taking Brilique with other medicines for blood clotting Your doctor will usually also tell you to take acetylsalicylic acid. This is a substance present in many medicines used to prevent blood clotting. Your doctor will tell you how much to take (usually between 75-150 mg daily). How to take Brilique Do not open the blister until it is time to take your medicine.  To take out the tablet, tear open the blister foil - do not push it through the foil because the tablet may break.  Put the tablet on your tongue and let it disintegrate.  You can then swallow it with or without water.  You can take the tablet with or without food. If you are in the hospital you may be given this tablet mixed with some water and given through a tube via the nose (nasogastric tube). If you take more Brilique than you should If you take more Brilique than you should, talk to a doctor or go to hospital straight away. Take the medicine pack with you. You may be at increased risk of bleeding. If you forget to take Brilique  If you forget to take a dose, just take your next dose as normal.  Do not take a double dose (two doses at the same time) to make up for the forgotten dose. If you stop taking Brilique Do not stop taking Brilique without talking to your doctor. Take this medicine on a regular basis and for as long as your doctor keeps prescribing it. If you stop taking Brilique, it may increase your chances of having another heart attack or stroke or dying from a disease related to your heart or blood vessels. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may happen with this medicine: Brilique affects blood clotting, so most side effects are related to bleeding. Bleeding may occur in any part of the body. Some bleeding is common (like bruising and nosebleeds). Severe bleeding is uncommon but can be life threatening. See a doctor straight away if you notice any of the following – you may need urgent medical treatment:  Bleeding into the brain or inside the skull is an uncommon side effect, and may cause signs of a stroke such as: - sudden numbness or weakness of your arm, leg or face, especially if only on one side of the body - sudden confusion, difficulty speaking or understanding others - sudden difficulty in walking or loss of balance or co-ordination - suddenly feeling dizzy or sudden severe headache with no known cause 110  Signs of bleeding such as: - bleeding that is severe or that you cannot control - unexpected bleeding or bleeding that lasts a long time - pink, red or brown urine - vomiting red blood or your vomit looks like ‘coffee grounds’ - red or black stools (look like tar) - coughing up or vomiting blood clots  Fainting (syncope) - a temporary loss of consciousness due to sudden drop in blood flow to the brain (common)  Signs of a blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP) such as: - fever and purplish spots (called purpura) on the skin or in the mouth, with or without yellowing of the skin or eyes (jaundice), unexplained extreme tiredness or confusion Discuss with your doctor if you notice any of the following:  Feeling short of breath - this is very common. It might be due to your heart disease or another cause, or it might be a side effect of Brilique. Brilique-related breathlessness is generally mild and characterised as a sudden, unexpected hunger for air usually occurring at rest and may appear in the first weeks of therapy and for many may disappear. If your feeling of shortness of breath gets worse or lasts a long time, tell your doctor. Your doctor will decide if it needs treatment or further investigations. Other possible side effects Very common (may affect more than 1 in 10 people)  High level of uric acid in your blood (as seen in tests)  Bleeding caused by blood disorders Common (may affect up to 1 in 10 people)  Bruising  Headache  Feeling dizzy or like the room is spinning  Diarrhoea or indigestion  Feeling sick (nausea)  Constipation  Rash  Itching  Severe pain and swelling in your joints – these are signs of gout  Feeling dizzy or light-headed, or having blurred vision – these are signs of low blood pressure  Nosebleed  Bleeding after surgery or from cuts (for example while shaving) and wounds more than is normal  Bleeding from your stomach lining (ulcer)  Bleeding gums Uncommon (may affect up to 1 in 100 people) 111  Allergic reaction – a rash, itching or a swollen face or swollen lips/tongue may be signs of an allergic reaction  Confusion  Visual problems caused by blood in your eye  Vaginal bleeding that is heavier, or happens at different times, than your normal period (menstrual) bleeding  Bleeding into your joints and muscles causing painful swelling  Blood in your ear  Internal bleeding, this may cause dizziness or light-headedness Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Brilique Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Brilique contains  The active substance is ticagrelor. Each orodispersible tablet contains 90 mg of ticagrelor.  The other ingredients are: mannitol (E421), microcrystalline cellulose (E460), crospovidone (E1202), xylitol (E967), anhydrous calcium hydrogen phosphate (E341), sodium stearyl fumarate, hydroxypropylcellulose (E463), colloidal anhydrous silica. What Brilique looks like and contents of the pack The orodispersible tablets are round, flat, bevelled edged, white to pale pink, marked with a “90” above “TI” on one side. Brilique is available in:  perforated unit dose blisters in cartons of 10 x 1, 56 x 1 and 60 x 1 orodispersible tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: AstraZeneca AB SE-151 85 Södertälje Sweden Manufacturer: http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 112 AstraZeneca AB Gärtunavägen SE-151 85 Södertälje Sweden Manufacturer: AstraZeneca UK Limited Silk Road Business Park Macclesfield, Cheshire, SK10 2NA United Kingdom For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien AstraZeneca S.A./N.V. Tel: +32 2 370 48 11 Lietuva UAB AstraZeneca Lietuva Tel: +370 5 2660550 България АстраЗенека България ЕООД Teл.: +359 2 44 55 000 Luxembourg/Luxemburg AstraZeneca S.A./N.V. Tél/Tel: +32 2 370 48 11 Česká republika AstraZeneca Czech Republic s.r.o Tel: +420 222 807 111 Magyarország AstraZeneca Kft. Tel.: +36 1 883 6500 Danmark AstraZeneca A/S Tlf: +45 43 66 64 62 Malta Associated Drug Co. Ltd Tel: +356 2277 8000 Deutschland AstraZeneca GmbH Tel: +49 41 03 7080 Nederland AstraZeneca BV Tel: +31 79 363 2222 Eesti AstraZeneca Tel: +372 6549 600 Norge AstraZeneca AS Tlf: +47 21 00 64 00 Ελλάδα AstraZeneca A.E. Τηλ: +30 2 106871500 Österreich AstraZeneca Österreich GmbH Tel: +43 1 711 31 0 España AstraZeneca Farmacéutica Spain, S.A. Tel: +34 91 301 91 00 Polska AstraZeneca Pharma Poland Sp. z o.o. Tel.: +48 22 245 73 00 France AstraZeneca Tél: +33 1 41 29 40 00 Portugal AstraZeneca Produtos Farmacêuticos, Lda. Tel: +351 21 434 61 00 Hrvatska AstraZeneca d.o.o. România AstraZeneca Pharma SRL 113 Tel: +385 1 4628 000 Tel: +40 21 317 60 41 Ireland AstraZeneca Pharmaceuticals (Ireland) DAC Tel: +353 1609 7100 Slovenija AstraZeneca UK Limited Tel: +386 1 51 35 600 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika AstraZeneca AB, o.z. Tel: +421 2 5737 7777 Italia AstraZeneca S.p.A. Tel: +39 02 9801 1 Suomi/Finland AstraZeneca Oy Puh/Tel: +358 10 23 010 Κύπρος Αλέκτωρ Φαρµακευτική Λτδ Τηλ: +357 22490305 Sverige AstraZeneca AB Tel: +46 8 553 26 000 Latvija SIA AstraZeneca Latvija Tel: +371 67377100 United Kingdom AstraZeneca UK Ltd Tel: +44 1582 836 836 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ 114 SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take brilique', 'Section_Content': "do not take brilique if: you are allergic to ticagrelor or any of the other ingredients of this medicine (listed in section 6). you are bleeding now. you have had a stroke caused by bleeding in the brain. you have severe liver disease. you are taking any of the following medicines: - ketoconazole (used to treat fungal infections) - clarithromycin (used to treat bacterial infections) - nefazodone (an antidepressant) - ritonavir and atazanavir (used to treat hiv infection and aids) do not take brilique if any of the above applies to you. if you are not sure, talk to your doctor or pharmacist before taking this medicine. warnings and precautions talk to your doctor or pharmacist before taking brilique if: you have an increased risk of bleeding because of: - a recent serious injury - recent surgery (including dental work, ask your dentist about this) - you have a condition that affects blood clotting - recent bleeding from your stomach or gut (such as a stomach ulcer or colon 'polyps') you are due to have surgery (including dental work) at any time while taking brilique. this is because of the increased risk of bleeding. your doctor may want you to stop taking this medicine 5 days prior to surgery. your heart rate is abnormally low (usually lower than 60 beats per minute) and you do not already have in place a device that paces your heart (pacemaker). you have asthma or other lung problems or breathing difficulties. you have had any problems with your liver or have previously had any disease which may have affected your liver. you have had a blood test that showed more than the usual amount of uric acid. if any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking this medicine. if you are taking both brilique and heparin: your doctor may require a sample of your blood for diagnostic tests if they suspect a rare platelet disorder caused by heparin. it is important that you inform your doctor that you are taking both brilique and heparin, as brilique may affect the diagnostic test. children and adolescents brilique is not recommended for children and adolescents under 18 years. other medicines and brilique please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. this is because brilique can affect the way some medicines work and some medicines can have an effect on brilique. tell your doctor or pharmacist if you are taking any of the following medicines: more than 40 mg daily of either simvastatin or lovastatin (medicines used to treat high cholesterol) rifampicin (an antibiotic) phenytoin, carbamazepine and phenobarbital (used to control seizures) 92 digoxin (used to treat heart failure) cyclosporine (used to lessen your body's defenses) quinidine and diltiazem (used to treat abnormal heart rhythms) beta blockers and verapamil (used to treat high blood pressure) morphine and other opioids (used to treat severe pain) in particular, tell your doctor or pharmacist if you are taking any of the following medicines that increase your risk of bleeding: 'oral anticoagulants' often referred to as 'blood thinners' which include warfarin. non-steroidal anti-inflammatory drugs (abbreviated as nsaids) often taken as painkillers such as ibuprofen and naproxen. selective serotonin reuptake inhibitors (abbreviated as ssris) taken as antidepressants such as paroxetine, sertraline and citalopram. other medicines such as ketoconazole (used to treat fungal infections), clarithromycin (used to treat bacterial infections), nefazodone (an antidepressant), ritonavir and atazanavir (used to treat hiv infection and aids), cisapride (used to treat heartburn), ergot alkaloids (used to treat migraines and headaches). also tell your doctor that because you are taking brilique, you may have an increased risk of bleeding if your doctor gives you fibrinolytics, often called 'clot dissolvers', such as streptokinase or alteplase. pregnancy and breast-feeding it is not recommended to use brilique if you are pregnant or may become pregnant. women should use appropriate contraceptive measures to avoid pregnancy while taking this medicine. talk to your doctor before taking this medicine if you are breast-feeding. your doctor will discuss with you the benefits and risks of taking brilique during this time. if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. driving and using machines brilique is not likely to affect your ability to drive or use machines. if you feel dizzy or confused while taking this medicine, be careful while driving or using machines. sodium content this medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 'sodium-free'.", 'Entity_Recognition': [{'Text': 'brilique', 'Type': 'PRODUCT_NAME', 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{'Title': '3. how to take brilique', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. how much to take the usual dose is one tablet of 60 mg twice a day. continue taking brilique as long as your doctor tells you. take this medicine around the same time every day (for example, one tablet in the morning and one in the evening). taking brilique with other medicines for blood clotting 93 your doctor will usually also tell you to take acetylsalicylic acid. this is a substance present in many medicines used to prevent blood clotting. your doctor will tell you how much to take (usually between 75-150 mg daily). how to take brilique you can take the tablet with or without food. you can check when you last took a tablet of brilique by looking on the blister. there is a sun (for the morning) and a moon (for the evening). this will tell you whether you have taken the dose. if you have trouble swallowing the tablet if you have trouble swallowing the tablet you can crush it and mix with water as follows: crush the tablet to a fine powder. pour the powder into half a glass of water. stir and drink immediately. to make sure there is no medicine left, rinse the empty glass with another half a glass of water and drink it. if you are in the hospital you may be given this tablet mixed with some water and given through a tube via the nose (nasogastric tube). if you take more brilique than you should if you take more brilique than you should, talk to a doctor or go to hospital straight away. take the medicine pack with you. you may be at increased risk of bleeding. if you forget to take brilique if you forget to take a dose, just take your next dose as normal. do not take a double dose (two doses at the same time) to make up for the forgotten dose. if you stop taking brilique do not stop taking brilique without talking to your doctor. take this medicine on a regular basis and for as long as 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. the following side effects may happen with this medicine: brilique affects blood clotting, so most side effects are related to bleeding. bleeding may occur in any part of the body. some bleeding is common (like bruising and nosebleeds). severe bleeding is uncommon but can be life threatening. see a doctor straight away if you notice any of the following you may need urgent medical treatment: bleeding into the brain or inside the skull is an uncommon side effect, and may cause signs of a stroke such as: - sudden numbness or weakness of your arm, leg or face, especially if only on one side of the body - sudden confusion, difficulty speaking or understanding others - sudden difficulty in walking or loss of balance or co-ordination 94 - suddenly feeling dizzy or sudden severe headache with no known cause signs of bleeding such as: - bleeding that is severe or that you cannot control - unexpected bleeding or bleeding that lasts a long time - pink, red or brown urine - vomiting red blood or your vomit looks like 'coffee grounds' - red or black stools (look like tar) - coughing up or vomiting blood clots fainting (syncope) - a temporary loss of consciousness due to sudden drop in blood flow to the brain (common) signs of a blood clotting problem called thrombotic thrombocytopenic purpura (ttp) such as: - fever and purplish spots (called purpura) on the skin or in the mouth, with or without yellowing of the skin or eyes (jaundice), unexplained extreme tiredness or confusion discuss with your doctor if you notice any of the following: feeling short of breath - this is very common. it might be due to your heart disease or another cause, or it might be a side effect of brilique. brilique-related breathlessness is generally mild and characterised as a sudden, unexpected hunger for air usually occurring at rest and may appear in the first weeks of therapy and for many may disappear. if your feeling of shortness of breath gets worse or lasts a long time, tell your doctor. your doctor will decide if it needs treatment or further investigations. other possible side effects very common (may affect more than 1 in 10 people) high level of uric acid in your blood (as seen in tests) bleeding caused by blood disorders common (may affect up to 1 in 10 people) bruising headache feeling dizzy or like the room is spinning diarrhoea or indigestion feeling sick (nausea) constipation rash itching severe pain and swelling in your joints these are signs of gout feeling dizzy or light-headed, or having blurred vision these are signs of low blood pressure nosebleed bleeding after surgery or from cuts (for example while shaving) and wounds more than is normal bleeding from your stomach lining (ulcer) bleeding gums uncommon (may affect up to 1 in 100 people) 95 allergic reaction a rash, itching or a swollen face or swollen lips/tongue may be signs of an allergic reaction confusion visual problems caused by blood in your eye vaginal bleeding that is heavier, or happens at different times, than your normal period (menstrual) bleeding bleeding into your joints and muscles causing painful swelling blood in your ear internal bleeding, this may cause dizziness or light-headedness reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'brilique', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 14, 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{'Title': '5. how to store brilique', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what brilique contains the active substance is ticagrelor. each film-coated tablet contains 60 mg of ticagrelor. the other ingredients are: tablet core: mannitol (e421), calcium hydrogen phosphate dihydrate, sodium starch glycolate type a, hydroxypropylcellulose (e463), magnesium stearate (e470b). tablet film-coating: hypromellose (e464), titanium dioxide (e171), macrogol 400, iron oxide black (e172), iron oxide red (e172). what brilique looks like and contents of the pack film-coated tablet (tablet): the tablets are round, biconvex, pink, film-coated marked with a "60" above "t" on one side. brilique is available in: standard blisters (with sun/moon symbols) in cartons of 60 and 180 tablets calendar blisters (with sun/moon symbols) in cartons of 14, 56 and 168 tablets not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'brilique', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, 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4B4322A0A2CA4BE3D81A8A3BC62E2E3A

https://www.ema.europa.eu/documents/product-information/cosentyx-epar-product-information_en.pdf

Cosentyx

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg powder for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial of powder contains 150 mg secukinumab. After reconstitution, 1 ml of solution contains 150 mg secukinumab. Secukinumab is a recombinant fully human monoclonal antibody produced in Chinese Hamster Ovary (CHO) cells. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for solution for injection The powder is a white solid lyophilisate. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adult plaque psoriasis Cosentyx is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Paediatric plaque psoriasis Cosentyx is indicated for the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6 years who are candidates for systemic therapy. Psoriatic arthritis Cosentyx, alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate (see section 5.1). Axial spondyloarthritis (axSpA) Ankylosing spondylitis (AS, radiographic axial spondyloarthritis) Cosentyx is indicated for the treatment of active ankylosing spondylitis in adults who have responded inadequately to conventional therapy. Non-radiographic axial spondyloarthritis (nr-axSpA) Cosentyx is indicated for the treatment of active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence in adults who have responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs). 3 4.2 Posology and method of administration Cosentyx is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which Cosentyx is indicated. Posology Adult plaque psoriasis The recommended dose is 300 mg of secukinumab by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 300 mg dose is given as two subcutaneous injections of 150 mg. Paediatric plaque psoriasis (adolescents and children from the age of 6 years) The recommended dose is based on body weight (Table 1) and administered by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 75 mg dose is given as one subcutaneous injection of 75 mg. Each 150 mg dose is given as one subcutaneous injection of 150 mg. Each 300 mg dose is given as two subcutaneous injections of 150 mg. Table 1 Recommended dose for paediatric plaque psoriasis Body weight at time of dosing Recommended Dose <25 kg 75 mg 25 to <50 kg 75 mg ≥50 kg 150 mg (*may be increased to 300 mg) *Some patients may derive additional benefit from the higher dose. Psoriatic arthritis For patients with concomitant moderate to severe plaque psoriasis or who are anti-TNFα inadequate responders (IR), the recommended dose is 300 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 300 mg dose is given as two subcutaneous injections of 150 mg. For other patients, the recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg. Axial spondyloarthritis (axSpA) Ankylosing spondylitis (AS, radiographic axial spondyloarthritis) The recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg. Each 300 mg dose is given as two subcutaneous injections of 150 mg. Non-radiographic axial spondyloarthritis (nr-axSpA) The recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. For all of the above indications, available data suggest that a clinical response is usually achieved within 16 weeks of treatment. Consideration should be given to discontinuing treatment in patients who have shown no response by 16 weeks of treatment. Some patients with an initial partial response may subsequently improve with continued treatment beyond 16 weeks. Special populations Elderly patients (aged 65 years and over) No dose adjustment is required (see section 5.2). 4 Renal impairment / hepatic impairment Cosentyx has not been studied in these patient populations. No dose recommendations can be made. Paediatric population The safety and efficacy of Cosentyx in children with plaque psoriasis below the age of 6 years have not been established. The safety and efficacy of Cosentyx in children below the age of 18 years in other indications have not yet been established. No data are available. Method of administration Cosentyx is to be administered by subcutaneous injection. If possible, areas of the skin that show psoriasis should be avoided as injection sites. The powder for solution for injection must be reconstituted before use. The reconstitution, dose preparation and administration of the powder for solution for injection is to be done by a healthcare professional. For instructions on reconstitution of the medicinal product before administration, see section 6.6 and the Instructions for Use in the package leaflet. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Clinically important, active infection, e.g. active tuberculosis (see section 4.4). 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Infections Secukinumab has the potential to increase the risk of infections. Serious infections have been observed in patients receiving secukinumab in the post-marketing setting. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, the patient should be closely monitored and secukinumab should not be administered until the infection resolves. In clinical studies, infections have been observed in patients receiving secukinumab (see section 4.8). Most of these were mild or moderate upper respiratory tract infections such as nasopharyngitis and did not require treatment discontinuation. Related to the mechanism of action of secukinumab, non-serious mucocutaneous candida infections were more frequently reported for secukinumab than placebo in the psoriasis clinical studies (3.55 per 100 patient years for secukinumab 300 mg versus 1.00 per 100 patient years for placebo) (see section 4.8). No increased susceptibility to tuberculosis was reported from clinical studies. However, secukinumab should not be given to patients with active tuberculosis. Anti-tuberculosis therapy should be considered prior to initiation of secukinumab in patients with latent tuberculosis. 5 Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis) Cases of new or exacerbations of inflammatory bowel disease have been reported with secukinumab (see section 4.8). Secukinumab is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation of pre-existing inflammatory bowel disease, secukinumab should be discontinued and appropriate medical management should be initiated. Hypersensitivity reactions In clinical studies, rare cases of anaphylactic reactions have been observed in patients receiving secukinumab. If an anaphylactic or other serious allergic reactions occur, administration of secukinumab should be discontinued immediately and appropriate therapy initiated. Vaccinations Live vaccines should not be given concurrently with secukinumab. Patients receiving secukinumab may receive concurrent inactivated or non-live vaccinations. In a study, after meningococcal and inactivated influenza vaccinations, a similar proportion of healthy volunteers treated with 150 mg of secukinumab and those treated with placebo were able to mount an adequate immune response of at least a 4-fold increase in antibody titres to meningococcal and influenza vaccines. The data suggest that secukinumab does not suppress the humoral immune response to the meningococcal or influenza vaccines. Prior to initiating therapy with Cosentyx, it is recommended that paediatric patients receive all age-appropriate immunisations as per current immunisation guidelines. Concomitant immunosuppressive therapy In psoriasis studies, the safety and efficacy of secukinumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Secukinumab was administered concomitantly with methotrexate (MTX), sulfasalazine and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and ankylosing spondylitis). Caution should be exercised when considering concomitant use of other immunosuppressants and secukinumab (see also section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction Live vaccines should not be given concurrently with secukinumab (see also section 4.4). In a study in adult subjects with plaque psoriasis, no interaction was observed between secukinumab and midazolam (CYP3A4 substrate). No interaction was seen when secukinumab was administered concomitantly with methotrexate (MTX) and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and axial spondyloarthritis). 6 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential should use an effective method of contraception during treatment and for at least 20 weeks after treatment. Pregnancy There are no adequate data from the use of secukinumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Cosentyx during pregnancy. Breast-feeding It is not known whether secukinumab is excreted in human milk. Immunoglobulins are excreted in human milk and it is not known if secukinumab is absorbed systemically after ingestion. Because of the potential for adverse reactions in nursing infants from secukinumab, a decision on whether to discontinue breast-feeding during treatment and up to 20 weeks after treatment or to discontinue therapy with Cosentyx must be made taking into account the benefit of breast-feeding to the child and the benefit of therapy to the woman. Fertility The effect of secukinumab on human fertility has not been evaluated. Animal studies do not indicate direct or indirect harmful effects with respect to fertility. 4.7 Effects on ability to drive and use machines Cosentyx has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse drug reactions (ADRs) are upper respiratory tract infections (most frequently nasopharyngitis, rhinitis). Tabulated list of adverse reactions ADRs from clinical studies and post-marketing reports (Table 2) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data). Over 18,000 patients have been treated with secukinumab in blinded and open-label clinical studies in various indications (plaque psoriasis, psoriatic arthritis, axial spondyloarthritis and other autoimmune conditions), representing 30,565 patient years of exposure. Of these, over 11,700 patients were exposed to secukinumab for at least one year. The safety profile of secukinumab is consistent across all indications. 7 Table 2 List of adverse reactions in clinical studies1) and post-marketing experience System Organ Class Frequency Adverse reaction Infections and infestations Very common Upper respiratory tract infections Common Oral herpes Tinea pedis Uncommon Oral candidiasis Otitis externa Lower respiratory tract infections Not known Mucosal and cutaneous candidiasis (including oesophageal candidiasis) Blood and lymphatic system disorders Uncommon Neutropenia Immune system disorders Rare Anaphylactic reactions Nervous system disorders Common Headache Eye disorders Uncommon Conjunctivitis Respiratory, thoracic and mediastinal disorders Common Rhinorrhoea Gastrointestinal disorders Common Diarrhoea Common Nausea Uncommon Inflammatory bowel disease Skin and subcutaneous tissue disorders Uncommon Urticaria Rare Exfoliative dermatitis2) General disorders and administration site conditions Common Fatigue 1) Placebo-controlled clinical studies (phase III) in plaque psoriasis, PsA, AS and nr-axSpA patients exposed to 300 mg, 150 mg, 75 mg or placebo up to 12 weeks (psoriasis) or 16 weeks (PsA, AS and nr-axSpA) treatment duration 2) Cases were reported in patients with psoriasis diagnosis Description of selected adverse reactions Infections In the placebo-controlled period of clinical studies in plaque psoriasis (a total of 1,382 patients treated with secukinumab and 694 patients treated with placebo for up to 12 weeks), infections were reported in 28.7% of patients treated with secukinumab compared with 18.9% of patients treated with placebo. The majority of infections consisted of non-serious and mild to moderate upper respiratory tract infections, such as nasopharyngitis, which did not necessitate treatment discontinuation. There was an increase in mucosal or cutaneous candidiasis, consistent with the mechanism of action, but the cases were mild or moderate in severity, non-serious, responsive to standard treatment and did not necessitate treatment discontinuation. Serious infections occurred in 0.14% of patients treated with secukinumab and in 0.3% of patients treated with placebo (see section 4.4). Over the entire treatment period (a total of 3,430 patients treated with secukinumab for up to 52 weeks for the majority of patients), infections were reported in 47.5% of patients treated with secukinumab (0.9 per patient-year of follow-up). Serious infections were reported in 1.2% of patients treated with secukinumab (0.015 per patient-year of follow-up). Infection rates observed in psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) clinical studies were similar to those observed in the psoriasis studies. 8 Neutropenia In psoriasis phase III clinical studies, neutropenia was more frequently observed with secukinumab than with placebo, but most cases were mild, transient and reversible. Neutropenia <1.0-0.5x109/l (CTCAE grade 3) was reported in 18 out of 3,430 (0.5%) patients on secukinumab, with no dose dependence and no temporal relationship to infections in 15 out of 18 cases. There were no reported cases of more severe neutropenia. Non-serious infections with usual response to standard care and not requiring discontinuation of secukinumab were reported in the remaining 3 cases. The frequency of neutropenia in psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) was similar to psoriasis. Rare cases of neutropenia <0.5x109/l (CTCAE grade 4) were reported. Hypersensitivity reactions In clinical studies, urticaria and rare cases of anaphylactic reaction to secukinumab were observed (see also section 4.4). Immunogenicity In psoriasis, psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non- radiographic axial spondyloarthritis) clinical studies, less than 1% of patients treated with secukinumab developed antibodies to secukinumab up to 52 weeks of treatment. About half of the treatment-emergent anti-drug antibodies were neutralising, but this was not associated with loss of efficacy or pharmacokinetic abnormalities. Paediatric population Undesirable effects in paediatric patients from the age of 6 years with plaque psoriasis The safety of secukinumab was assessed in two phase III studies in paediatric patients with plaque psoriasis. The first study (paediatric study 1) was a double-blind, placebo-controlled study of 162 patients from 6 to less than 18 years of age with severe plaque psoriasis. The second study (paediatric study 2) is an open-label study of 84 patients from 6 to less than 18 years of age with moderate to severe plaque psoriasis. The safety profile reported in these two studies was consistent with the safety profile reported in adult plaque psoriasis patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Doses up to 30 mg/kg (approximately 2000 to 3000 mg) have been administered intravenously in clinical studies without dose-limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC10 Mechanism of action Secukinumab is a fully human IgG1/κ monoclonal antibody that selectively binds to and neutralises the proinflammatory cytokine interleukin-17A (IL-17A). Secukinumab works by targeting IL-17A and inhibiting its interaction with the IL-17 receptor, which is expressed on various cell types including keratinocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to autoimmune and inflammatory diseases. Clinically relevant levels of secukinumab reach the skin and reduce local inflammatory markers. As a direct consequence treatment with secukinumab reduces erythema, induration and desquamation present in plaque psoriasis lesions. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis, psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) and is up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients and in synovial tissue of psoriatic arthritis patients. The frequency of IL-17-producing cells was also significantly higher in the subchondral bone marrow of facet joints from patients with ankylosing spondylitis. Increased numbers of IL-17A producing lymphocytes have also been found in patients with non-radiographic axial spondyloarthritis. Inhibition of IL-17A was shown to be effective in the treatment of ankylosing spondylitis, thus establishing the key role of this cytokine in axial spondyloarthritis. Pharmacodynamic effects Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are initially increased in patients receiving secukinumab. This is followed by a slow decrease due to reduced clearance of secukinumab-bound IL-17A, indicating that secukinumab selectively captures free IL-17A, which plays a key role in the pathogenesis of plaque psoriasis. In a study with secukinumab, infiltrating epidermal neutrophils and various neutrophil-associated markers that are increased in lesional skin of plaque psoriasis patients were significantly reduced after one to two weeks of treatment. Secukinumab has been shown to lower (within 1 to 2 weeks of treatment) levels of C-reactive protein, which is a marker of inflammation. Clinical efficacy and safety Adult plaque psoriasis The safety and efficacy of secukinumab were assessed in four randomised, double-blind, placebo-controlled phase III studies in patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy [ERASURE, FIXTURE, FEATURE, JUNCTURE]. The efficacy and safety of secukinumab 150 mg and 300 mg were evaluated versus either placebo or etanercept. In addition, one study assessed a chronic treatment regimen versus a “retreatment as needed” regimen [SCULPTURE]. Of the 2,403 patients who were included in the placebo-controlled studies, 79% were biologic-naive, 45% were non-biologic failures and 8% were biologic failures (6% were anti-TNF failures, and 2% were anti-p40 failures). Approximately 15 to 25% of patients in phase III studies had psoriatic arthritis (PsA) at baseline. 10 Psoriasis study 1 (ERASURE) evaluated 738 patients. Patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Psoriasis study 2 (FIXTURE) evaluated 1,306 patients. Patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients randomised to etanercept received 50 mg doses twice per week for 12 weeks followed by 50 mg every week. In both study 1 and study 2, patients randomised to receive placebo who were non-responders at week 12 then crossed over to receive secukinumab (either 150 mg or 300 mg) at weeks 12, 13, 14, and 15, followed by the same dose every month starting at week 16. All patients were followed for up to 52 weeks following first administration of study treatment. Psoriasis study 3 (FEATURE) evaluated 177 patients using a pre-filled syringe compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of secukinumab self-administration via the pre-filled syringe. Psoriasis study 4 (JUNCTURE) evaluated 182 patients using a pre-filled pen compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of secukinumab self-administration via the pre-filled pen. In both study 3 and study 4, patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients were also randomised to receive placebo at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Psoriasis study 5 (SCULPTURE) evaluated 966 patients. All patients received secukinumab 150 mg or 300 mg doses at weeks 0, 1, 2, 3, 4, 8 and 12 and then were randomised to receive either a maintenance regimen of the same dose every month starting at week 12 or a “retreatment as needed” regimen of the same dose. Patients randomised to “retreatment as needed” did not achieve adequate maintenance of response and therefore a fixed monthly maintenance regimen is recommended. The co-primary endpoints in the placebo and active-controlled studies were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 “clear” or “almost clear” response versus placebo at week 12 (see Tables 3 and 4). The 300 mg dose provided improved skin clearance particularly for “clear” or “almost clear” skin across the efficacy endpoints of PASI 90, PASI 100, and IGA mod 2011 0 or 1 response across all studies with peak effects seen at week 16, therefore this dose is recommended. 11 Table 3 Summary of PASI 50/75/90/100 & IGA⃰ mod 2011 “clear” or “almost clear” clinical response in psoriasis studies 1, 3 and 4 (ERASURE, FEATURE and JUNCTURE) Week 12 Week 16 Week 52 Placebo 150 mg 300 mg 150 mg 300 mg 150 mg 300 mg Study 1 Number of patients 246 244 245 244 245 244 245 PASI 50 response n (%) 22 (8.9%) 203 (83.5%) 222 (90.6%) 212 (87.2%) 224 (91.4%) 187 (77%) 207 (84.5%) PASI 75 response n (%) 11 (4.5%) 174 (71.6%)** 200 (81.6%)** 188 (77.4%) 211 (86.1%) 146 (60.1%) 182 (74.3%) PASI 90 response n (%) 3 (1.2%) 95 (39.1%)** 145 (59.2%)** 130 (53.5%) 171 (69.8%) 88 (36.2%) 147 (60.0%) PASI 100 response n (%) 2 (0.8%) 31 (12.8%) 70 (28.6%) 51 (21.0%) 102 (41.6%) 49 (20.2%) 96 (39.2%) IGA mod 2011 “clear” or “almost clear” response n (%) 6 (2.40%) 125 (51.2%)** 160 (65.3%)** 142 (58.2%) 180 (73.5%) 101 (41.4%) 148 (60.4%) Study 3 Number of patients 59 59 58 - - - - PASI 50 response n (%) 3 (5.1%) 51 (86.4%) 51 (87.9%) - - - - PASI 75 response n (%) 0 (0.0%) 41 (69.5%)** 44 (75.9%)** - - - - PASI 90 response n (%) 0 (0.0%) 27 (45.8%) 35 (60.3%) - - - - PASI 100 response n (%) 0 (0.0%) 5 (8.5%) 25 (43.1%) - - - - IGA mod 2011 “clear” or “almost clear” response n (%) 0 (0.0%) 31 (52.5%)** 40 (69.0%)** - - - - Study 4 Number of patients 61 60 60 - - - - PASI 50 response n (%) 5 (8.2%) 48 (80.0%) 58 (96.7%) - - - - PASI 75 response n (%) 2 (3.3%) 43 (71.7%)** 52 (86.7%)** - - - - PASI 90 response n (%) 0 (0.0%) 24 (40.0%) 33 (55.0%) - - - - PASI 100 response n(%) 0 (0.0%) 10 (16.7%) 16 (26.7%) - - - - IGA mod 2011 “clear” or “almost clear” response n (%) 0 (0.0%) 32 (53.3%)** 44 (73.3%)** - - - - * The IGA mod 2011 is a 5-category scale including “0 = clear”, “1 = almost clear”, “2 = mild”, “3 = moderate” or “4 = severe”, indicating the physician’s overall assessment of the psoriasis severity focusing on induration, erythema and scaling. Treatment success of “clear” or “almost clear” consisted of no signs of psoriasis or normal to pink colouration of lesions, no thickening of the plaque and none to minimal focal scaling. ** p values versus placebo and adjusted for multiplicity: p<0.0001. 12 Table 4 Summary of clinical response on psoriasis study 2 (FIXTURE) Week 12 Week 16 Week 52 Placebo 150 mg 300 mg Etanercept 150 mg 300 mg Etanercept 150 mg 300 mg Etanercept Number of patients 324 327 323 323 327 323 323 327 323 323 PASI 50 response n (%) 49 (15.1%) 266 (81.3%) 296 (91.6%) 226 (70.0%) 290 (88.7%) 302 (93.5%) 257 (79.6%) 249 (76.1%) 274 (84.8%) 234 (72.4%) PASI 75 response n (%) 16 (4.9%) 219 (67.0%) ** 249 (77.1%) ** 142 (44.0%) 247 (75.5%) 280 (86.7%) 189 (58.5%) 215 (65.7%) 254 (78.6%) 179 (55.4%) PASI 90 response n (%) 5 (1.5%) 137 (41.9%) 175 (54.2%) 67 (20.7%) 176 (53.8%) 234 (72.4%) 101 (31.3%) 147 (45.0%) 210 (65.0%) 108 (33.4%) PASI 100 response n (%) 0 (0%) 47 (14.4%) 78 (24.1%) 14 (4.3%) 84 (25.7%) 119 (36.8%) 24 (7.4%) 65 (19.9%) 117 (36.2%) 32 (9.9%) IGA mod 2011 “clear” or “almost clear” response n (%) 9 (2.8%) 167 (51.1%) ** 202 (62.5%) ** 88 (27.2%) 200 (61.2%) 244 (75.5%) 127 (39.3%) 168 (51.4%) 219 (67.8%) 120 (37.2%) ** p values versus etanercept: p=0.0250 In an additional psoriasis study (CLEAR) 676 patients were evaluated. Secukinumab 300 mg met the primary and secondary endpoints by showing superiority to ustekinumab based on PASI 90 response at week 16 (primary endpoint), speed of onset of PASI 75 response at week 4, and long-term PASI 90 response at week 52. Greater efficacy of secukinumab compared to ustekinumab for the endpoints PASI 75/90/100 and IGA mod 2011 0 or 1 response (“clear” or “almost clear”) was observed early and continued through to week 52. Table 5 Summary of clinical response on CLEAR study Week 4 Week 16 Week 52 Secukinumab 300 mg Ustekinumab* Secukinumab 300 mg Ustekinumab* Secukinumab 300 mg Ustekinumab* Number of patients 334 335 334 335 334 335 PASI 75 response n (%) 166 (49.7%)** 69 (20.6%) 311 (93.1%) 276 (82.4%) 306 (91.6%) 262 (78.2%) PASI 90 response n (%) 70 (21.0%) 18 (5.4%) 264 (79.0%)** 192 (57.3%) 250 (74.9%)*** 203 (60.6%) PASI 100 response n (%) 14 (4.2%) 3 (0.9%) 148 (44.3%) 95 (28.4%) 150 (44.9%) 123 (36.7%) IGA mod 2011 “clear” or “almost clear” response n (%) 128 (38.3%) 41 (12.2%) 278 (83.2%) 226 (67.5%) 261 (78.1%) 213 (63.6%) * Patients treated with secukinumab received 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every 4 weeks until week 52. Patients treated with ustekinumab received 45 mg or 90 mg at weeks 0 and 4, then every 12 weeks until week 52 (dosed by weight as per approved posology) ** p values versus ustekinumab: p<0.0001 for primary endpoint of PASI 90 at week 16 and secondary endpoint of PASI 75 at week 4 *** p values versus ustekinumab: p=0.0001 for secondary endpoint of PASI 90 at week 52 Secukinumab was efficacious in systemic treatment-naive, biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients. Improvements in PASI 75 in patients with concurrent psoriatic arthritis at baseline were similar to those in the overall plaque psoriasis population. Secukinumab was associated with a fast onset of efficacy with a 50% reduction in mean PASI by week 3 for the 300 mg dose. 13 Figure 1 Time course of percentage change from baseline of mean PASI score in study 1 (ERASURE) Specific locations/forms of plaque psoriasis In two additional placebo-controlled studies, improvement was seen in both nail psoriasis (TRANSFIGURE, 198 patients) and palmoplantar plaque psoriasis (GESTURE, 205 patients). In the TRANSFIGURE study, secukinumab was superior to placebo at week 16 (46.1% for 300 mg, 38.4% for 150 mg and 11.7% for placebo) as assessed by significant improvement from baseline in the Nail Psoriasis Severity Index (NAPSI %) for patients with moderate to severe plaque psoriasis with nail involvement. In the GESTURE study, secukinumab was superior to placebo at week 16 (33.3% for 300 mg, 22.1% for 150 mg, and 1.5% for placebo) as assessed by significant improvement of ppIGA 0 or 1 response (“clear” or “almost clear”) for patients with moderate to severe palmoplantar plaque psoriasis. A placebo-controlled study evaluated 102 patients with moderate to severe scalp psoriasis, defined as having a Psoriasis Scalp Severity Index (PSSI) score of ≥12, an IGA mod 2011 scalp only score of 3 or greater and at least 30% of the scalp surface area affected. Secukinumab 300 mg was superior to placebo at week 12 as assessed by significant improvement from baseline in both the PSSI 90 response (52.9% versus 2.0%) and IGA mod 2011 0 or 1 scalp only response (56.9% versus 5.9%). Improvement in both endpoints was sustained for secukinumab patients who continued treatment through to week 24. Quality of life/patient-reported outcomes Statistically significant improvements at week 12 (studies 1-4) from baseline compared to placebo were demonstrated in the DLQI (Dermatology Life Quality Index). Mean decreases (improvements) in DLQI from baseline ranged from -10.4 to -11.6 with secukinumab 300 mg, from -7.7 to -10.1 with secukinumab 150 mg, versus -1.1 to -1.9 for placebo at week 12. These improvements were maintained for 52 weeks (studies 1 and 2). Forty percent of the participants in studies 1 and 2 completed the Psoriasis Symptom Diary©. For the participants completing the diary in each of these studies, statistically significant improvements at week 12 from baseline compared to placebo in patient-reported signs and symptoms of itching, pain and scaling were demonstrated. Statistically significant improvements at week 4 from baseline in patients treated with secukinumab compared to patients treated with ustekinumab (CLEAR) were demonstrated in the DLQI and these improvements were maintained for up to 52 weeks. PASI % change from baseline Weeks of treatment n = number of patients evaluable secukinumab 150 mg (n=243) secukinumab 300 mg (n=245) Placebo (n=245) 14 Statistically significant improvements in patient-reported signs and symptoms of itching, pain and scaling at week 16 and week 52 (CLEAR) were demonstrated in the Psoriasis Symptom Diary© in patients treated with secukinumab compared to patients treated with ustekinumab. Statistically significant improvements (decreases) at week 12 from baseline in the scalp psoriasis study were demonstrated in patient reported signs and symptoms of scalp itching, pain and scaling compared to placebo. Psoriatic arthritis The safety and efficacy of secukinumab were assessed in 1,999 patients in three randomised, double-blind, placebo-controlled phase III studies in patients with active psoriatic arthritis (≥3 swollen and ≥3 tender joints) despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease-modifying anti-rheumatic drug (DMARD) therapy. Patients with each subtype of PsA were enrolled in these studies, including polyarticular arthritis with no evidence of rheumatoid nodules, spondylitis with peripheral arthritis, asymmetric peripheral arthritis, distal interphalangeal involvement and arthritis mutilans. Patients in these studies had a diagnosis of PsA of at least five years. The majority of patients also had active psoriasis skin lesions or a documented history of psoriasis. Over 61% and 42% of the PsA patients had enthesitis and dactylitis at baseline, respectively. For all studies, the primary endpoint was American College of Rheumatology (ACR) 20 response. For Psoriatic Arthritis study 1 (PsA study 1) and Psoriatic Arthritis study 2 (PsA study 2), the primary endpoint was at week 24. For Psoriatic Arthritis study 3 (PsA study 3), the primary endpoint was at week 16 with the key secondary endpoint, the change from baseline in modified Total Sharp Score (mTSS), at week 24. In PsA study 1, PsA study 2 and PsA study 3, 29%, 35% and 30% of patients, respectively, were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients). PsA study 1 (FUTURE 1) evaluated 606 patients, of whom 60.7% had concomitant MTX. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 75 mg or 150 mg subcutaneously every month starting at week 8. Patients randomised to placebo who were non-responders at week 16 (early rescue) and other placebo patients at week 24 were crossed over to receive secukinumab (either 75 mg or 150 mg subcutaneously) followed by the same dose every month. PsA study 2 (FUTURE 2) evaluated 397 patients, of whom 46.6% had concomitant MTX. Patients randomised to secukinumab received 75 mg, 150 mg or 300 mg subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients randomised to receive placebo who were non-responders at week 16 (early rescue) were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 16 followed by the same dose every month. Patients randomised to receive placebo who were responders at week 16 were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 24 followed by the same dose every month. PsA study 3 (FUTURE 5) evaluated 996 patients, of whom 50.1% had concomitant MTX. Patients were randomised to receive secukinumab 150 mg, 300 mg or placebo subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month, or a once monthly injection of secukinumab 150 mg (without loading). Patients randomised to receive placebo who were non-responders at week 16 (early rescue) were then crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 16 followed by the same dose every month. Patients randomised to receive placebo who were responders at week 16 were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 24 followed by the same dose every month. Signs and symptoms Treatment with secukinumab resulted in significant improvement in measures of disease activity compared to placebo at weeks 16 and 24 (see Table 6). 15 Table 6 Clinical response in PsA study 2 and PsA study 3 at week 16 and week 24 PsA study 2 PsA study 3 Placebo 150 mg1 300 mg1 Placebo 150 mg1 300 mg1 Number of patients randomised 98 100 100 332 220 222 ACR20 response n (%) Week 16 18 (18.4%) 60 (60.0%***) 57 (57.0%***) 91◊ (27.4%) 122◊ (55.5%***) 139◊ (62.6%***) Week 24 15◊ (15.3%) 51◊ (51.0%***) 54◊ (54.0%***) 78 (23.5%) 117 (53.2%***) 141 (63.5%***) ACR50 response n (%) Week 16 6 (6.1%) 37 (37.0%***) 35 (35.0%***) 27 (8.1%) 79 (35.9%*) 88 (39.6%*) Week 24 7 (7.1%) 35 (35.0%) 35 (35.0%**) 29 (8.7%) 86 (39.1%***) 97 (43.7%***) ACR70 response n (%) Week 16 2 (2.0%) 17 (17.0%**) 15 (15.0%**) 14 (4.2%) 40 (18.2%***) 45 (20.3%***) Week 24 1 (1.0%) 21 (21.0%**) 20 (20.0%**) 13 (3.9%) 53 (24.1%***) 57 (25.7%***) DAS28-CRP Week 16 -0.50 -1.45*** -1.51*** -0.63 -1.29* -1.49* Week 24 -0.96 -1.58** -1.61** -0.84 -1.57*** -1.68*** Number of patients with ≥3% BSA psoriasis skin involvement at baseline 43 (43.9%) 58 (58.0%) 41 (41.0%) 162 (48.8%) 125 (56.8%) 110 (49.5%) PASI 75 response n (%) Week 16 3 (7.0%) 33 (56.9%***) 27 (65.9%***) 20 (12.3%) 75 (60.0%*) 77 (70.0%*) Week 24 7 (16.3%) 28 (48.3%**) 26 (63.4%***) 29 (17.9%) 80 (64.0%***) 78 (70.9%***) PASI 90 response n (%) Week 16 3 (7.0%) 22 (37.9%***) 18 (43.9%***) 15 (9.3%) 46 (36.8%*) 59 (53.6%*) Week 24 4 (9.3%) 19 (32.8%**) 20 (48.8%***) 19 (11.7%) 51 (40.8%***) 60 (54.5%***) Dactylitis resolution n (%) † Week 16 10 (37%) 21 (65.6%*) 26 (56.5%) 40 (32.3%) 46 (57.5%*) 54 (65.9%*) Week 24 4 (14.8%) 16 (50.0%**) 26 (56.5%**) 42 (33.9%) 51 (63.8%***) 52 (63.4%***) 16 Enthesitis resolution n (%) ‡ Week 16 17 (26.2%) 32 (50.0%**) 32 (57.1%***) 68 (35.4%) 77 (54.6%*) 78 (55.7%*) Week 24 14 (21.5%) 27 (42.2%*) 27 (48.2%**) 66 (34.4%) 77 (54.6%***) 86 (61.4%***) * p<0.05, ** p<0.01, *** p<0.001; versus placebo All p-values are adjusted for multiplicity of testing based on pre-defined hierarchy at week 24 for PsA study 2, except for ACR70, Dactylitis and Enthesitis, which were exploratory endpoints and all endpoints at week 16. All p-values are adjusted for multiplicity of testing based on pre-defined hierarchy at week 16 for PsA study 3, except for ACR70 which was an exploratory endpoint and all endpoints at week 24. Non-responder imputation used for missing binary endpoint. ACR: American College of Rheumatology; PASI: Psoriasis Area and Severity Index; DAS: Disease Activity Score; BSA: Body Surface Area ◊Primary Endpoint 1Secukinumab 150 mg or 300 mg s.c. at weeks 0, 1, 2, 3, and 4 followed by the same dose every month †In patients with dactylitis at baseline (n=27, 32, 46, respectively for PsA study 2 and n=124, 80, 82, respectively for PsA study 3) ‡In patients with enthesitis at baseline (n=65, 64, 56, respectively for PsA study 2 and n=192, 141, 140, respectively for PsA study 3) The onset of action of secukinumab occurred as early as week 2. Statistically significant difference in ACR 20 versus placebo was reached at week 3. The percentage of patients achieving ACR 20 response by visit is shown in Figure 2. Figure 2 ACR20 response in PsA study 2 over time up to week 52 Percentage of responders Time (Weeks) 17 Similar responses for primary and key secondary endpoints were seen in PsA patients regardless of whether they were on concomitant MTX treatment or not. In PsA study 2, at week 24, secukinumab- treated patients with concomitant MTX use had a higher ACR 20 response (47.7% and 54.4% for 150 mg and 300 mg, respectively, compared to placebo 20.0%) and ACR 50 response (31.8% and 38.6% for 150 mg and 300 mg, respectively, compared to placebo 8.0%). Secukinumab-treated patients without concomitant MTX use had a higher ACR 20 response (53.6% and 53.6% for 150 mg and 300 mg, respectively, compared to placebo 10.4%) and ACR 50 response (37.5% and 32.1% for 150 mg and 300 mg, respectively, compared to placebo 6.3%). In PsA study 2, both anti-TNFα-naive and anti-TNFα-IR secukinumab-treated patients had a significantly higher ACR 20 response compared to placebo at week 24, with a slightly higher response in the anti-TNFα-naive group (anti-TNFα-naive: 64% and 58% for 150 mg and 300 mg, respectively, compared to placebo 15.9%; anti-TNFα-IR: 30% and 46% for 150 mg and 300 mg, respectively, compared to placebo 14.3%). In the anti-TNFα-IR patients subgroup, only the 300 mg dose showed significantly higher response rate for ACR 20 compared to placebo (p<0.05) and demonstrated clinical meaningful benefit over 150 mg on multiple secondary endpoints. Improvements in the PASI 75 response were seen in both subgroups and the 300 mg dose showed statistically significant benefit in the anti-TNFα-IR patients. The number of PsA patients with axial involvement was too small to allow meaningful assessment. Improvements were shown in all components of the ACR scores, including patient assessment of pain. In PsA study 2, the proportion of patients achieving a modified PsA Response Criteria (PsARC) response was greater in the secukinumab-treated patients (59.0% and 61.0% for 150 mg and 300 mg, respectively) compared to placebo (26.5%) at week 24. In PsA study 1 and PsA study 2, efficacy was maintained up to week 104. In PsA study 2, among 200 patients initially randomised to secukinumab 150 mg and 300 mg, 178 (89%) patients were still on treatment at week 52. Of the 100 patients randomised to secukinumab 150 mg, 64, 39 and 20 had an ACR 20/50/70 response, respectively. Of the 100 patients randomised to secukinumab 300 mg, 64, 44 and 24 had an ACR 20/50/70 response, respectively. Radiographic response In PsA study 3, inhibition of progression of structural damage was assessed radiographically and expressed by the modified Total Sharp Score (mTSS) and its components, the Erosion Score (ES) and the Joint Space Narrowing Score (JSN). Radiographs of hands, wrists, and feet were obtained at baseline, week 16 and/or week 24 and scored independently by at least two readers who were blinded to treatment group and visit number. Secukinumab 150 mg and 300 mg treatment significantly inhibited the rate of progression of peripheral joint damage compared with placebo treatment as measured by change from baseline in mTSS at week 24 (Table 7). Inhibition of progression of structural damage was also assessed in PsA study 1 at weeks 24 and 52, compared to baseline. Week 24 data are presented in Table 7. 18 Table 7 Change in modified Total Sharp Score in psoriatic arthritis PsA study 3 PsA study 1 Placebo n=296 secukinumab 150 mg1 n=213 secukinumab 300 mg1 n=217 Placebo n=179 secukinumab 150 mg2 n=185 Total score Baseline (SD) 15.0 (38.2) 13.5 (25.6) 12.9 (23.8) 28.4 (63.5) 22.3 (48.0) Mean change at Week 24 0.50 0.13* 0.02* 0.57 0.13* *p<0.05 based on nominal, but non adjusted, p-value 1secukinumab 150 mg or 300 mg s.c. at weeks 0, 1, 2, 3, and 4 followed by the same dose every month 210 mg/kg at weeks 0, 2 and 4 followed by subcutaneous doses of 75 mg or 150 mg In PsA study 1, inhibition of structural damage was maintained with secukinumab treatment up to week 52. In PsA study 3, the percentage of patients with no disease progression (defined as a change from baseline in mTSS of ≤0.5) from randomisation to week 24 was 80.3%, 88.5% and 73.6% for secukinumab 150 mg, 300 mg and placebo, respectively. An effect of inhibition of structural damage was observed in anti-TNFα-naïve and anti-TNFα-IR patients and in patients treated with and without concomitant MTX. In PsA study 1, the percentage of patients with no disease progression (defined as a change from baseline in mTSS of ≤0.5) from randomisation to week 24 was 82.3% in secukinumab 10 mg/kg intravenous load – 150 mg subcutaneous maintenance and 75.7% in placebo. The percentage of patients with no disease progression from week 24 to week 52 for secukinumab 10 mg/kg intravenous load – followed by 150 mg subcutaneous maintenance and for placebo patients who switched to 75 mg or 150 mg subcutaneous every 4 weeks at week 16 or week 24 was 85.7% and 86.8%, respectively. Physical function and health-related quality of life In PsA study 2 and PsA study 3, patients treated with secukinumab 150 mg (p=0.0555 and p<0.0001) and 300 mg (p=0.0040 and p<0.0001) showed improvement in physical function compared to patients treated with placebo as assessed by Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 24 and week 16, respectively. Improvements in HAQ-DI scores were seen regardless of previous anti-TNFα exposure. Similar responses were seen in PsA study 1. Secukinumab-treated patients reported significant improvements in health-related quality of life as measured by the Short Form-36 Health Survey Physical Component Summary (SF-36 PCS) score (p<0.001). There were also statistically significant improvements demonstrated in exploratory endpoints assessed by the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) scores for 150 mg and 300 mg compared to placebo (7.97, 5.97 versus 1.63, respectively) and these improvements were maintained up to week 104 in PsA study 2. Similar responses were seen in PsA study 1 and efficacy was maintained up to week 52. 19 Axial spondyloarthritis (axSpA) Ankylosing spondylitis (AS) / Radiographic axial spondyloarthritis The safety and efficacy of secukinumab were assessed in 816 patients in three randomised, double-blind, placebo-controlled phase III studies in patients with active ankylosing spondylitis (AS) with a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease-modifying anti-rheumatic drug (DMARD) therapy. Patients in Ankylosing Spondylitis study 1 (AS study 1) and Ankylosing Spondylitis study 2 (AS study 2) had a diagnosis of AS for a median of 2.7 to 5.8 years. For both studies, the primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society (ASAS 20) criteria at week 16. In Ankylosing Spondylitis study 1 (AS study 1), Ankylosing Spondylitis study 2 (AS study 2), and Ankylosing Spondylitis study 3 (AS study 3), 27.0%, 38.8%, and 23.5% of patients, respectively, were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients). AS study 1 (MEASURE 1) evaluated 371 patients, of whom 14.8% and 33.4% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 75 mg or 150 mg subcutaneously every month starting at week 8. Patients randomised to placebo who were non-responders at week 16 (early rescue) and all other placebo patients at week 24 were crossed over to receive secukinumab (either 75 mg or 150 mg subcutaneously), followed by the same dose every month. AS study 2 (MEASURE 2) evaluated 219 patients, of whom 11.9% and 14.2% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 75 mg or 150 mg subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. At week 16, patients who were randomised to placebo at baseline were re-randomised to receive secukinumab (either 75 mg or 150 mg subcutaneously) every month. AS study 3 (MEASURE 3) evaluated 226 patients, of whom 13.3% and 23.5% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 150 mg or 300 mg subcutaneously every month. At week 16, patients who were randomised to placebo at baseline were re-randomised to receive secukinumab (either 150 mg or 300 mg subcutaneously) every month. The primary endpoint was ASAS 20 at week 16. Patients were blinded to the treatment regimen up to week 52, and the study continued to week 156. Signs and symptoms: In AS study 2, treatment with secukinumab 150 mg resulted in greater improvement in measures of disease activity compared with placebo at week 16 (see Table 8). 20 Table 8 Clinical response in AS study 2 at week 16 Outcome (p-value versus placebo) Placebo (n = 74) 75 mg (n = 73) 150 mg (n = 72) ASAS 20 response, % 28.4 41.1 61.1*** ASAS 40 response, % 10.8 26.0 36.1*** hsCRP, (post-BSL/BSL ratio) 1.13 0.61 0.55*** ASAS 5/6, % 8.1 34.2 43.1*** ASAS partial remission, % 4.1 15.1 13.9 BASDAI 50, % 10.8 24.7* 30.6** ASDAS-CRP major improvement 4.1 15.1* 25.0*** * p<0.05, ** p<0.01, *** p<0.001; versus placebo All p-values adjusted for multiplicity of testing based on pre-defined hierarchy, except BASDAI 50 and ASDAS-CRP Non-responder imputation used for missing binary endpoint ASAS: Assessment of SpondyloArthritis International Society Criteria; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; hsCRP: high-sensitivity C-reactive protein; ASDAS: Ankylosing Spondylitis Disease Activity Score; BSL: baseline The onset of action of secukinumab 150 mg occurred as early as week 1 for ASAS 20 and week 2 for ASAS 40 (superior to placebo) in AS study 2. ASAS 20 responses were improved at week 16 in both anti-TNFα-naïve patients (68.2% versus 31.1%; p<0.05) and anti-TNFα-IR patients (50.0% versus 24.1%; p<0.05) for secukinumab 150 mg compared with placebo, respectively. In AS study 1 and AS study 2, secukinumab-treated patients (150 mg in AS study 2 and both regimens in AS study 1) demonstrated significantly improved signs and symptoms at week 16, with comparable magnitude of response and efficacy maintained up to week 52 in both anti-TNFα-naive and anti-TNFα-IR patients. In AS study 2, among 72 patients initially randomised to secukinumab 150 mg, 61 (84.7%) patients were still on treatment at week 52. Of the 72 patients randomised to secukinumab 150 mg, 45 and 35 had an ASAS 20/40 response, respectively. In AS study 3, patients treated with secukinumab (150 mg and 300 mg) demonstrated improved signs and symptoms, and had comparable efficacy responses regardless of dose that were superior to placebo at week 16 for the primary endpoint (ASAS 20). Overall, the efficacy response rates for the 300 mg group were consistently greater compared to the 150 mg group for the secondary endpoints. During the blinded period, the ASAS 20 and ASAS 40 responses were 69.7% and 47.6% for 150 mg and 74.3% and 57.4% for 300 mg at week 52, respectively. The ASAS 20 and ASAS 40 responses were maintained up to week 156 (69.5% and 47.6% for 150 mg versus 74.8% and 55.6% for 300 mg). Greater response rates favouring 300 mg were also observed for ASAS partial remission (ASAS PR) response at week 16 and were maintained up to week 156. Larger differences in response rates, favouring 300 mg over 150 mg, were observed in anti-TNFα-IR patients (n=36) compared to anti-TNFα-naïve patients (n=114). Spinal mobility: Patients treated with secukinumab 150 mg showed improvements in spinal mobility as measured by change from baseline in BASMI at week 16 for both AS study 1 (-0.40 versus -0.12 for placebo; p=0.0114) and AS study 2 (-0.51 versus -0.22 for placebo; p=0.0533). These improvements were sustained up to week 52. 21 Physical function and health-related quality of life: In AS study 1 and study 2, patients treated with secukinumab 150 mg showed improvements in health- related quality of life as measured by AS Quality of Life Questionnaire (ASQoL) (p=0.001) and SF-36 Physical Component Summary (SF-36PCS) (p<0.001). Patients treated with secukinumab 150 mg also showed statistically significant improvements on exploratory endpoints in physical function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI) compared to placebo (-2.15 versus -0.68), and in fatigue as assessed by the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue) scale compared to placebo (8.10 versus 3.30). These improvements were sustained up to week 52. Non-radiographic axial spondyloarthritis (nr-axSpA) The safety and efficacy of secukinumab were assessed in 555 patients in one randomised, double-blind, placebo-controlled phase III study (PREVENT), consisting of a 2-year core phase and a 2-year extension phase, in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) fulfilling the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA) with no radiographic evidence of changes in the sacroiliac joints that would meet the modified New York criteria for ankylosing spondylitis (AS). Patients enrolled had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4, a Visual Analogue Scale (VAS) for total back pain of ≥40 (on a scale of 0-100 mm), despite current or previous non-steroidal anti-inflammatory drug (NSAID) therapy and increased C-reactive protein (CRP) and/or evidence of sacroiliitis on Magnetic Resonance Imaging (MRI). Patients in this study had a diagnosis of axSpA for a mean of 2.1 to 3.0 years and 54% of the study participants were female. In the PREVENT study, 9.7% of patients were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients). In the PREVENT study, 9.9% and 14.8% of patients used concomitant MTX or sulfasalazine, respectively. In the double-blind period, patients received either placebo or secukinumab for 52 weeks. Patients randomised to secukinumab received 150 mg subcutaneously at weeks 0, 1, 2, 3 and 4 followed by the same dose every month, or a once monthly injection of secukinumab 150 mg. The primary endpoint was at least 40% improvement in Assessment of Spondyloarthritis International Society (ASAS 40) at Week 16 in anti-TNFα-naive patients. Signs and symptoms: In the PREVENT study, treatment with secukinumab 150 mg resulted in significant improvements in the measures of disease activity compared to placebo at week 16. These measures include ASAS 40, ASAS 5/6, BASDAI score, BASDAI 50, high-sensitivity CRP (hsCRP), ASAS 20 and ASAS partial remission response compared to placebo (Table 9). Responses were maintained up to week 52. 22 Table 9 Clinical response in the PREVENT study at week 16 Outcome (p-value versus placebo) Placebo 150 mg1 Number of anti-TNFα-naive patients randomised 171 164 ASAS 40 response, % 29.2 41.5* Total number of patients randomised 186 185 ASAS 40 response, % 28.0 40.0* ASAS 5/6, % 23.7 40.0* BASDAI, LS mean change from baseline score -1.46 -2.35* BASDAI 50, % 21.0 37.3* hsCRP, (post-BSL/BSL ratio) 0.91 0.64* ASAS 20 response, % 45.7 56.8* ASAS partial remission, % 7.0 21.6* *p<0.05 versus placebo All p-values adjusted for multiplicity of testing based on pre-defined hierarchy Non-responder imputation used for missing binary endpoint 1secukinumab 150 mg s.c. at weeks 0, 1, 2, 3, and 4 followed by the same dose every month ASAS: Assessment of SpondyloArthritis International Society Criteria; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; hsCRP: high-sensitivity C-reactive protein; BSL: baseline; LS: Least square The onset of action of secukinumab 150 mg occurred as early as week 3 for ASAS 40 in anti-TNFα naive patients (superior to placebo) in the PREVENT study. The percentage of patients achieving an ASAS 40 response in anti-TNFα naive patients by visit is shown in Figure 3. Figure 3 ASAS 40 responses in anti-TNFα naive patients in the PREVENT study over time up to week 16 ASAS 40 responses were also improved at week 16 in anti-TNFα-IR patients for secukinumab 150 mg compared with placebo. Percentage of responders Time (Weeks) Secukinumab 150 mg Load Placebo 23 Physical function and health-related quality of life: Patients treated with secukinumab 150 mg showed statistically significant improvements by week 16 compared to placebo-treated patients in physical function as assessed by the BASFI (week 16: -1.75 versus -1.01, p<0.05). Patients treated with secukinumab reported significant improvements compared to placebo-treated patients by week 16 in health-related quality of life as measured by ASQoL (LS mean change: week 16: -3.45 versus -1.84, p<0.05) and SF-36 Physical Component Summary (SF-36 PCS) (LS mean change: week 16: 5.71 versus 2.93, p<0.05). These improvements were sustained up to week 52. Spinal mobility: Spinal mobility was assessed by BASMI up to week 16. Numerically greater improvements were demonstrated in patients treated with secukinumab compared with placebo-treated patients at weeks 4, 8, 12 and 16. Inhibition of inflammation in magnetic resonance imaging (MRI): Signs of inflammation were assessed by MRI at baseline and week 16 and expressed as change from baseline in Berlin SI-joint oedema score for sacroiliac joints and ASspiMRI-a score and Berlin spine score for the spine. Inhibition of inflammatory signs in both sacroiliac joints and the spine was observed in patients treated with secukinumab. Mean change from baseline in Berlin SI-joint oedema score was -1.68 for patients treated with secukinumab 150 mg (n=180) versus -0.39 for the placebo-treated patients (n=174) (p<0.05). Paediatric population Paediatric plaque psoriasis Secukinumab has been shown to improve signs and symptoms, and health-related quality of life in paediatric patients 6 years and older with plaque psoriasis (see Tables 11 and 13). Severe plaque psoriasis The safety and efficacy of secukinumab were assessed in a randomised, double-blind, placebo and etanercept-controlled phase III study in paediatric patients from 6 to <18 years of age with severe plaque psoriasis, as defined by a PASI score ≥20, an IGA mod 2011 score of 4, and BSA involvement of ≥10%, who were candidates for systemic therapy. Approximately 43% of the patients had prior exposure to phototherapy, 53% to conventional systemic therapy, 3% to biologics, and 9% had concomitant psoriatic arthritis. The paediatric psoriasis study 1 evaluated 162 patients who were randomised to receive low dose secukinumab (75 mg for body weight <50 kg or 150 mg for body weight ≥50 kg), high dose secukinumab (75 mg for body weight <25 kg, 150 mg for body weight between ≥25 kg and <50 kg, or 300 mg for body weight ≥50 kg), or placebo at weeks 0, 1, 2, 3, and 4 followed by the same dose every 4 weeks, or etanercept. Patients randomised to etanercept received 0.8 mg/kg weekly (up to a maximum of 50 mg). Patient distribution by weight and age at randomisation is described in Table 10. Table 10 Patient distribution by weight and age for paediatric psoriasis study 1 Randomisation strata Description Secukinumab low dose n=40 Secukinumab high dose n=40 Placebo n=41 Etanercept n=41 Total N=162 Age 6-<12 years 8 9 10 10 37 ≥12- <18 years 32 31 31 31 125 Weight <25 kg 2 3 3 4 12 ≥25-<50 kg 17 15 17 16 65 ≥50 kg 21 22 21 21 85 24 Patients randomised to receive placebo who were non-responders at week 12 were switched to either the secukinumab low or high dose group (dose based on body weight group) and received study drug at weeks 12, 13, 14, and 15, followed by the same dose every 4 weeks starting at week 16. The co- primary endpoints were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ (0 or 1) response at week 12. During the 12 week placebo-controlled period, the efficacy of both the low and the high dose of secukinumab was comparable for the co-primary endpoints. The odds ratio estimates in favour of both secukinumab doses were statistically significant for both the PASI 75 and IGA mod 2011 0 or 1 responses. All patients were followed for efficacy and safety during the 52 weeks following the first dose. The proportion of patients achieving PASI 75 and IGA mod 2011 ‘clear’ or ‘almost clear’ (0 or 1) responses showed separation between secukinumab treatment groups and placebo at the first post- baseline visit at week 4, the difference becoming more prominent at week 12. The response was maintained throughout the 52 week time period (see Table 11). Improvement in PASI 50, 90, 100 responder rates and Children’s Dermatology Life Quality Index (CDLQI) scores of 0 or 1 were also maintained throughout the 52 week time period. In addition, PASI 75, IGA 0 or 1, PASI 90 response rates at weeks 12 and 52 for both secukinumab low and high dose groups were higher than the rates for patients treated with etanercept (see Table 11). Beyond week 12, efficacy of both the low and the high dose of secukinumab was comparable although the efficacy of the high dose was higher for patients ≥50 kg. The safety profiles of the low dose and the high dose were comparable and consistent with the safety profile in adults. Table 11 Summary of clinical response in severe paediatric psoriasis at weeks 12 and 52 (paediatric psoriasis study 1)* Response criterion Treatment comparison 'test' 'control' odds ratio 'test' vs. 'control' n**/m (%) n**/m (%) estimate (95% CI) p-value At week 12*** PASI 75 secukinumab low dose vs. placebo 32/40 (80.0) 6/41 (14.6) 25.78 (7.08, 114.66) <0.0001 secukinumab high dose vs. placebo 31/40 (77.5) 6/41 (14.6) 22.65 (6.31, 98.93) <0.0001 secukinumab low dose vs. etanercept 32/40 (80.0) 26/41 (63.4) 2.25 (0.73, 7.38) secukinumab high dose vs. etanercept 31/40 (77.5) 26/41 (63.4) 1.92 (0.64, 6.07) IGA 0/1 secukinumab low dose vs. placebo 28/40 (70.0) 2/41 (4.9) 51.77 (10.02, 538.64) <0.0001 secukinumab high dose vs. placebo 24/40 (60.0) 2/41 (4.9) 32.52 (6.48, 329.52) <0.0001 secukinumab low dose vs. etanercept 28/40 (70.0) 14/41 (34.1) 4.49 (1.60, 13.42) secukinumab high dose vs. etanercept 24/40 (60.0) 14/41 (34.1) 2.86 (1.05, 8.13) PASI 90 secukinumab low dose vs. placebo 29/40 (72.5) 1/41 (2.4) 133.67 (16.83, 6395.22) <0.0001 secukinumab high dose vs. placebo 27/40 (67.5) 1/41 (2.4) 102.86 (13.22, 4850.13) <0.0001 secukinumab low dose vs. etanercept 29/40 (72.5) 12/41 (29.3) 7.03 (2.34, 23.19) secukinumab high dose vs. etanercept 27/40 (67.5) 12/41 (29.3) 5.32 (1.82, 16.75) At week 52 PASI 75 secukinumab low dose vs. etanercept 35/40 (87.5) 28/41 (68.3) 3.12 (0.91, 12.52) secukinumab high dose vs. etanercept 35/40 (87.5) 28/41 (68.3) 3.09 (0.90, 12.39) IGA 0/1 secukinumab low dose vs. etanercept 29/40 (72.5) 23/41 (56.1) 2.02 (0.73, 5.77) secukinumab high dose vs. etanercept 30/40 (75.0) 23/41 (56.1) 2.26 (0.81, 6.62) PASI 90 secukinumab low dose vs. etanercept 30/40 (75.0) 21/41 (51.2) 2.85 (1.02, 8.38) secukinumab high dose vs. etanercept 32/40 (80.0) 21/41 (51.2) 3.69 (1.27, 11.61) * non-responder imputation was used to handle missing values ** n is the number of responders, m = number of patients evaluable *** extended visit window at week 12 Odds ratio, 95% confidence interval, and p-value are from an exact logistic regression model with treatment group, baseline body-weight category and age category as factors 25 A higher proportion of paediatric patients treated with secukinumab reported improvement in health- related quality of life as measured by a CDLQI score of 0 or 1 compared to placebo at week 12 (low dose 44.7%, high dose 50%, placebo 15%). Over time up to and including week 52 both secukinumab dose groups were numerically higher than the etanercept group (low dose 60.6%, high dose 66.7%, etanercept 44.4%). Moderate to severe plaque psoriasis Secukinumab was predicted to be effective for the treatment of paediatric patients with moderate plaque psoriasis based on the demonstrated efficacy and exposure response relationship in adult patients with moderate to severe plaque psoriasis, and the similarity of the disease course, pathophysiology, and drug effect in adult and paediatric patients at the same exposure levels. Moreover, the safety and efficacy of secukinumab was assessed in an open-label, two-arm, parallel-group, multicentre phase III study in paediatric patients from 6 to <18 years of age with moderate to severe plaque psoriasis, as defined by a PASI score ≥12, an IGA mod 2011 score of ≥3, and BSA involvement of ≥10%, who were candidates for systemic therapy. The paediatric psoriasis study 2 evaluated 84 patients who were randomised to receive low dose secukinumab (75 mg for body weight <50 kg or 150 mg for body weight ≥50 kg) or high dose secukinumab (75 mg for body weight <25 kg, 150 mg for body weight between ≥25 kg and <50 kg, or 300 mg for body weight ≥50 kg) at weeks 0, 1, 2, 3, and 4 followed by the same dose every 4 weeks. Patient distribution by weight and age at randomisation is described in Table 12. Table 12 Patient distribution by weight and age for paediatric psoriasis study 2 Sub-groups Description Secukinumab low dose n=42 Secukinumab high dose n=42 Total N=84 Age 6-<12 years 17 16 33 ≥12-<18 years 25 26 51 Weight <25 kg 4 4 8 ≥25-<50 kg 13 12 25 ≥50 kg 25 26 51 The co-primary endpoints were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ (0 or 1) response at week 12. The efficacy of both the low and the high dose of secukinumab was comparable and showed statistically significant improvement compared to historical placebo for the co-primary endpoints. The estimated posterior probability of a positive treatment effect was 100%. All patients were followed for efficacy for at least 24 weeks following first administration (see Table 13). Efficacy (defined as PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ [0 or 1]) was observed as early as the first post-baseline visit at week 2 and the proportion of patients who achieved a PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ (0 or 1) increased throughout the 24 week time period. Improvement in PASI 90 and PASI 100 were also observed at week 12 and increased throughout the 24 week time period. Beyond week 12, efficacy of both the low and the high dose of secukinumab was comparable. The safety profiles of the low dose and the high dose were comparable and consistent with the safety profile in adults. 26 Table 13 Summary of clinical response in moderate to severe paediatric psoriasis at weeks 12 and 24 (paediatric psoriasis study 2)* Week 12 Week 24 Secukinumab low dose Secukinumab high dose Secukinumab low dose Secukinumab high dose Number of patients 42 42 42 42 PASI 75 response n (%) 39 (92.9%) 39 (92.9%) 40 (95.2%) 40 (95.2%) IGA mod 2011 ‘clear’ or ‘almost clear’ response n (%) 33 (78.6%) 35 (83.3%) 37 (88.1%) 39 (92.9%) PASI 90 response n (%) 29 (69%) 32 (76.2%) 37 (88.1%) 37 (88.1%) PASI 100 response n (%) 25 (59.5%) 23 (54.8%) 28 (66.7%) 28 (66.7%) * non-responder imputation was used to handle missing values These outcomes in the paediatric moderate to severe plaque psoriasis population confirmed the predictive assumptions based on the efficacy and exposure response relationship in adult patients, mentioned above. In the low dose group, 50% and 70.7% of patients achieved a CDLQI 0 or 1 score at weeks 12 and 24, respectively. In the high dose group, 61.9% and 60.5% achieved a CDLQI 0 or 1 score at weeks 12 and 24, respectively. The European Medicines Agency has waived the obligation to submit the results of studies with Cosentyx in plaque psoriasis in paediatric patients aged from birth to less than 6 years and in chronic idiopathic arthritis for paediatric patients aged from birth to less than 2 years (see section 4.2 for information on paediatric use). The European Medicines Agency has deferred the obligation to submit the results of studies with Cosentyx in chronic idiopathic arthritis for paediatric patients aged from 2 years to less than 18 years (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Most pharmacokinetics properties observed in patients with plaque psoriasis, psoriatic arthritis and ankylosing spondylitis were similar. Absorption Following a single subcutaneous dose of 300 mg as a liquid formulation in healthy volunteers, secukinumab reached peak serum concentrations of 43.2±10.4 μg/ml between 2 and 14 days post dose. Based on population pharmacokinetic analysis, following a single subcutaneous dose of either 150 mg or 300 mg in plaque psoriasis patients, secukinumab reached peak serum concentrations of 13.7±4.8 µg/ml or 27.3±9.5 µg/ml, respectively, between 5 and 6 days post dose. After initial weekly dosing during the first month, time to reach the maximum concentration was between 31 and 34 days based on population pharmacokinetic analysis. On the basis of simulated data, peak concentrations at steady-state (Cmax,ss) following subcutaneous administration of 150 mg or 300 mg were 27.6 µg/ml and 55.2 µg/ml, respectively. Population pharmacokinetic analysis suggests that steady-state is reached after 20 weeks with monthly dosing regimens. Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 2-fold increase in peak serum concentrations and area under the curve (AUC) following repeated monthly dosing during maintenance. 27 Population pharmacokinetic analysis showed that secukinumab was absorbed with an average absolute bioavailability of 73% in patients with plaque psoriasis. Across studies, absolute bioavailabilities in the range between 60 and 77% were calculated. The bioavailability of secukinumab in PsA patients was 85% on the basis of the population pharmacokinetic model. Distribution The mean volume of distribution during the terminal phase (Vz) following single intravenous administration ranged from 7.10 to 8.60 litres in plaque psoriasis patients, suggesting that secukinumab undergoes limited distribution to peripheral compartments. Biotransformation The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or receptor mediated endocytosis. Elimination Mean systemic clearance (CL) following a single intravenous administration to patients with plaque psoriasis ranged from 0.13 to 0.36 l/day. In a population pharmacokinetic analysis, the mean systemic clearance (CL) was 0.19 l/day in plaque psoriasis patients. The CL was not impacted by gender. Clearance was dose- and time-independent. The mean elimination half-life, as estimated from population pharmacokinetic analysis, was 27 days in plaque psoriasis patients, ranging from 18 to 46 days across psoriasis studies with intravenous administration. Linearity/non-linearity The single and multiple dose pharmacokinetics of secukinumab in plaque psoriasis patients were determined in several studies with intravenous doses ranging from 1x 0.3 mg/kg to 3x 10 mg/kg and with subcutaneous doses ranging from 1x 25 mg to multiple doses of 300 mg. Exposure was dose proportional across all dosing regimens. Special populations Elderly patients Based on population pharmacokinetic analysis with a limited number of elderly patients (n=71 for age ≥65 years and n=7 for age ≥75 years), clearance in elderly patients and patients less than 65 years of age was similar. Patients with renal or hepatic impairment No pharmacokinetic data are available in patients with renal or hepatic impairment. The renal elimination of intact secukinumab, an IgG monoclonal antibody, is expected to be low and of minor importance. IgGs are mainly eliminated via catabolism and hepatic impairment is not expected to influence clearance of secukinumab. Effect of weight on pharmacokinetics Secukinumab clearance and volume of distribution increase as body weight increases. 28 Paediatric population In a pool of the two paediatric studies, patients with moderate to severe plaque psoriasis (6 to less than 18 years of age) were administered secukinumab at the recommended paediatric dosing regimen. At week 24, patients weighing ≥25 and <50 kg had a mean ± SD steady-state trough concentration of 19.8 ± 6.96 µg/ml (n=24) after 75 mg of secukinumab and patients weighing ≥50 kg had mean ±SD trough concentration of 27.3 ± 10.1 µg/ml (n=36) after 150 mg of secukinumab. The mean ± SD steady-state trough concentration in patients weighing <25 kg (n=8) was 32.6 ± 10.8 µg/ml at week 24 after 75 mg dose. 5.3 Preclinical safety data Non-clinical data revealed no special hazard for humans (adult or paediatric) based on conventional studies of safety pharmacology, repeated dose and reproductive toxicity, or tissue cross-reactivity. Animal studies have not been conducted to evaluate the carcinogenic potential of secukinumab. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sucrose Histidine Histidine hydrochloride monohydrate Polysorbate 80 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life 3 years After reconstitution Chemical and physical in-use stability has been demonstrated for 24 hours at 2ºC to 8ºC. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). For storage conditions after reconstitution of the medicinal product, see section 6.3 6.5 Nature and contents of container Cosentyx is supplied in a colourless glass vial with a grey coated rubber stopper and aluminium cap with a white flip-off component containing 150 mg of secukinumab. Cosentyx is available in packs containing one vial. 29 6.6 Special precautions for disposal and other handling The single-use vial contains 150 mg secukinumab for reconstitution with sterile water for injections. The resulting solution should be clear and colourless to slightly yellow. Do not use if the lyophilised powder has not fully dissolved or if the liquid contains easily visible particles, is cloudy or is distinctly brown. Reconstitution Cosentyx 150 mg powder for solution for injection must be prepared by a healthcare professional. The preparation of the solution for subcutaneous injection must be done without interruption and ensuring that aseptic technique is used. The preparation time from piercing the stopper until end of reconstitution takes 20 minutes on average and should not exceed 90 minutes. 1. Bring the vial of powder to room temperature and ensure that the sterile water for injections is at room temperature. 2. Withdraw slightly more than 1.0 ml sterile water for injections into a 1 ml graduated disposable syringe and adjust to 1.0 ml. 3. Remove the plastic cap from the vial. 4. Insert the syringe needle into the vial containing the powder through the centre of the rubber stopper and reconstitute the powder by slowly injecting 1.0 ml of sterile water for injections into the vial. The stream of sterile water for injections should be directed onto the powder. 5. Tilt the vial to an angle of approx. 45° and gently rotate between the fingertips for approx. 1 minute. Do not shake or invert the vial. 6. Keep the vial standing at room temperature for a minimum of 10 minutes to allow for dissolution. Note that foaming of the solution may occur. 7. Tilt the vial to an angle of approx. 45° and gently rotate between the fingertips for approx. 1 minute. Do not shake or invert the vial. 8. Allow the vial to stand undisturbed at room temperature for approximately 5 minutes. The resulting solution should be clear. Its colour may vary from colourless to slightly yellow. Do not use if the lyophilised powder has not fully dissolved or if the liquid contains easily visible particles, is cloudy or is distinctly brown. 9. Prepare the required number of vials (2 vials for the 300 mg dose). Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Use in the paediatric population For paediatric patients receiving the 75 mg dose, it is currently recommended to use the single-use vial containing 150 mg secukinumab for reconstitution with sterile water for injections. Slightly more than 0.5 ml of the reconstituted solution for subcutaneous injection have to be withdrawn and the rest of the solution must be discarded immediately. Detailed instructions for use are provided in the package leaflet. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 30 8. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 15 January 2015 Date of latest renewal: 03 September 2019 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 31 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg solution for injection in pre-filled syringe Cosentyx 300 mg solution for injection in pre-filled syringe Cosentyx 150 mg solution for injection in pre-filled pen Cosentyx 300 mg solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Cosentyx 150 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 150 mg secukinumab in 1 ml. Cosentyx 300 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 300 mg secukinumab in 2 ml. Cosentyx 150 mg solution for injection in pre-filled pen Each pre-filled pen contains 150 mg secukinumab in 1 ml. Cosentyx 300 mg solution for injection in pre-filled pen Each pre-filled pen contains 300 mg secukinumab in 2 ml. Secukinumab is a recombinant fully human monoclonal antibody produced in Chinese Hamster Ovary (CHO) cells. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection) The solution is clear and colourless to slightly yellow. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adult plaque psoriasis Cosentyx is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Paediatric plaque psoriasis Cosentyx is indicated for the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6 years who are candidates for systemic therapy. 32 Psoriatic arthritis Cosentyx, alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate (see section 5.1). Axial spondyloarthritis (axSpA) Ankylosing spondylitis (AS, radiographic axial spondyloarthritis) Cosentyx is indicated for the treatment of active ankylosing spondylitis in adults who have responded inadequately to conventional therapy. Non-radiographic axial spondyloarthritis (nr-axSpA) Cosentyx is indicated for the treatment of active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence in adults who have responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs). 4.2 Posology and method of administration Cosentyx is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which Cosentyx is indicated. Posology Adult plaque psoriasis The recommended dose is 300 mg of secukinumab by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg. Paediatric plaque psoriasis (adolescents and children from the age of 6 years) The recommended dose is based on body weight (Table 1) and administered by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 75 mg dose is given as one subcutaneous injection of 75 mg. Each 150 mg dose is given as one subcutaneous injection of 150 mg. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg. Table 1 Recommended dose for paediatric plaque psoriasis Body weight at time of dosing Recommended Dose <25 kg 75 mg 25 to <50 kg 75 mg ≥50 kg 150 mg (*may be increased to 300 mg) *Some patients may derive additional benefit from the higher dose. The 150 mg solution for injection in pre-filled syringe is not indicated for administration to paediatric patients with a weight <50 kg. The 150 mg powder for solution for injection presentation is appropriate for administration to this population. Psoriatic arthritis For patients with concomitant moderate to severe plaque psoriasis or who are anti-TNFα inadequate responders (IR), the recommended dose is 300 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg. 33 For other patients, the recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg. Axial spondyloarthritis (axSpA) Ankylosing spondylitis (AS, radiographic axial spondyloarthritis) The recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg. Non-radiographic axial spondyloarthritis (nr-axSpA) The recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. For all of the above indications, available data suggest that a clinical response is usually achieved within 16 weeks of treatment. Consideration should be given to discontinuing treatment in patients who have shown no response by 16 weeks of treatment. Some patients with an initial partial response may subsequently improve with continued treatment beyond 16 weeks. Special populations Elderly patients (aged 65 years and over) No dose adjustment is required (see section 5.2). Renal impairment / hepatic impairment Cosentyx has not been studied in these patient populations. No dose recommendations can be made. Paediatric population The safety and efficacy of Cosentyx in children with plaque psoriasis below the age of 6 years have not been established. The safety and efficacy of Cosentyx in children below the age of 18 years in other indications have not yet been established. No data are available. Method of administration Cosentyx is to be administered by subcutaneous injection. If possible, areas of the skin that show psoriasis should be avoided as injection sites. The solution in the syringe or pen must not be shaken. After proper training in subcutaneous injection technique, patients may self-inject Cosentyx or be injected by a caregiver if a physician determines that this is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients or caregivers should be instructed to inject the full amount of Cosentyx according to the instructions provided in the package leaflet. Comprehensive instructions for administration are given in the package leaflet. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Clinically important, active infection, e.g. active tuberculosis (see section 4.4). 34 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Infections Secukinumab has the potential to increase the risk of infections. Serious infections have been observed in patients receiving secukinumab in the post-marketing setting. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, the patient should be closely monitored and secukinumab should not be administered until the infection resolves. In clinical studies, infections have been observed in patients receiving secukinumab (see section 4.8). Most of these were mild or moderate upper respiratory tract infections such as nasopharyngitis and did not require treatment discontinuation. Related to the mechanism of action of secukinumab, non-serious mucocutaneous candida infections were more frequently reported for secukinumab than placebo in the psoriasis clinical studies (3.55 per 100 patient years for secukinumab 300 mg versus 1.00 per 100 patient years for placebo) (see section 4.8). No increased susceptibility to tuberculosis was reported from clinical studies. However, secukinumab should not be given to patients with active tuberculosis. Anti-tuberculosis therapy should be considered prior to initiation of secukinumab in patients with latent tuberculosis. Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis) Cases of new or exacerbations of inflammatory bowel disease have been reported with secukinumab (see section 4.8). Secukinumab is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation of pre-existing inflammatory bowel disease, secukinumab should be discontinued and appropriate medical management should be initiated. Hypersensitivity reactions In clinical studies, rare cases of anaphylactic reactions have been observed in patients receiving secukinumab. If an anaphylactic or other serious allergic reactions occur, administration of secukinumab should be discontinued immediately and appropriate therapy initiated. Latex-sensitive individuals – Cosentyx 150 mg solution for injection in pre-filled syringe and 150 mg solution for injection in pre-filled pen only The removable needle cap of Cosentyx 150 mg solution for injection in pre-filled syringe and Cosentyx 150 mg solution for injection in pre-filled pen contains a derivative of natural rubber latex. No natural rubber latex has to date been detected in the removable needle cap. Nevertheless, the use of Cosentyx 150 mg solution for injection in pre-filled syringe and Cosentyx 150 mg solution for injection in pre-filled pen in latex-sensitive individuals has not been studied and there is therefore a potential risk of hypersensitivity reactions which cannot be completely ruled out. 35 Vaccinations Live vaccines should not be given concurrently with secukinumab. Patients receiving secukinumab may receive concurrent inactivated or non-live vaccinations. In a study, after meningococcal and inactivated influenza vaccinations, a similar proportion of healthy volunteers treated with 150 mg of secukinumab and those treated with placebo were able to mount an adequate immune response of at least a 4-fold increase in antibody titres to meningococcal and influenza vaccines. The data suggest that secukinumab does not suppress the humoral immune response to the meningococcal or influenza vaccines. Prior to initiating therapy with Cosentyx, it is recommended that paediatric patients receive all age-appropriate immunisations as per current immunisation guidelines. Concomitant immunosuppressive therapy In psoriasis studies, the safety and efficacy of secukinumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Secukinumab was administered concomitantly with methotrexate (MTX), sulfasalazine and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and ankylosing spondylitis). Caution should be exercised when considering concomitant use of other immunosuppressants and secukinumab (see also section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction Live vaccines should not be given concurrently with secukinumab (see also section 4.4). In a study in adult subjects with plaque psoriasis, no interaction was observed between secukinumab and midazolam (CYP3A4 substrate). No interaction was seen when secukinumab was administered concomitantly with methotrexate (MTX) and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and axial spondyloarthritis). 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential should use an effective method of contraception during treatment and for at least 20 weeks after treatment. Pregnancy There are no adequate data from the use of secukinumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Cosentyx during pregnancy. 36 Breast-feeding It is not known whether secukinumab is excreted in human milk. Immunoglobulins are excreted in human milk and it is not known if secukinumab is absorbed systemically after ingestion. Because of the potential for adverse reactions in nursing infants from secukinumab, a decision on whether to discontinue breast-feeding during treatment and up to 20 weeks after treatment or to discontinue therapy with Cosentyx must be made taking into account the benefit of breast-feeding to the child and the benefit of therapy to the woman. Fertility The effect of secukinumab on human fertility has not been evaluated. Animal studies do not indicate direct or indirect harmful effects with respect to fertility. 4.7 Effects on ability to drive and use machines Cosentyx has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse drug reactions (ADRs) are upper respiratory tract infections (most frequently nasopharyngitis, rhinitis). Tabulated list of adverse reactions ADRs from clinical studies and post-marketing reports (Table 2) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data). Over 18,000 patients have been treated with secukinumab in blinded and open-label clinical studies in various indications (plaque psoriasis, psoriatic arthritis, axial spondyloarthritis and other autoimmune conditions), representing 30,565 patient years of exposure. Of these, over 11,700 patients were exposed to secukinumab for at least one year. The safety profile of secukinumab is consistent across all indications. 37 Table 2 List of adverse reactions in clinical studies1) and post-marketing experience System Organ Class Frequency Adverse reaction Infections and infestations Very common Upper respiratory tract infections Common Oral herpes Tinea pedis Uncommon Oral candidiasis Otitis externa Lower respiratory tract infections Not known Mucosal and cutaneous candidiasis (including oesophageal candidiasis) Blood and lymphatic system disorders Uncommon Neutropenia Immune system disorders Rare Anaphylactic reactions Nervous system disorders Common Headache Eye disorders Uncommon Conjunctivitis Respiratory, thoracic and mediastinal disorders Common Rhinorrhoea Gastrointestinal disorders Common Diarrhoea Common Nausea Uncommon Inflammatory bowel disease Skin and subcutaneous tissue disorders Uncommon Urticaria Rare Exfoliative dermatitis2) General disorders and administration site conditions Common Fatigue 1) Placebo-controlled clinical studies (phase III) in plaque psoriasis, PsA, AS and nr-axSpA patients exposed to 300 mg, 150 mg, 75 mg or placebo up to 12 weeks (psoriasis) or 16 weeks (PsA, AS and nr-axSpA) treatment duration 2) Cases were reported in patients with psoriasis diagnosis Description of selected adverse reactions Infections In the placebo-controlled period of clinical studies in plaque psoriasis (a total of 1,382 patients treated with secukinumab and 694 patients treated with placebo for up to 12 weeks), infections were reported in 28.7% of patients treated with secukinumab compared with 18.9% of patients treated with placebo. The majority of infections consisted of non-serious and mild to moderate upper respiratory tract infections, such as nasopharyngitis, which did not necessitate treatment discontinuation. There was an increase in mucosal or cutaneous candidiasis, consistent with the mechanism of action, but the cases were mild or moderate in severity, non-serious, responsive to standard treatment and did not necessitate treatment discontinuation. Serious infections occurred in 0.14% of patients treated with secukinumab and in 0.3% of patients treated with placebo (see section 4.4). Over the entire treatment period (a total of 3,430 patients treated with secukinumab for up to 52 weeks for the majority of patients), infections were reported in 47.5% of patients treated with secukinumab (0.9 per patient-year of follow-up). Serious infections were reported in 1.2% of patients treated with secukinumab (0.015 per patient-year of follow-up). Infection rates observed in psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) clinical studies were similar to those observed in the psoriasis studies. 38 Neutropenia In psoriasis phase III clinical studies, neutropenia was more frequently observed with secukinumab than with placebo, but most cases were mild, transient and reversible. Neutropenia <1.0-0.5x109/l (CTCAE grade 3) was reported in 18 out of 3,430 (0.5%) patients on secukinumab, with no dose dependence and no temporal relationship to infections in 15 out of 18 cases. There were no reported cases of more severe neutropenia. Non-serious infections with usual response to standard care and not requiring discontinuation of secukinumab were reported in the remaining 3 cases. The frequency of neutropenia in psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) was similar to psoriasis. Rare cases of neutropenia <0.5x109/l (CTCAE grade 4) were reported. Hypersensitivity reactions In clinical studies, urticaria and rare cases of anaphylactic reaction to secukinumab were observed (see also section 4.4). Immunogenicity In psoriasis, psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non- radiographic axial spondyloarthritis) clinical studies, less than 1% of patients treated with secukinumab developed antibodies to secukinumab up to 52 weeks of treatment. About half of the treatment-emergent anti-drug antibodies were neutralising, but this was not associated with loss of efficacy or pharmacokinetic abnormalities. Paediatric population Undesirable effects in paediatric patients from the age of 6 years with plaque psoriasis The safety of secukinumab was assessed in two phase III studies in paediatric patients with plaque psoriasis. The first study (paediatric study 1) was a double-blind, placebo-controlled study of 162 patients from 6 to less than 18 years of age with severe plaque psoriasis. The second study (paediatric study 2) is an open-label study of 84 patients from 6 to less than 18 years of age with moderate to severe plaque psoriasis. The safety profile reported in these two studies was consistent with the safety profile reported in adult plaque psoriasis patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Doses up to 30 mg/kg (approximately 2000 to 3000 mg) have been administered intravenously in clinical studies without dose-limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 39 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC10 Mechanism of action Secukinumab is a fully human IgG1/κ monoclonal antibody that selectively binds to and neutralises the proinflammatory cytokine interleukin-17A (IL-17A). Secukinumab works by targeting IL-17A and inhibiting its interaction with the IL-17 receptor, which is expressed on various cell types including keratinocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to autoimmune and inflammatory diseases. Clinically relevant levels of secukinumab reach the skin and reduce local inflammatory markers. As a direct consequence treatment with secukinumab reduces erythema, induration and desquamation present in plaque psoriasis lesions. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis, psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) and is up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients and in synovial tissue of psoriatic arthritis patients. The frequency of IL-17-producing cells was also significantly higher in the subchondral bone marrow of facet joints from patients with ankylosing spondylitis. Increased numbers of IL-17A producing lymphocytes have also been found in patients with non-radiographic axial spondyloarthritis. Inhibition of IL-17A was shown to be effective in the treatment of ankylosing spondylitis, thus establishing the key role of this cytokine in axial spondyloarthritis. Pharmacodynamic effects Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are initially increased in patients receiving secukinumab. This is followed by a slow decrease due to reduced clearance of secukinumab-bound IL-17A, indicating that secukinumab selectively captures free IL-17A, which plays a key role in the pathogenesis of plaque psoriasis. In a study with secukinumab, infiltrating epidermal neutrophils and various neutrophil-associated markers that are increased in lesional skin of plaque psoriasis patients were significantly reduced after one to two weeks of treatment. Secukinumab has been shown to lower (within 1 to 2 weeks of treatment) levels of C-reactive protein, which is a marker of inflammation. Clinical efficacy and safety Adult plaque psoriasis The safety and efficacy of secukinumab were assessed in four randomised, double-blind, placebo-controlled phase III studies in patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy [ERASURE, FIXTURE, FEATURE, JUNCTURE]. The efficacy and safety of secukinumab 150 mg and 300 mg were evaluated versus either placebo or etanercept. In addition, one study assessed a chronic treatment regimen versus a “retreatment as needed” regimen [SCULPTURE]. 40 Of the 2,403 patients who were included in the placebo-controlled studies, 79% were biologic-naive, 45% were non-biologic failures and 8% were biologic failures (6% were anti-TNF failures, and 2% were anti-p40 failures). Approximately 15 to 25% of patients in phase III studies had psoriatic arthritis (PsA) at baseline. Psoriasis study 1 (ERASURE) evaluated 738 patients. Patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Psoriasis study 2 (FIXTURE) evaluated 1,306 patients. Patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients randomised to etanercept received 50 mg doses twice per week for 12 weeks followed by 50 mg every week. In both study 1 and study 2, patients randomised to receive placebo who were non-responders at week 12 then crossed over to receive secukinumab (either 150 mg or 300 mg) at weeks 12, 13, 14, and 15, followed by the same dose every month starting at week 16. All patients were followed for up to 52 weeks following first administration of study treatment. Psoriasis study 3 (FEATURE) evaluated 177 patients using a pre-filled syringe compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of secukinumab self-administration via the pre-filled syringe. Psoriasis study 4 (JUNCTURE) evaluated 182 patients using a pre-filled pen compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of secukinumab self-administration via the pre-filled pen. In both study 3 and study 4, patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients were also randomised to receive placebo at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Psoriasis study 5 (SCULPTURE) evaluated 966 patients. All patients received secukinumab 150 mg or 300 mg doses at weeks 0, 1, 2, 3, 4, 8 and 12 and then were randomised to receive either a maintenance regimen of the same dose every month starting at week 12 or a “retreatment as needed” regimen of the same dose. Patients randomised to “retreatment as needed” did not achieve adequate maintenance of response and therefore a fixed monthly maintenance regimen is recommended. The co-primary endpoints in the placebo and active-controlled studies were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 “clear” or “almost clear” response versus placebo at week 12 (see Tables 3 and 4). The 300 mg dose provided improved skin clearance particularly for “clear” or “almost clear” skin across the efficacy endpoints of PASI 90, PASI 100, and IGA mod 2011 0 or 1 response across all studies with peak effects seen at week 16, therefore this dose is recommended. 41 Table 3 Summary of PASI 50/75/90/100 & IGA⃰ mod 2011 “clear” or “almost clear” clinical response in psoriasis studies 1, 3 and 4 (ERASURE, FEATURE and JUNCTURE) Week 12 Week 16 Week 52 Placebo 150 mg 300 mg 150 mg 300 mg 150 mg 300 mg Study 1 Number of patients 246 244 245 244 245 244 245 PASI 50 response n (%) 22 (8.9%) 203 (83.5%) 222 (90.6%) 212 (87.2%) 224 (91.4%) 187 (77%) 207 (84.5%) PASI 75 response n (%) 11 (4.5%) 174 (71.6%)** 200 (81.6%)** 188 (77.4%) 211 (86.1%) 146 (60.1%) 182 (74.3%) PASI 90 response n (%) 3 (1.2%) 95 (39.1%)** 145 (59.2%)** 130 (53.5%) 171 (69.8%) 88 (36.2%) 147 (60.0%) PASI 100 response n (%) 2 (0.8%) 31 (12.8%) 70 (28.6%) 51 (21.0%) 102 (41.6%) 49 (20.2%) 96 (39.2%) IGA mod 2011 “clear” or “almost clear” response n (%) 6 (2.40%) 125 (51.2%)** 160 (65.3%)** 142 (58.2%) 180 (73.5%) 101 (41.4%) 148 (60.4%) Study 3 Number of patients 59 59 58 - - - - PASI 50 response n (%) 3 (5.1%) 51 (86.4%) 51 (87.9%) - - - - PASI 75 response n (%) 0 (0.0%) 41 (69.5%)** 44 (75.9%)** - - - - PASI 90 response n (%) 0 (0.0%) 27 (45.8%) 35 (60.3%) - - - - PASI 100 response n (%) 0 (0.0%) 5 (8.5%) 25 (43.1%) - - - - IGA mod 2011 “clear” or “almost clear” response n (%) 0 (0.0%) 31 (52.5%)** 40 (69.0%)** - - - - Study 4 Number of patients 61 60 60 - - - - PASI 50 response n (%) 5 (8.2%) 48 (80.0%) 58 (96.7%) - - - - PASI 75 response n (%) 2 (3.3%) 43 (71.7%)** 52 (86.7%)** - - - - PASI 90 response n (%) 0 (0.0%) 24 (40.0%) 33 (55.0%) - - - - PASI 100 response n(%) 0 (0.0%) 10 (16.7%) 16 (26.7%) - - - - IGA mod 2011 “clear” or “almost clear” response n (%) 0 (0.0%) 32 (53.3%)** 44 (73.3%)** - - - - * The IGA mod 2011 is a 5-category scale including “0 = clear”, “1 = almost clear”, “2 = mild”, “3 = moderate” or “4 = severe”, indicating the physician’s overall assessment of the psoriasis severity focusing on induration, erythema and scaling. Treatment success of “clear” or “almost clear” consisted of no signs of psoriasis or normal to pink colouration of lesions, no thickening of the plaque and none to minimal focal scaling. ** p values versus placebo and adjusted for multiplicity: p<0.0001. 42 Table 4 Summary of clinical response on psoriasis study 2 (FIXTURE) Week 12 Week 16 Week 52 Placebo 150 mg 300 mg Etanercept 150 mg 300 mg Etanercept 150 mg 300 mg Etanercept Number of patients 324 327 323 323 327 323 323 327 323 323 PASI 50 response n (%) 49 (15.1%) 266 (81.3%) 296 (91.6%) 226 (70.0%) 290 (88.7%) 302 (93.5%) 257 (79.6%) 249 (76.1%) 274 (84.8%) 234 (72.4%) PASI 75 response n (%) 16 (4.9%) 219 (67.0%) ** 249 (77.1%) ** 142 (44.0%) 247 (75.5%) 280 (86.7%) 189 (58.5%) 215 (65.7%) 254 (78.6%) 179 (55.4%) PASI 90 response n (%) 5 (1.5%) 137 (41.9%) 175 (54.2%) 67 (20.7%) 176 (53.8%) 234 (72.4%) 101 (31.3%) 147 (45.0%) 210 (65.0%) 108 (33.4%) PASI 100 response n (%) 0 (0%) 47 (14.4%) 78 (24.1%) 14 (4.3%) 84 (25.7%) 119 (36.8%) 24 (7.4%) 65 (19.9%) 117 (36.2%) 32 (9.9%) IGA mod 2011 “clear” or “almost clear” response n (%) 9 (2.8%) 167 (51.1%) ** 202 (62.5%) ** 88 (27.2%) 200 (61.2%) 244 (75.5%) 127 (39.3%) 168 (51.4%) 219 (67.8%) 120 (37.2%) ** p values versus etanercept: p=0.0250 In an additional psoriasis study (CLEAR) 676 patients were evaluated. Secukinumab 300 mg met the primary and secondary endpoints by showing superiority to ustekinumab based on PASI 90 response at week 16 (primary endpoint), speed of onset of PASI 75 response at week 4, and long-term PASI 90 response at week 52. Greater efficacy of secukinumab compared to ustekinumab for the endpoints PASI 75/90/100 and IGA mod 2011 0 or 1 response (“clear” or “almost clear”) was observed early and continued through to week 52. Table 5 Summary of clinical response on CLEAR study Week 4 Week 16 Week 52 Secukinumab 300 mg Ustekinumab* Secukinumab 300 mg Ustekinumab* Secukinumab 300 mg Ustekinumab* Number of patients 334 335 334 335 334 335 PASI 75 response n (%) 166 (49.7%)** 69 (20.6%) 311 (93.1%) 276 (82.4%) 306 (91.6%) 262 (78.2%) PASI 90 response n (%) 70 (21.0%) 18 (5.4%) 264 (79.0%)** 192 (57.3%) 250 (74.9%)*** 203 (60.6%) PASI 100 response n (%) 14 (4.2%) 3 (0.9%) 148 (44.3%) 95 (28.4%) 150 (44.9%) 123 (36.7%) IGA mod 2011 “clear” or “almost clear” response n (%) 128 (38.3%) 41 (12.2%) 278 (83.2%) 226 (67.5%) 261 (78.1%) 213 (63.6%) * Patients treated with secukinumab received 300 mg doses at weeks 0, 1, 2 3 and 4, followed by the same dose every 4 weeks until week 52. Patients treated with ustekinumab received 45 mg or 90 mg at weeks 0 and 4, then every 12 weeks until week 52 (dosed by weight as per approved posology) ** p values versus ustekinumab: p<0.0001 for primary endpoint of PASI 90 at week 16 and secondary endpoint of PASI 75 at week 4 *** p values versus ustekinumab: p=0.0001 for secondary endpoint of PASI 90 at week 52 Secukinumab was efficacious in systemic treatment-naive, biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients. Improvements in PASI 75 in patients with concurrent psoriatic arthritis at baseline were similar to those in the overall plaque psoriasis population. Secukinumab was associated with a fast onset of efficacy with a 50% reduction in mean PASI by week 3 for the 300 mg dose. 43 Figure 1 Time course of percentage change from baseline of mean PASI score in study 1 (ERASURE) Specific locations/forms of plaque psoriasis In two additional placebo-controlled studies, improvement was seen in both nail psoriasis (TRANSFIGURE, 198 patients) and palmoplantar plaque psoriasis (GESTURE, 205 patients). In the TRANSFIGURE study, secukinumab was superior to placebo at week 16 (46.1% for 300 mg, 38.4% for 150 mg and 11.7% for placebo) as assessed by significant improvement from baseline in the Nail Psoriasis Severity Index (NAPSI %) for patients with moderate to severe plaque psoriasis with nail involvement. In the GESTURE study, secukinumab was superior to placebo at week 16 (33.3% for 300 mg, 22.1% for 150 mg, and 1.5% for placebo) as assessed by significant improvement of ppIGA 0 or 1 response (“clear” or “almost clear”) for patients with moderate to severe palmoplantar plaque psoriasis. A placebo-controlled study evaluated 102 patients with moderate to severe scalp psoriasis, defined as having a Psoriasis Scalp Severity Index (PSSI) score of ≥12, an IGA mod 2011 scalp only score of 3 or greater and at least 30% of the scalp surface area affected. Secukinumab 300 mg was superior to placebo at week 12 as assessed by significant improvement from baseline in both the PSSI 90 response (52.9% versus 2.0%) and IGA mod 2011 0 or 1 scalp only response (56.9% versus 5.9%). Improvement in both endpoints was sustained for secukinumab patients who continued treatment through to week 24. Quality of life/patient-reported outcomes Statistically significant improvements at week 12 (studies 1-4) from baseline compared to placebo were demonstrated in the DLQI (Dermatology Life Quality Index). Mean decreases (improvements) in DLQI from baseline ranged from -10.4 to -11.6 with secukinumab 300 mg, from -7.7 to -10.1 with secukinumab 150 mg, versus -1.1 to -1.9 for placebo at week 12. These improvements were maintained for 52 weeks (studies 1 and 2). Forty percent of the participants in studies 1 and 2 completed the Psoriasis Symptom Diary©. For the participants completing the diary in each of these studies, statistically significant improvements at week 12 from baseline compared to placebo in patient-reported signs and symptoms of itching, pain and scaling were demonstrated. Statistically significant improvements at week 4 from baseline in patients treated with secukinumab compared to patients treated with ustekinumab (CLEAR) were demonstrated in the DLQI and these improvements were maintained for up to 52 weeks. PASI % change from baseline Weeks of treatment n = number of patients evaluable secukinumab 150 mg (n=243) secukinumab 300 mg (n=245) Placebo (n=245) 44 Statistically significant improvements in patient-reported signs and symptoms of itching, pain and scaling at week 16 and week 52 (CLEAR) were demonstrated in the Psoriasis Symptom Diary© in patients treated with secukinumab compared to patients treated with ustekinumab. Statistically significant improvements (decreases) at week 12 from baseline in the scalp psoriasis study were demonstrated in patient reported signs and symptoms of scalp itching, pain and scaling compared to placebo. Psoriatic arthritis The safety and efficacy of secukinumab were assessed in 1,999 patients in three randomised, double-blind, placebo-controlled phase III studies in patients with active psoriatic arthritis (≥3 swollen and ≥3 tender joints) despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease-modifying anti-rheumatic drug (DMARD) therapy. Patients with each subtype of PsA were enrolled in these studies, including polyarticular arthritis with no evidence of rheumatoid nodules, spondylitis with peripheral arthritis, asymmetric peripheral arthritis, distal interphalangeal involvement and arthritis mutilans. Patients in these studies had a diagnosis of PsA of at least five years. The majority of patients also had active psoriasis skin lesions or a documented history of psoriasis. Over 61% and 42% of the PsA patients had enthesitis and dactylitis at baseline, respectively. For all studies, the primary endpoint was American College of Rheumatology (ACR) 20 response. For Psoriatic Arthritis study 1 (PsA study 1) and Psoriatic Arthritis study 2 (PsA study 2), the primary endpoint was at week 24. For Psoriatic Arthritis study 3 (PsA study 3), the primary endpoint was at week 16 with the key secondary endpoint, the change from baseline in modified Total Sharp Score (mTSS), at week 24. In PsA study 1, PsA study 2 and PsA study 3, 29%, 35% and 30% of patients, respectively, were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients). PsA study 1 (FUTURE 1) evaluated 606 patients, of whom 60.7% had concomitant MTX. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 75 mg or 150 mg subcutaneously every month starting at week 8. Patients randomised to placebo who were non-responders at week 16 (early rescue) and other placebo patients at week 24 were crossed over to receive secukinumab (either 75 mg or 150 mg subcutaneously) followed by the same dose every month. PsA study 2 (FUTURE 2) evaluated 397 patients, of whom 46.6% had concomitant MTX. Patients randomised to secukinumab received 75 mg, 150 mg or 300 mg subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients randomised to receive placebo who were non-responders at week 16 (early rescue) were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 16 followed by the same dose every month. Patients randomised to receive placebo who were responders at week 16 were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 24 followed by the same dose every month. PsA study 3 (FUTURE 5) evaluated 996 patients, of whom 50.1% had concomitant MTX. Patients were randomised to receive secukinumab 150 mg, 300 mg or placebo subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month, or a once monthly injection of secukinumab 150 mg (without loading). Patients randomised to receive placebo who were non-responders at week 16 (early rescue) were then crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 16 followed by the same dose every month. Patients randomised to receive placebo who were responders at week 16 were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 24 followed by the same dose every month. Signs and symptoms Treatment with secukinumab resulted in significant improvement in measures of disease activity compared to placebo at weeks 16 and 24 (see Table 6). 45 Table 6 Clinical response in PsA study 2 and PsA study 3 at week 16 and week 24 PsA study 2 PsA study 3 Placebo 150 mg1 300 mg1 Placebo 150 mg1 300 mg1 Number of patients randomised 98 100 100 332 220 222 ACR20 response n (%) Week 16 18 (18.4%) 60 (60.0%***) 57 (57.0%***) 91◊ (27.4%) 122◊ (55.5%***) 139◊ (62.6%***) Week 24 15◊ (15.3%) 51◊ (51.0%***) 54◊ (54.0%***) 78 (23.5%) 117 (53.2%***) 141 (63.5%***) ACR50 response n (%) Week 16 6 (6.1%) 37 (37.0%***) 35 (35.0%***) 27 (8.1%) 79 (35.9%*) 88 (39.6%*) Week 24 7 (7.1%) 35 (35.0%) 35 (35.0%**) 29 (8.7%) 86 (39.1%***) 97 (43.7%***) ACR70 response n (%) Week 16 2 (2.0%) 17 (17.0%**) 15 (15.0%**) 14 (4.2%) 40 (18.2%***) 45 (20.3%***) Week 24 1 (1.0%) 21 (21.0%**) 20 (20.0%**) 13 (3.9%) 53 (24.1%***) 57 (25.7%***) DAS28-CRP Week 16 -0.50 -1.45*** -1.51*** -0.63 -1.29* -1.49* Week 24 -0.96 -1.58** -1.61** -0.84 -1.57*** -1.68*** Number of patients with ≥3% BSA psoriasis skin involvement at baseline 43 (43.9%) 58 (58.0%) 41 (41.0%) 162 (48.8%) 125 (56.8%) 110 (49.5%) PASI 75 response n (%) Week 16 3 (7.0%) 33 (56.9%***) 27 (65.9%***) 20 (12.3%) 75 (60.0%*) 77 (70.0%*) Week 24 7 (16.3%) 28 (48.3%**) 26 (63.4%***) 29 (17.9%) 80 (64.0%***) 78 (70.9%***) PASI 90 response n (%) Week 16 3 (7.0%) 22 (37.9%***) 18 (43.9%***) 15 (9.3%) 46 (36.8%*) 59 (53.6%*) Week 24 4 (9.3%) 19 (32.8%**) 20 (48.8%***) 19 (11.7%) 51 (40.8%***) 60 (54.5%***) Dactylitis resolution n (%) † Week 16 10 (37%) 21 (65.6%*) 26 (56.5%) 40 (32.3%) 46 (57.5%*) 54 (65.9%*) Week 24 4 (14.8%) 16 (50.0%**) 26 (56.5%**) 42 (33.9%) 51 (63.8%***) 52 (63.4%***) 46 Enthesitis resolution n (%) ‡ Week 16 17 (26.2%) 32 (50.0%**) 32 (57.1%***) 68 (35.4%) 77 (54.6%*) 78 (55.7%*) Week 24 14 (21.5%) 27 (42.2%*) 27 (48.2%**) 66 (34.4%) 77 (54.6%***) 86 (61.4%***) * p<0.05, ** p<0.01, *** p<0.001; versus placebo All p-values are adjusted for multiplicity of testing based on pre-defined hierarchy at week 24 for PsA study 2, except for ACR70, Dactylitis and Enthesitis, which were exploratory endpoints and all endpoints at week 16. All p-values are adjusted for multiplicity of testing based on pre-defined hierarchy at week 16 for PsA study 3, except for ACR70 which was an exploratory endpoint and all endpoints at week 24. Non-responder imputation used for missing binary endpoint. ACR: American College of Rheumatology; PASI: Psoriasis Area and Severity Index; DAS: Disease Activity Score; BSA: Body Surface Area ◊Primary Endpoint 1Secukinumab 150 mg or 300 mg s.c. at weeks 0, 1, 2, 3, and 4 followed by the same dose every month †In patients with dactylitis at baseline (n=27, 32, 46, respectively for PsA study 2 and n=124, 80, 82, respectively for PsA study 3) ‡In patients with enthesitis at baseline (n=65, 64, 56, respectively for PsA study 2 and n=192, 141, 140, respectively for PsA study 3) The onset of action of secukinumab occurred as early as week 2. Statistically significant difference in ACR 20 versus placebo was reached at week 3. The percentage of patients achieving ACR 20 response by visit is shown in Figure 2. Figure 2 ACR20 response in PsA study 2 over time up to week 52 Percentage of responders Time (Weeks) 47 Similar responses for primary and key secondary endpoints were seen in PsA patients regardless of whether they were on concomitant MTX treatment or not. In PsA study 2, at week 24, secukinumab- treated patients with concomitant MTX use had a higher ACR 20 response (47.7% and 54.4% for 150 mg and 300 mg, respectively, compared to placebo 20.0%) and ACR 50 response (31.8% and 38.6% for 150 mg and 300 mg, respectively, compared to placebo 8.0%). Secukinumab-treated patients without concomitant MTX use had a higher ACR 20 response (53.6% and 53.6% for 150 mg and 300 mg, respectively, compared to placebo 10.4%) and ACR 50 response (37.5% and 32.1% for 150 mg and 300 mg, respectively, compared to placebo 6.3%). In PsA study 2, both anti-TNFα-naive and anti-TNFα-IR secukinumab-treated patients had a significantly higher ACR 20 response compared to placebo at week 24, with a slightly higher response in the anti-TNFα-naive group (anti-TNFα-naive: 64% and 58% for 150 mg and 300 mg, respectively, compared to placebo 15.9%; anti-TNFα-IR: 30% and 46% for 150 mg and 300 mg, respectively, compared to placebo 14.3%). In the anti-TNFα-IR patients subgroup, only the 300 mg dose showed significantly higher response rate for ACR 20 compared to placebo (p<0.05) and demonstrated clinical meaningful benefit over 150 mg on multiple secondary endpoints. Improvements in the PASI 75 response were seen in both subgroups and the 300 mg dose showed statistically significant benefit in the anti-TNFα-IR patients. The number of PsA patients with axial involvement was too small to allow meaningful assessment. Improvements were shown in all components of the ACR scores, including patient assessment of pain. In PsA study 2, the proportion of patients achieving a modified PsA Response Criteria (PsARC) response was greater in the secukinumab-treated patients (59.0% and 61.0% for 150 mg and 300 mg, respectively) compared to placebo (26.5%) at week 24. In PsA study 1 and PsA study 2, efficacy was maintained up to week 104. In PsA study 2, among 200 patients initially randomised to secukinumab 150 mg and 300 mg, 178 (89%) patients were still on treatment at week 52. Of the 100 patients randomised to secukinumab 150 mg, 64, 39 and 20 had an ACR 20/50/70 response, respectively. Of the 100 patients randomised to secukinumab 300 mg, 64, 44 and 24 had an ACR 20/50/70 response, respectively. Radiographic response In PsA study 3, inhibition of progression of structural damage was assessed radiographically and expressed by the modified Total Sharp Score (mTSS) and its components, the Erosion Score (ES) and the Joint Space Narrowing Score (JSN). Radiographs of hands, wrists, and feet were obtained at baseline, week 16 and/or week 24 and scored independently by at least two readers who were blinded to treatment group and visit number. Secukinumab 150 mg and 300 mg treatment significantly inhibited the rate of progression of peripheral joint damage compared with placebo treatment as measured by change from baseline in mTSS at week 24 (Table 7). Inhibition of progression of structural damage was also assessed in PsA study 1 at weeks 24 and 52, compared to baseline. Week 24 data are presented in Table 7. 48 Table 7 Change in modified Total Sharp Score in psoriatic arthritis PsA study 3 PsA study 1 Placebo n=296 secukinumab 150 mg1 n=213 secukinumab 300 mg1 n=217 Placebo n=179 secukinumab 150 mg2 n=185 Total score Baseline (SD) 15.0 (38.2) 13.5 (25.6) 12.9 (23.8) 28.4 (63.5) 22.3 (48.0) Mean change at Week 24 0.50 0.13* 0.02* 0.57 0.13* *p<0.05 based on nominal, but non adjusted, p-value 1secukinumab 150 mg or 300 mg s.c. at weeks 0, 1, 2, 3, and 4 followed by the same dose every month 210 mg/kg at weeks 0, 2 and 4 followed by subcutaneous doses of 75 mg or 150 mg In PsA study 1, inhibition of structural damage was maintained with secukinumab treatment up to week 52. In PsA study 3, the percentage of patients with no disease progression (defined as a change from baseline in mTSS of ≤0.5) from randomisation to week 24 was 80.3%, 88.5% and 73.6% for secukinumab 150 mg, 300 mg and placebo, respectively. An effect of inhibition of structural damage was observed in anti-TNFα-naïve and anti-TNFα-IR patients and in patients treated with and without concomitant MTX. In PsA study 1, the percentage of patients with no disease progression (defined as a change from baseline in mTSS of ≤0.5) from randomisation to week 24 was 82.3% in secukinumab 10 mg/kg intravenous load – 150 mg subcutaneous maintenance and 75.7% in placebo. The percentage of patients with no disease progression from week 24 to week 52 for secukinumab 10 mg/kg intravenous load – followed by 150 mg subcutaneous maintenance and for placebo patients who switched to 75 mg or 150 mg subcutaneous every 4 weeks at week 16 or week 24 was 85.7% and 86.8%, respectively. Physical function and health-related quality of life In PsA study 2 and PsA study 3, patients treated with secukinumab 150 mg (p=0.0555 and p<0.0001) and 300 mg (p=0.0040 and p<0.0001) showed improvement in physical function compared to patients treated with placebo as assessed by Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 24 and week 16, respectively. Improvements in HAQ-DI scores were seen regardless of previous anti-TNFα exposure. Similar responses were seen in PsA study 1. Secukinumab-treated patients reported significant improvements in health-related quality of life as measured by the Short Form-36 Health Survey Physical Component Summary (SF-36 PCS) score (p<0.001). There were also statistically significant improvements demonstrated in exploratory endpoints assessed by the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) scores for 150 mg and 300 mg compared to placebo (7.97, 5.97 versus 1.63, respectively) and these improvements were maintained up to week 104 in PsA study 2. Similar responses were seen in PsA study 1 and efficacy was maintained up to week 52. 49 Axial spondyloarthritis (axSpA) Ankylosing spondylitis (AS) / Radiographic axial spondyloarthritis The safety and efficacy of secukinumab were assessed in 816 patients in three randomised, double-blind, placebo-controlled phase III studies in patients with active ankylosing spondylitis (AS) with a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease-modifying anti-rheumatic drug (DMARD) therapy. Patients in Ankylosing Spondylitis study 1 (AS study 1) and Ankylosing Spondylitis study 2 (AS study 2) had a diagnosis of AS for a median of 2.7 to 5.8 years. For both studies, the primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society (ASAS 20) criteria at week 16. In Ankylosing Spondylitis study 1 (AS study 1), Ankylosing Spondylitis study 2 (AS study 2), and Ankylosing Spondylitis study 3 (AS study 3), 27.0%, 38.8%, and 23.5% of patients, respectively, were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients). AS study 1 (MEASURE 1) evaluated 371 patients, of whom 14.8% and 33.4% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 75 mg or 150 mg subcutaneously every month starting at week 8. Patients randomised to placebo who were non-responders at week 16 (early rescue) and all other placebo patients at week 24 were crossed over to receive secukinumab (either 75 mg or 150 mg subcutaneously), followed by the same dose every month. AS study 2 (MEASURE 2) evaluated 219 patients, of whom 11.9% and 14.2% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 75 mg or 150 mg subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. At week 16, patients who were randomised to placebo at baseline were re-randomised to receive secukinumab (either 75 mg or 150 mg subcutaneously) every month. AS study 3 (MEASURE 3) evaluated 226 patients, of whom 13.3% and 23.5% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 150 mg or 300 mg subcutaneously every month. At week 16, patients who were randomised to placebo at baseline were re-randomised to receive secukinumab (either 150 mg or 300 mg subcutaneously) every month. The primary endpoint was ASAS 20 at week 16. Patients were blinded to the treatment regimen up to week 52, and the study continued to week 156. Signs and symptoms: In AS study 2, treatment with secukinumab 150 mg resulted in greater improvement in measures of disease activity compared with placebo at week 16 (see Table 8). 50 Table 8 Clinical response in AS study 2 at week 16 Outcome (p-value versus placebo) Placebo (n = 74) 75 mg (n = 73) 150 mg (n = 72) ASAS 20 response, % 28.4 41.1 61.1*** ASAS 40 response, % 10.8 26.0 36.1*** hsCRP, (post-BSL/BSL ratio) 1.13 0.61 0.55*** ASAS 5/6, % 8.1 34.2 43.1*** ASAS partial remission, % 4.1 15.1 13.9 BASDAI 50, % 10.8 24.7* 30.6** ASDAS-CRP major improvement 4.1 15.1* 25.0*** * p<0.05, ** p<0.01, *** p<0.001; versus placebo All p-values adjusted for multiplicity of testing based on pre-defined hierarchy, except BASDAI 50 and ASDAS-CRP Non-responder imputation used for missing binary endpoint ASAS: Assessment of SpondyloArthritis International Society Criteria; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; hsCRP: high-sensitivity C-reactive protein; ASDAS: Ankylosing Spondylitis Disease Activity Score; BSL: baseline The onset of action of secukinumab 150 mg occurred as early as week 1 for ASAS 20 and week 2 for ASAS 40 (superior to placebo) in AS study 2. ASAS 20 responses were improved at week 16 in both anti-TNFα-naïve patients (68.2% versus 31.1%; p<0.05) and anti-TNFα-IR patients (50.0% versus 24.1%; p<0.05) for secukinumab 150 mg compared with placebo, respectively. In AS study 1 and AS study 2, secukinumab-treated patients (150 mg in AS study 2 and both regimens in AS study 1) demonstrated significantly improved signs and symptoms at week 16, with comparable magnitude of response and efficacy maintained up to week 52 in both anti-TNFα-naive and anti-TNFα-IR patients. In AS study 2, among 72 patients initially randomised to secukinumab 150 mg, 61 (84.7%) patients were still on treatment at week 52. Of the 72 patients randomised to secukinumab 150 mg, 45 and 35 had an ASAS 20/40 response, respectively. In AS study 3, patients treated with secukinumab (150 mg and 300 mg) demonstrated improved signs and symptoms, and had comparable efficacy responses regardless of dose that were superior to placebo at week 16 for the primary endpoint (ASAS 20). Overall, the efficacy response rates for the 300 mg group were consistently greater compared to the 150 mg group for the secondary endpoints. During the blinded period, the ASAS 20 and ASAS 40 responses were 69.7% and 47.6% for 150 mg and 74.3% and 57.4% for 300 mg at week 52, respectively. The ASAS 20 and ASAS 40 responses were maintained up to week 156 (69.5% and 47.6% for 150 mg versus 74.8% and 55.6% for 300 mg). Greater response rates favouring 300 mg were also observed for ASAS partial remission (ASAS PR) response at week 16 and were maintained up to week 156. Larger differences in response rates, favouring 300 mg over 150 mg, were observed in anti-TNFα-IR patients (n=36) compared to anti-TNFα-naïve patients (n=114). Spinal mobility: Patients treated with secukinumab 150 mg showed improvements in spinal mobility as measured by change from baseline in BASMI at week 16 for both AS study 1 (-0.40 versus -0.12 for placebo; p=0.0114) and AS study 2 (-0.51 versus -0.22 for placebo; p=0.0533). These improvements were sustained up to week 52. 51 Physical function and health-related quality of life: In AS study 1 and study 2, patients treated with secukinumab 150 mg showed improvements in health- related quality of life as measured by AS Quality of Life Questionnaire (ASQoL) (p=0.001) and SF-36 Physical Component Summary (SF-36PCS) (p<0.001). Patients treated with secukinumab 150 mg also showed statistically significant improvements on exploratory endpoints in physical function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI) compared to placebo (-2.15 versus -0.68), and in fatigue as assessed by the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue) scale compared to placebo (8.10 versus 3.30). These improvements were sustained up to week 52. Non-radiographic axial spondyloarthritis (nr-axSpA) The safety and efficacy of secukinumab were assessed in 555 patients in one randomised, double-blind, placebo-controlled phase III study (PREVENT), consisting of a 2-year core phase and a 2-year extension phase, in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) fulfilling the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA) with no radiographic evidence of changes in the sacroiliac joints that would meet the modified New York criteria for ankylosing spondylitis (AS). Patients enrolled had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4, a Visual Analogue Scale (VAS) for total back pain of ≥40 (on a scale of 0-100 mm), despite current or previous non-steroidal anti-inflammatory drug (NSAID) therapy and increased C-reactive protein (CRP) and/or evidence of sacroiliitis on Magnetic Resonance Imaging (MRI). Patients in this study had a diagnosis of axSpA for a mean of 2.1 to 3.0 years and 54% of the study participants were female. In the PREVENT study, 9.7% of patients were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients). In the PREVENT study, 9.9% and 14.8% of patients used concomitant MTX or sulfasalazine, respectively. In the double-blind period, patients received either placebo or secukinumab for 52 weeks. Patients randomised to secukinumab received 150 mg subcutaneously at weeks 0, 1, 2, 3 and 4 followed by the same dose every month, or a once monthly injection of secukinumab 150 mg. The primary endpoint was at least 40% improvement in Assessment of Spondyloarthritis International Society (ASAS 40) at Week 16 in anti-TNFα-naive patients. Signs and symptoms: In the PREVENT study, treatment with secukinumab 150 mg resulted in significant improvements in the measures of disease activity compared to placebo at week 16. These measures include ASAS 40, ASAS 5/6, BASDAI score, BASDAI 50, high-sensitivity CRP (hsCRP), ASAS 20 and ASAS partial remission response compared to placebo (Table 9). Responses were maintained up to week 52. 52 Table 9 Clinical response in the PREVENT study at week 16 Outcome (p-value versus placebo) Placebo 150 mg1 Number of anti-TNFα-naive patients randomised 171 164 ASAS 40 response, % 29.2 41.5* Total number of patients randomised 186 185 ASAS 40 response, % 28.0 40.0* ASAS 5/6, % 23.7 40.0* BASDAI, LS mean change from baseline score -1.46 -2.35* BASDAI 50, % 21.0 37.3* hsCRP, (post-BSL/BSL ratio) 0.91 0.64* ASAS 20 response, % 45.7 56.8* ASAS partial remission, % 7.0 21.6* *p<0.05 versus placebo All p-values adjusted for multiplicity of testing based on pre-defined hierarchy Non-responder imputation used for missing binary endpoint 1secukinumab 150 mg s.c. at weeks 0, 1, 2, 3, and 4 followed by the same dose every month ASAS: Assessment of SpondyloArthritis International Society Criteria; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; hsCRP: high-sensitivity C-reactive protein; BSL: baseline; LS: Least square The onset of action of secukinumab 150 mg occurred as early as week 3 for ASAS 40 in anti-TNFα naive patients (superior to placebo) in the PREVENT study. The percentage of patients achieving an ASAS 40 response in anti-TNFα naive patients by visit is shown in Figure 3. Figure 3 ASAS 40 responses in anti-TNFα naive patients in the PREVENT study over time up to week 16 ASAS 40 responses were also improved at week 16 in anti-TNFα-IR patients for secukinumab 150 mg compared with placebo. Percentage of responders Time (Weeks) Secukinumab 150 mg Load Placebo 53 Physical function and health-related quality of life: Patients treated with secukinumab 150 mg showed statistically significant improvements by week 16 compared to placebo-treated patients in physical function as assessed by the BASFI (week 16: -1.75 versus -1.01, p<0.05). Patients treated with secukinumab reported significant improvements compared to placebo-treated patients by week 16 in health-related quality of life as measured by ASQoL (LS mean change: week 16: -3.45 versus -1.84, p<0.05) and SF-36 Physical Component Summary (SF-36 PCS) (LS mean change: week 16: 5.71 versus 2.93, p<0.05). These improvements were sustained up to week 52. Spinal mobility: Spinal mobility was assessed by BASMI up to week 16. Numerically greater improvements were demonstrated in patients treated with secukinumab compared with placebo-treated patients at weeks 4, 8, 12 and 16. Inhibition of inflammation in magnetic resonance imaging (MRI): Signs of inflammation were assessed by MRI at baseline and week 16 and expressed as change from baseline in Berlin SI-joint oedema score for sacroiliac joints and ASspiMRI-a score and Berlin spine score for the spine. Inhibition of inflammatory signs in both sacroiliac joints and the spine was observed in patients treated with secukinumab. Mean change from baseline in Berlin SI-joint oedema score was -1.68 for patients treated with secukinumab 150 mg (n=180) versus -0.39 for the placebo-treated patients (n=174) (p<0.05). Paediatric population Paediatric plaque psoriasis Secukinumab has been shown to improve signs and symptoms, and health-related quality of life in paediatric patients 6 years and older with plaque psoriasis (see Tables 11 and 13). Severe plaque psoriasis The safety and efficacy of secukinumab were assessed in a randomised, double-blind, placebo and etanercept-controlled phase III study in paediatric patients from 6 to <18 years of age with severe plaque psoriasis, as defined by a PASI score ≥20, an IGA mod 2011 score of 4, and BSA involvement of ≥10%, who were candidates for systemic therapy. Approximately 43% of the patients had prior exposure to phototherapy, 53% to conventional systemic therapy, 3% to biologics, and 9% had concomitant psoriatic arthritis. The paediatric psoriasis study 1 evaluated 162 patients who were randomised to receive low dose secukinumab (75 mg for body weight <50 kg or 150 mg for body weight ≥50 kg), high dose secukinumab (75 mg for body weight <25 kg, 150 mg for body weight between ≥25 kg and <50 kg, or 300 mg for body weight ≥50 kg), or placebo at weeks 0, 1, 2, 3, and 4 followed by the same dose every 4 weeks, or etanercept. Patients randomised to etanercept received 0.8 mg/kg weekly (up to a maximum of 50 mg). Patient distribution by weight and age at randomisation is described in Table 10. Table 10 Patient distribution by weight and age for paediatric psoriasis study 1 Randomisation strata Description Secukinumab low dose n=40 Secukinumab high dose n=40 Placebo n=41 Etanercept n=41 Total N=162 Age 6-<12 years 8 9 10 10 37 ≥12- <18 years 32 31 31 31 125 Weight <25 kg 2 3 3 4 12 ≥25-<50 kg 17 15 17 16 65 ≥50 kg 21 22 21 21 85 54 Patients randomised to receive placebo who were non-responders at week 12 were switched to either the secukinumab low or high dose group (dose based on body weight group) and received study drug at weeks 12, 13, 14, and 15, followed by the same dose every 4 weeks starting at week 16. The co- primary endpoints were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ (0 or 1) response at week 12. During the 12 week placebo-controlled period, the efficacy of both the low and the high dose of secukinumab was comparable for the co-primary endpoints. The odds ratio estimates in favour of both secukinumab doses were statistically significant for both the PASI 75 and IGA mod 2011 0 or 1 responses. All patients were followed for efficacy and safety during the 52 weeks following the first dose. The proportion of patients achieving PASI 75 and IGA mod 2011 ‘clear’ or ‘almost clear’ (0 or 1) responses showed separation between secukinumab treatment groups and placebo at the first post- baseline visit at week 4, the difference becoming more prominent at week 12. The response was maintained throughout the 52 week time period (see Table 11). Improvement in PASI 50, 90, 100 responder rates and Children’s Dermatology Life Quality Index (CDLQI) scores of 0 or 1 were also maintained throughout the 52 week time period. In addition, PASI 75, IGA 0 or 1, PASI 90 response rates at weeks 12 and 52 for both secukinumab low and high dose groups were higher than the rates for patients treated with etanercept (see Table 11). Beyond week 12, efficacy of both the low and the high dose of secukinumab was comparable although the efficacy of the high dose was higher for patients ≥50 kg. The safety profiles of the low dose and the high dose were comparable and consistent with the safety profile in adults. Table 11 Summary of clinical response in severe paediatric psoriasis at weeks 12 and 52 (paediatric psoriasis study 1)* Response criterion Treatment comparison 'test' 'control' odds ratio 'test' vs. 'control' n**/m (%) n**/m (%) estimate (95% CI) p-value At week 12*** PASI 75 secukinumab low dose vs. placebo 32/40 (80.0) 6/41 (14.6) 25.78 (7.08, 114.66) <0.0001 secukinumab high dose vs. placebo 31/40 (77.5) 6/41 (14.6) 22.65 (6.31, 98.93) <0.0001 secukinumab low dose vs. etanercept 32/40 (80.0) 26/41 (63.4) 2.25 (0.73, 7.38) secukinumab high dose vs. etanercept 31/40 (77.5) 26/41 (63.4) 1.92 (0.64, 6.07) IGA 0/1 secukinumab low dose vs. placebo 28/40 (70.0) 2/41 (4.9) 51.77 (10.02, 538.64) <0.0001 secukinumab high dose vs. placebo 24/40 (60.0) 2/41 (4.9) 32.52 (6.48, 329.52) <0.0001 secukinumab low dose vs. etanercept 28/40 (70.0) 14/41 (34.1) 4.49 (1.60, 13.42) secukinumab high dose vs. etanercept 24/40 (60.0) 14/41 (34.1) 2.86 (1.05, 8.13) PASI 90 secukinumab low dose vs. placebo 29/40 (72.5) 1/41 (2.4) 133.67 (16.83, 6395.22) <0.0001 secukinumab high dose vs. placebo 27/40 (67.5) 1/41 (2.4) 102.86 (13.22, 4850.13) <0.0001 secukinumab low dose vs. etanercept 29/40 (72.5) 12/41 (29.3) 7.03 (2.34, 23.19) secukinumab high dose vs. etanercept 27/40 (67.5) 12/41 (29.3) 5.32 (1.82, 16.75) At week 52 PASI 75 secukinumab low dose vs. etanercept 35/40 (87.5) 28/41 (68.3) 3.12 (0.91, 12.52) secukinumab high dose vs. etanercept 35/40 (87.5) 28/41 (68.3) 3.09 (0.90, 12.39) IGA 0/1 secukinumab low dose vs. etanercept 29/40 (72.5) 23/41 (56.1) 2.02 (0.73, 5.77) secukinumab high dose vs. etanercept 30/40 (75.0) 23/41 (56.1) 2.26 (0.81, 6.62) PASI 90 secukinumab low dose vs. etanercept 30/40 (75.0) 21/41 (51.2) 2.85 (1.02, 8.38) secukinumab high dose vs. etanercept 32/40 (80.0) 21/41 (51.2) 3.69 (1.27, 11.61) * non-responder imputation was used to handle missing values ** n is the number of responders, m = number of patients evaluable *** extended visit window at week 12 Odds ratio, 95% confidence interval, and p-value are from an exact logistic regression model with treatment group, baseline body-weight category and age category as factors 55 A higher proportion of paediatric patients treated with secukinumab reported improvement in health- related quality of life as measured by a CDLQI score of 0 or 1 compared to placebo at week 12 (low dose 44.7%, high dose 50%, placebo 15%). Over time up to and including week 52 both secukinumab dose groups were numerically higher than the etanercept group (low dose 60.6%, high dose 66.7%, etanercept 44.4%). Moderate to severe plaque psoriasis Secukinumab was predicted to be effective for the treatment of paediatric patients with moderate plaque psoriasis based on the demonstrated efficacy and exposure response relationship in adult patients with moderate to severe plaque psoriasis, and the similarity of the disease course, pathophysiology, and drug effect in adult and paediatric patients at the same exposure levels. Moreover, the safety and efficacy of secukinumab was assessed in an open-label, two-arm, parallel-group, multicentre phase III study in paediatric patients from 6 to <18 years of age with moderate to severe plaque psoriasis, as defined by a PASI score ≥12, an IGA mod 2011 score of ≥3, and BSA involvement of ≥10%, who were candidates for systemic therapy. The paediatric psoriasis study 2 evaluated 84 patients who were randomised to receive low dose secukinumab (75 mg for body weight <50 kg or 150 mg for body weight ≥50 kg) or high dose secukinumab (75 mg for body weight <25 kg, 150 mg for body weight between ≥25 kg and <50 kg, or 300 mg for body weight ≥50 kg) at weeks 0, 1, 2, 3, and 4 followed by the same dose every 4 weeks. Patient distribution by weight and age at randomisation is described in Table 12. Table 12 Patient distribution by weight and age for paediatric psoriasis study 2 Sub-groups Description Secukinumab low dose n=42 Secukinumab high dose n=42 Total N=84 Age 6-<12 years 17 16 33 ≥12-<18 years 25 26 51 Weight <25 kg 4 4 8 ≥25-<50 kg 13 12 25 ≥50 kg 25 26 51 The co-primary endpoints were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ (0 or 1) response at week 12. The efficacy of both the low and the high dose of secukinumab was comparable and showed statistically significant improvement compared to historical placebo for the co-primary endpoints. The estimated posterior probability of a positive treatment effect was 100%. All patients were followed for efficacy for at least 24 weeks following first administration (see Table 13). Efficacy (defined as PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ [0 or 1]) was observed as early as the first post-baseline visit at week 2 and the proportion of patients who achieved a PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ (0 or 1) increased throughout the 24 week time period. Improvement in PASI 90 and PASI 100 were also observed at week 12 and increased throughout the 24 week time period. Beyond week 12, efficacy of both the low and the high dose of secukinumab was comparable. The safety profiles of the low dose and the high dose were comparable and consistent with the safety profile in adults. 56 Table 13 Summary of clinical response in moderate to severe paediatric psoriasis at weeks 12 and 24 (paediatric psoriasis study 2)* Week 12 Week 24 Secukinumab low dose Secukinumab high dose Secukinumab low dose Secukinumab high dose Number of patients 42 42 42 42 PASI 75 response n (%) 39 (92.9%) 39 (92.9%) 40 (95.2%) 40 (95.2%) IGA mod 2011 ‘clear’ or ‘almost clear’ response n (%) 33 (78.6%) 35 (83.3%) 37 (88.1%) 39 (92.9%) PASI 90 response n (%) 29 (69%) 32 (76.2%) 37 (88.1%) 37 (88.1%) PASI 100 response n (%) 25 (59.5%) 23 (54.8%) 28 (66.7%) 28 (66.7%) * non-responder imputation was used to handle missing values These outcomes in the paediatric moderate to severe plaque psoriasis population confirmed the predictive assumptions based on the efficacy and exposure response relationship in adult patients, mentioned above. In the low dose group, 50% and 70.7% of patients achieved a CDLQI 0 or 1 score at weeks 12 and 24, respectively. In the high dose group, 61.9% and 60.5% achieved a CDLQI 0 or 1 score at weeks 12 and 24, respectively. The European Medicines Agency has waived the obligation to submit the results of studies with Cosentyx in plaque psoriasis in paediatric patients aged from birth to less than 6 years and in chronic idiopathic arthritis for paediatric patients aged from birth to less than 2 years (see section 4.2 for information on paediatric use). The European Medicines Agency has deferred the obligation to submit the results of studies with Cosentyx in chronic idiopathic arthritis for paediatric patients aged from 2 years to less than 18 years (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Most pharmacokinetics properties observed in patients with plaque psoriasis, psoriatic arthritis and ankylosing spondylitis were similar. Absorption Following a single subcutaneous dose of 300 mg as a liquid formulation in healthy volunteers, secukinumab reached peak serum concentrations of 43.2±10.4 μg/ml between 2 and 14 days post dose. Based on population pharmacokinetic analysis, following a single subcutaneous dose of either 150 mg or 300 mg in plaque psoriasis patients, secukinumab reached peak serum concentrations of 13.7±4.8 µg/ml or 27.3±9.5 µg/ml, respectively, between 5 and 6 days post dose. After initial weekly dosing during the first month, time to reach the maximum concentration was between 31 and 34 days based on population pharmacokinetic analysis. On the basis of simulated data, peak concentrations at steady-state (Cmax,ss) following subcutaneous administration of 150 mg or 300 mg were 27.6 µg/ml and 55.2 µg/ml, respectively. Population pharmacokinetic analysis suggests that steady-state is reached after 20 weeks with monthly dosing regimens. Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 2-fold increase in peak serum concentrations and area under the curve (AUC) following repeated monthly dosing during maintenance. 57 Population pharmacokinetic analysis showed that secukinumab was absorbed with an average absolute bioavailability of 73% in patients with plaque psoriasis. Across studies, absolute bioavailabilities in the range between 60 and 77% were calculated. The bioavailability of secukinumab in PsA patients was 85% on the basis of the population pharmacokinetic model. Following a single subcutaneous injection of 300 mg solution for injection in pre-filled syringe in plaque psoriasis patients, secukinumab systemic exposure was similar to what was observed previously with two injections of 150 mg. Distribution The mean volume of distribution during the terminal phase (Vz) following single intravenous administration ranged from 7.10 to 8.60 litres in plaque psoriasis patients, suggesting that secukinumab undergoes limited distribution to peripheral compartments. Biotransformation The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or receptor mediated endocytosis. Elimination Mean systemic clearance (CL) following a single intravenous administration to patients with plaque psoriasis ranged from 0.13 to 0.36 l/day. In a population pharmacokinetic analysis, the mean systemic clearance (CL) was 0.19 l/day in plaque psoriasis patients. The CL was not impacted by gender. Clearance was dose- and time-independent. The mean elimination half-life, as estimated from population pharmacokinetic analysis, was 27 days in plaque psoriasis patients, ranging from 18 to 46 days across psoriasis studies with intravenous administration. Linearity/non-linearity The single and multiple dose pharmacokinetics of secukinumab in plaque psoriasis patients were determined in several studies with intravenous doses ranging from 1x 0.3 mg/kg to 3x 10 mg/kg and with subcutaneous doses ranging from 1x 25 mg to multiple doses of 300 mg. Exposure was dose proportional across all dosing regimens. Special populations Elderly patients Based on population pharmacokinetic analysis with a limited number of elderly patients (n=71 for age ≥65 years and n=7 for age ≥75 years), clearance in elderly patients and patients less than 65 years of age was similar. Patients with renal or hepatic impairment No pharmacokinetic data are available in patients with renal or hepatic impairment. The renal elimination of intact secukinumab, an IgG monoclonal antibody, is expected to be low and of minor importance. IgGs are mainly eliminated via catabolism and hepatic impairment is not expected to influence clearance of secukinumab. Effect of weight on pharmacokinetics Secukinumab clearance and volume of distribution increase as body weight increases. 58 Paediatric population In a pool of the two paediatric studies, patients with moderate to severe plaque psoriasis (6 to less than 18 years of age) were administered secukinumab at the recommended paediatric dosing regimen. At week 24, patients weighing ≥25 and <50 kg had a mean ± SD steady-state trough concentration of 19.8 ± 6.96 µg/ml (n=24) after 75 mg of secukinumab and patients weighing ≥50 kg had mean ±SD trough concentration of 27.3 ± 10.1 µg/ml (n=36) after 150 mg of secukinumab. The mean ± SD steady-state trough concentration in patients weighing <25 kg (n=8) was 32.6 ± 10.8 µg/ml at week 24 after 75 mg dose. 5.3 Preclinical safety data Non-clinical data revealed no special hazard for humans (adult or paediatric) based on conventional studies of safety pharmacology, repeated dose and reproductive toxicity, or tissue cross-reactivity. Animal studies have not been conducted to evaluate the carcinogenic potential of secukinumab. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Trehalose dihydrate Histidine Histidine hydrochloride monohydrate Methionine Polysorbate 80 Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 18 months If necessary, Cosentyx may be stored unrefrigerated for a single period of up to 4 days at room temperature, not above 30°C. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the original package in order to protect from light. 6.5 Nature and contents of container Cosentyx 150 mg solution for injection in pre-filled syringe Cosentyx 150 mg solution for injection in pre-filled syringe is supplied in a pre-filled 1 ml glass syringe with a silicone-coated bromobutyl rubber plunger stopper, staked 27G x ½″ needle and rigid needle shield of styrene butadiene rubber assembled in an automatic needle guard of polycarbonate. Cosentyx 150 mg solution for injection in pre-filled syringe is available in unit packs containing 1 or 2 pre-filled syringes and in multipacks containing 6 (3 packs of 2) pre-filled syringes. 59 Cosentyx 300 mg solution for injection in pre-filled syringe Cosentyx 300 mg solution for injection in pre-filled syringe is supplied in a pre-filled 2.25 ml glass syringe with a silicone-coated bromobutyl rubber plunger stopper, staked 27G x ½″ needle and rigid needle shield of synthetic polyisoprene rubber assembled in an automatic needle guard of polycarbonate. Cosentyx 300 mg solution for injection in pre-filled syringe is available in unit packs containing 1 pre-filled syringe and in multipacks containing 3 (3 packs of 1) pre-filled syringes. Cosentyx 150 mg solution for injection in pre-filled pen Cosentyx 150 mg solution for injection in pre-filled pen is supplied in a single-use pre-filled syringe assembled into a triangular-shaped pen with transparent window and label. The pre-filled syringe inside the pen is a 1 ml glass syringe with a silicone-coated bromobutyl rubber plunger stopper, staked 27G x ½″ needle and rigid needle shield of styrene butadiene rubber. Cosentyx 150 mg solution for injection in pre-filled pen is available in unit packs containing 1 or 2 pre-filled pens and in multipacks containing 6 (3 packs of 2) pre-filled pens. Cosentyx 300 mg solution for injection in pre-filled pen Cosentyx 300 mg solution for injection in pre-filled pen is supplied in a single-use pre-filled syringe assembled into a squared-shaped pen with transparent window and label. The pre-filled syringe inside the pen is a 2.25 ml glass syringe with a silicone-coated bromobutyl rubber plunger stopper, staked 27G x ½″ needle and rigid needle shield of synthetic polyisoprene rubber. Cosentyx 300 mg solution for injection in pre-filled pen is available in unit packs containing 1 pre-filled pen and in multipacks containing 3 (3 packs of 1) pre-filled pens. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Cosentyx 150 mg solution for injection in pre-filled syringe Cosentyx 150 mg solution for injection is supplied in a single-use pre-filled syringe for individual use. The syringe should be taken out of the refrigerator 20 minutes before injecting to allow it to reach room temperature. Cosentyx 300 mg solution for injection in pre-filled syringe Cosentyx 300 mg solution for injection is supplied in a single-use pre-filled syringe for individual use. The syringe should be taken out of the refrigerator 30-45 minutes before injecting to allow it to reach room temperature. Cosentyx 150 mg solution for injection in pre-filled pen Cosentyx 150 mg solution for injection is supplied in a single-use pre-filled pen for individual use. The pen should be taken out of the refrigerator 20 minutes before injecting to allow it to reach room temperature. Cosentyx 300 mg solution for injection in pre-filled pen Cosentyx 300 mg solution for injection is supplied in a single-use pre-filled pen for individual use. The pen should be taken out of the refrigerator 30-45 minutes before injecting to allow it to reach room temperature. 60 Prior to use, a visual inspection of the pre-filled syringe or pre-filled pen is recommended. The liquid should be clear. Its colour may vary from colourless to slightly yellow. You may see a small air bubble, which is normal. Do not use if the liquid contains easily visible particles, is cloudy or is distinctly brown. Detailed instructions for use are provided in the package leaflet. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) Cosentyx 150 mg solution for injection in pre-filled syringe EU/1/14/980/002 EU/1/14/980/003 EU/1/14/980/006 Cosentyx 300 mg solution for injection in pre-filled syringe EU/1/14/980/008-009 Cosentyx150 mg solution for injection in pre-filled pen EU/1/14/980/004 EU/1/14/980/005 EU/1/14/980/007 Cosentyx 300 mg solution for injection in pre-filled pen EU/1/14/980/010-011 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 15 January 2015 Date of latest renewal: 03 September 2019 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 61 ANNEX II A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 62 A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers of the biological active substance Novartis Pharma S.A.S. Centre de Biotechnologie 8, rue de l’Industrie F-68330 Huningue France Sandoz GmbH Business Unit Biologics Technical Development and Manufacturing Drug Substance Schaftenau (BTDM DSS) Biochemiestrasse 10 6336 Langkampfen Austria Name and address of the manufacturer responsible for batch release Powder for solution for injection Novartis Pharma GmbH Roonstraße 25 90429 Nuremberg Germany Solution for injection in pre-filled syringe / Solution for injection in pre-filled pen Novartis Pharma GmbH Roonstraße 25 90429 Nuremberg Germany Sandoz GmbH Biochemiestrasse 10 6336 Langkampfen Austria The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. 63 D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 64 ANNEX III LABELLING AND PACKAGE LEAFLET 65 A. LABELLING 66 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON – vial 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg powder for solution for injection secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial contains 150 mg secukinumab. After reconstitution, 1 ml of solution contains 150 mg secukinumab. 3. LIST OF EXCIPIENTS Also contains: Sucrose, histidine, histidine hydrochloride monohydrate, polysorbate 80. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for solution for injection 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. 67 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 68 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Cosentyx 150 mg powder for solution for injection secukinumab SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 69 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK – pre-filled syringe 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg solution for injection in pre-filled syringe secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe contains 150 mg secukinumab in 1 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled syringe 2 pre-filled syringes 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 70 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. Keep the pre-filled syringes in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/002 Pack containing 1 pre-filled syringe EU/1/14/980/003 Pack containing 2 pre-filled syringes 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 71 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) – pre-filled syringe 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg solution for injection in pre-filled syringe secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe contains 150 mg secukinumab in 1 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection Multipack: 6 (3 packs of 2) pre-filled syringes 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 72 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled syringes in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/006 Multipack containing 6 (3 x 2) pre-filled syringes 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 73 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) – pre-filled syringe 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg solution for injection in pre-filled syringe secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe contains 150 mg secukinumab in 1 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 2 pre-filled syringes. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 74 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled syringes in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/006 Multipack containing 6 (3 x 2) pre-filled syringes 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 75 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER OF PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg solution for injection in pre-filled syringe secukinumab 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 76 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SYRINGE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Cosentyx 150 mg injection secukinumab SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 77 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK – pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg solution for injection in pre-filled pen secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains 150 mg secukinumab in 1 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled SensoReady pen 2 pre-filled SensoReady pens 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 78 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled pen in the outer carton in order to protect from light. Keep the pre-filled pens in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/004 Pack containing 1 pre-filled pen EU/1/14/980/005 Pack containing 2 pre-filled pens 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 79 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) – pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg solution for injection in pre-filled pen secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains 150 mg secukinumab in 1 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection Multipack: 6 (3 packs of 2) pre-filled pens 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 80 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled pens in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/007 Multipack containing 6 (3 x 2) pre-filled pens 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 81 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) – pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 150 mg solution for injection in pre-filled pen secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains 150 mg secukinumab in 1 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 2 pre-filled pens. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 82 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled pens in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/007 Multipack containing 6 (3 x 2) pre-filled pens 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 150 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 83 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PEN LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Cosentyx 150 mg solution for injection in pre-filled pen secukinumab SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER SensoReady pen 84 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK – pre-filled syringe 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 300 mg solution for injection in pre-filled syringe secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe contains 300 mg secukinumab in 2 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled syringe 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 85 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/008 Pack containing 1 pre-filled syringe 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 300 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 86 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) – pre-filled syringe 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 300 mg solution for injection in pre-filled syringe secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe contains 300 mg secukinumab in 2 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection Multipack: 3 (3 packs of 1) pre-filled syringes 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 87 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled syringes in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/009 Multipack containing 3 (3 x 1) pre-filled syringes 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 300 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 88 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) – pre-filled syringe 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 300 mg solution for injection in pre-filled syringe secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled syringe contains 300 mg secukinumab in 2 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled syringe. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 89 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/009 Multipack containing 3 (3 x 1) pre-filled syringes 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 300 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 90 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER OF PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 300 mg solution for injection in pre-filled syringe secukinumab 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 91 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SYRINGE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Cosentyx 300 mg injection secukinumab SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 92 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF UNIT PACK – pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 300 mg solution for injection in pre-filled pen secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains 300 mg secukinumab in 2 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled UnoReady pen 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 93 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/010 Pack containing 1 pre-filled pen 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 300 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 94 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) – pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 300 mg solution for injection in pre-filled pen secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains 300 mg secukinumab in 2 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection Multipack: 3 (3 packs of 1) pre-filled pens 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 95 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled pens in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/011 Multipack containing 3 (3 x 1) pre-filled pens 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 300 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 96 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) – pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT Cosentyx 300 mg solution for injection in pre-filled pen secukinumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains 300 mg secukinumab in 2 ml of solution. 3. LIST OF EXCIPIENTS Also contains: Trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled pen. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Subcutaneous use Single use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 97 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the pre-filled pen in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/980/011 Multipack containing 3 (3 x 1) pre-filled pens 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Cosentyx 300 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 98 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PEN LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Cosentyx 300 mg injection secukinumab SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER UnoReady pen 99 B. PACKAGE LEAFLET 100 Package leaflet: Information for the patient Cosentyx 150 mg powder for solution for injection secukinumab Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Cosentyx is and what it is used for 2. What you need to know before you use Cosentyx 3. How to use Cosentyx 4. Possible side effects 5. How to store Cosentyx 6. Contents of the pack and other information 1. What Cosentyx is and what it is used for Cosentyx contains the active substance secukinumab. Secukinumab is a monoclonal antibody which belongs to a group of medicines called interleukin (IL) inhibitors. This medicine works by neutralising the activity of a protein called IL-17A, which is present at increased levels in diseases such as psoriasis, psoriatic arthritis and axial spondyloarthritis. Cosentyx is used for the treatment of the following inflammatory diseases:  Plaque psoriasis  Psoriatic arthritis  Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Plaque psoriasis Cosentyx is used to treat a skin condition called “plaque psoriasis”, which causes inflammation affecting the skin. Cosentyx reduces the inflammation and other symptoms of the disease. Cosentyx is used in adults, adolescents and children (6 years of age and older) with moderate to severe plaque psoriasis. Using Cosentyx in plaque psoriasis will benefit you by leading to improvements of skin clearance and reducing your symptoms such as scaling, itching and pain. Psoriatic arthritis Cosentyx is used to treat a condition called “psoriatic arthritis”. The condition is an inflammatory disease of the joints, often accompanied by psoriasis. If you have active psoriatic arthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of active psoriatic arthritis, improve physical function and slow down the damage to the cartilage and bone of the joints involved in the disease. Cosentyx is used in adults with active psoriatic arthritis and can be used alone or with another medicine called methotrexate. 101 Using Cosentyx in psoriatic arthritis will benefit you by reducing the signs and symptoms of the disease, slowing down the damage to the cartilage and bone of the joints and improving your ability to do normal daily activities. Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Cosentyx is used to treat conditions called “ankylosing spondylitis” and “non-radiographic axial spondyloarthritis”. These conditions are inflammatory diseases primarily affecting the spine which cause inflammation of the spinal joints. If you have ankylosing spondylitis or non-radiographic axial spondyloarthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of the disease, reduce inflammation and improve your physical function. Cosentyx is used in adults with active ankylosing spondylitis and active non-radiographic axial spondyloarthritis. Using Cosentyx in ankylosing spondylitis and non-radiographic axial spondyloarthritis will benefit you by reducing the signs and symptoms of your disease and improving your physical function. 2. What you need to know before you use Cosentyx Do not use Cosentyx:  if you are allergic to secukinumab or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice before using Cosentyx.  if you have an active infection which your doctor thinks is important. Warnings and precautions Talk to your doctor, nurse or pharmacist before using Cosentyx:  if you currently have an infection  if you have long-term or repeated infections.  if you have tuberculosis.  if you have an inflammatory disease affecting your gut called Crohn’s disease.  if you have an inflammation of your large intestine called ulcerative colitis.  if you have recently had a vaccination or if you are due to have a vaccination during treatment with Cosentyx.  if you are receiving any other treatment for psoriasis, such as another immunosuppressant or phototherapy with ultraviolet (UV) light. Inflammatory bowel disease (Crohn’s disease or ulcerative colitis) Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice abdominal cramps and pain, diarrhoea, weight loss, blood in the stool or any other signs of bowel problems. Look out for infections and allergic reactions Cosentyx can potentially cause serious side effects, including infections and allergic reactions. You must look out for signs of these conditions while you are taking Cosentyx. Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice any signs indicating a possible serious infection or an allergic reaction. Such signs are listed under “Serious side effects” in section 4. 102 Children and adolescents Cosentyx is not recommended for children younger than 6 years of age with plaque psoriasis because it has not been studied in this age group. Cosentyx is not recommended for children and adolescents (under 18 years of age) in other indications because it has not been studied in this age group. Other medicines and Cosentyx Tell your doctor or pharmacist:  if you are taking, have recently taken or might take any other medicines.  if you have recently had or are due to have a vaccination. You should not be given certain types of vaccines (live vaccines) while using Cosentyx. Pregnancy, breast-feeding and fertility  It is preferable to avoid the use of Cosentyx in pregnancy. The effects of this medicine in pregnant women are not known. If you are a woman of childbearing potential, you are advised to avoid becoming pregnant and must use adequate contraception while using Cosentyx and for at least 20 weeks after the last Cosentyx dose. Talk to your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.  Talk to your doctor if you are breast-feeding or are planning to breast-feed. You and your doctor should decide if you will breast-feed or use Cosentyx. You should not do both. After using Cosentyx you should not breast-feed for at least 20 weeks after the last dose. Driving and using machines Cosentyx is unlikely to influence your ability to drive and use machines. 3. How to use Cosentyx Cosentyx is given via injection under your skin (known as a subcutaneous injection) by a healthcare professional. Make sure you discuss with your doctor when you will have your injections and your follow-up appointments. How much Cosentyx is given and for how long Your doctor will decide how much Cosentyx you need and for how long. Plaque psoriasis Adult  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as two injections of 150 mg. 103 Children aged 6 years and older  The recommended dose given by subcutaneous injection is based on body weight as follows: o Weight below 25 kg: 75 mg using the powder for solution for injection. o Weight 25 kg or above and below 50 kg: 75 mg using the powder for solution for injection. o Weight 50 kg or above: 150 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen. Your doctor may increase the dose to 300 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen.  Each 75 mg dose is given as one injection of 75 mg. Each 150 mg dose is given as one injection of 150 mg. Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Psoriatic arthritis For psoriatic arthritis patients who also have moderate to severe plaque psoriasis or patients who did not respond well to medicines called tumour necrosis factor (TNF) blockers:  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as two injections of 150 mg. For other psoriatic arthritis patients:  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Ankylosing spondylitis (Radiographic axial spondyloarthritis)  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Each 300 mg dose is given as two injections of 150 mg. Non-radiographic axial spondyloarthritis  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Cosentyx is for long-term treatment. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect. 104 If you use more Cosentyx than you should If you have received more Cosentyx than you should or the dose has been administered sooner than according to your doctor’s prescription, inform your doctor. If you forget to use Cosentyx If you have missed a Cosentyx injection, talk to your doctor. If you stop using Cosentyx It is not dangerous to stop using Cosentyx. However, if you stop, your psoriasis, psoriatic arthritis or axial spondyloarthritis symptoms may come back. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects Stop using Cosentyx and tell your doctor or seek medical help immediately if you get any of the following side effects: Possible serious infection - the signs may include:  fever, flu-like symptoms, night sweats  feeling tired or short of breath, cough which will not go away  warm, red and painful skin, or a painful skin rash with blisters  burning sensation when passing urine. Serious allergic reaction - the signs may include:  difficulty breathing or swallowing  low blood pressure, which can cause dizziness or light-headedness  swelling of the face, lips, tongue or throat  severe itching of the skin, with a red rash or raised bumps. Your doctor will decide if and when you may restart the treatment. Other side effects Most of the following side effects are mild to moderate. If any of these side effects becomes severe, tell your doctor, pharmacist or nurse. Very common (may affect more than 1 in 10 people):  upper respiratory tract infections with symptoms such as sore throat and stuffy nose (nasopharyngitis, rhinitis) Common (may affect up to 1 in 10 people):  cold sores (oral herpes)  diarrhoea  runny nose (rhinorrhoea)  athlete’s foot (tinea pedis)  headache  nausea  fatigue 105 Uncommon (may affect up to 1 in 100 people):  oral thrush (oral candidiasis)  signs of low levels of white blood cells, such as fever, sore throat or mouth ulcers due to infections (neutropenia)  infection of the external ear (otitis externa)  discharge from the eye with itching, redness and swelling (conjunctivitis)  itchy rash (urticaria)  lower respiratory tract infections  abdominal cramps and pain, diarrhoea, weight loss or blood in the stool (signs of bowel problems) Rare (may affect up to 1 in 1,000 people):  severe allergic reaction with shock (anaphylactic reaction)  redness and shedding of skin over a larger area of the body, which may be itchy or painful (exfoliative dermatitis) Not known (frequency cannot be estimated from the available data):  fungal infections of the skin and mucous membranes (including oesophageal candidiasis) Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Cosentyx Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the outer box or vial after “EXP”. Before reconstitution: Store the vial in the refrigerator between 2°C and 8°C. After reconstitution: The solution can be used immediately or can be stored at 2°C to 8°C for up to 24 hours. Do not freeze. The solution should be administered within one hour after removal from 2°C to 8°C storage. Do not use this medicine if you notice that the powder has not fully dissolved or if the liquid contains easily visible particles, is cloudy or is distinctly brown. This medicine is for single use only. Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 106 6. Contents of the pack and other information What Cosentyx contains - The active substance is secukinumab. Each vial of powder for solution for injection contains 150 mg secukinumab. After reconstitution, 1 ml of solution contains 150 mg secukinumab. - The other ingredients are sucrose, histidine, histidine hydrochloride monohydrate and polysorbate 80. What Cosentyx looks like and contents of the pack Cosentyx powder for solution for injection is a white solid powder in a glass vial. Cosentyx is supplied in a pack containing one vial. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 90429 Nuremberg Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 107 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu http://www.ema.europa.eu/ 108 Instructions for use of Cosentyx powder for solution for injection The following information is intended for medical or healthcare professionals only. The preparation of the solution for subcutaneous injection must be done without interruption and ensuring that aseptic technique is used. The preparation time from piercing the stopper until end of reconstitution takes 20 minutes on average and should not exceed 90 minutes. To prepare Cosentyx 150 mg powder for solution for injection, please adhere to the following instructions: Instructions for reconstitution of Cosentyx 150 mg powder for solution for injection: 1. Bring the vial of powder to room temperature and ensure that the sterile water for injections is at room temperature. 2. Withdraw slightly more than 1.0 ml sterile water for injections into a 1 ml graduated disposable syringe and adjust to 1.0 ml. 3. Remove the plastic cap from the vial. 4. Insert the syringe needle into the vial containing the powder through the centre of the rubber stopper and reconstitute the powder by slowly injecting 1.0 ml of sterile water for injections into the vial. The stream of sterile water for injections should be directed onto the powder. 5. Tilt the vial to an angle of approx. 45° and gently rotate between the fingertips for approx. 1 minute. Do not shake or invert the vial. 6. Keep the vial standing at room temperature for a minimum of 10 minutes to allow for dissolution. Note that foaming of the solution may occur. 7. Tilt the vial to an angle of approx. 45° and gently rotate between the fingertips for approx. 1 minute. Do not shake or invert the vial. 8. Allow the vial to stand undisturbed at room temperature for approximately 5 minutes. The resulting solution should be clear. Its colour may vary from colourless to slightly yellow. Do not use if the lyophilised powder has not fully dissolved or if the liquid contains easily visible particles, is cloudy or is distinctly brown. 109 9. Prepare the required number of vials (1 vial for the 75 mg dose, 1 vial for the 150 mg dose, 2 vials for the 300 mg dose). After storage at 2°C to 8°C, the solution should be allowed to come to room temperature for approximately 20 minutes before administration. Instructions for administration of Cosentyx solution 1. Tilt the vial to an angle of approximately 45° and position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. DO NOT invert the vial. 2. For the 150 mg and 300 mg doses, carefully withdraw slightly more than 1.0 ml of the solution for subcutaneous injection from the vial into a 1 ml graduated disposable syringe using a suitable needle (e.g. 21G x 2″). This needle will only be used for withdrawing Cosentyx into the disposable syringe. Prepare the required number of syringes (2 syringes for the 300 mg dose). For a child receiving the 75 mg dose, carefully withdraw slightly more than 0.5 ml of the solution for subcutaneous injection and discard the rest immediately. 3. With the needle pointing upward, gently tap the syringe to move any air bubbles to the top. 4. Replace the attached needle with a 27G x ½″ needle. 5. Expel the air bubbles and advance the plunger to the 1.0 ml mark for the 150 mg dose. Expel the air bubbles and advance the plunger to the 0.5 ml mark for the 75 mg dose. 6. Clean the injection site with an alcohol swab. 110 7. Inject the Cosentyx solution subcutaneously into the front of thighs, lower abdomen (but not the area 5 centimetres around the navel) or outer upper arms. Choose a different site each time an injection is administered. Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid areas with scars or stretch marks. 8. Any remaining solution in the vial must not be used and should be discarded in accordance with local requirements. Vials are for single use only. Dispose of the used syringe in a sharps container (closable, puncture-resistant container). For the safety and health of you and others, needles and used syringes must never be re-used. 111 Package leaflet: Information for the patient Cosentyx 150 mg solution for injection in pre-filled syringe secukinumab Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Cosentyx is and what it is used for 2. What you need to know before you use Cosentyx 3. How to use Cosentyx 4. Possible side effects 5. How to store Cosentyx 6. Contents of the pack and other information 1. What Cosentyx is and what it is used for Cosentyx contains the active substance secukinumab. Secukinumab is a monoclonal antibody which belongs to a group of medicines called interleukin (IL) inhibitors. This medicine works by neutralising the activity of a protein called IL-17A, which is present at increased levels in diseases such as psoriasis, psoriatic arthritis and axial spondyloarthritis. Cosentyx is used for the treatment of the following inflammatory diseases:  Plaque psoriasis  Psoriatic arthritis  Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Plaque psoriasis Cosentyx is used to treat a skin condition called “plaque psoriasis”, which causes inflammation affecting the skin. Cosentyx reduces the inflammation and other symptoms of the disease. Cosentyx is used in adults, adolescents and children (6 years of age and older) with moderate to severe plaque psoriasis. Using Cosentyx in plaque psoriasis will benefit you by leading to improvements of skin clearance and reducing your symptoms such as scaling, itching and pain. Psoriatic arthritis Cosentyx is used to treat a condition called “psoriatic arthritis”. The condition is an inflammatory disease of the joints, often accompanied by psoriasis. If you have active psoriatic arthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of active psoriatic arthritis, improve physical function and slow down the damage to the cartilage and bone of the joints involved in the disease. Cosentyx is used in adults with active psoriatic arthritis and can be used alone or with another medicine called methotrexate. 112 Using Cosentyx in psoriatic arthritis will benefit you by reducing the signs and symptoms of the disease, slowing down the damage to the cartilage and bone of the joints and improving your ability to do normal daily activities. Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Cosentyx is used to treat conditions called “ankylosing spondylitis” and “non-radiographic axial spondyloarthritis”. These conditions are inflammatory diseases primarily affecting the spine which cause inflammation of the spinal joints. If you have ankylosing spondylitis or non-radiographic axial spondyloarthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of the disease, reduce inflammation and improve your physical function. Cosentyx is used in adults with active ankylosing spondylitis and active non-radiographic axial spondyloarthritis. Using Cosentyx in ankylosing spondylitis and non-radiographic axial spondyloarthritis will benefit you by reducing the signs and symptoms of your disease and improving your physical function. 2. What you need to know before you use Cosentyx Do not use Cosentyx:  if you are allergic to secukinumab or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice before using Cosentyx.  if you have an active infection which your doctor thinks is important. Warnings and precautions Talk to your doctor, nurse or pharmacist before using Cosentyx:  if you currently have an infection  if you have long-term or repeated infections.  if you have tuberculosis.  if you have ever had an allergic reaction to latex.  if you have an inflammatory disease affecting your gut called Crohn’s disease.  if you have an inflammation of your large intestine called ulcerative colitis.  if you have recently had a vaccination or if you are due to have a vaccination during treatment with Cosentyx.  if you are receiving any other treatment for psoriasis, such as another immunosuppressant or phototherapy with ultraviolet (UV) light. Inflammatory bowel disease (Crohn’s disease or ulcerative colitis) Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice abdominal cramps and pain, diarrhoea, weight loss, blood in the stool or any other signs of bowel problems. Look out for infections and allergic reactions Cosentyx can potentially cause serious side effects, including infections and allergic reactions. You must look out for signs of these conditions while you are taking Cosentyx. Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice any signs indicating a possible serious infection or an allergic reaction. Such signs are listed under “Serious side effects” in section 4. 113 Children and adolescents Cosentyx is not recommended for children younger than 6 years of age with plaque psoriasis because it has not been studied in this age group. Cosentyx is not recommended for children and adolescents (under 18 years of age) in other indications because it has not been studied in this age group. Other medicines and Cosentyx Tell your doctor or pharmacist:  if you are taking, have recently taken or might take any other medicines.  if you have recently had or are due to have a vaccination. You should not be given certain types of vaccines (live vaccines) while using Cosentyx. Pregnancy, breast-feeding and fertility  It is preferable to avoid the use of Cosentyx in pregnancy. The effects of this medicine in pregnant women are not known. If you are a woman of childbearing potential, you are advised to avoid becoming pregnant and must use adequate contraception while using Cosentyx and for at least 20 weeks after the last Cosentyx dose. Talk to your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.  Talk to your doctor if you are breast-feeding or are planning to breast-feed. You and your doctor should decide if you will breast-feed or use Cosentyx. You should not do both. After using Cosentyx you should not breast-feed for at least 20 weeks after the last dose. Driving and using machines Cosentyx is unlikely to influence your ability to drive and use machines. 3. How to use Cosentyx Always use this medicine exactly as your doctor has told you. Check with your doctor, nurse or pharmacist if you are not sure. Cosentyx is given via injection under your skin (known as a subcutaneous injection). You and your doctor should decide if you should inject Cosentyx yourself. It is important not to try to inject yourself until you have been trained by your doctor, nurse or pharmacist. A caregiver may also give you your Cosentyx injection after proper training. For detailed instructions on how to inject Cosentyx, see “Instructions for use of Cosentyx 150 mg pre-filled syringe” at the end of this leaflet. How much Cosentyx is given and for how long Your doctor will decide how much Cosentyx you need and for how long. Plaque psoriasis Adult  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as two injections of 150 mg. 114 Children aged 6 years and older  The recommended dose given by subcutaneous injection is based on body weight as follows: o Weight below 25 kg: 75 mg using the powder for solution for injection. o Weight 25 kg or above and below 50 kg: 75 mg using the powder for solution for injection. o Weight 50 kg or above: 150 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen. Your doctor may increase the dose to 300 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen.  Each 75 mg dose is given as one injection of 75 mg. Each 150 mg dose is given as one injection of 150 mg. Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Psoriatic arthritis For psoriatic arthritis patients who also have moderate to severe plaque psoriasis or patients who did not respond well to medicines called tumour necrosis factor (TNF) blockers:  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as two injections of 150 mg. For other psoriatic arthritis patients:  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Ankylosing spondylitis (Radiographic axial spondyloarthritis)  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Each 300 mg dose is given as two injections of 150 mg. Non-radiographic axial spondyloarthritis  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Cosentyx is for long-term treatment. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect. 115 If you use more Cosentyx than you should If you have received more Cosentyx than you should or the dose has been administered sooner than according to your doctor’s prescription, inform your doctor. If you forget to use Cosentyx If you have forgotten to inject a dose of Cosentyx, inject the next dose as soon as you remember. Then talk to your doctor to discuss when you should inject the next dose. If you stop using Cosentyx It is not dangerous to stop using Cosentyx. However, if you stop, your psoriasis, psoriatic arthritis or axial spondyloarthritis symptoms may come back. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects Stop using Cosentyx and tell your doctor or seek medical help immediately if you get any of the following side effects: Possible serious infection - the signs may include:  fever, flu-like symptoms, night sweats  feeling tired or short of breath, cough which will not go away  warm, red and painful skin, or a painful skin rash with blisters  burning sensation when passing urine. Serious allergic reaction - the signs may include:  difficulty breathing or swallowing  low blood pressure, which can cause dizziness or light-headedness  swelling of the face, lips, tongue or throat  severe itching of the skin, with a red rash or raised bumps. Your doctor will decide if and when you may restart the treatment. Other side effects Most of the following side effects are mild to moderate. If any of these side effects becomes severe, tell your doctor, pharmacist or nurse. Very common (may affect more than 1 in 10 people):  upper respiratory tract infections with symptoms such as sore throat and stuffy nose (nasopharyngitis, rhinitis) Common (may affect up to 1 in 10 people):  cold sores (oral herpes)  diarrhoea  runny nose (rhinorrhoea)  athlete’s foot (tinea pedis)  headache  nausea  fatigue 116 Uncommon (may affect up to 1 in 100 people):  oral thrush (oral candidiasis)  signs of low levels of white blood cells, such as fever, sore throat or mouth ulcers due to infections (neutropenia)  infection of the external ear (otitis externa)  discharge from the eye with itching, redness and swelling (conjunctivitis)  itchy rash (urticaria)  lower respiratory tract infections  abdominal cramps and pain, diarrhoea, weight loss or blood in the stool (signs of bowel problems) Rare (may affect up to 1 in 1,000 people):  severe allergic reaction with shock (anaphylactic reaction)  redness and shedding of skin over a larger area of the body, which may be itchy or painful (exfoliative dermatitis) Not known (frequency cannot be estimated from the available data):  fungal infections of the skin and mucous membranes (including oesophageal candidiasis) Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Cosentyx Keep this medicine out of the sight and reach of children. Do not use this medicine:  after the expiry date which is stated on the outer box or the label on the syringe after “EXP”.  if the liquid contains easily visible particles, is cloudy or is distinctly brown. Store the syringe sealed in its box to protect from light. Store in the refrigerator between 2°C and 8°C. Do not freeze. Do not shake. If necessary, Cosentyx can be left out of the refrigerator for a single period of up to 4 days at room temperature, not above 30°C. This medicine is for single use only. Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 117 6. Contents of the pack and other information What Cosentyx contains - The active substance is secukinumab. Each pre-filled syringe contains 150 mg secukinumab. - The other ingredients are trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80 and water for injections. What Cosentyx looks like and contents of the pack Cosentyx solution for injection is a clear liquid. Its colour may vary from colourless to slightly yellow. Cosentyx 150 mg solution for injection in pre-filled syringe is available in unit packs containing 1 or 2 pre-filled syringe(s) and in multipacks containing 6 (3 packs of 2) pre-filled syringes. Not all pack sizes may be marketed. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 90429 Nuremberg Germany Sandoz GmbH Biochemiestrasse 10 6336 Langkampfen Austria For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 118 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu http://www.ema.europa.eu/ 119 Instructions for use of Cosentyx 150 mg pre-filled syringe Read ALL the way through these instructions before injecting. It is important not to try to inject yourself or a person in your care until you have been trained by your doctor, nurse or pharmacist. The box contains Cosentyx 150 mg pre-filled syringe(s) individually sealed in a plastic blister. Your Cosentyx 150 mg pre-filled syringe After the medicine has been injected the syringe guard will be activated to cover the needle. This is intended to aid in the protection of healthcare professionals, patients who self-inject doctor-prescribed medicines, and individuals who assist self-injecting patients from accidental needlestick injuries. What you additionally need for your injection:  Alcohol swab.  Cotton ball or gauze.  Sharps disposal container. Important safety information Caution: Keep the syringe out of the sight and reach of children. 1. The needle cap of the syringe may contain dry rubber (latex), which should not be handled by persons sensitive to this substance. 2. Do not open the sealed outer box until you are ready to use this medicine. 3. Do not use this medicine if either the seal on the outer box or the seal of the blister is broken, as it may not be safe for you to use. 4. Never leave the syringe lying around where others might tamper with it. 5. Do not shake the syringe. 6. Be careful not to touch the syringe guard wings before use. By touching them, the syringe guard may be activated too early. 7. Do not remove the needle cap until just before you give the injection. 8. The syringe cannot be re-used. Dispose of the used syringe immediately after use in a sharps container. Storage of the Cosentyx 150 mg pre-filled syringe 1. Store this medicine sealed in its outer box to protect it from light. Store in the refrigerator between 2°C and 8°C. DO NOT FREEZE. 2. Remember to take the syringe out of the refrigerator and allow it to reach room temperature before preparing it for injection (15-30 minutes). Needle cap Syringe guard Viewing window, label & expiry date Finger grips Syringe guard wings Plunger Plunger head 120 3. Do not use the syringe after the expiry date which is stated on the outer box or syringe label after “EXP”. If it has expired, return the entire pack to the pharmacy. The injection site The injection site is the place on the body where you are going to use the syringe.  The recommended site is the front of your thighs. You may also use the lower abdomen, but not the area 5 centimetres around the navel (belly button).  Choose a different site each time you give yourself an injection.  Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid areas with scars or stretch marks. If a caregiver is giving you the injection, the outer upper arms may also be used. Preparing the Cosentyx 150 mg pre-filled syringe ready for use Note: For a 150 mg dose, prepare 1 pre-filled syringe and inject the content. For a 300 mg dose, prepare 2 pre-filled syringes and inject the contents of both. 1. Take the box containing the syringe out of the refrigerator and leave it unopened for about 15-30 minutes so that it reaches room temperature. 2. When you are ready to use the syringe, wash your hands thoroughly with soap and water. 3. Clean the injection site with an alcohol swab. 4. Remove the syringe from the outer box and take it out of the blister by holding the syringe guard body. 5. Inspect the syringe. The liquid should be clear. Its colour may vary from colourless to slightly yellow. You may see a small air bubble, which is normal. DO NOT USE if the liquid contains easily visible particles, is cloudy or is distinctly brown. DO NOT USE if the syringe is broken. In all these cases, return the entire product pack to the pharmacy. How to use the Cosentyx 150 mg pre-filled syringe Carefully remove the needle cap from the syringe by holding the syringe guard body. Discard the needle cap. You may see a drop of liquid at the end of the needle. This is normal. 121 Gently pinch the skin at the injection site and insert the needle as shown. Push the needle all the way in to ensure that the medicine can be fully administered. Hold the syringe as shown. Slowly depress the plunger as far as it will go so that the plunger head is completely between the syringe guard wings. Keep the plunger pressed fully down while you hold the syringe in place for 5 seconds. Keep the plunger fully depressed while you carefully lift the needle straight out from the injection site. Slowly release the plunger and allow the syringe guard to automatically cover the exposed needle. There may be a small amount of blood at the injection site. You can press a cotton ball or gauze over the injection site and hold it for 10 seconds. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if needed. Disposal instructions Dispose of the used syringe in a sharps container (closable, puncture resistant container). For the safety and health of you and others, needles and used syringes must never be re-used. 122 Package leaflet: Information for the patient Cosentyx 150 mg solution for injection in pre-filled pen secukinumab Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Cosentyx is and what it is used for 2. What you need to know before you use Cosentyx 3. How to use Cosentyx 4. Possible side effects 5. How to store Cosentyx 6. Contents of the pack and other information 1. What Cosentyx is and what it is used for Cosentyx contains the active substance secukinumab. Secukinumab is a monoclonal antibody which belongs to a group of medicines called interleukin (IL) inhibitors. This medicine works by neutralising the activity of a protein called IL-17A, which is present at increased levels in diseases such as psoriasis, psoriatic arthritis and axial spondyloarthritis. Cosentyx is used for the treatment of the following inflammatory diseases:  Plaque psoriasis  Psoriatic arthritis  Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Plaque psoriasis Cosentyx is used to treat a skin condition called “plaque psoriasis”, which causes inflammation affecting the skin. Cosentyx reduces the inflammation and other symptoms of the disease. Cosentyx is used in adults, adolescents and children (6 years of age and older) with moderate to severe plaque psoriasis. Using Cosentyx in plaque psoriasis will benefit you by leading to improvements of skin clearance and reducing your symptoms such as scaling, itching and pain. Psoriatic arthritis Cosentyx is used to treat a condition called “psoriatic arthritis”. The condition is an inflammatory disease of the joints, often accompanied by psoriasis. If you have active psoriatic arthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of active psoriatic arthritis, improve physical function and slow down the damage to the cartilage and bone of the joints involved in the disease. Cosentyx is used in adults with active psoriatic arthritis and can be used alone or with another medicine called methotrexate. 123 Using Cosentyx in psoriatic arthritis will benefit you by reducing the signs and symptoms of the disease, slowing down the damage to the cartilage and bone of the joints and improving your ability to do normal daily activities. Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Cosentyx is used to treat conditions called “ankylosing spondylitis” and “non-radiographic axial spondyloarthritis”. These conditions are inflammatory diseases primarily affecting the spine which cause inflammation of the spinal joints. If you have ankylosing spondylitis or non-radiographic axial spondyloarthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of the disease, reduce inflammation and improve your physical function. Cosentyx is used in adults with active ankylosing spondylitis and active non-radiographic axial spondyloarthritis. Using Cosentyx in ankylosing spondylitis and non-radiographic axial spondyloarthritis will benefit you by reducing the signs and symptoms of your disease and improving your physical function. 2. What you need to know before you use Cosentyx Do not use Cosentyx:  if you are allergic to secukinumab or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice before using Cosentyx.  if you have an active infection which your doctor thinks is important. Warnings and precautions Talk to your doctor, nurse or pharmacist before using Cosentyx:  if you currently have an infection  if you have long-term or repeated infections.  if you have tuberculosis.  if you have ever had an allergic reaction to latex.  if you have an inflammatory disease affecting your gut called Crohn’s disease.  if you have an inflammation of your large intestine called ulcerative colitis.  if you have recently had a vaccination or if you are due to have a vaccination during treatment with Cosentyx.  if you are receiving any other treatment for psoriasis, such as another immunosuppressant or phototherapy with ultraviolet (UV) light. Inflammatory bowel disease (Crohn’s disease or ulcerative colitis) Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice abdominal cramps and pain, diarrhoea, weight loss, blood in the stool or any other signs of bowel problems. Look out for infections and allergic reactions Cosentyx can potentially cause serious side effects, including infections and allergic reactions. You must look out for signs of these conditions while you are taking Cosentyx. Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice any signs indicating a possible serious infection or an allergic reaction. Such signs are listed under “Serious side effects” in section 4. 124 Children and adolescents Cosentyx is not recommended for children younger than 6 years of age with plaque psoriasis because it has not been studied in this age group. Cosentyx is not recommended for children and adolescents (under 18 years of age) in other indications because it has not been studied in this age group. Other medicines and Cosentyx Tell your doctor or pharmacist:  if you are taking, have recently taken or might take any other medicines.  if you have recently had or are due to have a vaccination. You should not be given certain types of vaccines (live vaccines) while using Cosentyx. Pregnancy, breast-feeding and fertility  It is preferable to avoid the use of Cosentyx in pregnancy. The effects of this medicine in pregnant women are not known. If you are a woman of childbearing potential, you are advised to avoid becoming pregnant and must use adequate contraception while using Cosentyx and for at least 20 weeks after the last Cosentyx dose. Talk to your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.  Talk to your doctor if you are breast-feeding or are planning to breast-feed. You and your doctor should decide if you will breast-feed or use Cosentyx. You should not do both. After using Cosentyx you should not breast-feed for at least 20 weeks after the last dose. Driving and using machines Cosentyx is unlikely to influence your ability to drive and use machines. 3. How to use Cosentyx Always use this medicine exactly as your doctor has told you. Check with your doctor, nurse or pharmacist if you are not sure. Cosentyx is given via injection under your skin (known as a subcutaneous injection). You and your doctor should decide if you should inject Cosentyx yourself. It is important not to try to inject yourself until you have been trained by your doctor, nurse or pharmacist. A caregiver may also give you your Cosentyx injection after proper training. For detailed instructions on how to inject Cosentyx, see “Instructions for use of the Cosentyx SensoReady pen 150 mg” at the end of this leaflet. How much Cosentyx is given and for how long Your doctor will decide how much Cosentyx you need and for how long. Plaque psoriasis Adult  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as two injections of 150 mg. 125 Children aged 6 years and older  The recommended dose given by subcutaneous injection is based on body weight as follows: o Weight below 25 kg: 75 mg using the powder for solution for injection. o Weight 25 kg or above and below 50 kg: 75 mg using the powder for solution for injection. o Weight 50 kg or above: 150 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen. Your doctor may increase the dose to 300 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen.  Each 75 mg dose is given as one injection of 75 mg. Each 150 mg dose is given as one injection of 150 mg. Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Psoriatic arthritis For psoriatic arthritis patients who also have moderate to severe plaque psoriasis or patients who did not respond well to medicines called tumour necrosis factor (TNF) blockers:  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as two injections of 150 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as two injections of 150 mg. For other psoriatic arthritis patients:  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Ankylosing spondylitis (Radiographic axial spondyloarthritis)  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Each 300 mg dose is given as two injections of 150 mg. Non-radiographic axial spondyloarthritis  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Cosentyx is for long-term treatment. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect. 126 If you use more Cosentyx than you should If you have received more Cosentyx than you should or the dose has been administered sooner than according to your doctor’s prescription, inform your doctor. If you forget to use Cosentyx If you have forgotten to inject a dose of Cosentyx, inject the next dose as soon as you remember. Then talk to your doctor to discuss when you should inject the next dose. If you stop using Cosentyx It is not dangerous to stop using Cosentyx. However, if you stop, your psoriasis, psoriatic arthritis or axial spondyloarthritis symptoms may come back. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects Stop using Cosentyx and tell your doctor or seek medical help immediately if you get any of the following side effects: Possible serious infection - the signs may include:  fever, flu-like symptoms, night sweats  feeling tired or short of breath, cough which will not go away  warm, red and painful skin, or a painful skin rash with blisters  burning sensation when passing urine. Serious allergic reaction - the signs may include:  difficulty breathing or swallowing  low blood pressure, which can cause dizziness or light-headedness  swelling of the face, lips, tongue or throat  severe itching of the skin, with a red rash or raised bumps. Your doctor will decide if and when you may restart the treatment. Other side effects Most of the following side effects are mild to moderate. If any of these side effects becomes severe, tell your doctor, pharmacist or nurse. Very common (may affect more than 1 in 10 people):  upper respiratory tract infections with symptoms such as sore throat and stuffy nose (nasopharyngitis, rhinitis) Common (may affect up to 1 in 10 people):  cold sores (oral herpes)  diarrhoea  runny nose (rhinorrhoea)  athlete’s foot (tinea pedis)  headache  nausea  fatigue 127 Uncommon (may affect up to 1 in 100 people):  oral thrush (oral candidiasis)  signs of low levels of white blood cells, such as fever, sore throat or mouth ulcers due to infections (neutropenia)  infection of the external ear (otitis externa)  discharge from the eye with itching, redness and swelling (conjunctivitis)  itchy rash (urticaria)  lower respiratory tract infections  abdominal cramps and pain, diarrhoea, weight loss or blood in the stool (signs of bowel problems) Rare (may affect up to 1 in 1,000 people):  severe allergic reaction with shock (anaphylactic reaction)  redness and shedding of skin over a larger area of the body, which may be itchy or painful (exfoliative dermatitis) Not known (frequency cannot be estimated from the available data):  fungal infections of the skin and mucous membranes (including oesophageal candidiasis) Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Cosentyx Keep this medicine out of the sight and reach of children. Do not use this medicine:  after the expiry date which is stated on the outer box or the label on the pen after “EXP”.  if the liquid contains easily visible particles, is cloudy or is distinctly brown. Store the pen sealed in its box to protect from light. Store in the refrigerator between 2°C and 8°C. Do not freeze. Do not shake. If necessary, Cosentyx can be left out of the refrigerator for a single period of up to 4 days at room temperature, not above 30°C. This medicine is for single use only. Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 128 6. Contents of the pack and other information What Cosentyx contains - The active substance is secukinumab. Each pre-filled pen contains 150 mg secukinumab. - The other ingredients are trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80 and water for injections. What Cosentyx looks like and contents of the pack Cosentyx solution for injection is a clear liquid. Its colour may vary from colourless to slightly yellow. Cosentyx 150 mg solution for injection in pre-filled pen is available in unit packs containing 1 or 2 pre-filled pen(s) and in multipacks containing 6 (3 packs of 2) pre-filled pens. Not all pack sizes may be marketed. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 90429 Nuremberg Germany Sandoz GmbH Biochemiestrasse 10 6336 Langkampfen Austria For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 129 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu http://www.ema.europa.eu/ 130 Instructions for use of the Cosentyx SensoReady pen 150 mg Cosentyx SensoReady pen 150 mg Solution for injection in a pre-filled pen Secukinumab Patient Instructions for Use Read ALL the way through these instructions before injecting. These instructions are to help you to inject correctly using the Cosentyx SensoReady pen. It is important not to try to inject yourself or the person in your care until you have been trained by your doctor, nurse or pharmacist. Your Cosentyx SensoReady pen 150 mg: Cosentyx SensoReady pen 150 mg shown with the cap removed. Do not remove the cap until you are ready to inject. Store your boxed pen in a refrigerator between 2°C and 8°C and out of the reach of children.  Do not freeze the pen.  Do not shake the pen.  Do not use the pen if it has been dropped with the cap removed. For a more comfortable injection, take the pen out of the refrigerator 15-30 minutes before injecting to allow it to reach room temperature. What you need for your injection: Included in the carton: A new and unused Cosentyx SensoReady pen 150 mg (1 pen is needed for a 150 mg dose and 2 pens are needed for a 300 mg dose). Not included in the carton:  Alcohol swab.  Cotton ball or gauze.  Sharps disposal container. Needle Needle guard Cap Inspection window Internal needle cover 131 Before your injection: 1. Important safety checks before you inject: The liquid should be clear. Its colour may vary from colourless to slightly yellow. Do not use if the liquid contains easily visible particles, is cloudy or is distinctly brown. You may see a small air bubble, which is normal. Do not use the pen if the expiry date has passed. Do not use if the safety seal has been broken. Contact your pharmacist if the pen fails any of these checks. 2a. Choose your injection site:  The recommended site is the front of the thighs. You may also use the lower abdomen, but not the area 5 centimetres around the navel (belly button).  Choose a different site each time you give yourself an injection.  Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid areas with scars or stretch marks. 2b. Caregivers and healthcare professionals only:  If a caregiver or healthcare professional is giving you your injection, they may also inject into your outer upper arm. 3. Cleaning your injection site:  Wash your hands with soap and hot water.  Using a circular motion, clean the injection site with the alcohol swab. Leave it to dry before injecting.  Do not touch the cleaned area again before injecting. 132 Your injection: 4. Removing the cap:  Only remove the cap when you are ready to use the pen.  Twist off the cap in the direction of the arrows.  Once removed, throw away the cap. Do not try to re-attach the cap.  Use the pen within 5 minutes of removing the cap. 5. Holding your pen:  Hold the pen at 90 degrees to the cleaned injection site. Correct Incorrect YOU MUST READ THIS BEFORE INJECTING. During the injection you will hear 2 loud clicks. The 1st click indicates that the injection has started. Several seconds later a 2nd click will indicate that the injection is almost finished. You must keep holding the pen firmly against your skin until you see a green indicator fill the window and stop moving. 6. Starting your injection:  Press the pen firmly against the skin to start the injection.  The 1st click indicates the injection has started.  Keep holding the pen firmly against your skin.  The green indicator shows the progress of the injection. 7. Completing your injection:  Listen for the 2nd click. This indicates the injection is almost complete.  Check the green indicator fills the window and has stopped moving.  The pen can now be removed. 133 After your injection: 8. Check the green indicator fills the window:  This means the medicine has been delivered. Contact your doctor if the green indicator is not visible.  There may be a small amount of blood at the injection site. You can press a cotton ball or gauze over the injection site and hold it for 10 seconds. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if needed. 9. Disposing of your Cosentyx SensoReady pen:  Dispose of the used pen in a sharps disposal container (i.e. a puncture-resistant closable container, or similar).  Never try to reuse your pen. 134 Package leaflet: Information for the patient Cosentyx 300 mg solution for injection in pre-filled syringe secukinumab Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Cosentyx is and what it is used for 2. What you need to know before you use Cosentyx 3. How to use Cosentyx 4. Possible side effects 5. How to store Cosentyx 6. Contents of the pack and other information 1. What Cosentyx is and what it is used for Cosentyx contains the active substance secukinumab. Secukinumab is a monoclonal antibody which belongs to a group of medicines called interleukin (IL) inhibitors. This medicine works by neutralising the activity of a protein called IL-17A, which is present at increased levels in diseases such as psoriasis, psoriatic arthritis and axial spondyloarthritis. Cosentyx is used for the treatment of the following inflammatory diseases:  Plaque psoriasis  Psoriatic arthritis  Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Plaque psoriasis Cosentyx is used to treat a skin condition called “plaque psoriasis”, which causes inflammation affecting the skin. Cosentyx reduces the inflammation and other symptoms of the disease. Cosentyx is used in adults, adolescents and children (6 years of age and older) with moderate to severe plaque psoriasis. Using Cosentyx in plaque psoriasis will benefit you by leading to improvements of skin clearance and reducing your symptoms such as scaling, itching and pain. Psoriatic arthritis Cosentyx is used to treat a condition called “psoriatic arthritis”. The condition is an inflammatory disease of the joints, often accompanied by psoriasis. If you have active psoriatic arthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of active psoriatic arthritis, improve physical function and slow down the damage to the cartilage and bone of the joints involved in the disease. Cosentyx is used in adults with active psoriatic arthritis and can be used alone or with another medicine called methotrexate. 135 Using Cosentyx in psoriatic arthritis will benefit you by reducing the signs and symptoms of the disease, slowing down the damage to the cartilage and bone of the joints and improving your ability to do normal daily activities. Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Cosentyx is used to treat conditions called “ankylosing spondylitis” and “non-radiographic axial spondyloarthritis”. These conditions are inflammatory diseases primarily affecting the spine which cause inflammation of the spinal joints. If you have ankylosing spondylitis or non-radiographic axial spondyloarthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of the disease, reduce inflammation and improve your physical function. Cosentyx is used in adults with active ankylosing spondylitis and active non-radiographic axial spondyloarthritis. Using Cosentyx in ankylosing spondylitis and non-radiographic axial spondyloarthritis will benefit you by reducing the signs and symptoms of your disease and improving your physical function. 2. What you need to know before you use Cosentyx Do not use Cosentyx:  if you are allergic to secukinumab or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice before using Cosentyx.  if you have an active infection which your doctor thinks is important. Warnings and precautions Talk to your doctor, nurse or pharmacist before using Cosentyx:  if you currently have an infection  if you have long-term or repeated infections.  if you have tuberculosis.  if you have an inflammatory disease affecting your gut called Crohn’s disease.  if you have an inflammation of your large intestine called ulcerative colitis.  if you have recently had a vaccination or if you are due to have a vaccination during treatment with Cosentyx.  if you are receiving any other treatment for psoriasis, such as another immunosuppressant or phototherapy with ultraviolet (UV) light. Inflammatory bowel disease (Crohn’s disease or ulcerative colitis) Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice abdominal cramps and pain, diarrhoea, weight loss, blood in the stool or any other signs of bowel problems. Look out for infections and allergic reactions Cosentyx can potentially cause serious side effects, including infections and allergic reactions. You must look out for signs of these conditions while you are taking Cosentyx. Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice any signs indicating a possible serious infection or an allergic reaction. Such signs are listed under “Serious side effects” in section 4. 136 Children and adolescents Cosentyx is not recommended for children younger than 6 years of age with plaque psoriasis because it has not been studied in this age group. Cosentyx is not recommended for children and adolescents (under 18 years of age) in other indications because it has not been studied in this age group. Other medicines and Cosentyx Tell your doctor or pharmacist:  if you are taking, have recently taken or might take any other medicines.  if you have recently had or are due to have a vaccination. You should not be given certain types of vaccines (live vaccines) while using Cosentyx. Pregnancy, breast-feeding and fertility  It is preferable to avoid the use of Cosentyx in pregnancy. The effects of this medicine in pregnant women are not known. If you are a woman of childbearing potential, you are advised to avoid becoming pregnant and must use adequate contraception while using Cosentyx and for at least 20 weeks after the last Cosentyx dose. Talk to your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.  Talk to your doctor if you are breast-feeding or are planning to breast-feed. You and your doctor should decide if you will breast-feed or use Cosentyx. You should not do both. After using Cosentyx you should not breast-feed for at least 20 weeks after the last dose. Driving and using machines Cosentyx is unlikely to influence your ability to drive and use machines. 3. How to use Cosentyx Always use this medicine exactly as your doctor has told you. Check with your doctor, nurse or pharmacist if you are not sure. Cosentyx is given via injection under your skin (known as a subcutaneous injection). You and your doctor should decide if you should inject Cosentyx yourself. It is important not to try to inject yourself until you have been trained by your doctor, nurse or pharmacist. A caregiver may also give you your Cosentyx injection after proper training. For detailed instructions on how to inject Cosentyx, see “Instructions for use of Cosentyx 300 mg pre-filled syringe” at the end of this leaflet. How much Cosentyx is given and for how long Your doctor will decide how much Cosentyx you need and for how long. Plaque psoriasis Adult  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as one injection of 300 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as one injection of 300 mg. 137 Children aged 6 years and older  The recommended dose given by subcutaneous injection is based on body weight as follows: o Weight below 25 kg: 75 mg using the powder for solution for injection. o Weight 25 kg or above and below 50 kg: 75 mg using the powder for solution for injection. o Weight 50 kg or above: 150 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen. Your doctor may increase the dose to 300 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen.  Each 75 mg dose is given as one injection of 75 mg. Each 150 mg dose is given as one injection of 150 mg. Each 300 mg dose is given as one injection of 300 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Psoriatic arthritis For psoriatic arthritis patients who also have moderate to severe plaque psoriasis or patients who did not respond well to medicines called tumour necrosis factor (TNF) blockers:  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as one injection of 300 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as one injection of 300 mg. For other psoriatic arthritis patients:  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Ankylosing spondylitis (Radiographic axial spondyloarthritis)  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Each 300 mg dose is given as one injection of 300 mg. Non-radiographic axial spondyloarthritis  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Cosentyx is for long-term treatment. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect. If you use more Cosentyx than you should If you have received more Cosentyx than you should or the dose has been administered sooner than according to your doctor’s prescription, inform your doctor. 138 If you forget to use Cosentyx If you have forgotten to inject a dose of Cosentyx, inject the next dose as soon as you remember. Then talk to your doctor to discuss when you should inject the next dose. If you stop using Cosentyx It is not dangerous to stop using Cosentyx. However, if you stop, your psoriasis, psoriatic arthritis or axial spondyloarthritis symptoms may come back. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects Stop using Cosentyx and tell your doctor or seek medical help immediately if you get any of the following side effects: Possible serious infection - the signs may include:  fever, flu-like symptoms, night sweats  feeling tired or short of breath, cough which will not go away  warm, red and painful skin, or a painful skin rash with blisters  burning sensation when passing urine. Serious allergic reaction - the signs may include:  difficulty breathing or swallowing  low blood pressure, which can cause dizziness or light-headedness  swelling of the face, lips, tongue or throat  severe itching of the skin, with a red rash or raised bumps. Your doctor will decide if and when you may restart the treatment. Other side effects Most of the following side effects are mild to moderate. If any of these side effects becomes severe, tell your doctor, pharmacist or nurse. Very common (may affect more than 1 in 10 people):  upper respiratory tract infections with symptoms such as sore throat and stuffy nose (nasopharyngitis, rhinitis) Common (may affect up to 1 in 10 people):  cold sores (oral herpes)  diarrhoea  runny nose (rhinorrhoea)  athlete’s foot (tinea pedis)  headache  nausea  fatigue 139 Uncommon (may affect up to 1 in 100 people):  oral thrush (oral candidiasis)  signs of low levels of white blood cells, such as fever, sore throat or mouth ulcers due to infections (neutropenia)  infection of the external ear (otitis externa)  discharge from the eye with itching, redness and swelling (conjunctivitis)  itchy rash (urticaria)  lower respiratory tract infections  abdominal cramps and pain, diarrhoea, weight loss or blood in the stool (signs of bowel problems) Rare (may affect up to 1 in 1,000 people):  severe allergic reaction with shock (anaphylactic reaction)  redness and shedding of skin over a larger area of the body, which may be itchy or painful (exfoliative dermatitis) Not known (frequency cannot be estimated from the available data):  fungal infections of the skin and mucous membranes (including oesophageal candidiasis) Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Cosentyx Keep this medicine out of the sight and reach of children. Do not use this medicine:  after the expiry date which is stated on the outer box or the label on the syringe after “EXP”.  if the liquid contains easily visible particles, is cloudy or is distinctly brown. Store the syringe sealed in its box to protect from light. Store in the refrigerator between 2°C and 8°C. Do not freeze. Do not shake. If necessary, Cosentyx can be left out of the refrigerator for a single period of up to 4 days at room temperature, not above 30°C. This medicine is for single use only. Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 140 6. Contents of the pack and other information What Cosentyx contains - The active substance is secukinumab. Each pre-filled syringe contains 300 mg secukinumab. - The other ingredients are trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80 and water for injections. What Cosentyx looks like and contents of the pack Cosentyx solution for injection is a clear liquid. Its colour may vary from colourless to slightly yellow. Cosentyx 300 mg solution for injection in pre-filled syringe is available in a pack containing 1 pre-filled syringe and in multipacks containing 3 (3 packs of 1) pre-filled syringes. Not all pack sizes may be marketed. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 90429 Nuremberg Germany Sandoz GmbH Biochemiestrasse 10 6336 Langkampfen Austria For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 141 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu http://www.ema.europa.eu/ 142 Instructions for use of Cosentyx 300 mg pre-filled syringe Read ALL the way through these instructions before injecting. It is important not to try to inject yourself until you have been trained by your doctor, nurse or pharmacist. The box contains the Cosentyx 300 mg pre-filled syringe individually sealed in a plastic blister. Your Cosentyx 300 mg pre-filled syringe After the medicine has been injected the syringe guard will be activated to cover the needle. This is intended to aid in the protection of healthcare professionals, patients who self-inject doctor-prescribed medicines, and individuals who assist self-injecting patients from accidental needlestick injuries. What you additionally need for your injection:  Alcohol swab.  Cotton ball or gauze.  Sharps disposal container. Important safety information Caution: Keep the syringe out of the sight and reach of children. 1. Do not open the sealed outer box until you are ready to use this medicine. 2. Do not use this medicine if either the seal on the outer box or the seal of the blister is broken, as it may not be safe for you to use. 3. Never leave the syringe lying around where others might tamper with it. 4. Do not shake the syringe. 5. Be careful not to touch the syringe guard wings before use. By touching them, the syringe guard may be activated too early. 6. Do not remove the needle cap until just before you give the injection. 7. The syringe cannot be re-used. Dispose of the used syringe immediately after use in a sharps container. Storage of the Cosentyx 300 mg pre-filled syringe 1. Store this medicine sealed in its outer box to protect it from light. Store in the refrigerator between 2°C and 8°C. DO NOT FREEZE. 2. Remember to take the syringe out of the refrigerator and allow it to reach room temperature before preparing it for injection (30-45 minutes). 3. Do not use the syringe after the expiry date which is stated on the outer box or syringe label after “EXP”. If it has expired, return the entire pack to the pharmacy. Needle cap Syringe guard Viewing window label & expiry date Finger grips Syringe guard wings Plunger Plunger head 143 The injection site The injection site is the place on the body where you are going to use the syringe.  The recommended site is the front of your thighs. You may also use the lower abdomen, but not the area 5 centimetres around the navel (belly button).  Choose a different site each time you give yourself an injection.  Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid areas with scars or stretch marks. If a caregiver is giving you the injection, the outer upper arms may also be used. Preparing the Cosentyx 300 mg pre-filled syringe ready for use 1. Take the box containing the syringe out of the refrigerator and leave it unopened for about 30-45 minutes so that it reaches room temperature. 2. When you are ready to use the syringe, wash your hands thoroughly with soap and water. 3. Clean the injection site with an alcohol swab. 4. Remove the syringe from the outer box and take it out of the blister by holding the syringe guard body. 5. Inspect the syringe. The liquid should be clear. Its colour may vary from colourless to slightly yellow. You may see a small air bubble, which is normal. DO NOT USE if the liquid contains easily visible particles, is cloudy or is distinctly brown. DO NOT USE if the syringe is broken. In all these cases, return the entire product pack to the pharmacy. How to use the Cosentyx 300 mg pre-filled syringe Carefully remove the needle cap from the syringe by holding the syringe guard body. Discard the needle cap. You may see a drop of liquid at the end of the needle. This is normal. Gently pinch the skin at the injection site and insert the needle as shown. Push the needle all the way in to ensure that the medicine can be fully administered. 144 Hold the syringe as shown. Slowly depress the plunger as far as it will go so that the plunger head is completely between the syringe guard wings. Keep the plunger pressed fully down while you hold the syringe in place for 5 seconds. Keep the plunger fully depressed while you carefully lift the needle straight out from the injection site. Slowly release the plunger and allow the syringe guard to automatically cover the exposed needle. There may be a small amount of blood at the injection site. You can press a cotton ball or gauze over the injection site and hold it for 10 seconds. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if needed. Disposal instructions Dispose of the used syringe in a sharps container (closable, puncture resistant container). For the safety and health of you and others, needles and used syringes must never be re-used. 145 Package leaflet: Information for the patient Cosentyx 300 mg solution for injection in pre-filled pen secukinumab Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Cosentyx is and what it is used for 2. What you need to know before you use Cosentyx 3. How to use Cosentyx 4. Possible side effects 5. How to store Cosentyx 6. Contents of the pack and other information 1. What Cosentyx is and what it is used for Cosentyx contains the active substance secukinumab. Secukinumab is a monoclonal antibody which belongs to a group of medicines called interleukin (IL) inhibitors. This medicine works by neutralising the activity of a protein called IL-17A, which is present at increased levels in diseases such as psoriasis, psoriatic arthritis and axial spondyloarthritis. Cosentyx is used for the treatment of the following inflammatory diseases:  Plaque psoriasis  Psoriatic arthritis  Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Plaque psoriasis Cosentyx is used to treat a skin condition called “plaque psoriasis”, which causes inflammation affecting the skin. Cosentyx reduces the inflammation and other symptoms of the disease. Cosentyx is used in adults, adolescents and children (6 years of age and older) with moderate to severe plaque psoriasis. Using Cosentyx in plaque psoriasis will benefit you by leading to improvements of skin clearance and reducing your symptoms such as scaling, itching and pain. Psoriatic arthritis Cosentyx is used to treat a condition called “psoriatic arthritis”. The condition is an inflammatory disease of the joints, often accompanied by psoriasis. If you have active psoriatic arthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of active psoriatic arthritis, improve physical function and slow down the damage to the cartilage and bone of the joints involved in the disease. Cosentyx is used in adults with active psoriatic arthritis and can be used alone or with another medicine called methotrexate. 146 Using Cosentyx in psoriatic arthritis will benefit you by reducing the signs and symptoms of the disease, slowing down the damage to the cartilage and bone of the joints and improving your ability to do normal daily activities. Axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis Cosentyx is used to treat conditions called “ankylosing spondylitis” and “non-radiographic axial spondyloarthritis”. These conditions are inflammatory diseases primarily affecting the spine which cause inflammation of the spinal joints. If you have ankylosing spondylitis or non-radiographic axial spondyloarthritis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Cosentyx to reduce the signs and symptoms of the disease, reduce inflammation and improve your physical function. Cosentyx is used in adults with active ankylosing spondylitis and active non-radiographic axial spondyloarthritis. Using Cosentyx in ankylosing spondylitis and non-radiographic axial spondyloarthritis will benefit you by reducing the signs and symptoms of your disease and improving your physical function. 2. What you need to know before you use Cosentyx Do not use Cosentyx:  if you are allergic to secukinumab or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice before using Cosentyx.  if you have an active infection which your doctor thinks is important. Warnings and precautions Talk to your doctor, nurse or pharmacist before using Cosentyx:  if you currently have an infection  if you have long-term or repeated infections.  if you have tuberculosis.  if you have an inflammatory disease affecting your gut called Crohn’s disease.  if you have an inflammation of your large intestine called ulcerative colitis.  if you have recently had a vaccination or if you are due to have a vaccination during treatment with Cosentyx.  if you are receiving any other treatment for psoriasis, such as another immunosuppressant or phototherapy with ultraviolet (UV) light. Inflammatory bowel disease (Crohn’s disease or ulcerative colitis) Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice abdominal cramps and pain, diarrhoea, weight loss, blood in the stool or any other signs of bowel problems. Look out for infections and allergic reactions Cosentyx can potentially cause serious side effects, including infections and allergic reactions. You must look out for signs of these conditions while you are taking Cosentyx. Stop using Cosentyx and tell your doctor or seek medical help immediately if you notice any signs indicating a possible serious infection or an allergic reaction. Such signs are listed under “Serious side effects” in section 4. 147 Children and adolescents Cosentyx is not recommended for children younger than 6 years of age with plaque psoriasis because it has not been studied in this age group. Cosentyx is not recommended for children and adolescents (under 18 years of age) in other indications because it has not been studied in this age group. Other medicines and Cosentyx Tell your doctor or pharmacist:  if you are taking, have recently taken or might take any other medicines.  if you have recently had or are due to have a vaccination. You should not be given certain types of vaccines (live vaccines) while using Cosentyx. Pregnancy, breast-feeding and fertility  It is preferable to avoid the use of Cosentyx in pregnancy. The effects of this medicine in pregnant women are not known. If you are a woman of childbearing potential, you are advised to avoid becoming pregnant and must use adequate contraception while using Cosentyx and for at least 20 weeks after the last Cosentyx dose. Talk to your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.  Talk to your doctor if you are breast-feeding or are planning to breast-feed. You and your doctor should decide if you will breast-feed or use Cosentyx. You should not do both. After using Cosentyx you should not breast-feed for at least 20 weeks after the last dose. Driving and using machines Cosentyx is unlikely to influence your ability to drive and use machines. 3. How to use Cosentyx Always use this medicine exactly as your doctor has told you. Check with your doctor, nurse or pharmacist if you are not sure. Cosentyx is given via injection under your skin (known as a subcutaneous injection). You and your doctor should decide if you should inject Cosentyx yourself. It is important not to try to inject yourself until you have been trained by your doctor, nurse or pharmacist. A caregiver may also give you your Cosentyx injection after proper training. For detailed instructions on how to inject Cosentyx, see “Instructions for use of the Cosentyx UnoReady pen 300 mg” at the end of this leaflet. How much Cosentyx is given and for how long Your doctor will decide how much Cosentyx you need and for how long. Plaque psoriasis Adult  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as one injection of 300 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as one injection of 300 mg. 148 Children aged 6 years and older  The recommended dose given by subcutaneous injection is based on body weight as follows: o Weight below 25 kg: 75 mg using the powder for solution for injection. o Weight 25 kg or above and below 50 kg: 75 mg using the powder for solution for injection. o Weight 50 kg or above: 150 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen. Your doctor may increase the dose to 300 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen.  Each 75 mg dose is given as one injection of 75 mg. Each 150 mg dose is given as one injection of 150 mg. Each 300 mg dose is given as one injection of 300 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Psoriatic arthritis For psoriatic arthritis patients who also have moderate to severe plaque psoriasis or patients who did not respond well to medicines called tumour necrosis factor (TNF) blockers:  The recommended dose is 300 mg by subcutaneous injection.  Each 300 mg dose is given as one injection of 300 mg. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. At each timepoint you will receive a 300 mg dose given as one injection of 300 mg. For other psoriatic arthritis patients:  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Ankylosing spondylitis (Radiographic axial spondyloarthritis)  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Based on your response, your doctor may increase your dose to 300 mg. Each 300 mg dose is given as one injection of 300 mg. Non-radiographic axial spondyloarthritis  The recommended dose is 150 mg by subcutaneous injection. After the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. Cosentyx is for long-term treatment. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect. If you use more Cosentyx than you should If you have received more Cosentyx than you should or the dose has been administered sooner than according to your doctor’s prescription, inform your doctor. 149 If you forget to use Cosentyx If you have forgotten to inject a dose of Cosentyx, inject the next dose as soon as you remember. Then talk to your doctor to discuss when you should inject the next dose. If you stop using Cosentyx It is not dangerous to stop using Cosentyx. However, if you stop, your psoriasis, psoriatic arthritis or axial spondyloarthritis symptoms may come back. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects Stop using Cosentyx and tell your doctor or seek medical help immediately if you get any of the following side effects: Possible serious infection - the signs may include:  fever, flu-like symptoms, night sweats  feeling tired or short of breath, cough which will not go away  warm, red and painful skin, or a painful skin rash with blisters  burning sensation when passing urine. Serious allergic reaction - the signs may include:  difficulty breathing or swallowing  low blood pressure, which can cause dizziness or light-headedness  swelling of the face, lips, tongue or throat  severe itching of the skin, with a red rash or raised bumps. Your doctor will decide if and when you may restart the treatment. Other side effects Most of the following side effects are mild to moderate. If any of these side effects becomes severe, tell your doctor, pharmacist or nurse. Very common (may affect more than 1 in 10 people):  upper respiratory tract infections with symptoms such as sore throat and stuffy nose (nasopharyngitis, rhinitis) Common (may affect up to 1 in 10 people):  cold sores (oral herpes)  diarrhoea  runny nose (rhinorrhoea)  athlete’s foot (tinea pedis)  headache  nausea  fatigue 150 Uncommon (may affect up to 1 in 100 people):  oral thrush (oral candidiasis)  signs of low levels of white blood cells, such as fever, sore throat or mouth ulcers due to infections (neutropenia)  infection of the external ear (otitis externa)  discharge from the eye with itching, redness and swelling (conjunctivitis)  itchy rash (urticaria)  lower respiratory tract infections  abdominal cramps and pain, diarrhoea, weight loss or blood in the stool (signs of bowel problems) Rare (may affect up to 1 in 1,000 people):  severe allergic reaction with shock (anaphylactic reaction)  redness and shedding of skin over a larger area of the body, which may be itchy or painful (exfoliative dermatitis) Not known (frequency cannot be estimated from the available data):  fungal infections of the skin and mucous membranes (including oesophageal candidiasis) Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Cosentyx Keep this medicine out of the sight and reach of children. Do not use this medicine:  after the expiry date which is stated on the outer box or the label on the pen after “EXP”.  if the liquid contains easily visible particles, is cloudy or is distinctly brown. Store the pen sealed in its box to protect from light. Store in the refrigerator between 2°C and 8°C. Do not freeze. Do not shake. If necessary, Cosentyx can be left out of the refrigerator for a single period of up to 4 days at room temperature, not above 30°C. This medicine is for single use only. Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 151 6. Contents of the pack and other information What Cosentyx contains - The active substance is secukinumab. Each pre-filled pen contains 300 mg secukinumab. - The other ingredients are trehalose dihydrate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80 and water for injections. What Cosentyx looks like and contents of the pack Cosentyx solution for injection is a clear liquid. Its colour may vary from colourless to slightly yellow. Cosentyx 300 mg solution for injection in pre-filled pen is available in a pack containing 1 pre-filled pen and in multipacks containing 3 (3 packs of 1) pre-filled pens. Not all pack sizes may be marketed. Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 90429 Nuremberg Germany Sandoz GmbH Biochemiestrasse 10 6336 Langkampfen Austria For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 152 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu http://www.ema.europa.eu/ 153 Instructions for use of Cosentyx UnoReady pen 300 mg secukinumab Read ALL the way through these instructions before injecting. These instructions are to help you to inject correctly using the Cosentyx UnoReady pen. It is important not to try to inject yourself until you have been trained by your doctor, nurse or pharmacist. Your Cosentyx UnoReady pen 300 mg: Cosentyx UnoReady pen 300 mg is shown above with the cap removed. Do not remove the cap until you are ready to inject. Do not use the Cosentyx UnoReady pen if the seal on the outer carton is broken. Keep the Cosentyx UnoReady pen in the sealed outer carton until you are ready to use it to protect it from light. Store your Cosentyx UnoReady pen in a refrigerator between 2°C and 8°C and out of the reach of children.  Do not freeze the pen.  Do not shake the pen.  Do not use the pen if it has been dropped with the cap removed. The needle is covered by the needle guard and the needle will not be seen. Do not touch or push the needle guard because you could get a needle stick injury. What you need for your injection: Included in the carton: A new and unused Cosentyx UnoReady pen 300 mg. Not included in the carton:  Alcohol swab.  Cotton ball or gauze.  Sharps disposal container. Cap Needle guard Internal needle cover Viewing window 154 Before your injection: Take the Cosentyx UnoReady pen 300 mg out of the refrigerator 30 to 45 minutes before injecting to allow it to reach room temperature. 1. Important safety checks before you inject: For the “Viewing window”: The liquid should be clear. Its colour may vary from colourless to slightly yellow. Do not use if the liquid contains easily visible particles, is cloudy or is distinctly brown. You may see a small air bubble, which is normal. For the “Expiry date”: Look at the expiry date (EXP) on your Cosentyx UnoReady pen. Do not use the pen if the expiry date has passed. Check that your pen contains the correct medicine and dose. Contact your pharmacist if the pen fails any of these checks. 2a. Choose your injection site:  The recommended site is the front of the thighs. You may also use the lower abdomen, but not the area 5 centimetres around the navel (belly button).  Choose a different site each time you give yourself an injection.  Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid areas with scars or stretch marks. 2b. Caregivers and healthcare professionals only:  If a caregiver or healthcare professional is giving you your injection, they may also inject into your outer upper arm. 3. Cleaning your injection site:  Wash your hands with soap and hot water.  Using a circular motion, clean the injection site with the alcohol swab. Leave it to dry before injecting.  Do not touch the cleaned area again before injecting. Viewing window Expiry date (EXP) 155 Your injection: 4. Removing the cap:  Only remove the cap when you are ready to use the pen.  Pull the cap straight off in the direction of the arrow that is shown in the figure on the left.  Once removed, throw away the cap. Do not try to re-attach the cap.  Use the pen within 5 minutes of removing the cap. 5. Holding your pen:  Hold the pen at 90 degrees to the cleaned injection site. Correct Incorrect YOU MUST READ THIS BEFORE INJECTING. During the injection you will hear 2 clicks. The 1st click indicates that the injection has started. Several seconds later a 2nd click will indicate that the injection is almost finished. You must keep holding the pen firmly against your skin until you see a green indicator with a grey tip fill the window and stop moving. 6. Starting your injection:  Press the pen firmly against the skin to start the injection.  The 1st click indicates the injection has started.  Keep holding the pen firmly against your skin. The green indicator with the grey tip shows the progress of the injection. 1st CLICK 156 7. Completing your injection:  Listen for the 2nd click. This indicates the injection is almost complete.  Check the green indicator with the grey tip fills the window and has stopped moving.  The pen can now be removed. After your injection: 8. Check the green indicator fills the window:  This means the medicine has been delivered. Contact your doctor if the green indicator is not visible.  There may be a small amount of blood at the injection site. You can press a cotton ball or gauze over the injection site and hold it for 10 seconds. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if needed. 9. Disposing of your Cosentyx UnoReady pen 300 mg:  Dispose of the used pen in a sharps disposal container (i.e. a puncture-resistant closable container, or similar).  Never try to reuse your pen. 2nd CLICK SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what cosentyx is and what it is used for', 'Section_Content': 'cosentyx contains the active substance secukinumab. secukinumab is a monoclonal antibody which belongs to a group of medicines called interleukin (il) inhibitors. this medicine works by neutralising the activity of a protein called il-17a, which is present at increased levels in diseases such as psoriasis, psoriatic arthritis and axial spondyloarthritis. cosentyx is used for the treatment of the following inflammatory diseases: plaque psoriasis psoriatic arthritis axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis plaque psoriasis cosentyx is used to treat a skin condition called "plaque psoriasis", which causes inflammation affecting the skin. cosentyx reduces the inflammation and other symptoms of the disease. cosentyx is used in adults, adolescents and children (6 years of age and older) with moderate to severe plaque psoriasis. using cosentyx in plaque psoriasis will benefit you by leading to improvements of skin clearance and reducing your symptoms such as scaling, itching and pain. psoriatic arthritis cosentyx is used to treat a condition called "psoriatic arthritis". the condition is an inflammatory disease of the joints, often accompanied by psoriasis. if you have active psoriatic arthritis you will first be given other medicines. if you do not respond well enough to these medicines, you will be given cosentyx to reduce the signs and symptoms of active psoriatic arthritis, improve physical function and slow down the damage to the cartilage and bone of the joints involved in the disease. cosentyx is used in adults with active psoriatic arthritis and can be used alone or with another medicine called methotrexate. using cosentyx in psoriatic arthritis will benefit you by reducing the signs and symptoms of the disease, slowing down the damage to the cartilage and bone of the joints and improving your ability to do normal daily activities. axial spondyloarthritis, including ankylosing spondylitis (radiographic axial spondyloarthritis) and non-radiographic axial spondyloarthritis cosentyx is used to treat conditions called "ankylosing spondylitis" and "non-radiographic axial spondyloarthritis". these conditions are inflammatory diseases primarily affecting the spine which cause inflammation of the spinal joints. if you have ankylosing spondylitis or non-radiographic axial spondyloarthritis you will first be given other medicines. if you do not respond well enough to these medicines, you will be given cosentyx to reduce the signs and symptoms of the disease, reduce inflammation and improve your physical function. cosentyx is used in adults with active ankylosing spondylitis and active non-radiographic axial spondyloarthritis. using cosentyx in ankylosing spondylitis and non-radiographic axial spondyloarthritis will benefit you by reducing the signs and symptoms of your disease 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{'Title': '2. what you need to know before you use cosentyx', 'Section_Content': 'do not use cosentyx: if you are allergic to secukinumab or any of the other ingredients of this medicine (listed in section 6). if you think you may be allergic, ask your doctor for advice before using cosentyx. if you have an active infection which your doctor thinks is important. warnings and precautions talk to your doctor, nurse or pharmacist before using cosentyx: if you currently have an infection if you have long-term or repeated infections. if you have tuberculosis. if you have an inflammatory disease affecting your gut called crohn\'s disease. if you have an inflammation of your large intestine called ulcerative colitis. if you have recently had a vaccination or if you are due to have a vaccination during treatment with cosentyx. if you are receiving any other treatment for psoriasis, such as another immunosuppressant or phototherapy with ultraviolet (uv) light. inflammatory bowel disease (crohn\'s disease or ulcerative colitis) stop using cosentyx and tell your doctor or seek medical help immediately if you notice abdominal cramps and pain, diarrhoea, weight loss, blood in the stool or any other signs of bowel problems. look out for infections and allergic reactions cosentyx can potentially cause serious side effects, including infections and allergic reactions. you must look out for signs of these conditions while you are taking cosentyx. stop using cosentyx and tell your doctor or seek medical help immediately if you notice any signs indicating a possible serious infection or an allergic reaction. such signs are listed under "serious side effects" in section 4. children and adolescents cosentyx is not recommended for children younger than 6 years of age with plaque psoriasis because it has not been studied in this age group. cosentyx is not recommended for children and adolescents (under 18 years of age) in other indications because it has not been studied in this age group. other medicines and cosentyx tell your doctor or pharmacist: if you are taking, have recently taken or might take any other medicines. if you have recently had or are due to have a vaccination. you should not be given certain types of vaccines (live vaccines) while using cosentyx. pregnancy, breast-feeding and fertility it is preferable to avoid the use of cosentyx in pregnancy. the effects of this medicine in pregnant women are not known. if you are a woman of childbearing potential, you are advised to avoid becoming pregnant and must use adequate contraception while using cosentyx and for at least 20 weeks after the last cosentyx dose. talk to your doctor if you are pregnant, think you may be pregnant or are planning to have a baby. talk to your doctor if you are breast-feeding or are planning to breast-feed. you and your doctor should decide if you will breast-feed or use cosentyx. you should not do both. after using cosentyx you should not breast-feed for at least 20 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{'Title': '3. how to use cosentyx', 'Section_Content': "cosentyx is given via injection under your skin (known as a subcutaneous injection) by a healthcare professional. make sure you discuss with your doctor when you will have your injections and your follow-up appointments. how much cosentyx is given and for how long your doctor will decide how much cosentyx you need and for how long. plaque psoriasis adult the recommended dose is 300 mg by subcutaneous injection. each 300 mg dose is given as two injections of 150 mg. after the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. at each timepoint you will receive a 300 mg dose given as two injections of 150 mg. children aged 6 years and older the recommended dose given by subcutaneous injection is based on body weight as follows: o weight below 25 kg: 75 mg using the powder for solution for injection. o weight 25 kg or above and below 50 kg: 75 mg using the powder for solution for injection. o weight 50 kg or above: 150 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen. your doctor may increase the dose to 300 mg using the powder for solution for injection, the pre-filled syringe or the pre-filled pen. each 75 mg dose is given as one injection of 75 mg. each 150 mg dose is given as one injection of 150 mg. each 300 mg dose is given as two injections of 150 mg. after the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. psoriatic arthritis for psoriatic arthritis patients who also have moderate to severe plaque psoriasis or patients who did not respond well to medicines called tumour necrosis factor (tnf) blockers: the recommended dose is 300 mg by subcutaneous injection. each 300 mg dose is given as two injections of 150 mg. after the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. at each timepoint you will receive a 300 mg dose given as two injections of 150 mg. for other psoriatic arthritis patients: the recommended dose is 150 mg by subcutaneous injection. after the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. based on your response, your doctor may increase your dose to 300 mg. ankylosing spondylitis (radiographic axial spondyloarthritis) the recommended dose is 150 mg by subcutaneous injection. after the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. based on your response, your doctor may increase your dose to 300 mg. each 300 mg dose is given as two injections of 150 mg. non-radiographic axial spondyloarthritis the recommended dose is 150 mg by subcutaneous injection. after the first dose you will receive further weekly injections at weeks 1, 2, 3 and 4 followed by monthly injections. cosentyx is for long-term treatment. your doctor will regularly monitor your condition to check that the treatment is having the desired effect. if you use more cosentyx than you should if you have received more cosentyx than you should or the dose has been administered sooner than according to your doctor's prescription, inform your doctor. if you forget to use cosentyx if you have missed a cosentyx injection, talk to your doctor. if you stop using cosentyx it is not dangerous to stop using cosentyx. however, if you stop, your psoriasis, psoriatic arthritis or axial spondyloarthritis symptoms may come back. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.", 'Entity_Recognition': [{'Text': 'cosentyx', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 0, 'EndOffset': 8, 'Score': 0.6605772972106934, 'Text': 'cosentyx', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.38250043988227844, 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects stop using cosentyx and tell your doctor or seek medical help immediately if you get any of the following side effects: possible serious infection - the signs may include: fever, flu-like symptoms, night sweats feeling tired or short of breath, cough which will not go away warm, red and painful skin, or a painful skin rash with blisters burning sensation when passing urine. serious allergic reaction - the signs may include: difficulty breathing or swallowing low blood pressure, which can cause dizziness or light-headedness swelling of the face, lips, tongue or throat severe itching of the skin, with a red rash or raised bumps. your doctor will decide if and when you may restart the treatment. other side effects most of the following side effects are mild to moderate. if any of these side effects becomes severe, tell your doctor, pharmacist or nurse. very common (may affect more than 1 in 10 people): upper respiratory tract infections with symptoms such as sore throat and stuffy nose (nasopharyngitis, rhinitis) common (may affect up to 1 in 10 people): cold sores (oral herpes) diarrhoea runny nose (rhinorrhoea) athlete's foot (tinea pedis) headache nausea fatigue 105 uncommon (may affect up to 1 in 100 people): oral thrush (oral candidiasis) signs of low levels of white blood cells, such as fever, sore throat or mouth ulcers due to infections (neutropenia) infection of the external ear (otitis externa) discharge from the eye with itching, redness and swelling (conjunctivitis) itchy rash (urticaria) lower respiratory tract infections abdominal cramps and pain, diarrhoea, weight loss or blood in the stool (signs of bowel problems) rare (may affect up to 1 in 1,000 people): severe allergic reaction with shock (anaphylactic reaction) redness and shedding of skin over a larger area of the body, which may be itchy or painful (exfoliative dermatitis) not known (frequency cannot be estimated from the available data): fungal infections of the skin and mucous membranes (including oesophageal candidiasis) reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'cosentyx', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 24, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9665884971618652, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': 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'Score': 0.8586454391479492}]}, {'Id': 93, 'BeginOffset': 1724, 'EndOffset': 1742, 'Score': 0.9630969166755676, 'Text': 'blood in the stool', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.869324266910553}]}, {'Id': 94, 'BeginOffset': 1753, 'EndOffset': 1767, 'Score': 0.6460559368133545, 'Text': 'bowel problems', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7967491745948792}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1792, 'EndOffset': 1793}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 1797, 'EndOffset': 1802}, {'Text': 'severe allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 1812, 'EndOffset': 1836}, {'Text': 'shock (anaphylactic reaction', 'Type': 'PROBLEM', 'BeginOffset': 1842, 'EndOffset': 1870}, {'Id': 98, 'BeginOffset': 1872, 'EndOffset': 1879, 'Score': 0.9737643599510193, 'Text': 'redness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7333778142929077}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9485607147216797, 'RelationshipScore': 0.8144374489784241, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 22, 'BeginOffset': 1927, 'EndOffset': 1931, 'Text': 'body', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'shedding of skin', 'Type': 'PROBLEM', 'BeginOffset': 1884, 'EndOffset': 1900}, {'Id': 22, 'BeginOffset': 1927, 'EndOffset': 1931, 'Score': 0.9485607147216797, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 100, 'BeginOffset': 1946, 'EndOffset': 1951, 'Score': 0.5171404480934143, 'Text': 'itchy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9933069348335266, 'RelationshipScore': 0.8990774154663086, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 21, 'BeginOffset': 1896, 'EndOffset': 1900, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9485607147216797, 'RelationshipScore': 0.9920990467071533, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 22, 'BeginOffset': 1927, 'EndOffset': 1931, 'Text': 'body', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'painful (exfoliative dermatitis', 'Type': 'PROBLEM', 'BeginOffset': 1955, 'EndOffset': 1986}, {'Text': 'fungal infections of the skin', 'Type': 'PROBLEM', 'BeginOffset': 2055, 'EndOffset': 2084}, {'Id': 104, 'BeginOffset': 2089, 'EndOffset': 2105, 'Score': 0.9978252649307251, 'Text': 'mucous membranes', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 109, 'BeginOffset': 2117, 'EndOffset': 2140, 'Score': 0.8687208890914917, 'Text': 'oesophageal candidiasis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.899657130241394}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9818325042724609, 'RelationshipScore': 0.8558666110038757, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 103, 'BeginOffset': 2080, 'EndOffset': 2084, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9978252649307251, 'RelationshipScore': 0.574091374874115, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 104, 'BeginOffset': 2089, 'EndOffset': 2105, 'Text': 'mucous membranes', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 110, 'BeginOffset': 2155, 'EndOffset': 2167, 'Score': 0.942682147026062, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6116853952407837}]}, {'Id': 111, 'BeginOffset': 2183, 'EndOffset': 2195, 'Score': 0.9067538380622864, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6974326372146606}]}, {'Id': 112, 'BeginOffset': 2266, 'EndOffset': 2278, 'Score': 0.9491145014762878, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5971664786338806}]}, {'Id': 113, 'BeginOffset': 2327, 'EndOffset': 2339, 'Score': 0.8482092618942261, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6695796847343445}]}, {'Id': 114, 'BeginOffset': 2393, 'EndOffset': 2404, 'Score': 0.35527893900871277, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5758452415466309}]}, {'Id': 115, 'BeginOffset': 2418, 'EndOffset': 2430, 'Score': 0.852810800075531, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7159374356269836}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2486, 'EndOffset': 2499}]}

{'Title': '5. how to store cosentyx', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer box or vial after "exp". before reconstitution: store the vial in the refrigerator between 2 and 8. after reconstitution: the solution can be used immediately or can be stored at 2 to 8 for up to 24 hours. do not freeze. the solution should be administered within one hour after removal from 2 to 8 storage. do not use this medicine if you notice that the powder has not fully dissolved or if the liquid contains easily visible particles, is cloudy or is distinctly brown. this medicine is for single use only. do not throw away any medicines via wastewater. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'cosentyx', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 226, 'EndOffset': 227}, {'Text': '8.', 'Type': 'NUMBER', 'BeginOffset': 232, 'EndOffset': 234}, {'Text': 'the solution', 'Type': 'TREATMENT', 'BeginOffset': 257, 'EndOffset': 269}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 314, 'EndOffset': 315}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 319, 'EndOffset': 320}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 331, 'EndOffset': 333}, {'Text': 'the solution', 'Type': 'TREATMENT', 'BeginOffset': 356, 'EndOffset': 368}, {'Id': 0, 'BeginOffset': 414, 'EndOffset': 421, 'Score': 0.37041589617729187, 'Text': 'removal', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 427, 'EndOffset': 428}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 432, 'EndOffset': 433}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 454, 'EndOffset': 467}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 487, 'EndOffset': 497}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 577, 'EndOffset': 583}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 608, 'EndOffset': 621}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what cosentyx contains - the active substance is secukinumab. each vial of powder for solution for injection contains 150 mg secukinumab. after reconstitution, 1 ml of solution contains 150 mg secukinumab. - the other ingredients are sucrose, histidine, histidine hydrochloride monohydrate and polysorbate 80. what cosentyx looks like and contents of the pack cosentyx powder for solution for injection is a white solid powder in a glass vial. cosentyx is supplied in a pack containing one vial.', 'Entity_Recognition': [{'Text': 'cosentyx', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 13, 'Score': 0.3157576620578766, 'Text': 'cosentyx', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 49, 'EndOffset': 60, 'Score': 0.9891067147254944, 'Text': 'secukinumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.7139521837234497, 'RelationshipScore': 0.9988969564437866, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 75, 'EndOffset': 81, 'Text': 'powder', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.8473398089408875, 'RelationshipScore': 0.9999319314956665, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 86, 'EndOffset': 94, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.703673243522644, 'RelationshipScore': 0.9979404807090759, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 4, 'BeginOffset': 99, 'EndOffset': 108, 'Text': 'injection', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'powder', 'Type': 'TREATMENT', 'BeginOffset': 75, 'EndOffset': 81}, {'Text': 'injection', 'Type': 'TREATMENT', 'BeginOffset': 99, 'EndOffset': 108}, {'Text': '150', 'Type': 'NUMBER', 'BeginOffset': 118, 'EndOffset': 121}, {'Id': 6, 'BeginOffset': 125, 'EndOffset': 136, 'Score': 0.9944905042648315, 'Text': 'secukinumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8473398089408875, 'RelationshipScore': 0.9207471013069153, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 86, 'EndOffset': 94, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.703673243522644, 'RelationshipScore': 0.7982591986656189, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 4, 'BeginOffset': 99, 'EndOffset': 108, 'Text': 'injection', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8761274814605713, 'RelationshipScore': 0.9999485015869141, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 118, 'EndOffset': 124, 'Text': '150 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.99552983045578, 'RelationshipScore': 0.6673619747161865, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 160, 'EndOffset': 164, 'Text': '1 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9739412665367126, 'RelationshipScore': 0.9626463651657104, 'RelationshipType': 'FORM', 'Id': 8, 'BeginOffset': 168, 'EndOffset': 176, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'reconstitution', 'Type': 'TREATMENT', 'BeginOffset': 144, 'EndOffset': 158}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 160, 'EndOffset': 161}, {'Text': 'solution', 'Type': 'TREATMENT', 'BeginOffset': 168, 'EndOffset': 176}, {'Text': '150', 'Type': 'NUMBER', 'BeginOffset': 186, 'EndOffset': 189}, {'Id': 10, 'BeginOffset': 193, 'EndOffset': 204, 'Score': 0.9947223663330078, 'Text': 'secukinumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8761274814605713, 'RelationshipScore': 0.5195443034172058, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 118, 'EndOffset': 124, 'Text': '150 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.99552983045578, 'RelationshipScore': 0.9884152412414551, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 160, 'EndOffset': 164, 'Text': '1 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9739412665367126, 'RelationshipScore': 0.9702178239822388, 'RelationshipType': 'FORM', 'Id': 8, 'BeginOffset': 168, 'EndOffset': 176, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9086275100708008, 'RelationshipScore': 0.9999921321868896, 'RelationshipType': 'DOSAGE', 'Id': 9, 'BeginOffset': 186, 'EndOffset': 192, 'Text': '150 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 11, 'BeginOffset': 234, 'EndOffset': 241, 'Score': 0.6552903652191162, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 243, 'EndOffset': 252, 'Score': 0.979019820690155, 'Text': 'histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 254, 'EndOffset': 289, 'Score': 0.9878947138786316, 'Text': 'histidine hydrochloride monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5839322805404663}]}, {'Id': 14, 'BeginOffset': 294, 'EndOffset': 305, 'Score': 0.4956139326095581, 'Text': 'polysorbate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '80.', 'Type': 'NUMBER', 'BeginOffset': 306, 'EndOffset': 309}, {'Id': 15, 'BeginOffset': 315, 'EndOffset': 323, 'Score': 0.7074100375175476, 'Text': 'cosentyx', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.6435148119926453, 'RelationshipScore': 0.9823274612426758, 'RelationshipType': 'FORM', 'Id': 18, 'BeginOffset': 380, 'EndOffset': 388, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the pack cosentyx powder', 'Type': 'TREATMENT', 'BeginOffset': 351, 'EndOffset': 375}, {'Text': 'injection', 'Type': 'TREATMENT', 'BeginOffset': 393, 'EndOffset': 402}, {'Text': 'a white solid powder', 'Type': 'TREATMENT', 'BeginOffset': 406, 'EndOffset': 426}, {'Id': 19, 'BeginOffset': 444, 'EndOffset': 452, 'Score': 0.5673181414604187, 'Text': 'cosentyx', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}]}

5C61714547A198B17CE6A2C6D90A7556

https://www.ema.europa.eu/documents/product-information/viraferonpeg-epar-product-information_en.pdf

ViraferonPeg

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 50 micrograms powder and solvent for solution for injection ViraferonPeg 80 micrograms powder and solvent for solution for injection ViraferonPeg 100 micrograms powder and solvent for solution for injection ViraferonPeg 120 micrograms powder and solvent for solution for injection ViraferonPeg 150 micrograms powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ViraferonPeg 50 micrograms powder and solvent for solution for injection Each vial contains 50 micrograms of peginterferon alfa-2b as measured on a protein basis. Each vial provides 50 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. ViraferonPeg 80 micrograms powder and solvent for solution for injection Each vial contains 80 micrograms of peginterferon alfa-2b as measured on a protein basis. Each vial provides 80 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. ViraferonPeg 100 micrograms powder and solvent for solution for injection Each vial contains 100 micrograms of peginterferon alfa-2b as measured on a protein basis. Each vial provides 100 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. ViraferonPeg 120 micrograms powder and solvent for solution for injection Each vial contains 120 micrograms of peginterferon alfa-2b as measured on a protein basis. Each vial provides 120 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. ViraferonPeg 150 micrograms powder and solvent for solution for injection Each vial contains 150 micrograms of peginterferon alfa-2b as measured on a protein basis. Each vial provides 150 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. The active substance is a covalent conjugate of recombinant interferon alfa-2b* with monomethoxy polyethylene glycol. The potency of this product should not be compared to that of another pegylated or non-pegylated protein of the same therapeutic class (see section 5.1). *produced by rDNA technology in E. coli cells harbouring a genetically engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes. Excipients with known effect: Each vial contains 40 mg of sucrose per 0.5 ml. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. White powder. Clear and colourless solvent. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adults (tritherapy) ViraferonPeg in combination with ribavirin and boceprevir (tritherapy) is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adult patients (18 years of age and older) with compensated liver disease who are previously untreated or who have failed previous therapy (see section 5.1). Please refer to the ribavirin and boceprevir Summary of Product Characteristics (SmPCs) when ViraferonPeg is to be used in combination with these medicines. Adults (bitherapy and monotherapy) ViraferonPeg is indicated for the treatment of adult patients (18 years of age and older) with CHC who are positive for hepatitis C virus RNA (HCV-RNA), including patients with compensated cirrhosis and/or co-infected with clinically stable HIV (see section 4.4). ViraferonPeg in combination with ribavirin (bitherapy) is indicated for the treatment of CHC infection in adult patients who are previously untreated including patients with clinically stable HIV co-infection and in adult patients who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy (see section 5.1). Interferon monotherapy, including ViraferonPeg, is indicated mainly in case of intolerance or contraindication to ribavirin. Please refer to the ribavirin SmPC when ViraferonPeg is to be used in combination with ribavirin. Paediatric population (bitherapy) ViraferonPeg is indicated in a combination regimen with ribavirin for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, previously untreated, without liver decompensation, and who are positive for HCV-RNA. When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case basis (see section 4.4). Please refer to the ribavirin SmPC for capsules or oral solution when ViraferonPeg is to be used in combination with ribavirin. 4.2 Posology and method of administration Treatment should be initiated and monitored only by a physician experienced in the management of patients with hepatitis C. Posology ViraferonPeg should be administered as a once weekly subcutaneous injection. The dose administered in adults depends on whether it is used in combination therapy (bitherapy or tritherapy) or as monotherapy. ViraferonPeg combination therapy (bitherapy or tritherapy) Bitherapy (ViraferonPeg with ribavirin): applies to all adult and paediatric patients 3 years of age and older. Tritherapy (ViraferonPeg with ribavirin and boceprevir): applies to adult patients with genotype 1 CHC. 4 Adults – Dose to be administered ViraferonPeg 1.5 micrograms/kg/week in combination with ribavirin capsules. The intended dose of 1.5 g/kg of ViraferonPeg to be used in combination with ribavirin may be delivered in weight categories with the ViraferonPeg strengths according to Table 1. Ribavirin capsules are to be administered orally each day in two divided doses with food (morning and evening). Table 1 Dosing for combination therapy* Body weight (kg) ViraferonPeg Ribavirin capsules ViraferonPeg strength (g/0.5 ml) Administer once weekly (ml) Total daily ribavirin dose (mg) Number of capsules (200 mg) < 40 50 0.5 800 4a 40-50 80 0.4 800 4a 51-64 80 0.5 800 4a 65-75 100 0.5 1,000 5b 76-80 120 0.5 1,000 5b 81-85 120 0.5 1,200 6c 86-105 150 0.5 1,200 6c > 105 150 0.5 1,400 7 d a: 2 morning, 2 evening b: 2 morning, 3 evening c: 3 morning, 3 evening d: 3 morning, 4 evening * Refer to the SmPC of boceprevir for details about the dose of boceprevir to be administered in tritherapy. Adults - Duration of treatment – Naïve patients Tritherapy: Refer to the SmPC for boceprevir. Bitherapy: Predictability of sustained virological response - Patients infected with virus genotype 1 who fail to achieve undetectable HCV-RNA or demonstrate adequate virological response at week 4 or 12 are highly unlikely to become sustained virological responders and should be evaluated for discontinuation (see also section 5.1).  Genotype 1: - Patients who have undetectable HCV-RNA at treatment week 12, treatment should be continued for another nine month period (i.e., a total of 48 weeks). - Patients with detectable but ≥ 2 log decrease in HCV-RNA level from baseline at treatment week 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, they should continue with full course of therapy (i.e. a total of 48 weeks). However, if HCV-RNA is still detectable at treatment week 24, discontinuation of therapy should be considered. - In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24, the treatment could either be stopped after this 24 week treatment course or pursued for an additional 24 weeks (i.e. overall 48 weeks treatment duration). However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration (see section 5.1).  Genotypes 2 or 3: It is recommended that all patients be treated with bitherapy for 24 weeks, except for HCV/HIV co-infected patients who should receive 48 weeks of treatment.  Genotype 4: In general, patients infected with genotype 4 are considered harder to treat and limited study data (n=66) indicate they are compatible with a duration of treatment with bitherapy as for genotype 1. 5 Adults - Duration of treatment - HCV/HIV co-infection Bitherapy: The recommended duration of treatment for HCV/HIV co-infected patients is 48 weeks with bitherapy, regardless of genotype. Predictability of response and non-response in HCV/HIV co-infection - Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV-RNA, has been shown to be predictive for sustained response. The negative predictive value for sustained response in HCV/HIV co-infected patients treated with ViraferonPeg in combination with ribavirin was 99 % (67/68; Study 1) (see section 5.1). A positive predictive value of 50 % (52/104; Study 1) was observed for HCV/HIV co-infected patients receiving bitherapy. Adults - Duration of treatment - Retreatment Tritherapy: Refer to the SmPC for boceprevir. Bitherapy: Predictability of sustained virological response - All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at week 12 should receive 48 weeks of bitherapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNA below the limits of detection) at week 12 are unlikely to become sustained virological responders after 48 weeks of therapy (see also section 5.1). Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been studied with pegylated interferon alfa-2b and ribavirin combination therapy. Paediatric population (bitherapy only) – Dose to be administered Dosing for children 3 years of age and older and adolescent patients is determined by body surface area for ViraferonPeg and by body weight for ribavirin. The recommended dose of ViraferonPeg is 60 g/m2/week subcutaneously in combination with ribavirin 15 mg/kg/day orally in two divided doses with food (morning and evening). Paediatric population (bitherapy only) - Duration of treatment  Genotype 1: The recommended duration of treatment with bitherapy is 1 year. By extrapolation from clinical data on combination therapy with standard interferon in paediatric patients (negative predictive value 96 % for interferon alfa–2b/ribavirin), patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders. Therefore, it is recommended that children and adolescent patients receiving ViraferonPeg/ribavirin combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if they have detectable HCV-RNA at treatment week 24.  Genotype 2 or 3: The recommended duration of treatment with bitherapy is 24 weeks.  Genotype 4: Only 5 children and adolescents with Genotype 4 were treated in the ViraferonPeg/ribavirin clinical trial. The recommended duration of treatment with bitherapy is 1 year. It is recommended that children and adolescent patients receiving ViraferonPeg/ribavirin combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if they have detectable HCV-RNA at treatment week 24. ViraferonPeg monotherapy – Adults Dose to be administered As monotherapy the ViraferonPeg regimen is 0.5 or 1.0 g/kg/week. The lowest ViraferonPeg strength available is 50 g/0.5 ml; therefore for patients prescribed 0.5 g/kg/week, doses must be adjusted by volume as shown in Table 2. For the 1.0 g/kg dose, similar volume adjustments can be made or alternate strengths can be used as shown in Table 2. ViraferonPeg monotherapy was not studied in HCV/HIV co-infected patients. 6 Table 2 Monotherapy dosing 0.5 g/kg 1.0 g/kg Body weight (kg) ViraferonPeg strength (g/0.5 ml) Administer once weekly (ml) ViraferonPeg strength (g/0.5 ml) Administer once weekly (ml) 30-35 50* 0.15 80 0.2 36-45 50 0.2 50 0.4 46-56 50 0.25 50 0.5 57-72 80 0.2 80 0.4 73-88 50 0.4 80 0.5 89-106 50 0.5 100 0.5 107-120** 80 0.4 120 0.5 Minimum delivery for pen is 0.2 ml. * Must use vial. ** For patients > 120 kg, the ViraferonPeg dose should be calculated based on the individual patient weight. This may require combinations of various ViraferonPeg dose strengths and volumes. Duration of treatment For patients who exhibit virological response at week 12, treatment should be continued for at least another three-month period (i.e., a total of six months). The decision to extend therapy to one year of treatment should be based on prognostic factors (e.g., genotype, age > 40 years, male gender, bridging fibrosis). Dose modification for all patients (monotherapy and combination therapy) If severe adverse reactions or laboratory abnormalities develop during treatment with ViraferonPeg monotherapy or combination therapy, the dosages of ViraferonPeg and/or ribavirin must be modified as appropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended. Boceprevir must not be administered in the absence of ViraferonPeg and ribavirin. As adherence might be of importance for outcome of therapy, the dose of ViraferonPeg and ribavirin should be kept as close as possible to the recommended standard dose. Guidelines were developed in clinical trials for dose modification. Combination therapy dose reduction guidelines Table 2a Dose modification guidelines for combination therapy based on laboratory parameters Laboratory values Reduce only ribavirin daily dose (see note 1) if: Reduce only ViraferonPeg dose (see note 2) if: Discontinue combination therapy if: Haemoglobin ≥ 8.5 g/dl, and < 10 g/dl - < 8.5 g/dl Adults: Haemoglobin in Patients with history of stable cardiac disease Children and adolescents: not applicable  2 g/dl decrease in haemoglobin during any four week period during treatment (permanent dose reduction) < 12 g/dl after four weeks of dose reduction Leukocytes - ≥ 1.0 x 109/l, and < 1.5 x 109/l < 1.0 x 109/l Neutrophils - ≥ 0.5 x 109/l, and < 0.75 x 109/l < 0.5 x 109/l 7 Laboratory values Reduce only ribavirin daily dose (see note 1) if: Reduce only ViraferonPeg dose (see note 2) if: Discontinue combination therapy if: Platelets - ≥ 25 x 109/l, and < 50 x 109/l (adults) ≥ 50 x 109/l, and <70 x 109/l (children and adolescents) < 25 x 109/l (adults) < 50 x 109/l (children and adolescents) Bilirubin – direct - - 2.5 x ULN* Bilirubin - indirect > 5 mg/dl - > 4 mg/dl (for > 4 weeks) Serum Creatinine - - > 2.0 mg/dl Creatinine Clearance - - Discontinue ribavirin if CrCL < 50ml/min Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) - - 2 x baseline and > 10 x ULN* 2 x baseline and > 10 x ULN* * Upper limit of normal Note 1: In adult patients 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening. In children and adolescent patients 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day. Note 2: In adult patients 1st dose reduction of ViraferonPeg is to 1 µg/kg/week. If needed, 2nd dose reduction of ViraferonPeg is to 0.5 µg/kg/week. For patients on ViraferonPeg monotherapy: refer to monotherapy dose reduction guidelines section for dose reduction. In children and adolescent patients 1st dose reduction of ViraferonPeg is to 40 g/m2/week, 2nd dose reduction of ViraferonPeg is to 20 g/m2/week. Dose reduction of ViraferonPeg in adults may be accomplished by reducing the prescribed volume or by utilizing a lower dose strength as shown in Table 2b. Dose reduction of ViraferonPeg in children and adolescents is accomplished by modifying the recommended dose in a two-step process from the original starting dose of 60 g/m2/week, to 40 g/m2/week, then to 20 g/m2/week, if needed. Table 2b Two-step dose reduction of ViraferonPeg in combination therapy in adults First dose reduction to ViraferonPeg 1 µg/kg Second dose reduction to ViraferonPeg 0.5 µg/kg Body weight(k g) ViraferonPe g strength (g/0.5 ml) Amount of ViraferonPe g to administer (µg) Volume of ViraferonPe g to administer (ml) Body weigh t (kg) ViraferonPe g strength (g/0.5 ml) Amount of ViraferonPe g to administer (µg) Volume of ViraferonPe g to administer (ml) < 40 50 35 0.35 < 40 50 20 0.2 40 – 50 120 48 0.2 40 – 50 50 25 0.25 51 – 64 80 56 0.35 51 – 64 80 32 0.2 65 – 75 100 70 0.35 65 – 75 50 35 0.35 8 First dose reduction to ViraferonPeg 1 µg/kg Second dose reduction to ViraferonPeg 0.5 µg/kg Body weight(k g) ViraferonPe g strength (g/0.5 ml) Amount of ViraferonPe g to administer (µg) Volume of ViraferonPe g to administer (ml) Body weigh t (kg) ViraferonPe g strength (g/0.5 ml) Amount of ViraferonPe g to administer (µg) Volume of ViraferonPe g to administer (ml) 76 – 85 80 80 0.5 76 – 85 120 48 0.2 86 - 105 120 96 0.4 86 – 105 50 50 0.5 > 105 150 105 0.35 > 10 5 80 64 0.4 ViraferonPeg monotherapy dose reduction guidelines in adults Dose modification guidelines for adult patients who use ViraferonPeg monotherapy are shown in Table 3a. Table 3a Dose modification guidelines for ViraferonPeg monotherapy in adults based on laboratory parameters Laboratory values Reduce ViraferonPeg to one-half dose if: Discontinue ViraferonPeg if: Neutrophils ≥ 0.5 x 109/l, and < 0.75 x 109/l < 0.5 x 109/l Platelets ≥ 25 x 109/l, and < 50 x 109/l < 25 x 109/l For adult patients who use 0.5 g/kg ViraferonPeg monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half as shown in Table 3b. Table 3b Reduced ViraferonPeg dose (0.25 g/kg) for the 0.5 g/kg monotherapy regimen in adults Body weight (kg) ViraferonPeg strength (g/0.5 ml) Amount of ViraferonPeg to administer (g) Volume of ViraferonPeg to Administer (ml) 30-35 50* 8 0.08 36-45 50* 10 0.1 46-56 50* 13 0.13 57-72 80* 16 0.1 73-88 50 20 0.2 89-106 50 25 0.25 107-120** 80 32 0.2 Minimum delivery for pen is 0.2 ml. * Must use vial. ** For patients > 120 kg, the ViraferonPeg dose should be calculated based on the individual patient weight. This may require combinations of various ViraferonPeg dose strengths and volumes. For adult patients who use 1.0 g/kg ViraferonPeg monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half or by utilizing a lower dose strength as shown in Table 3c. 9 Table 3c Reduced ViraferonPeg dose (0.5 g/kg) for the 1.0 g/kg monotherapy regimen in adults Body weight (kg) ViraferonPeg strength (g/0.5 ml) Amount of ViraferonPeg to administer (g) Volume of ViraferonPeg to administer (ml) 30-35 50* 15 0.15 36-45 50 20 0.20 46-56 50 25 0.25 57-72 80 32 0.2 73-88 50 40 0.4 89-106 50 50 0.5 107-120** 80 64 0.4 Minimum delivery for pen is 0.2 ml. * Must use vial. ** For patients > 120 kg, the ViraferonPeg dose should be calculated based on the individual patient weight. This may require combinations of various ViraferonPeg dose strengths and volumes. Special populations Renal impairment Monotherapy ViraferonPeg should be used with caution in patients with moderate to severe renal impairment. In patients with moderate renal dysfunction (creatinine clearance 30-50 ml/minute), the starting dose of ViraferonPeg should be reduced by 25 %. Patients with severe renal dysfunction (creatinine clearance 15-29 ml/minute) should have the starting dose of ViraferonPeg reduced by 50 %. Data are not available for the use of ViraferonPeg in patients with creatinine clearance < 15 ml/minute (see section 5.2). Patients with severe renal impairment, including those on hemodialysis, should be closely monitored. If renal function decreases during treatment, ViraferonPeg therapy should be discontinued. Combination therapy Patients with creatinine clearance < 50 ml/minute must not be treated with ViraferonPeg in combination with ribavirin (see ribavirin SmPC). When administered in combination therapy, patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. Hepatic impairment The safety and efficacy of ViraferonPeg therapy has not been evaluated in patients with severe hepatic dysfunction, therefore ViraferonPeg must not be used for these patients. Elderly ( 65 years of age) There are no apparent age-related effects on the pharmacokinetics of ViraferonPeg. Data from elderly patients treated with a single dose of ViraferonPeg suggest no alteration in ViraferonPeg dose is necessary based on age (see section 5.2). Paediatric population ViraferonPeg can be used in combination with ribavirin in paediatric patients 3 years of age and older. Method of administration ViraferonPeg should be administered as a subcutaneous injection. For special handling information see section 6.6. Patients may self-inject ViraferonPeg if their physician determines that it is appropriate and with medical follow-up as necessary. 4.3 Contraindications - Hypersensitivity to the active substance or to any interferon or to any of the excipients listed in section 6.1; 10 - A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see section 4.4); - Severe, debilitating medical conditions; - Autoimmune hepatitis or a history of autoimmune disease; - Severe hepatic dysfunction or decompensated cirrhosis of the liver; - Pre-existing thyroid disease unless it can be controlled with conventional treatment; - Epilepsy and/or compromised central nervous system (CNS) function; - HCV/HIV patients with cirrhosis and a Child-Pugh score ≥ 6. - Combination of ViraferonPeg with telbivudine. Paediatric population - Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicidal attempt. Combination therapy Also see SmPCs for ribavirin and boceprevir if ViraferonPeg is to be administered in combination therapy in patients with chronic hepatitis C. 4.4 Special warnings and precautions for use Psychiatric and Central Nervous System (CNS) Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during ViraferonPeg therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal or homicidal ideation is identified, it is recommended that treatment with ViraferonPeg be discontinued, and the patient followed, with psychiatric intervention as appropriate. Patients with existence of, or history of severe psychiatric conditions If treatment with peginterferon alfa-2b is judged necessary in adult patients with existence or history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition. - The use of ViraferonPeg in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Among children and adolescents treated with interferon alfa-2b in combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult patients, children and adolescents experienced other psychiatric adverse events (e.g. depression, emotional lability, and somnolence). Patients with substance use/abuse HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended. Growth and development (children and adolescents) During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common. Long-term data available in children treated with the 11 combination therapy of pegylated interferon/ribavirin are indicative of substantial growth retardation. Thirty two percent (30/94) of subjects demonstrated > 15 percentile decrease in height-for-age percentile 5 years after completion of therapy (see sections 4.8 and 5.1). Case by case benefit/risk assessment in children The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1). - It is important to consider that the combination therapy induced a growth inhibition, that resulted in reduced height in some patients. - This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV genotype and viral load). Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. Although data are limited, no evidence of long-term effects on sexual maturation was noted in the 5-year observational follow-up study. More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses for oncology indications. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of interferon alpha. All patients in the selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to commencing treatment. Acute hypersensitivity Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment with ViraferonPeg, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment. Cardiovascular system As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, receiving ViraferonPeg therapy require close monitoring. It is recommended that patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of ViraferonPeg therapy. There are no data in children or adolescents with a history of cardiac disease. Hepatic Failure ViraferonPeg increases the risk of hepatic decompensation and death in patients with cirrhosis. As with all interferons, discontinue treatment with ViraferonPeg in patients who develop prolongation of coagulation markers which might indicate liver decompensation. Liver enzymes and hepatic function should be closely monitored in cirrhotic patients. Pyrexia While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out. Hydration Adequate hydration must be maintained in patients undergoing ViraferonPeg therapy since hypotension related to fluid depletion has been seen in some patients treated with alpha interferons. Fluid replacement may be necessary. 12 Pulmonary changes Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients. Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events. Autoimmune disease The development of auto-antibodies and autoimmune disorders has been reported during treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Thyroid changes and section 4.8). Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8). Ocular changes Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, serous retinal detachment, and retinal artery or vein occlusion have been reported in rare instances after treatment with alpha interferons (see section 4.8). All patients should have a baseline eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt and complete eye examination. Periodic visual examinations are recommended during ViraferonPeg therapy, particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of ViraferonPeg should be considered in patients who develop new or worsening ophthalmological disorders. Thyroid changes Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of children treated with ViraferonPeg/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2 % had a transient decrease below the lower limit of normal. Prior to initiation of ViraferonPeg therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Determine TSH levels if, during the course of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, ViraferonPeg treatment may be continued if TSH levels can be maintained in the normal range by medicine. Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH). Metabolic disturbances Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended. HCV/HIV Co-infection Mitochondrial toxicity and lactic acidosis Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding ViraferonPeg and ribavirin to HAART therapy (see ribavirin SmPC). Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentration. 13 Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed. Haematological abnormalities in HCV/HIV co-infected patients HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and HAART may be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed by dose reduction, close monitoring of haematological parameters should be undertaken in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8). Patients treated with ViraferonPeg and ribavirin combination therapy and zidovudine are at increased risk of developing anaemia and therefore the concomitant use of this combination with zidovudine is not recommended (see section 4.5). Patients with low CD4 counts In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in subjects with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of patients with low CD4 counts. Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ViraferonPeg and ribavirin. HCV/HBV Coinfection Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co- infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation appears to be low. All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; patients co-infected with hepatitis B and C must then be monitored and managed according to current clinical guidelines. Dental and periodontal disorders Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving ViraferonPeg and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of ViraferonPeg and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards. Organ transplant recipients The safety and efficacy of ViraferonPeg alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported. Other Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of ViraferonPeg in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk. Laboratory tests Standard haematologic tests, blood chemistry and a test of thyroid function must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of ViraferonPeg therapy are:  Platelets  100,000/mm3 14  Neutrophil count  1,500/mm3  TSH level must be within normal limits Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2). Long term maintenance monotherapy It has been demonstrated in a clinical study that peginterferon alfa-2b at low-dose (0.5 μg/kg/week) is not effective in long term maintenance monotherapy (for a mean duration of 2.5 years) for the prevention of disease progression in non responders with compensated cirrhosis. No statistically significant effect on the time to development of the first clinical event (liver decompensation, hepatocellular carcinoma, death and/or liver transplantation) was observed as compared to the absence of treatment. ViraferonPeg should therefore not be used as long term maintenance monotherapy. Important information about some of the ingredients of ViraferonPeg Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicine. This medicinal product contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially "sodium-free". 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults. Telbivudine A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SmPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of ViraferonPeg with telbivudine is contraindicated (see section 4.3). Methadone In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve to peginterferon alfa-2b, addition of 1.5 microgram/kg/week of ViraferonPeg subcutaneously for 4 weeks increased R-methadone AUC by approximately 15 % (95 % Cl for AUC ratio estimate 103 – 128 %). The clinical significance of this finding is unknown; however, patients should be monitored for signs and symptoms of increased sedative effect, as well as respiratory depression. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered. Effect of Peginterferon alfa-2b on Co-administered Medicines The potential interaction of peginterferon alfa-2b (ViraferonPeg) on substrates of metabolic enzymes was evaluated in 3 multiple-dose clinical pharmacology studies. In these studies, the effects of multiple-dose regimens of peginterferon alfa-2b (ViraferonPeg) were investigated in Hepatitis C subjects (1.5 mcg/week) or healthy subjects (1 mcg/week or 3 mcg/week) (Table 4). A clinically significant pharmacokinetic interaction was not observed between peginterferon alfa-2b (ViraferonPeg) and tolbutamide, midazolam or dapsone; therefore, no dosing adjustment is necessary when peginterferon alfa-2b (ViraferonPeg) is administered with medicines metabolized by CYP2C9, CYP3A4 and N-acetyltransferase. Concomitant administration of peginterferon alfa-2b (ViraferonPeg) with caffeine or desipramine modestly increased the exposure of caffeine and desipramine. When patients are administered ViraferonPeg with medications metabolized by CYP1A2 or CYP2D6, the extent of the decrease in cytochrome P 450 activity is unlikely to have a clinical impact, except with medicines which have a narrow therapeutic margin (Table 5). 15 Table 4 Effect of Peginterferon alfa-2b on Co-administered Medicines Co-administered Medicine Dose of peginterferon alfa-2b Study Population Geometric Mean Ratio (Ratio with/without peginterferon alfa-2b) AUC (90% CI) Cmax (90% CI) Caffeine (CYP1A2 substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=22) 1.39 (1.27, 1.51) 1.02 (0.95, 1.09) 1 mcg/kg/week (4 weeks) Healthy Subjects (N=24) 1.18 (1.07, 1.31) 1.12 (1.05, 1.19) 3 mcg/kg/week (2 weeks) Healthy Subjects (N=13) 1.36 (1.25, 1.49) 1.16 (1.10, 1.24) Tolbutamide (CYP2C9 substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=22) 1.1# (0.94, 1.28) NA 1 mcg/kg/week (4 weeks) Healthy Subjects (N=24) 0.90# (0.81, 1.00) NA 3 mcg/kg/week (2 weeks) Healthy Subjects (N=13) 0.95 (0.89, 1.01) 0.99 (0.92, 1.07) Dextromethorphan hydrobromide (CYP2D6 and CYP3A substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=22) 0.96## (0.73, 1.26) NA 1 mcg/kg/week (4 weeks) Healthy Subjects (N=24) 2.03# (1.55, 2.67) NA Desipramine (CYP2D6 substrate) 3 mcg/kg/week (2 weeks) Healthy Subjects (N=13) 1.30 (1.18, 1.43) 1.08 (1.00, 1.16) Midazolam (CYP3A4 substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=24) 1.07 (0.91, 1.25) 1.12 (0.94, 1.33) 1 mcg/kg/week (4 weeks) Healthy Subjects (N=24) 1.07 (0.99, 1.16) 1.33 (1.15, 1.53) 3 mcg/kg/week (2 weeks) Healthy Subjects (N=13) 1.18 (1.06, 1.32) 1.24 (1.07, 1.43) Dapsone (N-acetyltransferase substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=24) 1.05 (1.02, 1.08) 1.03 (1.00, 1.06) # Calculated from urine data collected over an interval of 48-hours ## Calculated from urine data collected over an interval of 24-hours 16 Table 5 Precautions for co-administration (ViraferonPeg should be administered with care when co-administered with the following medicines) Medicines Signs, Symptoms, and Treatment Mechanism and Risk Factors Theophylline Co-administration of theophylline with the product (ViraferonPeg) may increase the blood concentrations of theophylline. Careful co-administration of theophylline with the product (ViraferonPeg) is recommended. Package inserts of theophylline should be referred to when co-administering with the product (ViraferonPeg) Metabolism of theophylline is suppressed by inhibitory action of the product (ViraferonPeg) on CYP1A2. Thioridazine Co-administration of thioridazine with the product (ViraferonPeg) may increase the blood concentrations of thioridazine. Careful co-administration of thioridazine with the product (ViraferonPeg) is recommended. Package inserts of thioridazine should be referred to when co-administering with the product (ViraferonPeg) Metabolism of thioridazine is suppressed by inhibitory action of the product (ViraferonPeg) on CYP2D6. Theophylline, Antipyrine, Warfarin Elevation of blood concentrations of these medicines has been reported when administered in combination with other interferon preparations and therefore care should be taken. Metabolism of other medicines in the liver may be suppressed. Zidovudine When administered in combination with other interferon preparations, suppressive effect on bone marrow function may be strengthened and aggravation of blood cell reduction such as white blood cells decreased may occur. Mechanism of action is unknown, but it is considered that both medicines have bone marrow depressive effects. Immuno-suppressive therapy When administered in combination with other interferon preparations, effect of immunosuppressive therapy may be weakened in transplant (kidney, bone marrow, etc.) patients. It is considered that graft rejection reactions may be induced. No pharmacokinetic interactions were noted between ViraferonPeg and ribavirin in a multiple-dose pharmacokinetic study. HCV/HIV Co-infection Nucleoside analogues Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see ribavirin SmPC). 17 Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV, although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine-induced anaemia. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/contraception in males and females ViraferonPeg is recommended for use in fertile women only when they are using effective contraception during the treatment. Combination therapy with ribavirin Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking ViraferonPeg in combination with ribavirin. Females of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SmPC). Pregnancy There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Interferon alfa-2b has been shown to be abortifacient in primates. ViraferonPeg is likely to also cause this effect. The potential risk in humans is unknown. ViraferonPeg is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Combination therapy with ribavirin Ribavirin causes serious birth defects when administered during pregnancy, therefore ribavirin therapy is contraindicated in women who are pregnant. Breast-feeding It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding should be discontinued prior to initiation of treatment. Fertility There are no data available regarding potential effects of ViraferonPeg treatment on male or female fertility. 4.7 Effects on ability to drive and use machines Patients who develop fatigue, somnolence or confusion during treatment with ViraferonPeg are cautioned to avoid driving or operating machines. 4.8 Undesirable effects Adults Tritherapy Refer to the SmPC for boceprevir. Bitherapy and monotherapy Summary of the safety profile The most common treatment-related adverse reactions reported during clinical trials with ViraferonPeg in combination with ribavirin in adults, seen in more than half of the study subjects, were fatigue, headache, and injection site reaction. Additional adverse reactions reported in more than 18 25 % of subjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight decreased, depression, rash and irritability. The most frequently reported adverse reactions were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy. Fatigue, alopecia, pruritus, nausea, anorexia, weight decreased, irritability and insomnia occur at a notably lower rate in patients treated with ViraferonPeg monotherapy compared to those treated with combination therapy (see Table 6). Tabulated summary of adverse reactions The following treatment-related adverse reactions were reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including ViraferonPeg monotherapy or ViraferonPeg/ribavirin. These reactions are listed in table 6 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 6 Adverse reactions reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including ViraferonPeg monotherapy or ViraferonPeg + ribavirin Infections and infestations Very common: Viral infection*, pharyngitis* Common: Bacterial infection (including sepsis), fungal infection, influenza, upper respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis Uncommon: Injection site infection, lower respiratory tract infection Not known: Hepatitis B reactivation in HCV/HBV co-infected patients Blood and lymphatic system disorders Very common: Anaemia, neutropenia Common: Haemolytic anaemia, leukopenia, thrombocytopenia, lymphadenopathy Very rare: Aplastic anaemia Not known: Aplasia pure red cell Immune system disorders Uncommon: Drug hypersensitivity Rare: Sarcoidosis Not known: Acute hypersensitivity reactions including angioedema, anaphylaxis and anaphylactic reactions including anaphylactic shock, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, systemic lupus erythematosus Endocrine disorders Common: Hypothyroidism, hyperthyroidism Metabolism and nutrition disorders Very common: Anorexia Common: Hypocalcemia, hyperuricemia, dehydration, increased appetite Uncommon: Diabetes mellitus, hypertriglyceridaemia Rare: Diabetic ketoacidosis Psychiatric disorders Very common: Depression, anxiety*, emotional lability*, concentration impaired, insomnia Common: Aggression, agitation, anger, mood altered, abnormal behaviour, nervousness, sleep disorder, libido decreased, apathy, abnormal dreams, crying 19 Uncommon: Suicide, suicide attempt, suicidal ideation, psychosis, hallucination, panic attack Rare: Bipolar disorders Not known: Homicidal ideation, mania Nervous system disorders Very common: Headache, dizziness Common: Amnesia, memory impairment, syncope, migraine, ataxia, confusion, neuralgia, paraesthesia, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia Uncommon: Neuropathy, neuropathy peripheral Rare: Convulsion Very rare: Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy Not known: Facial palsy, mononeuropathies Eye disorders Common: Visual disturbance, vision blurred, photophobia, conjunctivitis, eye irritation, lacrimal disorder, eye pain, dry eye Uncommon: Retinal exudates Rare: Loss of visual acuity or visual fields, retinal haemorrhage, retinopathy, retinal artery occlusion, retinal vein occlusion, optic neuritis, papilloedema, macular oedema Not known: Serous retinal detachment Ear and labyrinth disorders Common: Hearing impaired/loss, tinnitus, vertigo Uncommon Ear pain Cardiac disorders Common: Palpitations, tachycardia Uncommon: Myocardial infarction Rare: Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis Very rare: Cardiac ischaemia Not known: Pericardial effusion Vascular disorders Common: Hypotension, hypertension, flushing Rare: Vasculitis Respiratory, thoracic and mediastinal disorders Very common: Dyspnoea*, cough* Common: Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain Very rare: Interstitial lung disease Not known: Pulmonary fibrosis, pulmonary arterial hypertension# Gastrointestinal disorders Very common: Vomiting*, nausea, abdominal pain, diarrhoea, dry mouth* Common: Dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration, glossodynia, gingival bleeding, constipation, flatulence, haemorrhoids, cheilitis, abdominal distension, gingivitis, glossitis, tooth disorder Uncommon: Pancreatitis, oral pain Rare: Colitis ischaemic Very rare: Colitis ulcerative Not known Tongue pigmentation 20 Hepatobiliary disorders Common: Hyperbilirubinemia, hepatomegaly Skin and subcutaneous tissue disorders Very common: Alopecia, pruritus*, dry skin*, rash* Common: Psoriasis, photosensitivity reaction, rash maculo-papular, dermatitis, erythematous rash, eczema, night sweats, hyperhidrosis, acne, furuncle, erythema, urticaria, abnormal hair texture, nail disorder Rare: Cutaneous sarcoidosis Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Musculoskeletal and connective tissue disorders Very common: Myalgia, arthralgia, musculoskeletal pain Common: Arthritis, back pain, muscle spasms, pain in extremity Uncommon: Bone pain, muscle weakness Rare: Rhabdomyolysis, myositis, rheumatoid arthritis Renal and urinary disorders Common: Micturition frequency, polyuria, urine abnormality Rare: Renal failure, renal insufficiency Reproductive system and breast disorders Common: Amenorrhoea, breast pain, menorrhagia, menstrual disorder, ovarian disorder, vaginal disorder, sexual dysfunction, prostatitis, erectile dysfunction General disorders and administration site conditions Very common: Injection site reaction*, injection site inflammation, fatigue, asthenia, irritability, chills, pyrexia, influenza like illness, pain Common: Chest pain, chest discomfort, injection site pain, malaise, face oedema, oedema peripheral, feeling abnormal, thirst Rare: Injection site necrosis Investigations Very common: Weight decreased *These adverse reactions were common (≥1/100 to < 1/10) in clinical trials in patients treated with ViraferonPeg monotherapy. #Class label for interferon products, see below Pulmonary arterial hypertension. Description of selected adverse reactions in adults Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of ViraferonPeg in combination with ribavirin (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]). In a clinical trial, approximately 1.2 % of patients treated with ViraferonPeg or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide (see section 4.4). Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients without prior evidence of cardiac disease. Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa. 21 Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies (including macular oedema), retinal haemorrhages, retinal artery or vein occlusion, retinal exudates, loss of visual acuity or visual field, optic neuritis, and papilloedema (see section 4.4). A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada syndrome (see also section 4.4). HCV/HIV co-infected patients Summary of the safety profile For HCV/HIV co-infected patients receiving ViraferonPeg in combination with ribavirin, other undesirable effects (that were not reported in mono-infected patients) which have been reported in the larger studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %). Description of selected adverse reactions Mitochondrial toxicity Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated ribavirin for co-HCV infection (see section 4.4). Laboratory values for HCV/HIV co-infected patients Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving ViraferonPeg in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving ViraferonPeg in combination with ribavirin. Anaemia (hemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with ViraferonPeg in combination with ribavirin. CD4 lymphocytes decrease Treatment with ViraferonPeg in combination with ribavirin was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of ViraferonPeg in combination with ribavirin had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N= 25) are available in co-infected patients with CD4+ cell counts < 200/µl (see section 4.4). Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ViraferonPeg in combination with ribavirin. Paediatric population Summary of the safety profile In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of ViraferonPeg and ribavirin, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with ViraferonPeg and ribavirin, growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients). 22 At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles respectively, and 20 % of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 subjects enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow- up among subjects treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40 % of subjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of the 5 year long-term follow-up compared to pre-treatment baseline percentile. Eleven percent of subjects (5/46) treated for 24 weeks and 13 % of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight- for-age percentiles decreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4). In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH. Tabulated summary of adverse reactions The following treatment-related adverse reactions were reported in the study in children and adolescent patients treated with ViraferonPeg in combination with ribavirin. These reactions are listed in Table 7 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 7 Adverse reactions very commonly, commonly and uncommonly reported in the clinical trial in children and adolescent patients treated with ViraferonPeg in combination with ribavirin Infections and infestations Common: Fungal infection, influenza, oral herpes, otitis media, pharyngitis streptococcal, nasopharyngitis, sinusitis Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Blood and lymphatic system disorders Very common: Anaemia, leucopenia, neutropenia Common: Thrombocytopenia, lymphadenopathy Endocrine disorders Common: Hypothyroidism Metabolism and nutrition disorders Very common: Anorexia, decreased appetite 23 Psychiatric disorders Common: Suicidal ideation§, suicide attempt§, depression, aggression, affect lability, anger, agitation, anxiety, mood altered, restlessness, nervousness, insomnia Uncommon: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare Nervous system disorders Very common: Headache, dizziness Common: Dysgeusia, syncope, disturbance in attention, somnolence, poor quality sleep Uncommon: Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotor hyperactivity, tremor Eye disorders Common: Eye pain Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia Ear and labyrinth disorders Common: Vertigo Cardiac disorders Common: Palpitations, tachycardia Vascular disorders Common: Flushing Uncommon: Hypotension, pallor Respiratory, thoracic and mediastinal disorders Common: Cough, epistaxis, pharyngolaryngeal pain Uncommon: Wheezing, nasal discomfort, rhinorrhoea Gastrointestinal disorders Very common: Abdominal pain, abdominal pain upper, vomiting, nausea Common: Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomach discomfort, oral pain Uncommon: Dyspepsia, gingivitis Hepatobiliary disorders Uncommon: Hepatomegaly Skin and subcutaneous tissue disorders Very common: Alopecia, dry skin Common: Pruritus, rash, rash erythematous, eczema, acne, erythema Uncommon: Photosensitivity reaction, rash maculo-papular, skin exfoliation, pigmentation disorder, dermatitis atopic, skin discolouration Musculoskeletal and connective tissue disorders Very common: Myalgia, arthralgia Common: Musculoskeletal pain, pain in extremity, back pain Uncommon: Muscle contracture, muscle twitching Renal and urinary disorders Uncommon: Proteinuria Reproductive system and breast disorders Uncommon: Female: Dysmenorrhoea General disorders and administration site conditions Very common: Injection site erythema, fatigue, pyrexia, rigors, influenza-like illness, asthenia, pain, malaise, irritability Common: Injection site reaction, injection site pruritus, injection site rash injection site dryness, injection site pain, feeling cold Uncommon: Chest pain, chest discomfort, facial pain 24 Investigations Very common: Growth rate decrease (height and/or weight decrease for age) Common: Blood thyroid stimulating hormone increased, thyroglobulin increased Uncommon: Anti-thyroid antibody positive Injury and poisoning Uncommon: Contusion §class effect of interferon-alfa containing products – reported with standard interferon therapy in adult and paediatric patients; with ViraferonPeg reported in adult patients. Description of selected adverse reactions in children and adolescents Most of the changes in laboratory values in the ViraferonPeg/ribavirin clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with ViraferonPeg used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Doses up to 10.5 times the intended dose have been reported. The maximum daily dose reported is 1,200 µg for one day. In general, the adverse events seen in overdose cases involving ViraferonPeg are consistent with the known safety profile for ViraferonPeg; however, the severity of the events may be increased. Standard methods to increase elimination of the medicinal product, e.g., dialysis, have not been shown to be useful. No specific antidote for ViraferonPeg is available; therefore, symptomatic treatment and close observation of the patient are recommended in cases of overdose. If available, prescribers are advised to consult with a poison control centre (PCC). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB10. Recombinant interferon alfa-2b is covalently conjugated with monomethoxy polyethylene glycol at an average degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 31,300 daltons of which the protein moiety constitutes approximately 19,300. Mechanism of action In vitro and in vivo studies suggest that the biological activity of ViraferonPeg is derived from its interferon alfa-2b moiety. Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Studies with other interferons have demonstrated species specificity. However, certain monkey species, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons. Once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virus- infected cells, suppression of cell proliferation and such immunomodulating activities as enhancement http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 25 of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon’s therapeutic effects. Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are unable to leave the cell. Pharmacodynamic effects ViraferonPeg pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examining changes in oral temperature, concentrations of effector proteins such as serum neopterin and 2’5’-oligoadenylate synthetase (2’5’-OAS), as well as white cell and neutrophil counts. Subjects treated with ViraferonPeg showed mild dose-related elevations in body temperature. Following single doses of ViraferonPeg between 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related manner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of ViraferonPeg. Clinical efficacy and safety – Adults Tritherapy with ViraferonPeg, ribavirin and boceprevir Refer to the SmPC for boceprevir. Monotherapy with ViraferonPeg and bitherapy with ViraferonPeg and ribavirin Naïve patients Two pivotal trials have been conducted, one (C/I97-010) with ViraferonPeg monotherapy; the other (C/I98-580) with ViraferonPeg in combination with ribavirin. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction (PCR) assay (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT. In the ViraferonPeg monotherapy trial, a total of 916 naïve chronic hepatitis C patients were treated with ViraferonPeg (0.5, 1.0 or 1.5 micrograms/kg/week) for one year with a follow-up period of six months. In addition, 303 patients received interferon alfa-2b (3 million International Units [MIU] three times a week) as a comparator. This study showed that ViraferonPeg was superior to interferon alfa-2b (Table 8). In the ViraferonPeg combination trial, 1,530 naïve patients were treated for one year with one of the following combination regimens: - ViraferonPeg (1.5 micrograms/kg/week) + ribavirin (800 mg/day), (n = 511). - ViraferonPeg (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) + ribavirin (1,000/1,200 mg/day), (n = 514). - Interferon alfa-2b (3 MIU three times a week) + ribavirin (1,000/1,200 mg/day) (n = 505). In this trial, the combination of ViraferonPeg (1.5 micrograms/kg/week) and ribavirin was significantly more effective than the combination of interferon alfa-2b and ribavirin (Table 8), particularly in patients infected with Genotype 1 (Table 9). Sustained response was assessed by the response rate six months after the cessation of treatment. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of ribavirin administered in combination with ViraferonPeg or interferon alfa-2b. In those patients that received > 10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received  10.6 mg/kg ribavirin (Table 9), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher. 26 Table 8 Sustained virological response (% patients HCV negative) ViraferonPeg monotherapy ViraferonPeg + ribavirin Treatment regimen P 1.5 P 1.0 P 0.5 I P 1.5/R P 0.5/R I/R Number of patients 304 297 315 303 511 514 505 Response at end of treatment 49 % 41 % 33 % 24 % 65 % 56 % 54 % Sustained response 23 %* 25 % 18 % 12 % 54 %** 47 % 47 % P 1.5 ViraferonPeg 1.5 micrograms/kg P 1.0 ViraferonPeg 1.0 microgram/kg P 0.5 ViraferonPeg 0.5 microgram/kg I Interferon alfa-2b 3 MIU P 1.5/R ViraferonPeg (1.5 micrograms/kg) + ribavirin (800 mg) P 0.5/R ViraferonPeg (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg) I/R Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg) * p < 0.001 P 1.5 vs. I ** p = 0.0143 P 1.5/R vs. I/R Table 9 Sustained response rates with ViraferonPeg + ribavirin (by ribavirin dose, genotype and viral load) HCV Genotype Ribavirin dose (mg/kg) P 1.5/R P 0.5/R I/R All Genotypes All 54 % 47 % 47 %  10.6 50 % 41 % 27 % > 10.6 61 % 48 % 47 % Genotype 1 All 42 % 34 % 33 %  10.6 38 % 25 % 20 % > 10.6 48 % 34 % 34 % Genotype 1  600,000 IU/ml All 73 % 51 % 45 %  10.6 74 % 25 % 33 % > 10.6 71 % 52 % 45 % Genotype 1 > 600,000 IU/ml All 30 % 27 % 29 %  10.6 27 % 25 % 17 % > 10.6 37 % 27 % 29 % Genotype 2/3 All 82 % 80 % 79 %  10.6 79 % 73 % 50 % > 10.6 88 % 80 % 80 % P 1.5/R ViraferonPeg (1.5 micrograms/kg) + ribavirin (800 mg) P 0.5/R ViraferonPeg (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg) I/R Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg) In the ViraferonPeg monotherapy study, the Quality of Life was generally less affected by 0.5 microgram/kg of ViraferonPeg than by either 1.0 microgram/kg of ViraferonPeg once weekly or 3 MIU of interferon alfa-2b three times a week. In a separate trial, 224 patients with genotype 2 or 3 received ViraferonPeg, 1.5 micrograms/kg subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg p.o. for 6 months (based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (Table 10). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4). 27 Table 10 Virologic response at end of treatment, Sustained Virologic Response and relapse by HCV Genotype and viral load* ViraferonPeg 1.5 g/kg once weekly plus Ribavirin 800-1,400 mg/day End of treatment response Sustained Virologic Response Relapse All subjects 94 % (211/224) 81 % (182/224) 12 % (27/224) HCV 2 100 % (42/42) 93 % (39/42) 7 % (3/42)  600,000 IU/ml 100 % (20/20) 95 % (19/20) 5 % (1/20) > 600,000 IU/ml 100 % (22/22) 91 % (20/22) 9 % (2/22) HCV 3 93 % (169/182) 79 % (143/182) 14 % (24/166)  600,000 IU/ml 93 % (92/99) 86 % (85/99) 8 % (7/91) > 600,000 IU/ml 93 % (77/83) 70 % (58/83) 23 % (17/75) * Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow-up. The 6 month treatment duration in this trial was better tolerated than one year of treatment in the pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %. In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received ViraferonPeg, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48). Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment). A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two ViraferonPeg/ribavirin regimens [ViraferonPeg 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 11). Table 11 Virologic response at treatment week 12, end of treatment response, relapse rate *and Sustained Virologic Response (SVR) Treatment group % (number) of patients ViraferonPeg 1.5 µg/kg + ribavirin ViraferonPeg 1 µg/kg + ribavirin peginterferon alfa-2a 180 µg + ribavirin Undetectable HCV- RNA at treatment week 12 40 (407/1,019) 36 (366/1,016) 45 (466/1,035) End of treatment response 53 (542/1,019) 49 (500/1,016) 64 (667/1,035) Relapse 24 (123/523) 20 (95/475) 32 (193/612) SVR 40 (406/1,019) 38 (386/1,016) 41 (423/1,035) SVR in patients with undetectable HCV- RNA at treatment week 12 81 (328/407) 83 (303/366) 74 (344/466) * (HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml) Lack of early virologic response by Treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from baseline) was a criterion for discontinuation of treatment. 28 In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with ViraferonPeg (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic response rate compared to ViraferonPeg 1 µg/kg dose. At the ViraferonPeg 1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml, and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %. Predictability of sustained virological response – Naïve patients: Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA.Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 12). Table 12 Predictive value of in-treatment Virologic Response while on ViraferonPeg 1.5 µg/kg/ribavirin 800-1,400 mg combination therapy Negative Positive No response at treatment week No sustained response Negative predictive value Response at treatment week Sustained response Positive predictive value Genotype 1* By week 4*** (n=950) HCV-RNA negative 834 539 65 % (539/834) 116 107 92 % (107/116) HCV-RNA negative or ≥ 1 log decrease in viral load 220 210 95 % (210/220) 730 392 54 % (392/730) By week 12*** (n=915) HCV-RNA negative 508 433 85 % (433/508) 407 328 81 % (328/407) HCV-RNA negative or ≥ 2 log decrease in viral load 206 205 N/A† 709 402 57 % (402/709) Genotype 2, 3** By week 12 (n= 215) HCV-RNA negative or ≥ 2 log decrease in viral load 2 1 50 % (1/2) 213 177 83 % (177/213) *Genotype 1 receive 48 weeks treatment **Genotype 2, 3 receive 24 weeks treatment ***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or week 12. † These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2log10 decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2log10 from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy. 29 The negative predictive value for sustained response in patients treated with ViraferonPeg in monotherapy was 98 %. HCV/HIV Co-infected patients Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 13. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either ViraferonPeg (1.5 µg/kg/week) plus ribavirin (800 mg/day) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either ViraferonPeg (100 or 150 µg/week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6-month follow-up period. Table 13 Sustained virological response based on genotype after ViraferonPeg in combination with Ribavirin in HCV/HIV Co-infected patients Study 11 Study 22 ViraferonPeg (1.5 µg/kg/ week) + ribavirin (800 mg) Interferon alfa-2b (3 MIU TIW) + ribavirin (800 mg) p valuea ViraferonPeg (100 or 150c µg/week) + ribavirin (800- 1,200 mg)d Interferon alfa-2b (3 MIU TIW) + ribavirin (800- 1,200 mg)d p valueb All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017 Genotype 1, 4 17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007 Genotype 2, 3 44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730 MIU = million international units; TIW = three times a week. a: p value based on Cochran-Mantel Haenszel Chi square test. b: p value based on chi-square test. c: subjects < 75 kg received 100 µg/week ViraferonPeg and subjects ≥ 75 kg received 150 µg/week ViraferonPeg. d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg. 1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848. 2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36. Histological response: Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with ViraferonPeg in combination with ribavirin. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3. ViraferonPeg/ribavirin retreatment of prior treatment failures In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with ViraferonPeg, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment). Patients who were HCV-RNA negative at treatment week 12 continued treatment for 48 weeks and were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV- 30 RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 14). Table 14 Rates of response to retreatment in prior treatment failures Patients with undetectable HCV–RNA at treatment week 12 and SVR upon retreatment interferon alpha/ribavirin peginterferon alpha/ribavirin Overall population* Response week 12 % (n/N) SVR % (n/N) 99% CI Response week 12 % (n/N) SVR % (n/N) 99% CI SVR % (n/N) 99 % CI Overall 38.6 (549/1,423) 59.4 (326/549) 54.0,64.8 31.5 (272/863) 50.4 (137/272) 42.6, 58.2 21.7 (497/2,293) 19.5, 23.9 Prior response Relapse 67.7 (203/300) 59.6 (121/203) 50.7, 68.5 58.1 (200/344) 52.5 (105/200) 43.4, 61.6 37.7 (243/645) 32.8, 42.6 Genotype 1/4 59.7 (129/216) 51.2 (66/129) 39.8, 62.5 48.6 (122/251) 44.3 (54/122) 32.7, 55.8 28.6 (134/468) 23.3, 34.0 Genotype 2/3 88.9 (72/81) 73.6 (53/72) (60.2, 87.0) 83.7 (77/92) 64.9 (50/77) 50.9, 78.9 61.3 (106/173) 51.7, 70.8 NR 28.6 (258/903) 57.0 (147/258) 49.0, 64.9 12.4 (59/476) 44.1 (26/59) 27.4, 60.7 13.6 (188/1,385) 11.2, 15.9 Genotype 1/4 23.0 (182/790) 51.6 (94/182) 42.1, 61.2 9.9 (44/446) 38.6 (17/44) 19.7, 57.5 9.9 (123/1,242) 7.7, 12.1 Genotype 2/3 67.9 (74/109) 70.3 (52/74) 56.6, 84.0 53.6 (15/28) 60.0 (9/15) 27.4, 92.6 46.0 (63/137) 35.0, 57.0 Genotype 1 30.2 (343/1,135) 51.3 (176/343) 44.4, 58.3 23.0 (162/704) 42.6 (69/162) 32.6, 52.6 14.6 (270/1,846) 12.5, 16.7 2/3 77.1 (185/240) 73.0 (135/185) 64.6, 81.4 75.6 (96/127) 63.5 (61/96) 50.9, 76.2 55.3 (203/367) 48.6, 62.0 4 42.5 (17/40) 70.6 (12/17) 42.1, 99.1 44.4 (12/27) 50.0 (6/12) 12.8, 87.2 28.4 (19/67) 14.2, 42.5 METAVIR Fibrosis score F2 46.0 (193/420) 66.8 (129/193) 58.1, 75.6 33.6 (78/232) 57.7 (45/78) 43.3, 72.1 29.2 (191/653) 24.7, 33.8 F3 38.0 (163/429) 62.6 (102/163) 52.8, 72.3 32.4 (78/241) 51.3 (40/78) 36.7, 65.9 21.9 (147/672) 17.8, 26.0 F4 33.6 (192/572) 49.5 (95/192) 40.2, 58.8 29.7 (116/390) 44.8 (52/116) 32.9, 56.7 16.5 (159/966) 13.4, 19.5 31 Patients with undetectable HCV–RNA at treatment week 12 and SVR upon retreatment interferon alpha/ribavirin peginterferon alpha/ribavirin Overall population* Response week 12 % (n/N) SVR % (n/N) 99% CI Response week 12 % (n/N) SVR % (n/N) 99% CI SVR % (n/N) 99 % CI Baseline Viral Load HVL (>600,000 IU/ml) 32.4 (280/864) 56.1 (157/280) 48.4, 63.7 26.5 (152/573) 41.4 (63/152) 31.2, 51.7 16.6 (239/1,441) 14.1, 19.1 LVL (≤600,000 IU/ml) 48.3 (269/557) 62.8 (169/269) 55.2, 70.4 41.0 (118/288) 61.0 (72/118) 49.5, 72.6 30.2 (256/848) 26.1, 34.2 NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment. Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory *Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed. Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels at week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior failure on therapy with nonpegylated interferon or pegylated interferon and negative at week 12, the sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients the SVR was 12 %. Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a week 12 response to retreatment than non-responders to nonpegylated interferon alpha/ribavirin (12.4 % vs. 28.6 %). However, if a week 12 response was achieved, there was little difference in SVR regardless of prior treatment or prior response. Long-term efficacy data-Adults A large long-term follow-up study enrolled 567 patients after treatment in a prior study with ViraferonPeg (with or without ribavirin). The purpose of the study was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. 327 patients completed at least 5 years of long-term follow-up and only 3 out of 366 sustained responders relapsed during the study. The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 99 % (95 % CI: 98-100 %). SVR after treatment of chronic HCV with ViraferonPeg (with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical “cure” from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma). Clinical efficacy and safety – paediatric population Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with ribavirin 15 mg/kg per day plus ViraferonPeg 60 g/m2 once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ViraferonPeg with ribavirin needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 15. 32 Table 15 Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects n = 107 24 weeks 48 weeks All Genotypes 26/27 (96 %) 44/80 (55 %) Genotype 1 - 38/72 (53 %) Genotype 2 14/15 (93 %) - Genotype 3c 12/12 (100 %) 2/3 (67 %) Genotype 4 - 4/5 (80 %) a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment lower limit of detection=125IU/ml b: n = number of responders/number of subjects with given genotype, and assigned treatment duration. c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment. Long-term efficacy data - paediatric population A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR had relapsed during the 5 years of follow-up. 5.2 Pharmacokinetic properties ViraferonPeg is a well characterized polyethylene glycol-modified (“pegylated”) derivative of interferon alfa-2b and is predominantly composed of monopegylated species. The plasma half-life of ViraferonPeg is prolonged compared with nonpegylated interferon alfa-2b. ViraferonPeg has a potential to depegylate to free interferon alfa-2b. The biologic activity of the pegylated isomers is qualitatively similar, but weaker than free interferon alfa-2b. Following subcutaneous administration, maximal serum concentrations occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours post-dose. ViraferonPeg Cmax and AUC measurements increase in a dose-related manner. Mean apparent volume of distribution is 0.99 l/kg. Upon multiple dosing, there is an accumulation of immunoreactive interferons. There is, however, only a modest increase in biologic activity as measured by a bioassay. Mean (SD) ViraferonPeg elimination half-life is approximately 40 hours (13.3 hours), with apparent clearance of 22.0 ml/hr/kg. The mechanisms involved in clearance of interferons in man have not yet been fully elucidated. However, renal elimination may account for a minority (approximately 30 %) of ViraferonPeg apparent clearance. Renal impairment Renal clearance appears to account for 30 % of total clearance of ViraferonPeg. In a single dose study (1.0 microgram/kg) in patients with impaired renal function, Cmax, AUC, and half-life increased in relation to the degree of renal impairment. Following multiple dosing of ViraferonPeg (1.0 microgram/kg subcutaneously administered every week for four weeks) the clearance of ViraferonPeg is reduced by a mean of 17 % in patients with moderate renal impairment (creatinine clearance 30-49 ml/minute) and by a mean of 44 % in patients with severe renal impairment (creatinine clearance 15-29 ml/minute) compared to subjects with normal renal function. Based on single dose data, clearance was similar in patients with severe renal impairment not on dialysis and in patients who were receiving hemodialysis. The dose of ViraferonPeg for monotherapy should be reduced in patients with moderate or severe renal impairment 33 (see sections 4.2 and 4.4). Patients with creatinine clearance < 50 ml/minute must not be treated with ViraferonPeg in combination with ribavirin (bitherapy or tritherapy) (see section 4.3). Because of marked inter-subject variability in interferon pharmacokinetics, it is recommended that patients with severe renal impairment be closely monitored during treatment with ViraferonPeg (see section 4.2) Hepatic impairment The pharmacokinetics of ViraferonPeg have not been evaluated in patients with severe hepatic dysfunction. Elderly ( 65 years of age) The pharmacokinetics of ViraferonPeg following a single subcutaneous dose of 1.0 microgram/kg were not affected by age. The data suggest that no alteration in ViraferonPeg dosage is necessary based on advancing age. Paediatric population Multiple-dose pharmacokinetic properties for ViraferonPeg and ribavirin (capsules and oral solution) in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of ViraferonPeg at 60 g/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 g/kg/week. Interferon neutralising factors Interferon neutralising factor assays were performed on serum samples of patients who received ViraferonPeg in the clinical trial. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors in patients who received ViraferonPeg 0.5 micrograms/kg is 1.1 %. Transfer into seminal fluid Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin. 5.3 Preclinical safety data ViraferonPeg Adverse events not observed in clinical trials were not seen in toxicity studies in monkeys. These studies were limited to four weeks due to the appearance of anti-interferon antibodies in most monkeys. Reproduction studies of ViraferonPeg have not been performed. Interferon alfa-2b has been shown to be an abortifacient in primates. ViraferonPeg is likely to also cause this effect. Effects on fertility have not been determined. It is not known whether the components of this medicinal product are excreted into experimental animal or human milk (see section 4.6 for relevant human data on pregnancy and lactation). ViraferonPeg showed no genotoxic potential. The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from ViraferonPeg by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicity studies in rodents and monkeys, standard embryo-foetal development studies and in in vitro mutagenicity assays. ViraferonPeg plus ribavirin When used in combination with ribavirin, ViraferonPeg did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible, mild to 34 moderate anaemia, the severity of which was greater than that produced by either active substance alone. No studies have been conducted in juvenile animals to examine the effects of treatment with ViraferonPeg on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3 of Rebetol SmPC if ViraferonPeg is to be administered in combination with ribavirin). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder Disodium phosphate, anhydrous Sodium dihydrogen phosphate dihydrate Sucrose Polysorbate 80 Solvent Water for injections 6.2 Incompatibilities This medicinal product should only be reconstituted with the solvent provided (see section 6.6). In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life Before reconstitution 3 years. After reconstitution Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8ºC. From a microbiological point of view, the product is to be used immediately. If not used immediately, in- use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). For storage conditions of the reconstituted medicinal product, see section 6.3. 6.5 Nature and contents of container The powder is contained in a 2 ml vial (Type I flint glass) with a butyl rubber stopper in an aluminium flip-off seal with a polypropylene bonnet. The solvent is presented in a 2 ml ampoule (Type I flint glass). ViraferonPeg is supplied as: - 1 vial of powder for solution for injection and 1 ampoule of solvent for parenteral use; - 1 vial of powder for solution for injection, 1 ampoule of solvent for parenteral use, 1 injection syringe, 2 injection needles and 1 cleansing swab; - 4 vials of powder for solution for injection and 4 ampoules of solvent for parenteral use; 35 - 4 vials of powder for solution for injection, 4 ampoules of solvent for parenteral use, 4 injection syringes, 8 injection needles and 4 cleansing swabs; - 6 vials of powder for solution for injection and 6 ampoules of solvent for parenteral use. - 12 vials of powder for solution for injection, 12 ampoules of solvent for parenteral use, 12 injection syringes, 24 injection needles and 12 cleansing swabs. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling ViraferonPeg 50 micrograms powder and solvent for solution for injection Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 50 micrograms/0.5 ml. ViraferonPeg 80 micrograms powder and solvent for solution for injection Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 80 micrograms/0.5 ml. ViraferonPeg 100 micrograms powder and solvent for solution for injection Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 100 micrograms/0.5 ml. ViraferonPeg 120 micrograms powder and solvent for solution for injection Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 120 micrograms/0.5 ml. ViraferonPeg 150 micrograms powder and solvent for solution for injection Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 150 micrograms/0.5 ml. Using a sterilised injection syringe and injection needle, 0.7 ml of water for injections is injected into the vial of ViraferonPeg. Dissolution of powder is completed by agitating it gently. The appropriate dose can then be withdrawn with a sterilised injection syringe and injected. A complete set of instructions is provided in the Annex to the Package Leaflet. As for all parenteral medicinal products, the reconstituted solution is to be inspected visually prior to administration. The reconstituted solution should be clear and colourless. If discolouration or particulate matter is present, the reconstituted solution should not be used. Any unused material is to be discarded. 36 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBERS ViraferonPeg 50 micrograms powder and solvent for solution for injection EU/1/00/132/001 EU/1/00/132/002 EU/1/00/132/003 EU/1/00/132/004 EU/1/00/132/005 EU/1/00/132/026 ViraferonPeg 80 micrograms powder and solvent for solution for injection EU/1/00/132/006 EU/1/00/132/007 EU/1/00/132/008 EU/1/00/132/009 EU/1/00/132/010 EU/1/00/132/027 ViraferonPeg 100 micrograms powder and solvent for solution for injection EU/1/00/132/011 EU/1/00/132/012 EU/1/00/132/013 EU/1/00/132/014 EU/1/00/132/015 EU/1/00/132/028 ViraferonPeg 120 micrograms powder and solvent for solution for injection EU/1/00/132/016 EU/1/00/132/017 EU/1/00/132/018 EU/1/00/132/019 EU/1/00/132/020 EU/1/00/132/029 ViraferonPeg 150 micrograms powder and solvent for solution for injection EU/1/00/132/021 EU/1/00/132/022 EU/1/00/132/023 EU/1/00/132/024 EU/1/00/132/025 EU/1/00/132/030 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 29 May 2000 Date of latest renewal: 29 May 2010 37 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the web-site of the European Medicines Agency http://www.ema.europa.eu. 38 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 50 micrograms powder and solvent for solution for injection in pre-filled pen ViraferonPeg 80 micrograms powder and solvent for solution for injection in pre-filled pen ViraferonPeg 100 micrograms powder and solvent for solution for injection in pre-filled pen ViraferonPeg 120 micrograms powder and solvent for solution for injection in pre-filled pen ViraferonPeg 150 micrograms powder and solvent for solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ViraferonPeg 50 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 50 microgram of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 50 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. ViraferonPeg 80 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 80 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 80 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. ViraferonPeg 100 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 100 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 100 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. ViraferonPeg 120 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 120 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 120 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. ViraferonPeg 150 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 150 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 150 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. The active substance is a covalent conjugate of recombinant interferon alfa-2b* with monomethoxy polyethylene glycol. The potency of this product should not be compared to that of another pegylated or non-pegylated protein of the same therapeutic class (see section 5.1). *produced by rDNA technology in E. coli cells harbouring a genetically engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes. Excipients with known effect: Each pre-filled pen contains 40 mg of sucrose per 0.5 ml. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection in pre-filled pen. White powder. Clear and colourless solvent. 39 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adults (tritherapy) ViraferonPeg in combination with ribavirin and boceprevir (tritherapy) is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adult patients (18 years of age and older) with compensated liver disease who are previously untreated or who have failed previous therapy (see section 5.1). Please refer to the ribavirin and boceprevir Summary of Product Characteristics (SmPCs) when ViraferonPeg is to be used in combination with these medicines. Adults (bitherapy and monotherapy) ViraferonPeg is indicated for the treatment of adult patients (18 years of age and older) with CHC who are positive for hepatitis C virus RNA (HCV-RNA), including patients with compensated cirrhosis and/or co-infected with clinically stable HIV (see section 4.4). ViraferonPeg in combination with ribavirin (bitherapy) is indicated for the treatment of CHC infection in adult patients who are previously untreated including patients with clinically stable HIV co-infection and in adult patients who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy (see section 5.1). Interferon monotherapy, including ViraferonPeg, is indicated mainly in case of intolerance or contraindication to ribavirin. Please refer to the ribavirin SmPC when ViraferonPeg is to be used in combination with ribavirin. Paediatric population (bitherapy) ViraferonPeg is indicated in a combination regimen with ribavirin for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, previously untreated, without liver decompensation, and who are positive for HCV-RNA. When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case basis (see section 4.4). Please refer to the ribavirin SmPC for capsules or oral solution when ViraferonPeg is to be used in combination with ribavirin. 4.2 Posology and method of administration Treatment should be initiated and monitored only by a physician experienced in the management of patients with hepatitis C. Posology ViraferonPeg should be administered as a once weekly subcutaneous injection. The dose administered in adults depends on whether it is used in combination therapy (bitherapy or tritherapy) or as monotherapy. ViraferonPeg combination therapy (bitherapy or tritherapy) Bitherapy (ViraferonPeg with ribavirin): applies to all adult and paediatric patients 3 years of age and older. Tritherapy (ViraferonPeg with ribavirin and boceprevir): applies to adult patients with genotype 1 CHC. 40 Adults – Dose to be administered ViraferonPeg 1.5 micrograms/kg/week in combination with ribavirin capsules. The intended dose of 1.5 g/kg of ViraferonPeg to be used in combination with ribavirin may be delivered in weight categories with the ViraferonPeg strengths according to Table 1. Ribavirin capsules are to be administered orally each day in two divided doses with food (morning and evening). Table 1 Dosing for combination therapy* Body weight (kg) ViraferonPeg Ribavirin capsules ViraferonPeg strength (g/0.5 ml) Administer once weekly (ml) Total daily ribavirin dose (mg) Number of capsules (200 mg) < 40 50 0.5 800 4a 40-50 80 0.4 800 4a 51-64 80 0.5 800 4a 65-75 100 0.5 1,000 5b 76-80 120 0.5 1,000 5b 81-85 120 0.5 1,200 6c 86-105 150 0.5 1,200 6c > 105 150 0.5 1,400 7 d a: 2 morning, 2 evening b: 2 morning, 3 evening c: 3 morning, 3 evening d: 3 morning, 4 evening * Refer to the SmPC of boceprevir for details about the dose of boceprevir to be administered in tritherapy. Adults - Duration of treatment – Naïve patients Tritherapy: Refer to the SmPC for boceprevir. Bitherapy: Predictability of sustained virological response - Patients infected with virus genotype 1 who fail to achieve undetectable HCV-RNA or demonstrate adequate virological response at week 4 or 12 are highly unlikely to become sustained virological responders and should be evaluated for discontinuation (see also section 5.1).  Genotype 1: - Patients who have undetectable HCV-RNA at treatment week 12, treatment should be continued for another nine month period (i.e., a total of 48 weeks). - Patients with detectable but ≥ 2 log decrease in HCV-RNA level from baseline at treatment week 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, they should continue with full course of therapy (i.e. a total of 48 weeks). However, if HCV-RNA is still detectable at treatment week 24, discontinuation of therapy should be considered. - In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24, the treatment could either be stopped after this 24 week treatment course or pursued for an additional 24 weeks (i.e. overall 48 weeks treatment duration). However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration (see section 5.1).  Genotypes 2 or 3: It is recommended that all patients be treated with bitherapy for 24 weeks, except for HCV/HIV co-infected patients who should receive 48 weeks of treatment.  Genotype 4: In general, patients infected with genotype 4 are considered harder to treat and limited study data (n=66) indicate they are compatible with a duration of treatment with bitherapy as for genotype 1. 41 Adults - Duration of treatment - HCV/HIV co-infection Bitherapy: The recommended duration of treatment for HCV/HIV co-infected patients is 48 weeks with bitherapy, regardless of genotype. Predictability of response and non-response in HCV/HIV co-infection - Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV-RNA, has been shown to be predictive for sustained response. The negative predictive value for sustained response in HCV/HIV co-infected patients treated with ViraferonPeg in combination with ribavirin was 99 % (67/68; Study 1) (see section 5.1). A positive predictive value of 50 % (52/104; Study 1) was observed for HCV/HIV co-infected patients receiving bitherapy. Adults - Duration of treatment - Retreatment Tritherapy: Refer to the SmPC for boceprevir. Bitherapy: Predictability of sustained virological response - All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at week 12 should receive 48 weeks of bitherapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNA below the limits of detection) at week 12 are unlikely to become sustained virological responders after 48 weeks of therapy (see also section 5.1). Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been studied with pegylated interferon alfa-2b and ribavirin combination therapy. Paediatric population (bitherapy only) – Dose to be administered Dosing for children 3 years of age and older and adolescent patients is determined by body surface area for ViraferonPeg and by body weight for ribavirin. The recommended dose of ViraferonPeg is 60 g/m2/week subcutaneously in combination with ribavirin 15 mg/kg/day orally in two divided doses with food (morning and evening). Paediatric population (bitherapy only) - Duration of treatment  Genotype 1: The recommended duration of treatment with bitherapy is 1 year. By extrapolation from clinical data on combination therapy with standard interferon in paediatric patients (negative predictive value 96 % for interferon alfa–2b/ribavirin), patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders. Therefore, it is recommended that children and adolescent patients receiving ViraferonPeg/ribavirin combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if they have detectable HCV-RNA at treatment week 24.  Genotype 2 or 3: The recommended duration of treatment with bitherapy is 24 weeks.  Genotype 4: Only 5 children and adolescents with Genotype 4 were treated in the ViraferonPeg/ribavirin clinical trial. The recommended duration of treatment with bitherapy is 1 year. It is recommended that children and adolescent patients receiving ViraferonPeg/ribavirin combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if they have detectable HCV-RNA at treatment week 24. ViraferonPeg monotherapy – Adults Dose to be administered As monotherapy the ViraferonPeg regimen is 0.5 or 1.0 g/kg/week. The lowest ViraferonPeg strength available is 50 g/0.5 ml; therefore for patients prescribed 0.5 g/kg/week, doses must be adjusted by volume as shown in Table 2. For the 1.0 g/kg dose, similar volume adjustments can be made or alternate strengths can be used as shown in Table 2. ViraferonPeg monotherapy was not studied in HCV/HIV co-infected patients. 42 Table 2 Monotherapy dosing 0.5 g/kg 1.0 g/kg Body weight (kg) ViraferonPeg strength (g/0.5 ml) Administer once weekly (ml) ViraferonPeg strength (g/0.5 ml) Administer once weekly (ml) 30-35 50* 0.15 80 0.2 36-45 50 0.2 50 0.4 46-56 50 0.25 50 0.5 57-72 80 0.2 80 0.4 73-88 50 0.4 80 0.5 89-106 50 0.5 100 0.5 107-120** 80 0.4 120 0.5 Minimum delivery for pen is 0.2 ml. * Must use vial. ** For patients > 120 kg, the ViraferonPeg dose should be calculated based on the individual patient weight. This may require combinations of various ViraferonPeg dose strengths and volumes. Duration of treatment For patients who exhibit virological response at week 12, treatment should be continued for at least another three-month period (i.e., a total of six months). The decision to extend therapy to one year of treatment should be based on prognostic factors (e.g., genotype, age > 40 years, male gender, bridging fibrosis). Dose modification for all patients (monotherapy and combination therapy) If severe adverse reactions or laboratory abnormalities develop during treatment with ViraferonPeg monotherapy or combination therapy, the dosages of ViraferonPeg and/or ribavirin must be modified as appropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended. Boceprevir must not be administered in the absence of ViraferonPeg and ribavirin. As adherence might be of importance for outcome of therapy, the dose of ViraferonPeg and ribavirin should be kept as close as possible to the recommended standard dose. Guidelines were developed in clinical trials for dose modification. Combination therapy dose reduction guidelines Table 2a Dose modification guidelines for combination therapy based on laboratory parameters Laboratory values Reduce only ribavirin daily dose (see note 1) if: Reduce only ViraferonPeg dose (see note 2) if: Discontinue combination therapy if: Haemoglobin ≥ 8.5 g/dl, and < 10 g/dl - < 8.5 g/dl Adults: Haemoglobin in Patients with history of stable cardiac disease Children and adolescents: not applicable  2 g/dl decrease in haemoglobin during any four week period during treatment (permanent dose reduction) < 12 g/dl after four weeks of dose reduction Leukocytes - ≥ 1.0 x 109/l, and < 1.5 x 109/l l < 1.0 x 109/l Neutrophils - ≥ 0.5 x 109/l, and < 0.75 x 109/l < 0.5 x 109/l 43 Laboratory values Reduce only ribavirin daily dose (see note 1) if: Reduce only ViraferonPeg dose (see note 2) if: Discontinue combination therapy if: Platelets - ≥ 25 x 109/l, and < 50 x 109/l (adults) ≥ 50 x 109/l, and <70 x 109/l (children and adolescents) < 25 x 109/l (adults) < 50 x 109/l (children and adolescents) Bilirubin – direct - - 2.5 x ULN* Bilirubin – indirect > 5 mg/dl - > 4 mg/dl (for > 4 weeks) Serum Creatinine - - > 2.0 mg/dl Creatinine Clearance - - Discontinue ribavirin if CrCL < 50ml/min Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) - - 2 x baseline and > 10 x ULN* 2 x baseline and > 10 x ULN* * Upper limit of normal Note 1: In adult patients 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening. In children and adolescent patients 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day. Note 2: In adult patients 1st dose reduction of ViraferonPeg is to 1 µg/kg/week. If needed, 2nd dose reduction of ViraferonPeg is to 0.5 µg/kg/week. For patients on ViraferonPeg monotherapy: refer to monotherapy dose reduction guidelines section for dose reduction. In children and adolescent patients 1st dose reduction of ViraferonPeg is to 40 g/m2/week, 2nd dose reduction of ViraferonPeg is to 20 g/m2/week. Dose reduction of ViraferonPeg in adults may be accomplished by reducing the prescribed volume or by utilizing a lower dose strength as shown in Table 2b. Dose reduction of ViraferonPeg in children and adolescents is accomplished by modifying the recommended dose in a two-step process from the original starting dose of 60 g/m2/week, to 40 g/m2/week, then to 20 g/m2/week, if needed. 44 Table 2b Two-step dose reduction of ViraferonPeg in combination therapy in adults First dose reduction to ViraferonPeg 1 µg/kg Second dose reduction to ViraferonPeg 0.5 µg/kg Body weigh t (kg) ViraferonPe g strength (µg/0.5 ml) Amount of ViraferonPe g to administer (µg) Volume of ViraferonPe g to administer (ml) Body weigh t (kg) ViraferonPe g strength (µg/0.5 ml) Amount of ViraferonPe g to administer (µg) Volume of ViraferonPe g to administer (ml) < 40 50 35 0.35 < 40 50 20 0.2 40 – 50 120 48 0.2 40 – 50 50 25 0.25 51 – 64 80 56 0.35 51 – 64 80 32 0.2 65 – 75 100 70 0.35 65 – 75 50 35 0.35 76 – 85 80 80 0.5 76 – 85 120 48 0.2 86 - 105 120 96 0.4 86 – 105 50 50 0.5 > 105 150 105 0.35 > 105 80 64 0.4 ViraferonPeg monotherapy dose reduction guidelines in adults Dose modification guidelines for adult patients who use ViraferonPeg monotherapy are shown in Table 3a. Table 3a Dose modification guidelines for ViraferonPeg monotherapy in adults based on laboratory parameters Laboratory values Reduce ViraferonPeg to one-half dose if: Discontinue ViraferonPeg if: Neutrophils ≥ 0.5 x 109/l, and < 0.75 x 109/l < 0.5 x 109/l Platelets ≥ 25 x 109/l, and < 50 x 109/l < 25 x 109/l For adult patients who use 0.5 g/kg ViraferonPeg monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half as shown in Table 3b. Table 3b Reduced ViraferonPeg dose (0.25 g/kg) for the 0.5 g/kg monotherapy regimen in adults Body weight (kg) ViraferonPeg strength (g/0.5 ml) Amount of ViraferonPeg to administer (g) Volume of ViraferonPeg to administer (ml) 30-35 50* 8 0.08 36-45 50* 10 0.1 46-56 50* 13 0.13 57-72 80* 16 0.1 73-88 50 20 0.2 89-106 50 25 0.25 107-120** 80 32 0.2 Minimum delivery for pen is 0.2 ml. * Must use vial. ** For patients > 120 kg, the ViraferonPeg dose should be calculated based on the individual patient weight. This may require combinations of various ViraferonPeg dose strengths and volumes. 45 For adult patients who use 1.0 g/kg ViraferonPeg monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half or by utilizing a lower dose strength as shown in Table 3c. Table 3c Reduced ViraferonPeg dose (0.5 g/kg) for the 1.0 g/kg monotherapy regimen in adults Body weight (kg) ViraferonPeg strength (g/0.5 ml) Amount of ViraferonPeg to administer (g) Volume of ViraferonPeg to administer (ml) 30-35 50* 15 0.15 36-45 50 20 0.20 46-56 50 25 0.25 57-72 80 32 0.2 73-88 50 40 0.4 89-106 50 50 0.5 107-120** 80 64 0.4 Minimum delivery for pen is 0.2 ml. * Must use vial. ** For patients > 120 kg, the ViraferonPeg dose should be calculated based on the individual patient weight. This may require combinations of various ViraferonPeg dose strengths and volumes. Special populations Renal impairment Monotherapy ViraferonPeg should be used with caution in patients with moderate to severe renal impairment. In patients with moderate renal dysfunction (creatinine clearance 30-50 ml/minute), the starting dose of ViraferonPeg should be reduced by 25 %. Patients with severe renal dysfunction (creatinine clearance 15-29 ml/minute) should have the starting dose of ViraferonPeg reduced by 50 %. Data are not available for the use of ViraferonPeg in patients with creatinine clearance < 15 ml/minute (see section 5.2). Patients with severe renal impairment, including those on hemodialysis, should be closely monitored. If renal function decreases during treatment, ViraferonPeg therapy should be discontinued. Combination therapy Patients with creatinine clearance < 50 ml/minute must not be treated with ViraferonPeg in combination with ribavirin (see ribavirin SmPC). When administered in combination therapy, patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. Hepatic impairment The safety and efficacy of ViraferonPeg therapy has not been evaluated in patients with severe hepatic dysfunction, therefore ViraferonPeg must not be used for these patients. Elderly ( 65 years of age) There are no apparent age-related effects on the pharmacokinetics of ViraferonPeg. Data from elderly patients treated with a single dose of ViraferonPeg suggest no alteration in ViraferonPeg dose is necessary based on age (see section 5.2). Paediatric population ViraferonPeg can be used in combination with ribavirin in paediatric patients 3 years of age and older. Method of administration ViraferonPeg should be administered as a subcutaneous injection. For special handling information see section 6.6. Patients may self-inject ViraferonPeg if their physician determines that it is appropriate and with medical follow-up as necessary. 46 4.3 Contraindications - Hypersensitivity to the active substance or to any interferon or to any of the excipients listed in section 6.1; - A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see section 4.4); - Severe, debilitating medical conditions; - Autoimmune hepatitis or a history of autoimmune disease; - Severe hepatic dysfunction or decompensated cirrhosis of the liver; - Pre-existing thyroid disease unless it can be controlled with conventional treatment; - Epilepsy and/or compromised central nervous system (CNS) function; - HCV/HIV patients with cirrhosis and a Child-Pugh score ≥ 6. - Combination of ViraferonPeg with telbivudine. Paediatric population - Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicidal attempt. Combination therapy Also see SmPCs for ribavirin and boceprevir if ViraferonPeg is to be administered in combination therapy in patients with chronic hepatitis C. 4.4 Special warnings and precautions for use Psychiatric and Central Nervous System (CNS) Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during ViraferonPeg therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal or homicidal ideation is identified, it is recommended that treatment with ViraferonPeg be discontinued, and the patient followed, with psychiatric intervention as appropriate. Patients with existence of, or history of severe psychiatric conditions If treatment with peginterferon alfa-2b is judged necessary in adult patients with existence or history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition. - The use of ViraferonPeg in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Among children and adolescents treated with interferon alfa-2b in combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult patients, children and adolescents experienced other psychiatric adverse events (e.g. depression, emotional lability, and somnolence). Patients with substance use/abuse HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended. 47 Growth and development (children and adolescents) During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common. Long-term data available in children treated with the combination therapy of pegylated interferon/ribavirin are indicative of substantial growth retardation. Thirty two percent (30/94) of subjects demonstrated > 15 percentile decrease in height-for-age percentile 5 years after completion of therapy (see sections 4.8 and 5.1). Case by case benefit/risk assessment in children The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1). - It is important to consider that the combination therapy induced a growth inhibition, that resulted in reduced height in some patients. - This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV genotype and viral load). Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. Although data are limited, no evidence of long-term effects on sexual maturation was noted in the 5-year observational follow-up study. More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses for oncology indications. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of interferon alpha. All patients in the selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to commencing treatment. Acute hypersensitivity Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment with ViraferonPeg, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment. Cardiovascular system As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, receiving ViraferonPeg therapy require close monitoring. It is recommended that patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of ViraferonPeg therapy. There are no data in children or adolescents with a history of cardiac disease. Hepatic Failure ViraferonPeg increases the risk of hepatic decompensation and death in patients with cirrhosis. As with all interferons, discontinue treatment with ViraferonPeg in patients who develop prolongation of coagulation markers which might indicate liver decompensation. Liver enzymes and hepatic function should be closely monitored in cirrhotic patients. Pyrexia While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out. 48 Hydration Adequate hydration must be maintained in patients undergoing ViraferonPeg therapy since hypotension related to fluid depletion has been seen in some patients treated with alpha interferons. Fluid replacement may be necessary. Pulmonary changes Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients. Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events. Autoimmune disease The development of auto-antibodies and autoimmune disorders has been reported during treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Thyroid changes and section 4.8). Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8). Ocular changes Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, serous retinal detachment, and retinal artery or vein occlusion have been reported in rare instances after treatment with alpha interferons (see section 4.8). All patients should have a baseline eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt and complete eye examination. Periodic visual examinations are recommended during ViraferonPeg therapy, particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of ViraferonPeg should be considered in patients who develop new or worsening ophthalmological disorders. Thyroid changes Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of children treated with ViraferonPeg/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2 % had a transient decrease below the lower limit of normal. Prior to initiation of ViraferonPeg therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Determine TSH levels if, during the course of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, ViraferonPeg treatment may be continued if TSH levels can be maintained in the normal range by medicine. Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH). Metabolic disturbances Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended. HCV/HIV Co-infection Mitochondrial toxicity and lactic acidosis Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding ViraferonPeg and ribavirin to HAART therapy (see ribavirin SmPC). 49 Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentration. Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed. Haematological abnormalities in HCV/HIV co-infected patients HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and HAART may be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed by dose reduction, close monitoring of haematological parameters should be undertaken in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8). Patients treated with ViraferonPeg and ribavirin combination therapy and zidovudine are at increased risk of developing anaemia and therefore the concomitant use of this combination with zidovudine is not recommended (see section 4.5). Patients with low CD4 counts In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in subjects with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of patients with low CD4 counts. Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ViraferonPeg and ribavirin. HCV/HBV Coinfection Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co- infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation appears to be low. All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; patients co-infected with hepatitis B and C must then be monitored and managed according to current clinical guidelines. Dental and periodontal disorders Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving ViraferonPeg and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of ViraferonPeg and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards. Organ transplant recipients The safety and efficacy of ViraferonPeg alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported. Other Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of ViraferonPeg in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk. 50 Laboratory tests Standard haematologic tests, blood chemistry and a test of thyroid function must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of ViraferonPeg therapy are:  Platelets  100,000/mm3  Neutrophil count  1,500/mm3  TSH level must be within normal limits Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2). Long term maintenance monotherapy It has been demonstrated in a clinical study that peginterferon alfa-2b at low-dose (0.5 μg/kg/week) is not effective in long term maintenance monotherapy (for a mean duration of 2.5 years) for the prevention of disease progression in non responders with compensated cirrhosis. No statistically significant effect on the time to development of the first clinical event (liver decompensation, hepatocellular carcinoma, death and/or liver transplantation) was observed as compared to the absence of treatment. ViraferonPeg should therefore not be used as long term maintenance monotherapy. Important information about some of the ingredients of ViraferonPeg Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicine. This medicinal product contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially "sodium-free". 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults. Telbivudine A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SmPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of ViraferonPeg with telbivudine is contraindicated (see section 4.3). Methadone In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve to peginterferon alfa-2b, addition of 1.5 microgram/kg/week of ViraferonPeg subcutaneously for 4 weeks increased R-methadone AUC by approximately 15 % (95 % Cl for AUC ratio estimate 103 – 128 %). The clinical significance of this finding is unknown; however, patients should be monitored for signs and symptoms of increased sedative effect, as well as respiratory depression. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered. Effect of Peginterferon alfa-2b on Co-administered Medicines The potential interaction of peginterferon alfa-2b (ViraferonPeg) on substrates of metabolic enzymes was evaluated in 3 multiple-dose clinical pharmacology studies. In these studies, the effects of multiple-dose regimens of peginterferon alfa-2b (ViraferonPeg) were investigated in Hepatitis C subjects (1.5 mcg/week) or healthy subjects (1 mcg/week or 3 mcg/week) (Table 4). A clinically significant pharmacokinetic interaction was not observed between peginterferon alfa-2b (ViraferonPeg) and tolbutamide, midazolam or dapsone; therefore, no dosing adjustment is necessary when peginterferon alfa-2b (ViraferonPeg) is administered with medicines metabolized by CYP2C9, CYP3A4 and N-acetyltransferase. Concomitant administration of peginterferon alfa-2b (ViraferonPeg) 51 with caffeine or desipramine modestly increased the exposure of caffeine and desipramine. When patients are administered ViraferonPeg with medications metabolized by CYP1A2 or CYP2D6, the extent of the decrease in cytochrome P 450 activity is unlikely to have a clinical impact, except with medicines which have a narrow therapeutic margin (Table 5). Table 4 Effect of Peginterferon alfa-2b on Co-administered Medicines Co-administered Medicine Dose of peginterferon alfa-2b Study Population Geometric Mean Ratio (Ratio with/without peginterferon alfa-2b) AUC (90% CI) Cmax (90% CI) Caffeine (CYP1A2 substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=22) 1.39 (1.27, 1.51) 1.02 (0.95, 1.09) 1 mcg/kg/week (4 weeks) Healthy Subjects (N=24) 1.18 (1.07, 1.31) 1.12 (1.05, 1.19) 3 mcg/kg/week (2 weeks) Healthy Subjects (N=13) 1.36 (1.25, 1.49) 1.16 (1.10, 1.24) Tolbutamide (CYP2C9 substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=22) 1.1# (0.94, 1.28) NA 1 mcg/kg/week (4 weeks) Healthy Subjects (N=24) 0.90# (0.81, 1.00) NA 3 mcg/kg/week (2 weeks) Healthy Subjects (N=13) 0.95 (0.89, 1.01) 0.99 (0.92, 1.07) Dextromethorphan hydrobromide (CYP2D6 and CYP3A substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=22) 0.96## (0.73, 1.26) NA 1 mcg/kg/week (4 weeks) Healthy Subjects (N=24) 2.03# (1.55, 2.67) NA Desipramine (CYP2D6 substrate) 3 mcg/kg/week (2 weeks) Healthy Subjects (N=13) 1.30 (1.18, 1.43) 1.08 (1.00, 1.16) Midazolam (CYP3A4 substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=24) 1.07 (0.91, 1.25) 1.12 (0.94, 1.33) 1 mcg/kg/week (4 weeks) Healthy Subjects (N=24) 1.07 (0.99, 1.16) 1.33 (1.15, 1.53) 3 mcg/kg/week (2 weeks) Healthy Subjects (N=13) 1.18 (1.06, 1.32) 1.24 (1.07, 1.43) Dapsone (N-acetyltransferase substrate) 1.5 mcg/kg/week (4 weeks) Chronic Hepatitis C Subjects (N=24) 1.05 (1.02, 1.08) 1.03 (1.00, 1.06) # Calculated from urine data collected over an interval of 48-hours ## Calculated from urine data collected over an interval of 24-hours 52 Table 5 Precautions for co-administration (ViraferonPeg should be administered with care when co-administered with the following medicines) Medicines Signs, Symptoms, and Treatment Mechanism and Risk Factors Theophylline Co-administration of theophylline with the product (ViraferonPeg) may increase the blood concentrations of theophylline. Careful co-administration of theophylline with the product (ViraferonPeg) is recommended. Package inserts of theophylline should be referred to when co-administering with the product (ViraferonPeg) Metabolism of theophylline is suppressed by inhibitory action of the product (ViraferonPeg) on CYP1A2. Thioridazine Co-administration of thioridazine with the product (ViraferonPeg) may increase the blood concentrations of thioridazine. Careful co-administration of thioridazine with the product (ViraferonPeg) is recommended. Package inserts of thioridazine should be referred to when co-administering with the product (ViraferonPeg) Metabolism of thioridazine is suppressed by inhibitory action of the product (ViraferonPeg) on CYP2D6. Theophylline, Antipyrine, Warfarin Elevation of blood concentrations of these medicines has been reported when administered in combination with other interferon preparations and therefore care should be taken. Metabolism of other medicines in the liver may be suppressed. Zidovudine When administered in combination with other interferon preparations, suppressive effect on bone marrow function may be strengthened and aggravation of blood cell reduction such as white blood cells decreased may occur. Mechanism of action is unknown, but it is considered that both medicines have bone marrow depressive effects. Immuno-suppressive therapy When administered in combination with other interferon preparations, effect of immunosuppressive therapy may be weakened in transplant (kidney, bone marrow, etc.) patients. It is considered that graft rejection reactions may be induced. No pharmacokinetic interactions were noted between ViraferonPeg and ribavirin in a multiple-dose pharmacokinetic study. HCV/HIV Co-infection Nucleoside analogues Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see ribavirin SmPC). 53 Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV, although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine-induced anaemia. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/contraception in males and females ViraferonPeg is recommended for use in fertile women only when they are using effective contraception during the treatment. Combination therapy with ribavirin Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking ViraferonPeg in combination with ribavirin. Females of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SmPC). Pregnancy There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Interferon alfa-2b has been shown to be abortifacient in primates. ViraferonPeg is likely to also cause this effect. The potential risk in humans is unknown. ViraferonPeg is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Combination therapy with ribavirin Ribavirin causes serious birth defects when administered during pregnancy, therefore ribavirin therapy is contraindicated in women who are pregnant. Breast-feeding It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding should be discontinued prior to initiation of treatment. Fertility There are no data available regarding potential effects of ViraferonPeg treatment on male or female fertility. 4.7 Effects on ability to drive and use machines Patients who develop fatigue, somnolence or confusion during treatment with ViraferonPeg are cautioned to avoid driving or operating machines. 4.8 Undesirable effects Adults Tritherapy Refer to the SmPC for boceprevir. Bitherapy and monotherapy Summary of the safety profile The most common treatment-related adverse reactions reported during clinical trials with ViraferonPeg in combination with ribavirin in adults, seen in more than half of the study subjects, were fatigue, headache, and injection site reaction. Additional adverse reactions reported in more than 54 25 % of subjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight decreased, depression, rash and irritability. The most frequently reported adverse reactions were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy. Fatigue, alopecia, pruritus, nausea, anorexia, weight decreased, irritability and insomnia occur at a notably lower rate in patients treated with ViraferonPeg monotherapy compared to those treated with combination therapy (see Table 6). Tabulated summary of adverse reactions The following treatment-related adverse reactions were reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including ViraferonPeg monotherapy or ViraferonPeg/ribavirin. These reactions are listed in table 6 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 6 Adverse reactions reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including ViraferonPeg monotherapy or ViraferonPeg + ribavirin Infections and infestations Very common: Viral infection*, pharyngitis* Common: Bacterial infection (including sepsis), fungal infection, influenza, upper respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis Uncommon: Injection site infection, lower respiratory tract infection Not known: Hepatitis B reactivation in HCV/HBV co-infected patients Blood and lymphatic system disorders Very common: Anaemia, neutropenia Common: Haemolytic anaemia, leukopenia, thrombocytopenia, lymphadenopathy Very rare: Aplastic anaemia Not known: Aplasia pure red cell Immune system disorders Uncommon: Drug hypersensitivity Rare: Sarcoidosis Not known: Acute hypersensitivity reactions including angioedema, anaphylaxis and anaphylactic reactions including anaphylactic shock, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, systemic lupus erythematosus Endocrine disorders Common: Hypothyroidism, hyperthyroidism Metabolism and nutrition disorders Very common: Anorexia Common: Hypocalcemia, hyperuricemia, dehydration, increased appetite Uncommon: Diabetes mellitus, hypertriglyceridaemia Rare: Diabetic ketoacidosis Psychiatric disorders Very common: Depression, anxiety*, emotional lability*, concentration impaired, insomnia Common: Aggression, agitation, anger, mood altered, abnormal behaviour, nervousness, sleep disorder, libido decreased, apathy, abnormal dreams, crying 55 Uncommon: Suicide, suicide attempt, suicidal ideation, psychosis, hallucination, panic attack Rare: Bipolar disorders Not known: Homicidal ideation, mania Nervous system disorders Very common: Headache, dizziness Common: Amnesia, memory impairment, syncope, migraine, ataxia, confusion, neuralgia, paraesthesia, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia Uncommon: Neuropathy, neuropathy peripheral Rare: Convulsion Very rare: Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy Not known: Facial palsy, mononeuropathies Eye disorders Common: Visual disturbance, vision blurred, photophobia, conjunctivitis, eye irritation, lacrimal disorder, eye pain, dry eye Uncommon: Retinal exudates Rare: Loss of visual acuity or visual fields, retinal haemorrhage, retinopathy, retinal artery occlusion, retinal vein occlusion, optic neuritis, papilloedema, macular oedema Not known: Serous retinal detachment Ear and labyrinth disorders Common: Hearing impaired/loss, tinnitus, vertigo Uncommon Ear pain Cardiac disorders Common: Palpitations, tachycardia Uncommon: Myocardial infarction Rare: Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis Very rare: Cardiac ischaemia Not known: Pericardial effusion Vascular disorders Common: Hypotension, hypertension, flushing Rare: Vasculitis Respiratory, thoracic and mediastinal disorders Very common: Dyspnoea*, cough* Common: Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain Very rare: Interstitial lung disease Not known: Pulmonary fibrosis, pulmonary arterial hypertension# Gastrointestinal disorders Very common: Vomiting*, nausea, abdominal pain, diarrhoea, dry mouth* Common: Dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration, glossodynia, gingival bleeding, constipation, flatulence, haemorrhoids, cheilitis, abdominal distension, gingivitis, glossitis, tooth disorder Uncommon: Pancreatitis, oral pain Rare: Colitis ischaemic Very rare: Colitis ulcerative Not known Tongue pigmentation 56 Hepatobiliary disorders Common: Hyperbilirubinemia, hepatomegaly Skin and subcutaneous tissue disorders Very common: Alopecia, pruritus*, dry skin*, rash* Common: Psoriasis, photosensitivity reaction, rash maculo-papular, dermatitis, erythematous rash, eczema, night sweats, hyperhidrosis, acne, furuncle, erythema, urticaria, abnormal hair texture, nail disorder Rare: Cutaneous sarcoidosis Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Musculoskeletal and connective tissue disorders Very common: Myalgia, arthralgia, musculoskeletal pain Common: Arthritis, back pain, muscle spasms, pain in extremity Uncommon: Bone pain, muscle weakness Rare: Rhabdomyolysis, myositis, rheumatoid arthritis Renal and urinary disorders Common: Micturition frequency, polyuria, urine abnormality Rare: Renal failure, renal insufficiency Reproductive system and breast disorders Common: Amenorrhoea, breast pain, menorrhagia, menstrual disorder, ovarian disorder, vaginal disorder, sexual dysfunction, prostatitis, erectile dysfunction General disorders and administration site conditions Very common: Injection site reaction*, injection site inflammation, fatigue, asthenia, irritability, chills, pyrexia, influenza like illness, pain Common: Chest pain, chest discomfort, injection site pain, malaise, face oedema, oedema peripheral, feeling abnormal, thirst Rare: Injection site necrosis Investigations Very common: Weight decreased *These adverse reactions were common (≥1/100 to < 1/10) in clinical trials in patients treated with ViraferonPeg monotherapy. #Class label for interferon products, see below Pulmonary arterial hypertension. Description of selected adverse reactions in adults Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of ViraferonPeg in combination with ribavirin (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]). In a clinical trial, approximately 1.2 % of patients treated with ViraferonPeg or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide (see section 4.4). Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients without prior evidence of cardiac disease. Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa. 57 Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies (including macular oedema), retinal haemorrhages, retinal artery or vein occlusion, retinal exudates, loss of visual acuity or visual field, optic neuritis, and papilloedema (see section 4.4). A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada syndrome (see also section 4.4). HCV/HIV co-infected patients Summary of the safety profile For HCV/HIV co-infected patients receiving ViraferonPeg in combination with ribavirin, other undesirable effects (that were not reported in mono-infected patients) which have been reported in the larger studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %). Description of selected adverse reactions Mitochondrial toxicity Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated ribavirin for co-HCV infection (see section 4.4). Laboratory values for HCV/HIV co-infected patients Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving ViraferonPeg in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving ViraferonPeg in combination with ribavirin. Anaemia (hemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with ViraferonPeg in combination with ribavirin. CD4 lymphocytes decrease Treatment with ViraferonPeg in combination with ribavirin was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of ViraferonPeg in combination with ribavirin had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N= 25) are available in co-infected patients with CD4+ cell counts < 200/µl (see section 4.4). Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ViraferonPeg in combination with ribavirin. Paediatric population Summary of the safety profile In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of ViraferonPeg and ribavirin, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with ViraferonPeg and ribavirin, growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients). 58 At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles respectively, and 20 % of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 subjects enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow- up among subjects treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40 % of subjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of the 5 year long-term follow-up compared to pre-treatment baseline percentile. Eleven percent of subjects (5/46) treated for 24 weeks and 13 % of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight- for-age percentiles decreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4). In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH. Tabulated summary of adverse reactions The following treatment-related adverse reactions were reported in the study in children and adolescent patients treated with ViraferonPeg in combination with ribavirin. These reactions are listed in Table 7 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 7 Adverse reactions very commonly, commonly and uncommonly reported in the clinical trial in children and adolescent patients treated with ViraferonPeg in combination with ribavirin Infections and infestations Common: Fungal infection, influenza, oral herpes, otitis media, pharyngitis streptococcal, nasopharyngitis, sinusitis Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Blood and lymphatic system disorders Very common: Anaemia, leucopenia, neutropenia Common: Thrombocytopenia, lymphadenopathy Endocrine disorders Common: Hypothyroidism Metabolism and nutrition disorders Very common: Anorexia, decreased appetite 59 Psychiatric disorders Common: Suicidal ideation§, suicide attempt§, depression, aggression, affect lability, anger, agitation, anxiety, mood altered, restlessness, nervousness, insomnia Uncommon: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare Nervous system disorders Very common: Headache, dizziness Common: Dysgeusia, syncope, disturbance in attention, somnolence, poor quality sleep Uncommon: Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotor hyperactivity, tremor Eye disorders Common: Eye pain Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia Ear and labyrinth disorders Common: Vertigo Cardiac disorders Common: Palpitations, tachycardia Vascular disorders Common: Flushing Uncommon: Hypotension, pallor Respiratory, thoracic and mediastinal disorders Common: Cough, epistaxis, pharyngolaryngeal pain Uncommon: Wheezing, nasal discomfort, rhinorrhoea Gastrointestinal disorders Very common: Abdominal pain, abdominal pain upper, vomiting, nausea Common: Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomach discomfort, oral pain Uncommon: Dyspepsia, gingivitis Hepatobiliary disorders Uncommon: Hepatomegaly Skin and subcutaneous tissue disorders Very common: Alopecia, dry skin Common: Pruritus, rash, rash erythematous, eczema, acne, erythema Uncommon: Photosensitivity reaction, rash maculo-papular, skin exfoliation, pigmentation disorder, dermatitis atopic, skin discolouration Musculoskeletal and connective tissue disorders Very common: Myalgia, arthralgia Common: Musculoskeletal pain, pain in extremity, back pain Uncommon: Muscle contracture, muscle twitching Renal and urinary disorders Uncommon: Proteinuria Reproductive system and breast disorders Uncommon: Female: Dysmenorrhoea General disorders and administration site conditions Very common: Injection site erythema, fatigue, pyrexia, rigors, influenza-like illness, asthenia, pain, malaise, irritability 60 Common: Injection site reaction, injection site pruritus, injection site rash injection site dryness, injection site pain, feeling cold Uncommon: Chest pain, chest discomfort, facial pain Investigations Very common: Growth rate decrease (height and/or weight decrease for age) Common: Blood thyroid stimulating hormone increased, thyroglobulin increased Uncommon: Anti-thyroid antibody positive Injury and poisoning Uncommon: Contusion §class effect of interferon-alfa containing products – reported with standard interferon therapy in adult and paediatric patients; with ViraferonPeg reported in adult patients. Description of selected adverse reactions in children and adolescents Most of the changes in laboratory values in the ViraferonPeg/ribavirin clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with ViraferonPeg used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Doses up to 10.5 times the intended dose have been reported. The maximum daily dose reported is 1,200 µg for one day. In general, the adverse events seen in overdose cases involving ViraferonPeg are consistent with the known safety profile for ViraferonPeg; however, the severity of the events may be increased. Standard methods to increase elimination of the medicinal product, e.g., dialysis, have not been shown to be useful. No specific antidote for ViraferonPeg is available; therefore, symptomatic treatment and close observation of the patient are recommended in cases of overdose. If available, prescribers are advised to consult with a poison control centre (PCC). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB10. Recombinant interferon alfa-2b is covalently conjugated with monomethoxy polyethylene glycol at an average degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 31,300 daltons of which the protein moiety constitutes approximately 19,300. Mechanism of action In vitro and in vivo studies suggest that the biological activity of ViraferonPeg is derived from its interferon alfa-2b moiety. Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Studies with other interferons have demonstrated species specificity. However, certain monkey species, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 61 Once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virus- infected cells, suppression of cell proliferation and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon’s therapeutic effects. Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are unable to leave the cell. Pharmacodynamic effects ViraferonPeg pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examining changes in oral temperature, concentrations of effector proteins such as serum neopterin and 2’5’-oligoadenylate synthetase (2’5’-OAS), as well as white cell and neutrophil counts. Subjects treated with ViraferonPeg showed mild dose-related elevations in body temperature. Following single doses of ViraferonPeg between 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related manner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of ViraferonPeg. Clinical efficacy and safety – Adults Tritherapy with ViraferonPeg, ribavirin and boceprevir Refer to the SmPC for boceprevir. Monotherapy with ViraferonPeg and bitherapy with ViraferonPeg and ribavirin Naïve patients Two pivotal trials have been conducted, one (C/I97-010) with ViraferonPeg monotherapy; the other (C/I98-580) with ViraferonPeg in combination with ribavirin. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction (PCR) assay (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT. In the ViraferonPeg monotherapy trial, a total of 916 naïve chronic hepatitis C patients were treated with ViraferonPeg (0.5, 1.0 or 1.5 micrograms/kg/week) for one year with a follow-up period of six months. In addition, 303 patients received interferon alfa-2b (3 million International Units [MIU] three times a week) as a comparator. This study showed that ViraferonPeg was superior to interferon alfa-2b (Table 8). In the ViraferonPeg combination trial, 1,530 naïve patients were treated for one year with one of the following combination regimens: - ViraferonPeg (1.5 micrograms/kg/week) + ribavirin (800 mg/day), (n = 511). - ViraferonPeg (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) + ribavirin (1,000/1,200 mg/day), (n = 514). - Interferon alfa-2b (3 MIU three times a week) + ribavirin (1,000/1,200 mg/day) (n = 505). In this trial, the combination of ViraferonPeg (1.5 micrograms/kg/week) and ribavirin was significantly more effective than the combination of interferon alfa-2b and ribavirin (Table 8), particularly in patients infected with Genotype 1 (Table 9). Sustained response was assessed by the response rate six months after the cessation of treatment. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of ribavirin administered in combination with ViraferonPeg or interferon alfa-2b. In those patients that received > 10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, 62 response rates were significantly higher than in those patients that received  10.6 mg/kg ribavirin (Table 9), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher. Table 8 Sustained virological response (% patients HCV negative) ViraferonPeg monotherapy ViraferonPeg + ribavirin Treatment regimen P 1.5 P 1.0 P 0.5 I P 1.5/R P 0.5/ R I/R Number of patients 304 297 315 303 511 514 505 Response at end of treatment 49 % 41 % 33 % 24 % 65 % 56 % 54 % Sustained response 23 %* 25 % 18 % 12 % 54 %** 47 % 47 % P 1.5 ViraferonPeg 1.5 micrograms/kg P 1.0 ViraferonPeg 1.0 microgram/kg P 0.5 ViraferonPeg 0.5 microgram/kg I Interferon alfa-2b 3 MIU P 1.5/R ViraferonPeg (1.5 micrograms/kg) + ribavirin (800 mg) P 0.5/R ViraferonPeg (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg) I/R Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg) * p < 0.001 P 1.5 vs. I ** p = 0.0143 P 1.5/R vs. I/R Table 9 Sustained response rates with ViraferonPeg + ribavirin (by ribavirin dose, genotype and viral load) HCV Genotype Ribavirin dose (mg/kg) P 1.5/R P 0.5/R I/R All Genotypes All 54 % 47 % 47 %  10.6 50 % 41 % 27 % > 10.6 61 % 48 % 47 % Genotype 1 All 42 % 34 % 33 %  10.6 38 % 25 % 20 % > 10.6 48 % 34 % 34 % Genotype 1  600,000 IU/ml All 73 % 51 % 45 %  10.6 74 % 25 % 33 % > 10.6 71 % 52 % 45 % Genotype 1 > 600,000 IU/ml All 30 % 27 % 29 %  10.6 27 % 25 % 17 % > 10.6 37 % 27 % 29 % Genotype 2/3 All 82 % 80 % 79 %  10.6 79 % 73 % 50 % > 10.6 88 % 80 % 80 % P 1.5/R ViraferonPeg (1.5 micrograms/kg) + ribavirin (800 mg) P 0.5/R ViraferonPeg (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg) I/R Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg) In the ViraferonPeg monotherapy study, the Quality of Life was generally less affected by 0.5 microgram/kg of ViraferonPeg than by either 1.0 microgram/kg of ViraferonPeg once weekly or 3 MIU of interferon alfa-2b three times a week. In a separate trial, 224 patients with genotype 2 or 3 received ViraferonPeg, 1.5 micrograms/kg subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg p.o. for 6 months (based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (Table 10). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4). 63 Table 10 Virologic response at end of treatment, Sustained Virologic Response and relapse by HCV Genotype and viral load* ViraferonPeg 1.5 g/kg once weekly plus Ribavirin 800-1,400 mg/day End of treatment response Sustained Virologic Response Relapse All subjects 94 % (211/224) 81 % (182/224) 12 % (27/224) HCV 2 100 % (42/42) 93 % (39/42) 7 % (3/42)  600,000 IU/ml 100 % (20/20) 95 % (19/20) 5 % (1/20) > 600,000 IU/ml 100 % (22/22) 91 % (20/22) 9 % (2/22) HCV 3 93 % (169/182) 79 % (143/182) 14 % (24/166)  600,000 IU/ml 93 % (92/99) 86 % (85/99) 8 % (7/91) > 600,000 IU/ml 93 % (77/83) 70 % (58/83) 23 % (17/75) * Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow-up. The 6 month treatment duration in this trial was better tolerated than one year of treatment in the pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %. In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received ViraferonPeg, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48). Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment). A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two ViraferonPeg/ribavirin regimens [ViraferonPeg 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 11). Table 11 Virologic response at treatment week 12, end of treatment response, relapse rate *and Sustained Virologic Response (SVR) Treatment group % (number) of patients ViraferonPeg 1.5 µg/kg + ribavirin ViraferonPeg 1 µg/kg + ribavirin peginterferon alfa-2a 180 µg + ribavirin Undetectable HCV- RNA at treatment week 12 40 (407/1,019) 36 (366/1,016) 45 (466/1,035) End of treatment response 53 (542/1,019) 49 (500/1,016) 64 (667/1,035) Relapse 24 (123/523) 20 (95/475) 32 (193/612) SVR 40 (406/1,019) 38 (386/1,016) 41 (423/1,035) 64 Treatment group % (number) of patients SVR in patients with undetectable HCV- RNA at treatment week 12 81 (328/407) 83 (303/366) 74 (344/466) * (HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml) Lack of early virologic response by Treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from baseline) was a criterion for discontinuation of treatment. In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with ViraferonPeg (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic response rate compared to ViraferonPeg 1 µg/kg dose. At the ViraferonPeg 1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml, and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %. Predictability of sustained virological response – Naïve patients: Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA.Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 12). Table 12 Predictive value of in-treatment Virologic Response while on ViraferonPeg 1.5 µg/kg/ribavirin 800-1,400 mg combination therapy Negative Positive No response at treatment week No sustained response Negative predictive value Response at treatment week Sustained response Positive predictive value Genotype 1* By week 4*** (n=950) HCV-RNA negative 834 539 65 % (539/834) 116 107 92 % (107/116) HCV-RNA negative or ≥ 1 log decrease in viral load 220 210 95 % (210/220) 730 392 54 % (392/730) By week 12*** (n=915) HCV-RNA negative 508 433 85 % (433/508) 407 328 81 % (328/407) HCV-RNA negative or ≥ 2 log decrease in viral load 206 205 N/A† 709 402 57 % (402/709) 65 Negative Positive No response at treatment week No sustained response Negative predictive value Response at treatment week Sustained response Positive predictive value Genotype 2, 3** By week 12 (n= 215) HCV-RNA negative or ≥ 2 log decrease in viral load 2 1 50 % (1/2) 213 177 83 % (177/213) *Genotype 1 receive 48 weeks treatment **Genotype 2, 3 receive 24 weeks treatment ***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or week 12. † These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2log10 decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2log10 from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy. The negative predictive value for sustained response in patients treated with ViraferonPeg in monotherapy was 98 %. HCV/HIV Co-infected patients Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 13. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either ViraferonPeg (1.5 µg/kg/week) plus ribavirin (800 mg/day) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either ViraferonPeg (100 or 150 µg/week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6-month follow-up period. 66 Table 13 Sustained virological response based on genotype after ViraferonPeg in combination with Ribavirin in HCV/HIV Co-infected patients Study 11 Study 22 ViraferonPeg (1.5 µg/kg/ week) + ribavirin (800 mg) Interferon alfa-2b (3 MIU TIW) + ribavirin (800 mg) p valuea ViraferonPeg (100 or 150c µg/week) + ribavirin (800- 1,200 mg)d Interferon alfa-2b (3 MIU TIW) + ribavirin (800- 1,200 mg)d p valueb All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017 Genotype 1, 4 17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007 Genotype 2, 3 44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730 MIU = million international units; TIW = three times a week. a: p value based on Cochran-Mantel Haenszel Chi square test. b: p value based on chi-square test. c: subjects < 75 kg received 100 µg/week ViraferonPeg and subjects ≥ 75 kg received 150 µg/week ViraferonPeg. d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg. 1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848. 2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36. Histological response: Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with ViraferonPeg in combination with ribavirin. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3. ViraferonPeg/ribavirin retreatment of prior treatment failures In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with ViraferonPeg, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment). Patients who were HCV-RNA negative at treatment week 12 continued treatment for 48 weeks and were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV- RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 14). 67 Table 14 Rates of response to retreatment in prior treatment failures Patients with undetectable HCV–RNA at treatment week 12 and SVR upon retreatment interferon alpha/ribavirin peginterferon alpha/ribavirin Overall population* Response week 12 % (n/N) SVR % (n/N) 99% CI Response week 12 % (n/N) SVR % (n/N) 99% CI SVR % (n/N) 99 % CI Overall 38.6 (549/1,423) 59.4 (326/549) 54.0,64.8 31.5 (272/863) 50.4 (137/272) 42.6, 58.2 21.7 (497/2,293) 19.5, 23.9 Prior response Relapse 67.7 (203/300) 59.6 (121/203) 50.7, 68.5 58.1 (200/344) 52.5 (105/200) 43.4, 61.6 37.7 (243/645) 32.8, 42.6 Genotype 1/4 59.7 (129/216) 51.2 (66/129) 39.8, 62.5 48.6 (122/251) 44.3 (54/122) 32.7, 55.8 28.6 (134/468) 23.3, 34.0 Genotype 2/3 88.9 (72/81) 73.6 (53/72) (60.2, 87.0) 83.7 (77/92) 64.9 (50/77) 50.9, 78.9 61.3 (106/173) 51.7, 70.8 NR 28.6 (258/903) 57.0 (147/258) 49.0, 64.9 12.4 (59/476) 44.1 (26/59) 27.4, 60.7 13.6 (188/1,385) 11.2, 15.9 Genotype 1/4 23.0 (182/790) 51.6 (94/182) 42.1, 61.2 9.9 (44/446) 38.6 (17/44) 19.7, 57.5 9.9 (123/1,242) 7.7, 12.1 Genotype 2/3 67.9 (74/109) 70.3 (52/74) 56.6, 84.0 53.6 (15/28) 60.0 (9/15) 27.4, 92.6 46.0 (63/137) 35.0, 57.0 Genotype 1 30.2 (343/1,135) 51.3 (176/343) 44.4, 58.3 23.0 (162/704) 42.6 (69/162) 32.6, 52.6 14.6 (270/1,846) 12.5, 16.7 2/3 77.1 (185/240) 73.0 (135/185) 64.6, 81.4 75.6 (96/127) 63.5 (61/96) 50.9, 76.2 55.3 (203/367) 48.6, 62.0 4 42.5 (17/40) 70.6 (12/17) 42.1, 99.1 44.4 (12/27) 50.0 (6/12) 12.8, 87.2 28.4 (19/67) 14.2, 42.5 METAVIR Fibrosis score F2 46.0 (193/420) 66.8 (129/193) 58.1, 75.6 33.6 (78/232) 57.7 (45/78) 43.3, 72.1 29.2 (191/653) 24.7, 33.8 F3 38.0 (163/429) 62.6 (102/163) 52.8, 72.3 32.4 (78/241) 51.3 (40/78) 36.7, 65.9 21.9 (147/672) 17.8, 26.0 F4 33.6 (192/572) 49.5 (95/192) 40.2, 58.8 29.7 (116/390) 44.8 (52/116) 32.9, 56.7 16.5 (159/966) 13.4, 19.5 68 Patients with undetectable HCV–RNA at treatment week 12 and SVR upon retreatment interferon alpha/ribavirin peginterferon alpha/ribavirin Overall population* Response week 12 % (n/N) SVR % (n/N) 99% CI Response week 12 % (n/N) SVR % (n/N) 99% CI SVR % (n/N) 99 % CI Baseline Viral Load HVL (>600,000 IU/ml) 32.4 (280/864) 56.1 (157/280) 48.4, 63.7 26.5 (152/573) 41.4 (63/152) 31.2, 51.7 16.6 (239/1,441) 14.1, 19.1 LVL (≤600,000 IU/ml) 48.3 (269/557) 62.8 (169/269) 55.2, 70.4 41.0 (118/288) 61.0 (72/118) 49.5, 72.6 30.2 (256/848) 26.1, 34.2 NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment. Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory *Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed. Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels at week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior failure on therapy with nonpegylated interferon or pegylated interferon and negative at week 12, the sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients the SVR was 12 %. Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a week 12 response to retreatment than non-responders to nonpegylated interferon alpha/ribavirin (12.4 % vs. 28.6 %). However, if a week 12 response was achieved, there was little difference in SVR regardless of prior treatment or prior response. Long-term efficacy data-Adults A large long-term follow-up study enrolled 567 patients after treatment in a prior study with ViraferonPeg (with or without ribavirin). The purpose of the study was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. 327 patients completed at least 5 years of long-term follow-up and only 3 out of 366 sustained responders relapsed during the study. The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 99 % (95 % CI: 98-100 %). SVR after treatment of chronic HCV with ViraferonPeg (with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical “cure” from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma). Clinical efficacy and safety – paediatric population Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with ribavirin 15 mg/kg per day plus ViraferonPeg 60 g/m2 once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ViraferonPeg with ribavirin needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 15. 69 Table 15 Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects n = 107 24 weeks 48 weeks All Genotypes 26/27 (96 %) 44/80 (55 %) Genotype 1 - 38/72 (53 %) Genotype 2 14/15 (93 %) - Genotype 3c 12/12 (100 %) 2/3 (67 %) Genotype 4 - 4/5 (80 %) a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment lower limit of detection=125IU/ml b: n = number of responders/number of subjects with given genotype, and assigned treatment duration. c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment. Long-term efficacy data - paediatric population A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR had relapsed during the 5 years of follow-up. 5.2 Pharmacokinetic properties ViraferonPeg is a well characterized polyethylene glycol-modified (“pegylated”) derivative of interferon alfa-2b and is predominantly composed of monopegylated species. The plasma half-life of ViraferonPeg is prolonged compared with nonpegylated interferon alfa-2b. ViraferonPeg has a potential to depegylate to free interferon alfa-2b. The biologic activity of the pegylated isomers is qualitatively similar, but weaker than free interferon alfa-2b. Following subcutaneous administration, maximal serum concentrations occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours post-dose. ViraferonPeg Cmax and AUC measurements increase in a dose-related manner. Mean apparent volume of distribution is 0.99 l/kg. Upon multiple dosing, there is an accumulation of immunoreactive interferons. There is, however, only a modest increase in biologic activity as measured by a bioassay. Mean (SD) ViraferonPeg elimination half-life is approximately 40 hours (13.3 hours), with apparent clearance of 22.0 ml/hr/kg. The mechanisms involved in clearance of interferons in man have not yet been fully elucidated. However, renal elimination may account for a minority (approximately 30 %) of ViraferonPeg apparent clearance. Renal impairment Renal clearance appears to account for 30 % of total clearance of ViraferonPeg. In a single dose study (1.0 microgram/kg) in patients with impaired renal function, Cmax, AUC, and half-life increased in relation to the degree of renal impairment. Following multiple dosing of ViraferonPeg (1.0 microgram/kg subcutaneously administered every week for four weeks) the clearance of ViraferonPeg is reduced by a mean of 17 % in patients with moderate renal impairment (creatinine clearance 30-49 ml/minute) and by a mean of 44 % in patients with severe renal impairment (creatinine clearance 15-29 ml/minute) compared to subjects with normal renal function. Based on single dose data, clearance was similar in patients with severe renal impairment not on dialysis and in patients who were receiving hemodialysis. The dose of ViraferonPeg for monotherapy should be reduced in patients with moderate or severe renal impairment 70 (see sections 4.2 and 4.4). Patients with creatinine clearance < 50 ml/minute must not be treated with ViraferonPeg in combination with ribavirin (bitherapy or tritherapy) (see section 4.3). Because of marked inter-subject variability in interferon pharmacokinetics, it is recommended that patients with severe renal impairment be closely monitored during treatment with ViraferonPeg (see section 4.2) Hepatic impairment The pharmacokinetics of ViraferonPeg have not been evaluated in patients with severe hepatic dysfunction. Elderly ( 65 years of age) The pharmacokinetics of ViraferonPeg following a single subcutaneous dose of 1.0 microgram/kg were not affected by age. The data suggest that no alteration in ViraferonPeg dosage is necessary based on advancing age. Paediatric population Multiple-dose pharmacokinetic properties for ViraferonPeg and ribavirin (capsules and oral solution) in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of ViraferonPeg at 60 g/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 g/kg/week. Interferon neutralising factors Interferon neutralising factor assays were performed on serum samples of patients who received ViraferonPeg in the clinical trial. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors in patients who received ViraferonPeg 0.5 micrograms/kg is 1.1 %. Transfer into seminal fluid Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin. 5.3 Preclinical safety data ViraferonPeg Adverse events not observed in clinical trials were not seen in toxicity studies in monkeys. These studies were limited to four weeks due to the appearance of anti-interferon antibodies in most monkeys. Reproduction studies of ViraferonPeg have not been performed. Interferon alfa-2b has been shown to be an abortifacient in primates. ViraferonPeg is likely to also cause this effect. Effects on fertility have not been determined. It is not known whether the components of this medicinal product are excreted into experimental animal or human milk (see section 4.6 for relevant human data on pregnancy and lactation). ViraferonPeg showed no genotoxic potential. The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from ViraferonPeg by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicity studies in rodents and monkeys, standard embryo-foetal development studies and in in vitro mutagenicity assays. ViraferonPeg plus ribavirin When used in combination with ribavirin, ViraferonPeg did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible, mild to 71 moderate anaemia, the severity of which was greater than that produced by either active substance alone. No studies have been conducted in juvenile animals to examine the effects of treatment with ViraferonPeg on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3 of Rebetol SmPC if ViraferonPeg is to be administered in combination with ribavirin). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder Disodium phosphate, anhydrous Sodium dihydrogen phosphate dihydrate Sucrose Polysorbate 80 Solvent Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life Before reconstitution 3 years. After reconstitution Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8ºC. From a microbiological point of view, the product is to be used immediately. If not used immediately, in- use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. For storage conditions of the reconstituted medicinal product, see section 6.3. 6.5 Nature and contents of container The powder and solvent are both contained in a two-chamber cartridge (Type I flint glass) separated by a bromobutyl rubber plunger. The cartridge is sealed at one end with a polypropylene cap containing a bromobutyl rubber liner and at the other end by a bromobutyl rubber plunger. ViraferonPeg is supplied as: - 1 pre-filled pen (CLEARCLICK) containing powder and solvent for solution for injection, 1 needle ("Push-On Needle"), 2 cleansing swabs; - 4 pre-filled pens (CLEARCLICK) containing powder and solvent for solution for injection, 4 needles ("Push-On Needle"), 72 8 cleansing swabs; - 12 pre-filled pens (CLEARCLICK) containing powder and solvent for solution for injection, 12 needles ("Push-On Needle"), 24 cleansing swabs. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling ViraferonPeg pre-filled pen is to be removed from the refrigerator before administration to allow the solvent to reach room temperature (not more than 25°C). ViraferonPeg 50 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 50 micrograms in 0.5 ml. ViraferonPeg 80 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 80 micrograms in 0.5 ml. ViraferonPeg 100 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 100 micrograms in 0.5 ml. ViraferonPeg 120 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 120 micrograms in 0.5 ml. ViraferonPeg 150 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 150 micrograms in 0.5 ml. ViraferonPeg is injected subcutaneously after reconstituting the powder as instructed, attaching a needle and setting the prescribed dose. A complete and illustrated set of instructions is provided in the Annex to the Package Leaflet. 73 As for all parenteral medicinal products, the reconstituted solution is to be inspected visually prior to administration. The reconstituted solution should be clear and colourless. If discolouration or particulate matter is present, the reconstituted solution should not be used. After administering the dose, the ViraferonPeg pre-filled pen and any unused solution contained in it is to be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBERS ViraferonPeg 50 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/132/031 EU/1/00/132/032 EU/1/00/132/034 ViraferonPeg 80 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/132/035 EU/1/00/132/036 EU/1/00/132/038 ViraferonPeg 100 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/132/039 EU/1/00/132/040 EU/1/00/132/042 ViraferonPeg 120 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/132/043 EU/1/00/132/044 EU/1/00/132/046 ViraferonPeg 150 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/132/047 EU/1/00/132/048 EU/1/00/132/050 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 29 May 2000 Date of latest renewal: 29 May 2010 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the web-site of the European Medicines Agency http://www.ema.europa.eu. 74 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 75 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance MSD International GmbH T/A MSD Ireland (Brinny) Brinny Innishannon Co. Cork Ireland Name and address of the manufacturer responsible for batch release SP Labo N.V. Industriepark 30 B-2220 Heist-op-den-Berg Belgium B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 76 ANNEX III LABELLING AND PACKAGE LEAFLET 77 A. LABELLING 78 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 50 micrograms 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 50 micrograms powder and solvent for solution for injection peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of powder contains 50 micrograms of peginterferon alfa-2b and provides 50 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. One ampoule of solvent contains 0.7 ml of water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial of powder, 1 ampoule of solvent 1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab 4 vials of powder, 4 ampoules of solvent 4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs 6 vials of powder, 6 ampoules of solvent 12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs 50 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 79 After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After withdrawal of the dose, any remaining solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/001 (1 vial of powder, 1 ampoule of solvent) EU/1/00/132/002 (1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab) EU/1/00/132/003 (4 vials of powder, 4 ampoules of solvent) EU/1/00/132/004 (4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs) EU/1/00/132/005 (6 vials of powder, 6 ampoules of solvent) EU/1/00/132/026 (12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 50 mcg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 80 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 81 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS ViraferonPeg 50 micrograms – vial of powder 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 50 micrograms powder for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 50 mcg/0.5 ml 6. OTHER 82 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 80 micrograms 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 80 micrograms powder and solvent for solution for injection peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of powder contains 80 micrograms of peginterferon alfa-2b and provides 80 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. One ampoule of solvent contains 0.7 ml of water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial of powder, 1 ampoule of solvent 1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab 4 vials of powder, 4 ampoules of solvent 4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs 6 vials of powder, 6 ampoules of solvent 12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs 80 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 83 After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After withdrawal of the dose, any remaining solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/006 (1 vial of powder, 1 ampoule of solvent) EU/1/00/132/007 (1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab) EU/1/00/132/008 (4 vials of powder, 4 ampoules of solvent) EU/1/00/132/009 (4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs) EU/1/00/132/010 (6 vials of powder, 6 ampoules of solvent) EU/1/00/132/027 (12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 80 mcg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 84 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 85 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS ViraferonPeg 80 micrograms - vial of powder 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 80 micrograms powder for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 80 mcg/0.5 ml 6. OTHER 86 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 100 micrograms 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 100 micrograms powder and solvent for solution for injection peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of powder contains 100 micrograms of peginterferon alfa-2b and provides 100 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. One ampoule of solvent contains 0.7 ml of water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial of powder, 1 ampoule of solvent 1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab 4 vials of powder, 4 ampoules of solvent 4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs 6 vials of powder, 6 ampoules of solvent 12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs 100 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 87 After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After withdrawal of the dose, any remaining solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/011 (1 vial of powder, 1 ampoule of solvent) EU/1/00/132/012 (1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab) EU/1/00/132/013 (4 vials of powder, 4 ampoules of solvent) EU/1/00/132/014 (4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs) EU/1/00/132/015 (6 vials of powder, 6 ampoules of solvent) EU/1/00/132/028 (12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 100 mcg 88 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 89 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS ViraferonPeg 100 micrograms - vial of powder 1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF ADMINISTRATION ViraferonPeg 100 micrograms powder for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 100 mcg/0.5 ml 6. OTHER 90 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 120 micrograms 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 120 micrograms powder and solvent for solution for injection peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of powder contains 120 micrograms of peginterferon alfa-2b and provides 120 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. One ampoule of solvent contains 0.7 ml of water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial of powder, 1 ampoule of solvent 1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab 4 vials of powder, 4 ampoules of solvent 4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs 6 vials of powder, 6 ampoules of solvent 12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs 120 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 91 After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After withdrawal of the dose, any remaining solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/016 (1 vial of powder, 1 ampoule of solvent) EU/1/00/132/017 (1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab) EU/1/00/132/018 (4 vials of powder, 4 ampoules of solvent) EU/1/00/132/019 (4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs) EU/1/00/132/020 (6 vials of powder, 6 ampoules of solvent) EU/1/00/132/029 (12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 120 mcg 92 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 93 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS ViraferonPeg 120 micrograms - vial of powder 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 120 micrograms powder for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 120 mcg/0.5 ml 6. OTHER 94 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 150 micrograms 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 150 micrograms powder and solvent for solution for injection peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of powder contains 150 micrograms of peginterferon alfa-2b and provides 150 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. One ampoule of solvent contains 0.7 ml of water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial of powder, 1 ampoule of solvent 1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab 4 vials of powder, 4 ampoules of solvent 4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs 6 vials of powder, 6 ampoules of solvent 12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs 150 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 95 After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After withdrawal of the dose, any remaining solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/021 (1 vial of powder, 1 ampoule of solvent) EU/1/00/132/022 (1 vial of powder, 1 ampoule of solvent, 1 injection syringe, 2 injection needles and 1 cleansing swab) EU/1/00/132/023 (4 vials of powder, 4 ampoules of solvent) EU/1/00/132/024 (4 vials of powder, 4 ampoules of solvent, 4 injection syringes, 8 injection needles and 4 cleansing swabs) EU/1/00/132/025 (6 vials of powder, 6 ampoules of solvent) EU/1/00/132/030 (12 vials of powder, 12 ampoules of solvent, 12 injection syringes, 24 injection needles and 12 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 150 mcg 96 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 97 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS ViraferonPeg 150 micrograms - vial of powder 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 150 micrograms powder for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 150 mcg/0.5 ml 6. OTHER 98 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS ViraferonPeg - ampoule of solvent 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Solvent for ViraferonPeg Water for injections 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.7 ml 6. OTHER 99 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 50 micrograms powder and solvent for solution for injection in pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 50 micrograms powder and solvent for solution for injection in pre-filled pen peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains a sufficient amount of peginterferon alfa-2b to provide 50 micrograms in 0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. Solvent: water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection in pre-filled pen 1 pen (CLEARCLICK), 1 injection needle and 2 cleansing swabs 4 pens (CLEARCLICK), 4 injection needles and 8 cleansing swabs 12 pens (CLEARCLICK), 12 injection needles and 24 cleansing swabs 50 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 100 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After injection of the dose, discard the pen in an appropriate container. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/031 (1 pen, 1 injection needle and 2 cleansing swabs) EU/1/00/132/032 (4 pens, 4 injection needles and 8 cleansing swabs) EU/1/00/132/034 (12 pens, 12 injection needles and 24 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 50 mcg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 101 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Pen label - ViraferonPeg 50 micrograms powder and solvent for solution for injection in pre- filled pen 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 50 micrograms powder and solvent for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 50 mcg/0.5 ml 6. OTHER Pen (CLEARCLICK) 102 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 80 micrograms powder and solvent for solution for injection in pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 80 micrograms powder and solvent for solution for injection in pre-filled pen peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains a sufficient amount of peginterferon alfa-2b to provide 80 micrograms in 0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. Solvent: water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection in pre-filled pen 1 pen (CLEARCLICK), 1 injection needle and 2 cleansing swabs 4 pens (CLEARCLICK), 4 injection needles and 8 cleansing swabs 12 pens (CLEARCLICK), 12 injection needles and 24 cleansing swabs 80 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 103 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After injection of the dose, discard the pen in an appropriate container. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/035 (1 pen, 1 injection needle and 2 cleansing swabs) EU/1/00/132/036 (4 pens, 4 injection needles and 8 cleansing swabs) EU/1/00/132/038 (12 pens, 12 injection needles and 24 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 80 mcg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 104 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Pen label - ViraferonPeg 80 micrograms powder and solvent for solution for injection in pre- filled pen 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 80 micrograms powder and solvent for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 80 mcg/0.5 ml 6. OTHER Pen (CLEARCLICK) 105 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 100 micrograms powder and solvent for solution for injection in pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 100 micrograms powder and solvent for solution for injection in pre-filled pen peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains a sufficient amount of peginterferon alfa-2b to provide 100 micrograms in 0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. Solvent: water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection in pre-filled pen 1 pen (CLEARCLICK), 1 injection needle and 2 cleansing swabs 4 pens (CLEARCLICK), 4 injection needles and 8 cleansing swabs 12 pens (CLEARCLICK), 12 injection needles and 24 cleansing swabs 100 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 106 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After injection of the dose, discard the pen in an appropriate container. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/039 (1 pen, 1 injection needle and 2 cleansing swabs) EU/1/00/132/040 (4 pens, 4 injection needles and 8 cleansing swabs) EU/1/00/132/042 (12 pens, 12 injection needles and 24 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 100 mcg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 107 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Pen label - ViraferonPeg 100 micrograms powder and solvent for solution for injection in pre- filled pen 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 100 micrograms powder and solvent for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 100 mcg/0.5 ml 6. OTHER Pen (CLEARCLICK) 108 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 120 micrograms powder and solvent for solution for injection in pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 120 micrograms powder and solvent for solution for injection in pre-filled pen peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains a sufficient amount of peginterferon alfa-2b to provide 120 micrograms in 0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. Solvent: water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection in pre-filled pen 1 pen (CLEARCLICK), 1 injection needle and 2 cleansing swabs 4 pens (CLEARCLICK), 4 injection needles and 8 cleansing swabs 12 pens (CLEARCLICK), 12 injection needles and 24 cleansing swabs 120 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 109 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After injection of the dose, discard the pen in an appropriate container. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/043 (1 pen, 1 injection needle and 2 cleansing swabs) EU/1/00/132/044 (4 pens, 4 injection needles and 8 cleansing swabs) EU/1/00/132/046 (12 pens, 12 injection needles and 24 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 120 mcg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 110 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Pen label - ViraferonPeg 120 micrograms powder and solvent for solution for injection in pre- filled pen 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 120 micrograms powder and solvent for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 120 mcg/0.5 ml 6. OTHER Pen (CLEARCLICK) 111 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 150 micrograms powder and solvent for solution for injection in pre-filled pen 1. NAME OF THE MEDICINAL PRODUCT ViraferonPeg 150 micrograms powder and solvent for solution for injection in pre-filled pen peginterferon alfa-2b 2. STATEMENT OF ACTIVE SUBSTANCE(S) One pre-filled pen contains a sufficient amount of peginterferon alfa-2b to provide 150 micrograms in 0.5 ml of peginterferon alfa-2b when reconstituted as recommended. 3. LIST OF EXCIPIENTS Excipients: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate, sucrose and polysorbate 80. Solvent: water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection in pre-filled pen 1 pen (CLEARCLICK), 1 injection needle and 2 cleansing swabs 4 pens (CLEARCLICK), 4 injection needles and 8 cleansing swabs 12 pens (CLEARCLICK), 12 injection needles and 24 cleansing swabs 150 micrograms/0.5 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Subcutaneous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP After reconstitution, use the reconstituted solution immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). 112 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE After injection of the dose, discard the pen in an appropriate container. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/00/132/047 (1 pen, 1 injection needle and 2 cleansing swabs) EU/1/00/132/048 (4 pens, 4 injection needles and 8 cleansing swabs) EU/1/00/132/050 (12 pens, 12 injection needles and 24 cleansing swabs) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE ViraferonPeg 150 mcg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN 113 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Pen label - ViraferonPeg 150 micrograms powder and solvent for solution for injection in pre- filled pen 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION ViraferonPeg 150 micrograms powder and solvent for injection peginterferon alfa-2b SC 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 150 mcg/0.5 ml 6. OTHER Pen (CLEARCLICK) 114 B. PACKAGE LEAFLET 115 Package leaflet: Information for the user ViraferonPeg 50 micrograms powder and solvent for solution for injection ViraferonPeg 80 micrograms powder and solvent for solution for injection ViraferonPeg 100 micrograms powder and solvent for solution for injection ViraferonPeg 120 micrograms powder and solvent for solution for injection ViraferonPeg 150 micrograms powder and solvent for solution for injection peginterferon alfa-2b Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What ViraferonPeg is and what it is used for 2. What you need to know before you use ViraferonPeg 3. How to use ViraferonPeg 4. Possible side effects 5. How to store ViraferonPeg 6. Contents of the pack and other information 1. What ViraferonPeg is and what it is used for The active substance in this medicine is a protein called peginterferon alfa-2b, which belongs to the class of medicines called interferons. Interferons are made by your body’s immune system to help fight infections and severe diseases. This medicine is injected into your body to work with your immune system. This medicine is used for the treatment of chronic hepatitis C, a viral infection of the liver. Adults The combination of this medicine, ribavirin and boceprevir is recommended for use for some types of chronic hepatitis C virus infection (also called HCV infection) in adults 18 years of age and older. It may be used in adults who have not been previously treated for HCV infection or who have previously used medicines called interferons and pegylated interferons. The combination of this medicine and ribavirin is recommended for adults 18 years of age and older who have not previously been treated with these medicines. This includes adults also infected with clinically stable HIV (Human Immunodeficiency Virus). The combination can also be used to treat adults who have already failed treatment with an interferon alpha or peginterferon alpha in combination with ribavirin or interferon alpha alone. If you have a medical condition making use of ribavirin dangerous or if you already have had a problem taking it, your doctor will likely prescribe this medicine alone. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. Children and adolescents This medicine is used in combination with ribavirin in children 3 years of age and older and adolescents who have not been treated previously for chronic hepatitis C. 116 2. What you need to know before you use ViraferonPeg Do not use ViraferonPeg You should tell your doctor before starting treatment if you, or the child you are caring for: - are allergic to peginterferon alfa-2b or any of the other ingredients of this medicine (listed in section 6). - are allergic to any interferon. - have had severe heart problems. - have heart disease that has not been well controlled during the past 6 months. - have severe medical conditions that leave you very weak. - have autoimmune hepatitis or any other problem with your immune system. - are taking medicine that suppresses (weakens) your immune system. - have advanced, uncontrolled liver disease (other than hepatitis C). - have thyroid disease that is not well controlled with medicines. - have epilepsy, a condition that causes convulsions (seizures, or “fits”). - are being treated with telbivudine (see section “Other medicines and ViraferonPeg”). You must not use ViraferonPeg if any of the conditions above should apply to you, or the child you are caring for. In addition, children and adolescents must not use this medicine if they have had serious nervous or mental problems, such as severe depression or thoughts of suicide. Reminder: Please also read the “Do not take” section of the Package Leaflet for ribavirin and boceprevir before using them in combination with this medicine. Warnings and precautions Seek medical help immediately in case of a severe allergic reaction (such as difficulty in breathing, wheezing, or hives). Talk to your doctor before taking this medicine if you, or the child you are caring for: - have had a severe nervous or mental disorder or have a history of substance abuse (e.g. alcohol or drugs). The use of this medicine in children and adolescents with existence of or history of severe psychiatric conditions is not allowed (see section “Do not use ViraferonPeg” above). - are being treated for a mental illness or had treatment in the past for any other nervous or mental disorder, including depression (such as feelings of sadness, dejection) or suicidal or homicidal behaviour (see section 4 “Possible side effects”). - have ever had a heart attack or a heart problem. - have kidney disease, your doctor may prescribe a lower than usual dose and monitor your kidney blood values regularly during treatment. If this medicine is used in combination with ribavirin, your doctor should monitor you, or the child you are caring for more carefully for a decrease in red blood cell count. - have cirrhosis or other liver problems (other than hepatitis C). - develop symptoms associated with a cold or other respiratory infection, such as fever, cough, or any difficulty in breathing. - are diabetic or have high blood pressure, your doctor may ask you, or the child you are caring for to have an eye examination. - have had any serious illness affecting breathing or blood. - have the skin disorders, psoriasis or sarcoidosis, which may become worse while you are using this medicine. - are planning to become pregnant, discuss this with your doctor before starting to use this medicine. - have received an organ transplant, either kidney or liver, interferon treatment may increase the risk of rejection. Be sure to discuss this with your doctor. - If you are also being treated for HIV (see section “Other medicines and ViraferonPeg”). - have a current or previous infection with the hepatitis B virus, since your doctor may want to monitor you more closely. 117 Reminder: Please read the “Warnings and precautions” section of the Package Leaflet for ribavirin before using it in combination with this medicine. Teeth and mouth problems have been reported in patients receiving this medicine in combination with ribavirin. You may develop gum disease, which could lead to loss of teeth. You may develop a dry mouth or vomiting, both of which can damage your teeth. It is important to brush your teeth thoroughly twice a day, rinse your mouth out if you vomit, and have regular dental check-ups. During treatment, some patients may experience eye problems, or loss of vision in rare instances. Your doctor should carry out an eye examination before starting your treatment. In case of any changes in vision, you must tell your doctor and have a prompt and complete eye examination. If you have a medical condition that may lead to future eye problems (e.g. diabetes or high blood pressure), you should receive regular eye exams during therapy. If your eye disorder becomes more severe or if you develop new eye disorders, your treatment will be discontinued. While being treated with ViraferonPeg, your doctor may advise to drink extra fluids to help prevent low blood pressure. Your doctor will test your blood before you begin therapy and throughout the treatment to make sure that the therapy you are getting is safe and effective. Children and adolescents This medicine is not recommended for use in patients under the age of 3 years. Other medicines and ViraferonPeg Please tell your doctor or pharmacist if you, or the child you are caring for: - are taking or have recently taken any other medicines or vitamins/nutritional supplements, including medicines obtained without a prescription. - are infected with both Human Immunodeficiency Virus (HIV-positive) and Hepatitis C Virus (HCV) and are being treated with an anti-HIV medicine(s) – [nucleoside reverse transcriptase inhibitor (NRTI), and/or highly active anti-retroviral therapy (HAART)]. Your doctor will monitor you for signs and symptoms of these conditions. o Taking this medicine in combination with ribavirin and an anti-HIV medicine(s) may increase the risk of lactic acidosis, liver failure, and blood abnormalities: reduction in number of red blood cells, white blood cells and blood clotting cells called platelets. Patients with advanced liver disease receiving HAART may be at increased risk of worsening liver function, therefore adding treatment with this medicine alone or in combination with ribavirin may increase their risk. o With zidovudine or stavudine, it is not certain if ribavirin will change the way these medicines work. Therefore, your blood will be checked regularly to be sure that the HIV infection is not getting worse. If it gets worse, your doctor will decide whether or not your ribavirin treatment needs to be changed. Additionally, patients treated with this medicine and ribavirin combination therapy and zidovudine could be at increased risk of developing anaemia (low number of red blood cells). Therefore the use of zidovudine with this medicine and ribavirin combination therapy is not recommended. Reminder: Please read the “Other medicines” section of the Package Leaflet for ribavirin before using it in combination with this medicine. - are taking telbivudine. If you take telbivudine with this medicine or any type of injectable interferon product, your risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations in the arms and/or legs) is higher. These events may also be more severe. Therefore, you must not take this medicine at the same time as telbivudine. 118 Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Pregnancy In studies in pregnant animals, interferons have sometimes caused miscarriage. The effect of this medicine on human pregnancy is not known. Girls or women of childbearing potential need to use effective birth control during the treatment with this medicine. Ribavirin can be very damaging to an unborn baby. Therefore, you and your partner must take special precautions in sexual activity if there is any chance for pregnancy to occur: - if you are a girl or a woman of childbearing age who is taking ribavirin: you must have a negative pregnancy test before treatment, each month during treatment, and for the 4 months after treatment is stopped. You must use an effective birth control during the time you are taking ribavirin and for 4 months after stopping treatment. This should be discussed with your doctor. - if you are a man who is taking ribavirin: do not have sex with a pregnant woman unless you use a condom. If your female partner is not pregnant but is of childbearing age, she must be tested for pregnancy each month during treatment and for the 7 months after treatment has stopped. You or your partner must use an effective birth control during the time you are taking ribavirin and for 7 months after stopping treatment. This should be discussed with your doctor. Breast-feeding It is not known whether this medicine is present in human milk. Therefore, you should not breast-feed an infant if you are taking this medicine. Ask your doctor for advice. Reminder: Please read the “Pregnancy and breast-feeding” section of the Package Leaflet for ribavirin before using it in combination with this medicine. Driving and using machines Do not drive or operate any tools or machines if you feel tired, sleepy or confused while taking this medicine. ViraferonPeg contains sucrose This medicine contains sucrose. If you have an intolerance to some sugars, contact your doctor before taking this medicine. This medicine contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially "sodium-free". 3. How to use ViraferonPeg Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. General information about taking this medicine Your doctor has determined the correct dose of this medicine based on how much you, or the child you are caring for weighs. If necessary, the dose may be changed during treatment. This medicine is intended for subcutaneous use. This means that it is injected through a short injection needle into the fatty tissue just under the skin. If you are injecting this medicine yourself, you will be instructed how to prepare and give the injection. Detailed instructions for subcutaneous administration are provided at the end of this leaflet (see section “How to self-inject ViraferonPeg”). Water for injection and ViraferonPeg powder are provided in separate ampoules. Prepare the dose by adding water for injection to ViraferonPeg powder just before you intend to inject it and use it 119 immediately. Look carefully at the solution you prepared before you use it. The solution should be clear and colourless. Do not use the solution if it is discoloured (changed its colour from the original) or if there are bits of particles in the solution. Discard any solution that is left in the vial after you give yourself the injection. For disposal instructions, see section 5 “How to store ViraferonPeg”. Inject this medicine once each week on the same day. Injecting it at the same time of day each week will help you not to forget to take it. Always use this medicine exactly as your doctor has told you. Do not exceed the recommended dosage, and take it for as long as prescribed. If your doctor prescribes this medicine with ribavirin or with ribavirin and boceprevir, please read the Package Leaflets of ribavirin and boceprevir before you begin combination treatment. Use in adults – ViraferonPeg in combination treatment This medicine, when given with ribavirin capsules, is usually given at a dose of 1.5 microgram per kilogram of body weight once a week. If you have kidney disease, your dose may be lower, depending upon your kidney function. Use in adults – ViraferonPeg alone This medicine, when given alone, is usually given at a dose of 0.5 or 1.0 microgram per kilogram of body weight once a week, for 6 months to 1 year. If you have kidney disease, your dose may be lower, depending upon your kidney function. Your doctor will determine the correct dose for you. Use in children 3 years of age and older and adolescents ViraferonPeg will be given in combination with ribavirin.The dose of ViraferonPeg is determined by a calculation accounting for both height and weight. Your doctor will determine the correct dose for you, or the child you are caring for. The duration of treatment is up to 1 year based on the doctor’s judgement for you, or the child you are caring for. All patients If you are injecting this medicine yourself, please be sure that the dose that has been prescribed is clearly provided on the package of medicine you receive. If you use more ViraferonPeg than you should Tell your doctor or healthcare professional or the doctor or healthcare professional of the child you are caring for as soon as possible. If you forget to take ViraferonPeg Take/administer the dose of this medicine as soon as you remember, but only if within 1-2 days after the forgotten dose. If it is very close to your next injection, do not double the dose to make up for the forgotten dose, but continue your treatment as usual. If you are uncertain, contact your doctor or pharmacist or the doctor or pharmacist of the child you are caring for. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Although not all of these side effects may occur, they may need medical attention if they do. When this medicine is used alone, some of these effects are less likely to occur, and some have not occurred at all. Psychiatric and central nervous system: Some people get depressed when taking this medicine alone or in combination treatment with ribavirin, and in some cases people have had thoughts about threatening the life of others, suicidal thoughts or aggressive behaviour (sometimes directed against others). Some patients have actually committed suicide. Seek emergency care if you notice that you are becoming depressed or have 120 suicidal thoughts or change in your behaviour. Ask a family member or close friend to help you stay alert to signs of depression or changes in your behaviour. Children and adolescents are particularly prone to develop depression when being treated with this medicine and ribavirin. Immediately contact the doctor or seek emergency treatment if they display any unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or others. Growth and development (children and adolescents): With up to one year of treatment with this medicine in combination with ribavirin, some children and adolescents did not grow or gain weight as much as expected. Some children did not reach their projected height within 1-5.5 years after completing treatment. Contact your doctor immediately if you notice any of the following serious side effects occurring during treatment: Very common side effects (may affect more than 1 in 10 people): - breathing problems (including shortness of breath), - feeling depressed - trouble sleeping, thinking or concentrating, dizziness, - severe stomach pain or cramps, - fever or chills beginning after a few weeks of treatment, - painful or inflamed muscles (sometimes severe), Common side effects (may affect up to 1 in 10 people): - chest pain, changes in the way your heart beats, - confusion, - difficulty remaining alert, numbness or tingling feeling, - pain in your lower back or side, difficulty or inability to pass urine, - problems with your eyes or your eyesight or hearing, - severe or painful reddening of your skin or mucous membrane, - severe bleeding from your nose, gums or any other part of your body. Uncommon side effects (may affect up to 1 in 100 people): - wanting to harm yourself, - hallucinations, Rare side effects (may affect up to 1 in 1,000 people): - convulsion (“fit”), - blood or clots in stool (or black, tarry stool), Unknown frequency side effects (frequency cannot be estimated from the available data): - Wanting to harm others. Other side effects that have been reported in adults include: Very common side effects (may affect more than 1 in 10 people): - feeling depressed, irritability, trouble falling asleep or staying asleep, feeling anxious or nervous, difficulty concentrating, mood swings, - headache, dizziness, tired feeling, shaking chills, fever, flu-like symptoms, virus infection, weakness, - difficult breathing, pharyngitis (sore throat), coughing, - stomach pain, vomiting, nausea, diarrhoea, loss of appetite, loss of weight, dry mouth, - hair loss, itching, dry skin, rash, irritation or redness (and rarely, skin damage) at the site of injection, - decreases in the number of red blood cells (that may cause fatigue, shortness of breath, dizziness), decrease in certain white blood cells (that makes you more susceptible to different infections), 121 - pain in joints and muscles, muscle and bone pain. Common side effects (may affect up to 1 in 10 people): - decrease in blood clotting cells called platelets, that may result in easy bruising and spontaneous bleeding, excess of uric acid (as in gout) in the blood, low calcium level in the blood, - decrease in thyroid gland activity (which may make you feel tired, depressed, increase your sensitivity to cold and other symptoms), increase in thyroid gland activity (which may cause nervousness, heat intolerance and excessive sweating, weight loss, palpitation, tremors), swollen glands (swollen lymph nodes), thirst, - changed behaviour or aggressive behaviour (sometimes directed against others), agitation, nervousness, feeling sleepy, trouble sleeping, unusual dreams, lack of interest in activities, lack of interest in sex, erectile problem, increased appetite, confusion, shaky hands, poor coordination, vertigo (spinning feeling), numbness, pain or tingling feeling, increased or decreased sensitivity to touch, tense muscles, limb pain, arthritis, migraine, increased sweating, - eye pain or infection, blurred vision, dry or teary eyes, changes in hearing/loss of hearing, ringing in ears, - sinusitis, respiratory infections, stuffy or runny nose, difficulty in speaking, nosebleed, cold sores (herpes simplex), fungal or bacterial infections, ear infection/earache, - indigestion (stomach upset), heartburn, redness or sores in mouth, burning sensation on tongue, red or bleeding gums, constipation, intestinal gas (flatus), bloating, hemorrhoids, sore tongue, change in taste, tooth problem, excessive loss of body water, enlarged liver, - psoriasis, sensitivity to sunlight, rash with raised spotted lesions, redness of skin or skin disorders, puffy face, puffy hands or feet, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), acne, hives, abnormal hair texture, nail disorder, pain at the site of injection, - difficult, irregular or no menstrual period, abnormally heavy and prolonged menstrual period, problem affecting ovary or vagina, pain in breast, sexual problem, irritation of prostate gland, increased need to pass urine, - chest pain, pain on the right side around your ribs, feeling unwell, low or high blood pressure, feeling faint, flushing, palpitations (pounding heart beat), rapid heart rate. Uncommon side effects (may affect up to 1 in 100 people): - suicide, attempted suicide, thoughts about threatening the life of yourself, panic attack, delusions, hallucination, - hypersensitivity reaction to the medication, heart attack, inflammation of the pancreas, pain in bone and diabetes mellitus, - cotton wool spots (white deposits on the retina). Rare side effects (may affect up to 1 in 1,000 people): - diabetic ketoacidosis (medical emergency due to build-up of ketone bodies in the blood as a result of out-of-control diabetes), - seizures (convulsions) and bipolar disorders (mood disorders characterized by alternating episodes of sadness and excitement), - eye problems including changes in vision, damage to the retina, obstruction of the retinal artery, inflammation of the optic nerve, swelling of the eye, - congestive heart failure, abnormal heart rhythm, pericarditis (inflammation of the lining of the heart), inflammation and degeneration of muscle tissue and peripheral nerves, kidney problems, - sarcoidosis (a disease characterized by persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands). Very rare side effects (may affect up to 1 in 10,000 people): - aplastic anaemia, stroke (cerebrovascular events), toxic epidermal necrolysis/Stevens Johnson Syndrome/erythema multiforme (a spectrum of rashes with varying degree of severity including death which may be associated with blisters in the mouth, nose, eyes and other mucosal membranes and sloughing of the affected area of the skin). - loss of consciousness has occurred very rarely with alpha interferons, mostly in elderly patients treated at high doses. 122 Side effects of unknown frequency (frequency cannot be estimated from the available data): - pure red cell aplasia (a condition where the body stopped or reduced the production of red blood cells). This causes severe anaemia, symptoms of which would include unusual tiredness and a lack of energy. - facial palsy (weakness and slumping on one side to the face), severe allergic reactions such as angioedema (an allergic skin disease characterized by patches of swelling involving the skin and its subcutaneous layers, the mucous membranes, and sometimes the internal organs), mania (excessive or unreasonable enthusiasm), pericardial effusion (a fluid collection that develops between the pericardium (the lining of the heart) and the heart itself), Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, skin and the membranes of the ears, brain and spinal cord), change in colour of the tongue. - thoughts about threatening the life of others. - pulmonary fibrosis (scarring of the lungs). - pulmonary arterial hypertension – a disease of severe narrowing of the blood vessels in the lungs resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This may occur in particular in patients with risk factors such as HIV infection or severe liver problems (cirrhosis). The side effect may develop at various time points during treatment, typically several months after starting treatment with ViraferonPeg. - hepatitis B reactivation in HCV/HBV co-infected patients (recurrence of hepatitis B disease). If you are an HCV/HIV co-infected adult patient receiving HAART, the addition of this medicine and ribavirin may increase your risk of lactic acidosis, liver failure, and development of blood abnormalities (reduction in number of red blood cells which carry oxygen, certain white blood cells that fight infection, and blood clotting cells called platelets). The following other side effects (not listed above) have occurred with the combination of this medicine and ribavirin capsules (adults) in HCV/HIV co-infected patients receiving HAART: - oral candidiasis (oral thrush), - defective metabolism of fat, - CD4 lymphocytes decreased, - appetite decreased, - back pain, - hepatitis, - limb pain, - and various laboratory blood values abnormalities. Side effects in children and adolescents The following effects have occurred in children and adolescents: Very common side effects (may affect more than 1 in 10 people): - loss of appetite, dizziness, headache, vomiting, nausea, stomach pain, - hair loss, dry skin, pain in joints and muscles, redness at the site of injection, - feeling irritable, tired feeling, feeling unwell, pain, chills, fever, flu-like symptoms, weakness, decrease in rate of growth (height and weight for age), - decreases in red blood cells that may cause fatigue, shortness of breath, dizziness. Common side effects (may affect up to 1 in 10 people): - fungal infection, common cold, cold sores, pharyngitis (sore throat), sinusitis, ear infection, coughing, throat pain, feeling cold, eye pain, - decrease in blood clotting cells called platelets, that may result in easy bruising and spontaneous bleeding, swollen glands (swollen lymph nodes), blood thyroid tests abnormalities, decrease in thyroid gland activity, which may make you feel tired, depressed, increase your sensitivity to cold and other symptoms, 123 - wanting or attempting to harm yourself aggressive behaviour, agitation, anger, mood changes, nervousness or restlessness, depression, feeling anxious, trouble falling asleep or staying asleep, emotional instability, poor quality sleep, feeling sleepy, disturbance in attention. - changes in taste, diarrhoea, stomach upset, oral pain, - fainting, palpitations (pounding heart beat), rapid heart rate, flushing, nosebleed, - sores in mouth, scaling lips and clefts in the corners of the mouth, rash, redness of skin, itching, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), acne, - back pain, muscle and bone pain, limb pain, dryness, pain, rash, irritation or itching at the site of injection. Uncommon side effects (may affect up to 1 in 100 people): - painful or difficult urination, urinary frequency, the presence of excess protein in the urine, painful menstruation, - itchy anal area (pinworms or ascarids), inflammation of the lining membrane of the stomach and the intestines, inflamed gums, enlarged liver, - abnormal behaviour, emotional disorder, fear, nightmare, tremor, decreased sensitivity to touch, numbness or tingling feeling, pain radiating along the course of one or more nerves, drowsiness, - bleeding of the mucous membrane that lines the inner surface of the eyelids, itchy eyes, eye pain, blurred vision, intolerance to light, - low blood pressure, paleness, nasal discomfort, runny nose, wheezing, difficult breathing, chest pain or discomfort, - redness, swelling, pain of skin, shingles, skin sensitive to sunlight, rash with raised spotted lesions, skin discolouration, peeling of skin, shortening of muscle tissue, muscle twitching, facial pain, bruising. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can also help provide more information on the safety of this medicine. Reminder to adult patients prescribed combination therapy of this medicine, boceprevir and ribavirin: Please read the “Possible side effects” section of these Package Leaflets. 5. How to store ViraferonPeg Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton, after EXP. Store in a refrigerator (2C - 8C). Use the reconstituted solution (solution you prepared by adding water for injection to the ViraferonPeg powder) immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). Do not use this medicine if you notice discolouration of the powder, which should be white. The reconstituted solution should be clear and colourless. Do not use if it is discoloured or if bits of particles are present. ViraferonPeg vials are for single use only. Discard any unused material. Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 124 6. Contents of the pack and other information What ViraferonPeg contains - The active substance is peginterferon alfa-2b. ViraferonPeg 50 micrograms powder and solvent for solution for injection Each vial contains 50 micrograms of peginterferon alfa-2b measured on a protein basis. Each vial provides 50 micrograms/0.5 ml of solution when reconstituted as recommended. ViraferonPeg 80 micrograms powder and solvent for solution for injection Each vial contains 80 micrograms of peginterferon alfa-2b measured on a protein basis. Each vial provides 80 micrograms/0.5 ml of solution when reconstituted as recommended. ViraferonPeg 100 micrograms powder and solvent for solution for injection Each vial contains 100 micrograms of peginterferon alfa-2b measured on a protein basis. Each vial provides 100 micrograms/0.5 ml of solution when reconstituted as recommended. ViraferonPeg 120 micrograms powder and solvent for solution for injection Each vial contains 120 micrograms of peginterferon alfa-2b measured on a protein basis. Each vial provides 120 micrograms/0.5 ml of solution when reconstituted as recommended. ViraferonPeg 150 micrograms powder and solvent for solution for injection Each vial contains 150 micrograms of peginterferon alfa-2b measured on a protein basis. Each vial provides 150 micrograms/0.5 ml of solution when reconstituted as recommended. - The other ingredients are: Powder: disodium phosphate; anhydrous, sodium dihydrogen phosphate dihydrate; sucrose and polysorbate 80. Solvent: water for injections. What ViraferonPeg looks like and contents of the pack This medicine is a powder and solvent (liquid) for solution for injection. The white powder is contained in a 2 ml glass vial and the clear and colourless solvent is presented in a 2 ml glass ampoule. ViraferonPeg is available in different pack sizes: - 1 vial of powder for solution for injection and 1 ampoule of solvent for injection; - 1 vial of powder for solution for injection, 1 ampoule of solvent for injection, 1 injection syringe, 2 injection needles and 1 cleansing swab; - 4 vials of powder for solution for injection and 4 ampoules of solvent for injection; - 4 vials of powder for solution for injection, 4 ampoules of solvent for injection, 4 injection syringes, 8 injection needles and 4 cleansing swabs; - 6 vials of powder for solution for injection and 6 ampoules of solvent for injection; - 12 vials of powder for solution for injection, 12 ampoules of solvent for injection, 12 injection syringes, 24 injection needles and 12 cleansing swabs. Not all pack sizes may be marketed. Marketing Authorisation Holder Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands Manufacturer SP Labo N.V. 125 Industriepark, 30 B-2220 Heist-op-den-Berg Belgium For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien MSD Belgium BVBA/SPRL Tel: 0800 38 693 (+32(0)27766211) dpoc_belux@merck.com Lietuva UAB Merck Sharp & Dohme Tel. +370 5 278 02 47 msd_lietuva@merck.com България Мерк Шарп и Доум България ЕООД Тел.: +359 2 819 3737 info-msdbg@merck.com Luxembourg/Luxemburg MSD Belgium BVBA/SPRL Tel: +32(0)27766211 dpoc_belux@merck.com Česká republika Merck Sharp & Dohme s.r.o. Tel: +420 233 010 111 dpoc_czechslovak@merck.com Magyarország MSD Pharma Hungary Kft. Tel.: +36 1 888 5300 hungary_msd@merck.com Danmark MSD Danmark ApS Tlf: + 45 4482 4000 dkmail@merck.com Malta Merck Sharp & Dohme Cyprus Limited Tel: 8007 4433 (+356 99917558) malta_info@merck.com Deutschland MSD SHARP & DOHME GMBH Tel: 0800 673 673 673 (+49 (0) 89 4561 2612) e-mail@msd.de Nederland Merck Sharp & Dohme BV Tel: 0800 9999000 (+31 23 5153153) medicalinfo.nl@merck.com Eesti Merck Sharp & Dohme OÜ Tel.: +372 6144 200 msdeesti@merck.com Norge MSD (Norge) AS Tlf: +47 32 20 73 00 msdnorge@msd.no Ελλάδα MSD Α.Φ.Β.Ε.Ε. Τηλ: +30 210 98 97 300 dpoc_greece @merck.com Österreich Merck Sharp & Dohme Ges.m.b.H. Tel: +43 (0) 1 26 044 msd-medizin@merck.com España Merck Sharp & Dohme de España, S.A. Tel: +34 91 321 06 00 msd_info@merck.com Polska MSD Polska Sp. z o.o. Tel: +48 22 549 51 00 msdpolska@merck.com France MSD France Tél: + 33-(0)1 80 46 40 40 Portugal Merck Sharp & Dohme, Lda Tel: +351 21 4465700 clic@merck.com Hrvatska Merck Sharp & Dohme d.o.o. Tel: + 385 1 6611 333 croatia_info@merck.com România Merck Sharp & Dohme Romania S.R.L. Tel: +40 21 529 2900 msdromania@merck.com 126 Ireland Merck Sharp & Dohme Ireland (Human Health) Limited Tel: +353 (0)1 2998700 medinfo_ireland@merck.com Slovenija Merck Sharp & Dohme, inovativna zdravila d.o.o. Tel: +386 1 5204 201 msd.slovenia@merck.com Ísland Vistor hf. Sími: + 354 535 7000 Slovenská republika Merck Sharp & Dohme, s. r. o. Tel: +421 2 58282010 dpoc_czechslovak@merck.com Italia MSD Italia S.r.l. Tel: +39 06 361911 medicalinformation.it@merck.com Suomi/Finland MSD Finland Oy Puh/Tel: +358 (0)9 804 650 info@msd.fi Κύπρος Merck Sharp & Dohme Cyprus Limited Τηλ.: 800 00 673 (+357 22866700) cyprus_info@merck.com Sverige Merck Sharp & Dohme (Sweden) AB Tel: +46 77 5700488 medicinskinfo@merck.com Latvija SIA Merck Sharp & Dohme Latvija Tel: +371 67364224 msd_lv@merck.com United Kingdom Merck Sharp & Dohme Limited Tel: +44 (0) 1992 467272 medicalinformationuk@merck.com This leaflet was last revised in MM/YYYY Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu. 127 How to self-inject ViraferonPeg? Your healthcare provider will instruct you how to self-inject this medicine. Do not attempt to inject yourself unless you are sure you understand the procedure and requirements of self- injection. The following instructions explain how to inject this medicine yourself. Please read the instructions carefully and follow them step by step. Preparation Collect the necessary items before you begin: - a vial of ViraferonPeg powder for injection; - an ampoule of water for injections solvent to prepare ViraferonPeg injection; - a 1 ml syringe; - a long needle (for example 0.8  40 mm [21 gauge 1.5 inch]) to be used to add water for injections to the ViraferonPeg powder vial; - a short needle (for example 0.3  13 mm [30 gauge 0.5 inch]) for the subcutaneous injection; - a cleansing swab. Wash your hands carefully. Reconstituting ViraferonPeg powder for injection Before reconstitution, this medicine may appear either as a white tablet-shaped solid that is whole or in pieces, or as a white powder. When the total amount of solvent is combined with the full amount of ViraferonPeg powder, the solution will be at the correct concentration to measure your dose (i.e., the labelled amount is contained in 0.5 ml). A small volume is lost during preparation of this medicine for injection and when the dose is measured and injected. Therefore, each vial contains an extra amount of solvent and ViraferonPeg powder to ensure delivery of the labeled dose in 0.5 ml of ViraferonPeg, solution for injection. - Remove the protective cap from the ViraferonPeg vial. - Clean the rubber top of the vial with a cleansing swab. You can save the swab to clean the skin area where you will inject the dose. - Remove the syringe from the wrapping and do not touch the tip of the syringe. - Take the long needle and place it firmly on to the tip of the syringe. - Remove the needle guard without touching the needle and keep the syringe with the needle in your hand. - Tap the top of the ampoule of solvent gently to make sure that all the liquid is at the bottom of the ampoule. - Break off the top of the ampoule of solvent. - Insert the needle in the ampoule of solvent and withdraw the total amount of solvent. - Then insert the needle through the rubber top of the ViraferonPeg vial. Gently place the needle tip against the glass wall of the vial without touching the cleaned top of the vial with your hands. - Inject the solvent SLOWLY, aiming the stream of liquid at the glass wall of the vial. Do not aim the stream directly at the white solid or powder, or inject the liquid quickly, as this causes a greater amount of bubbles. The solution may appear cloudy or bubbly for a few minutes. This is to be expected and is not a cause for concern. - Dissolve the entire contents by swirling the ViraferonPeg vial with a gentle rotary motion leaving the needle and attached syringe in the vial. - Do not shake, but gently turn the vial upside down until any powder at the top of the vial is dissolved. - The contents should now be completely dissolved. - Stand the vial upright and let any bubbles present in the solution rise to the top of the solution. Once all bubbles have risen to the top of the solution, you should have a clear solution with a small ring of tiny bubbles around the top. Use this solution immediately. If it cannot be used immediately, the solution may be refrigerated for up to 24 hours. 128 Measuring the dose of ViraferonPeg from the reconstituted powder for injection Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the ViraferonPeg reconstituted solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw just more than the dose prescribed by your doctor into the syringe. Hold the syringe with the needle in the vial pointing up. Remove the syringe from the long needle leaving the needle in the vial and without touching the tip of the syringe. Take the short needle and place it firmly on to the tip of the syringe. Remove the needle guard from the syringe needle and check for air bubbles in the syringe. If you see any bubbles, pull the plunger slightly back; tap the syringe gently, with the needle pointing upwards, until the bubbles disappear. Push up the plunger slowly back to the correct dose. Replace the needle guard and place the syringe with the needle on a flat surface. Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe between your palms. Inspect visually the reconstituted solution prior to administration: do not use if discolouration (change in the original colour of the solution) or particulate matter is present. You are now ready to inject the dose. Injecting the solution Select the injection site. The best sites for injection are tissues with a layer of fat between skin and muscle. These are thigh, outer surface of the upper arm (you may need the assistance of another person to use this site) and abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or outer surface of the arm for injection. Change your injection site each time. Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the needle guard. With one hand, pinch a fold of loose skin. With your other hand, hold the syringe as you would a pencil. Insert the needle into the pinched skin at an angle of approximately 45°. After the needle is inserted, remove the hand used to pinch the skin and use it to hold the syringe barrel. Pull back the plunger very slightly with one hand. If blood comes into the syringe, the needle has entered a blood vessel. Do not inject into this site; withdraw the needle and repeat the procedure. Inject the solution by pushing the plunger all the way down gently. Pull the needle straight out of the skin. Press the injection site with a small bandage or sterile gauze if necessary for several seconds. Do not massage the injection site. If there is bleeding, cover with an adhesive bandage. The vial, ampoule and injection materials intended for single use must be discarded. Dispose of the syringe and needles safely in a closed container. 129 Package leaflet: Information for the user ViraferonPeg 50 micrograms powder and solvent for solution for injection in pre-filled pen ViraferonPeg 80 micrograms powder and solvent for solution for injection in pre-filled pen ViraferonPeg 100 micrograms powder and solvent for solution for injection in pre-filled pen ViraferonPeg 120 micrograms powder and solvent for solution for injection in pre-filled pen ViraferonPeg 150 micrograms powder and solvent for solution for injection in pre-filled pen peginterferon alfa-2b Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What ViraferonPeg is and what it is used for 2. What you need to know before you use ViraferonPeg 3. How to use ViraferonPeg 4. Possible side effects 5. How to store ViraferonPeg 6. Contents of the pack and other information 1. What ViraferonPeg is and what it is used for The active substance in this medicine is a protein called peginterferon alfa-2b, which belongs to the class of medicines called interferons. Interferons are made by your body’s immune system to help fight infections and severe diseases. This medicine is injected into your body to work with your immune system. This medicine is used for the treatment of chronic hepatitis C, a viral infection of the liver. Adults The combination of this medicine, ribavirin and boceprevir is recommended for use for some types of chronic hepatitis C virus infection (also called HCV infection) in adults 18 years of age and older. It may be used in adults who have not been previously treated for HCV infection or who have previously used medicines called interferons and pegylated interferons. The combination of this medicine and ribavirin is recommended for adults 18 years of age and older who have not previously been treated with these medicines. This includes adults also infected with clinically stable HIV (Human Immunodeficiency Virus). The combination can also be used to treat adults who have already failed treatment with an interferon alpha or peginterferon alpha in combination with ribavirin or interferon alpha alone. If you have a medical condition making use of ribavirin dangerous or if you already have had a problem taking it, your doctor will likely prescribe this medicine alone. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. Children and adolescents This medicine is used in combination with ribavirin in children 3 years of age and older and adolescents who have not been treated previously for chronic hepatitis C. 130 2. What you need to know before you use ViraferonPeg Do not use ViraferonPeg You should tell your doctor before starting treatment if you, or the child you are caring for: - are allergic to peginterferon alfa-2b or any of the other ingredients of this medicine (listed in section 6). - are allergic to any interferon. - have had severe heart problems. - have heart disease that has not been well controlled during the past 6 months. - have severe medical conditions that leave you very weak. - have autoimmune hepatitis or any other problem with your immune system. - are taking medicine that suppresses (weakens) your immune system. - have advanced, uncontrolled liver disease (other than hepatitis C). - have thyroid disease that is not well controlled with medicines. - have epilepsy, a condition that causes convulsions (seizures, or “fits”). - are being treated with telbivudine (see section “Other medicines and ViraferonPeg”). You must not use ViraferonPeg if any of the conditions above should apply to you, or the child you are caring for. In addition, children and adolescents must not use this medicine if they have had serious nervous or mental problems, such as severe depression or thoughts of suicide. Reminder: Please also read the “Do not take” section of the Package Leaflet for ribavirin and boceprevir before using them in combination with this medicine. Warnings and precautions Seek medical help immediately in case of a severe allergic reaction (such as difficulty in breathing, wheezing, or hives). Talk to your doctor before taking this medicine if you, or the child you are caring for: - have had a severe nervous or mental disorder, or have a history of substance abuse (e.g. alcohol or drugs). The use of this medicine in children and adolescents with existence of or history of severe psychiatric conditions is not allowed (see section “Do not use ViraferonPeg” above). - are being treated for a mental illness or had treatment in the past for any other nervous or mental disorder, including depression (such as feelings of sadness, dejection) or suicidal or homicidal behaviour (see section 4 “Possible side effects”). - have ever had a heart attack or a heart problem. - have kidney disease, your doctor may prescribe a lower than usual dose and monitor your kidney blood values regularly during treatment. If this medicine is used in combination with ribavirin, your doctor should monitor you, or the child you are caring for more carefully for a decrease in red blood cell count. - have cirrhosis or other liver problems (other than hepatitis C). - develop symptoms associated with a cold or other respiratory infection, such as fever, cough, or any difficulty in breathing. - are diabetic or have high blood pressure, your doctor may ask you, or the child you are caring for to have an eye examination. - have had any serious illness affecting breathing or blood. - have the skin disorders, psoriasis or sarcoidosis, which may become worse while you are using this medicine. - are planning to become pregnant, discuss this with your doctor before starting to use this medicine. - have received an organ transplant, either kidney or liver, interferon treatment may increase the risk of rejection. Be sure to discuss this with your doctor. - If you are also being treated for HIV (see section “Other medicines and ViraferonPeg”). - have a current or previous infection with the hepatitis B virus, since your doctor may want to monitor you more closely. 131 Reminder: Please read the “Warnings and precautions” section of the Package Leaflet for ribavirin before using it in combination with this medicine. Teeth and mouth problems have been reported in patients receiving this medicine in combination with ribavirin. You may develop gum disease, which could lead to loss of teeth. You may develop a dry mouth or vomiting, both of which can damage your teeth. It is important to brush your teeth thoroughly twice a day, rinse your mouth out if you vomit, and have regular dental check-ups. During treatment, some patients may experience eye problems, or loss of vision in rare instances. Your doctor should carry out an eye examination before starting your treatment. In case of any changes in vision, you must tell your doctor and have a prompt and complete eye examination. If you have a medical condition that may lead to future eye problems (e.g. diabetes or high blood pressure), you should receive regular eye exams during therapy. If your eye disorder becomes more severe or if you develop new eye disorders, your treatment will be discontinued. While being treated with ViraferonPeg, your doctor may advise to drink extra fluids to help prevent low blood pressure. Your doctor will test your blood before you begin therapy and throughout the treatment to make sure that the therapy you are getting is safe and effective. Children and adolescents This medicine is not recommended for use in patients under the age of 3 years. Other medicines and ViraferonPeg Please tell your doctor or pharmacist if you, or the child you are caring for: - are taking or have recently taken any other medicines or vitamins/nutritional supplements, including medicines obtained without a prescription. - are infected with both Human Immunodeficiency Virus (HIV-positive) and Hepatitis C Virus (HCV) and are being treated with an anti-HIV medicine(s) – [nucleoside reverse transcriptase inhibitor (NRTI), and/or highly active anti-retroviral therapy (HAART)]. Your doctor will monitor you for signs and symptoms of these conditions. o Taking this medicine in combination with ribavirin and an anti-HIV medicine(s) may increase the risk of lactic acidosis, liver failure, and blood abnormalities: reduction in number of red blood cells, white blood cells and blood clotting cells called platelets. Patients with advanced liver disease receiving HAART may be at increased risk of worsening liver function, therefore adding treatment with this medicine alone or in combination with ribavirin may increase their risk. o With zidovudine or stavudine, it is not certain if ribavirin will change the way these medicines work. Therefore, your blood will be checked regularly to be sure that the HIV infection is not getting worse. If it gets worse, your doctor will decide whether or not your ribavirin treatment needs to be changed. Additionally, patients treated with this medicine and ribavirin combination therapy and zidovudine could be at increased risk of developing anaemia (low number of red blood cells). Therefore the use of zidovudine with this medicine and ribavirin combination therapy is not recommended. Reminder: Please read the “Other medicines” section of the Package Leaflet for ribavirin before using it in combination with this medicine. - are taking telbivudine. If you take telbivudine with this medicine or any type of injectable interferon product, your risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations in the arms and/or legs) is higher. These events may also be more severe. Therefore, you must not take this medicine at the same time as telbivudine. 132 Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Pregnancy In studies in pregnant animals, interferons have sometimes caused miscarriage. The effect of this medicine on human pregnancy is not known. Girls or women of childbearing potential need to use effective birth control during the treatment with this medicine. Ribavirin can be very damaging to an unborn baby. Therefore, you and your partner must take special precautions in sexual activity if there is any chance for pregnancy to occur: - if you are a girl or a woman of childbearing age who is taking ribavirin: you must have a negative pregnancy test before treatment, each month during treatment, and for the 4 months after treatment is stopped. You must use an effective birth control during the time you are taking ribavirin and for 4 months after stopping treatment. This should be discussed with your doctor. - if you are a man who is taking ribavirin: do not have sex with a pregnant woman unless you use a condom. If your female partner is not pregnant but is of childbearing age, she must be tested for pregnancy each month during treatment and for the 7 months after treatment has stopped. You or your partner must use an effective birth control during the time you are taking ribavirin and for 7 months after stopping treatment. This should be discussed with your doctor. Breast-feeding It is not known whether this medicine is present in human milk. Therefore, you shoud not breast-feed an infant if you are taking this medicine. Ask your doctor for advice. Reminder: Please read the “Pregnancy and breast-feeding” section of the Package Leaflet for ribavirin before using it in combination with this medicine. Driving and using machines Do not drive or operate any tools or machines if you feel tired, sleepy or confused while taking this medicine. ViraferonPeg contains sucrose This medicine contains sucrose. If you have an intolerance to some sugars, contact your doctor before taking this medicine. This medicine contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially "sodium-free". 3. How to use ViraferonPeg Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. General information about taking this medicine Your doctor has determined the correct dose of this medicine based on how much you, or the child you are caring for weighs. If necessary, the dose may be changed during treatment. This medicine is intended for subcutaneous use. This means that it is injected through a short needle into the fatty tissue just under the skin. If you are injecting this medicine yourself, you will be instructed how to prepare and give the injection. Detailed instructions for subcutaneous administration are provided at the end of this leaflet (see ANNEX TO THE PACKAGE LEAFLET “How to use the ViraferonPeg pre-filled pen”). Prepare the dose just before you intend to inject it and use it immediately. Look carefully at the solution you prepared before you use it. The solution should be clear and colourless. Do not use the 133 solution if it is discoloured (changed its colour from the original) or if there are bits of particles in the solution. Discard the ViraferonPeg pre-filled pen (CLEARCLICK) with any solution that is left in it after you give yourself the injection. For disposal instructions, see section 5 “How to store ViraferonPeg”. Inject this medicine once each week on the same day. Injecting it at the same time of day each week will help you not to forget to take it. Always use this medicine exactly as your doctor has told you. Do not exceed the recommended dosage, and take it for as long as prescribed. If your doctor prescribes this medicine with ribavirin or with ribavirin and boceprevir, please read the Package Leaflets of ribavirin and boceprevir before you begin combination treatment. Use in adults – ViraferonPeg in combination treatment This medicine, when given with ribavirin capsules, is usually given at a dose of 1.5 microgram per kilogram of body weight once a week. If you have kidney disease, your dose may be lower, depending upon your kidney function. Use in adults – ViraferonPeg alone This medicine, when given alone, is usually given at a dose of 0.5 or 1.0 microgram per kilogram of body weight once a week, for 6 months to 1 year. If you have kidney disease, your dose may be lower, depending upon your kidney function. Your doctor will determine the correct dose for you. Use in children 3 years of age and older and adolescents ViraferonPeg will be given in combination with ribavirin.The dose of ViraferonPeg is determined by a calculation accounting for both height and weight. Your doctor will determine the correct dose for you, or the child you are caring for. The duration of treatment is up to 1 year based on the doctor’s judgement for you, or the child you are caring for. All patients If you are injecting this medicine yourself, please be sure that the dose that has been prescribed is clearly provided on the package of medicine you receive. If you use more ViraferonPeg than you should Tell your doctor or healthcare professional or the doctor or healthcare professional of the child you are caring for as soon as possible. If you forget to take ViraferonPeg Take/administer the dose of this medicine as soon as you remember, but only if within 1-2 days after the forgotten dose. If it is very close to your next injection, do not double the dose to make up for the forgotten dose, but continue your treatment as usual. If you are uncertain, contact your doctor or pharmacist or the doctor or pharmacist of the child you are caring for. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Although not all of these side effects may occur, they may need medical attention if they do. When this medicine is used alone, some of these effects are less likely to occur, and some have not occurred at all. Psychiatric and central nervous system: Some people get depressed when taking this medicine alone or in combination treatment with ribavirin, and in some cases people have had thoughts about threatening the life of others, suicidal thoughts or aggressive behaviour (sometimes directed against others). Some patients have actually committed suicide. Seek emergency care if you notice that you are becoming depressed or have 134 suicidal thoughts or change in your behaviour. Ask a family member or close friend to help you stay alert to signs of depression or changes in your behaviour. Children and adolescents are particularly prone to develop depression when being treated with this medicine and ribavirin. Immediately contact the doctor or seek emergency treatment if they display any unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or others. Growth and development (children and adolescents): With up to one year of treatment with this medicine in combination with ribavirin, some children and adolescents did not grow or gain weight as much as expected. Some children did not reach their projected height within 1-5.5 years after completing treatment. Contact your doctor immediately if you notice any of the following serious side effects occurring during treatment: Very common side effects (may affect more than 1 in 10 people): - breathing problems (including shortness of breath), - feeling depressed, - trouble sleeping, thinking or concentrating, dizziness, - severe stomach pain or cramps, - fever or chills beginning after a few weeks of treatment, - painful or inflamed muscles (sometimes severe), Common side effects (may affect up to 1 in 10 people): - chest pain, changes in the way your heart beats, - confusion, - difficulty remaining alert, numbness or tingling feeling, - pain in your lower back or side, difficulty or inability to pass urine, - problems with your eyes or your eyesight or hearing, - severe or painful reddening of your skin or mucous membrane, - severe bleeding from your nose, gums or any other part of your body. Uncommon side effects (may affect up to 1 in 100 people): - wanting to harm yourself, - hallucinations, Rare side effects (may affect up to 1 in 1,000 people): - convulsion (“fit”), - blood or clots in stool (or black, tarry stool), Unknown frequency side effects (frequency cannot be estimated from the available data): - Wanting to harm others. Other side effects that have been reported in adults include: Very common side effects (may affect more than 1 in 10 people): - feeling depressed, irritability, trouble falling asleep or staying asleep, feeling anxious or nervous, difficulty concentrating, mood swings, - headache, dizziness, tired feeling, shaking chills, fever, flu-like symptoms, virus infection, weakness, - difficult breathing, pharyngitis (sore throat), coughing, - stomach pain, vomiting, nausea, diarrhoea, loss of appetite, loss of weight, dry mouth, - hair loss, itching, dry skin, rash, irritation or redness (and rarely, skin damage) at the site of injection, - decreases in the number of red blood cells (that may cause fatigue, shortness of breath, dizziness), decrease in certain white blood cells (that makes you more susceptible to different infections), 135 - pain in joints and muscles, muscle and bone pain. Common side effects (may affect up to 1 in 10 people): - decrease in blood clotting cells called platelets, that may result in easy bruising and spontaneous bleeding, excess of uric acid (as in gout) in the blood, low calcium level in the blood, - decrease in thyroid gland activity (which may make you feel tired, depressed, increase your sensitivity to cold and other symptoms), increase in thyroid gland activity (which may cause nervousness, heat intolerance and excessive sweating, weight loss, palpitation, tremors), swollen glands (swollen lymph nodes), thirst, - changed behaviour or aggressive behaviour (sometimes directed against others), agitation, nervousness, feeling sleepy, trouble sleeping, unusual dreams, lack of interest in activities, lack of interest in sex, erectile problem, increased appetite, confusion, shaky hands, poor coordination, vertigo (spinning feeling), numbness, pain or tingling feeling, increased or decreased sensitivity to touch, tense muscles, limb pain, arthritis, migraine, increased sweating, - eye pain or infection, blurred vision, dry or teary eyes, changes in hearing/loss of hearing, ringing in ears, - sinusitis, respiratory infections, stuffy or runny nose, difficulty in speaking, nosebleed, cold sores (herpes simplex), fungal or bacterial infections, ear infection/earache, - indigestion (stomach upset), heartburn, redness or sores in mouth, burning sensation on tongue, red or bleeding gums, constipation, intestinal gas (flatus), bloating, hemorrhoids, sore tongue, change in taste, tooth problem, excessive loss of body water, enlarged liver, - psoriasis, sensitivity to sunlight, rash with raised spotted lesions, redness of skin or skin disorders, puffy face, puffy hands or feet, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), acne, hives, abnormal hair texture, nail disorder, pain at the site of injection, - difficult, irregular or no menstrual period, abnormally heavy and prolonged menstrual period, problem affecting ovary or vagina, pain in breast, sexual problem, irritation of prostate gland, increased need to pass urine, - chest pain, pain on the right side around your ribs, feeling unwell, low or high blood pressure, feeling faint, flushing, palpitations (pounding heart beat), rapid heart rate. Uncommon side effects (may affect up to 1 in 100 people): - suicide, attempted suicide, thoughts about threatening the life of yourself, panic attack, delusions, hallucination, - hypersensitivity reaction to the medication, heart attack, inflammation of the pancreas, pain in bone and diabetes mellitus, - cotton wool spots (white deposits on the retina). Rare side effects (may affect up to 1 in 1,000 people): - diabetic ketoacidosis (medical emergency due to build-up of ketone bodies in the blood as a result of out-of-control diabetes), - seizures (convulsions) and bipolar disorders (mood disorders characterized by alternating episodes of sadness and excitement), - eye problems including changes in vision, damage to the retina, obstruction of the retinal artery, inflammation of the optic nerve, swelling of the eye, - congestive heart failure, abnormal heart rhythm, pericarditis (inflammation of the lining of the heart), inflammation and degeneration of muscle tissue and peripheral nerves, kidney problems, - sarcoidosis (a disease characterized by persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands). Very rare side effects (may affect up to 1 in 10,000 people): - aplastic anaemia, stroke (cerebrovascular events), toxic epidermal necrolysis/Stevens Johnson Syndrome/erythema multiforme (a spectrum of rashes with varying degree of severity including death which may be associated with blisters in the mouth, nose, eyes and other mucosal membranes and sloughing of the affected area of the skin). - loss of consciousness has occurred very rarely with alpha interferons, mostly in elderly patients treated at high doses. 136 Side effects of unknown frequency (frequency cannot be estimated from the available data): - pure red cell aplasia (a condition where the body stopped or reduced the production of red blood cells). This causes severe anaemia, symptoms of which would include unusual tiredness and a lack of energy. - facial palsy (weakness and slumping on one side to the face), severe allergic reactions such as angioedema (an allergic skin disease characterized by patches of swelling involving the skin and its subcutaneous layers, the mucous membranes, and sometimes the internal organs), mania (excessive or unreasonable enthusiasm), pericardial effusion (a fluid collection that develops between the pericardium (the lining of the heart) and the heart itself), Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, skin and the membranes of the ears, brain and spinal cord), change in colour of the tongue. - thoughts about threatening the life of others. - pulmonary fibrosis (scarring of the lungs). - pulmonary arterial hypertension – a disease of severe narrowing of the blood vessels in the lungs resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This may occur in particular in patients with risk factors such as HIV infection or severe liver problems (cirrhosis). The side effect may develop at various time points during treatment, typically several months after starting treatment with ViraferonPeg. - hepatitis B reactivation in HCV/HBV co-infected patients (recurrence of hepatitis B disease). If you are an HCV/HIV co-infected adult patient receiving HAART, the addition of this medicine and ribavirin may increase your risk of lactic acidosis, liver failure, and development of blood abnormalities (reduction in number of red blood cells which carry oxygen, certain white blood cells that fight infection, and blood clotting cells called platelets). The following other side effects (not listed above) have occurred with the combination of this medicine and ribavirin capsules (adults) in HCV/HIV co-infected patients receiving HAART: - oral candidiasis (oral thrush), - defective metabolism of fat, - CD4 lymphocytes decreased, - appetite decreased, - back pain, - hepatitis, - limb pain, - and various laboratory blood values abnormalities. Side effects in children and adolescents The following effects have occurred in children and adolescents: Very common side effects (may affect more than 1 in 10 people): - loss of appetite, dizziness, headache, vomiting, nausea, stomach pain, - hair loss, dry skin, pain in joints and muscles, redness at the site of injection, - feeling irritable, tired feeling, feeling unwell, pain, chills, fever, flu-like symptoms, weakness, decrease in rate of growth (height and weight for age), - decreases in red blood cells that may cause fatigue, shortness of breath, dizziness. Common side effects (may affect up to 1 in 10 people): - fungal infection, common cold, cold sores, pharyngitis (sore throat), sinusitis, ear infection, coughing, throat pain, feeling cold, eye pain, - decrease in blood clotting cells called platelets, that may result in easy bruising and spontaneous bleeding, swollen glands (swollen lymph nodes), blood thyroid tests abnormalities, decrease in thyroid gland activity, which may make you feel tired, depressed, increase your sensitivity to cold and other symptoms, - wanting or attempting to harm yourself, aggressive behaviour, agitation, anger, mood changes, nervousness or restlessness, depression, feeling anxious, trouble falling asleep or staying asleep, emotional instability, poor quality sleep, feeling sleepy, disturbance in attention. 137 - changes in taste, diarrhoea, stomach upset, oral pain, - fainting, palpitations (pounding heart beat), rapid heart rate, flushing, nosebleed, - sores in mouth, scaling lips and clefts in the corners of the mouth, rash, redness of skin, itching, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), acne, - back pain, muscle and bone pain, limb pain, dryness, pain, rash, irritation or itching at the site of injection. Uncommon side effects (may affect up to 1 in 100 people): - painful or difficult urination, urinary frequency, the presence of excess protein in the urine, painful menstruation, - itchy anal area (pinworms or ascarids), inflammation of the lining membrane of the stomach and the intestines, inflamed gums, enlarged liver, - abnormal behaviour, emotional disorder, fear, nightmare, tremor, decreased sensitivity to touch, numbness or tingling feeling, pain radiating along the course of one or more nerves, drowsiness, - bleeding of the mucous membrane that lines the inner surface of the eyelids, itchy eyes, eye pain, blurred vision, intolerance to light, - low blood pressure, paleness, nasal discomfort, runny nose, wheezing, difficult breathing, chest pain or discomfort, - redness, swelling, pain of skin, shingles, skin sensitive to sunlight, rash with raised spotted lesions, skin discolouration, peeling of skin, shortening of muscle tissue, muscle twitching, facial pain, bruising. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can also help provide more information on the safety of this medicine. Reminder to adult patients prescribed combination therapy of this medicine, boceprevir and ribavirin: Please read the “Possible side effects” section of these Package Leaflets. 5. How to store ViraferonPeg Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton, after EXP. Store in a refrigerator (2C - 8C). Do not freeze. Use the reconstituted solution (solution you prepared by mixing the powder and the liquid in the pre- filled pen) immediately or within 24 hours when stored in a refrigerator (2°C - 8°C). Do not use this medicine if you notice discolouration of the powder, which should be white. The reconstituted solution should be clear and colourless. Do not use if it is discoloured or if bits of particles are present. After administering the dose, discard the ViraferonPeg pre-filled pen (CLEARCLICK) and any unused solution contained in it. Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What ViraferonPeg contains - The active substance is peginterferon alfa-2b. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 138 ViraferonPeg 50 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 50 micrograms of peginterferon alfa-2b measured on a protein basis. Each pre-filled pen provides 50 micrograms/0.5 ml of solution when reconstituted as recommended. ViraferonPeg 80 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 80 micrograms of peginterferon alfa-2b measured on a protein basis. Each pre-filled pen provides 80 micrograms/0.5 ml of solution when reconstituted as recommended. ViraferonPeg 100 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 100 micrograms of peginterferon alfa-2b measured on a protein basis. Each pre-filled pen provides 100 micrograms/0.5 ml of solution when reconstituted as recommended. ViraferonPeg 120 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 120 micrograms of peginterferon alfa-2b measured on a protein basis. Each pre-filled pen provides 120 micrograms/0.5 ml of solution when reconstituted as recommended. ViraferonPeg 150 micrograms powder and solvent for solution for injection in pre-filled pen Each pre-filled pen contains 150 micrograms of peginterferon alfa-2b measured on a protein basis. Each pre-filled pen provides 150 micrograms/0.5 ml of solution when reconstituted as recommended. - The other ingredients are: Powder: disodium phosphate, anhydrous; sodium dihydrogen phosphate dihydrate; sucrose and polysorbate 80. Solvent: water for injections. What ViraferonPeg looks like and contents of the pack This medicine is a powder and solvent (liquid) for solution for injection in a pre-filled pen (CLEARCLICK). The white powder and the clear and colourless solvent are both contained in a two-chamber glass cartridge assembled into a single use pre-filled pen. ViraferonPeg is available in different pack sizes: - 1 pre-filled pen containing powder and solvent for solution for injection, 1 needle ("Push-On Needle"), 2 cleansing swabs; - 4 pre-filled pens containing powder and solvent for solution for injection, 4 needles ("Push-On Needle"), 8 cleansing swabs; - 12 pre-filled pens containing powder and solvent for solution for injection, 12 needles ("Push-On Needle"), 24 cleansing swabs. Not all pack sizes may be marketed. Marketing Authorisation Holder Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands Manufacturer SP Labo N.V. Industriepark, 30 B-2220 Heist-op-den-Berg Belgium 139 For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien MSD Belgium BVBA/SPRL Tel: 0800 38 693 (+32(0)27766211) dpoc_belux@merck.com Lietuva UAB Merck Sharp & Dohme Tel. +370 5 278 02 47 msd_lietuva@merck.com България Мерк Шарп и Доум България ЕООД Тел.: +359 2 819 3737 info-msdbg@merck.com Luxembourg/Luxemburg MSD Belgium BVBA/SPRL Tel: +32(0)27766211 dpoc_belux@merck.com Česká republika Merck Sharp & Dohme s.r.o. Tel: +420 233 010 111 dpoc_czechslovak@merck.com Magyarország MSD Pharma Hungary Kft. Tel.: +36 1 888 5300 hungary_msd@merck.com Danmark MSD Danmark ApS Tlf: + 45 4482 4000 dkmail@merck.com Malta Merck Sharp & Dohme Cyprus Limited Tel: 8007 4433 (+356 99917558) malta_info@merck.com Deutschland MSD SHARP & DOHME GMBH Tel: 0800 673 673 673 (+49 (0) 89 4561 2612) e-mail@msd.de Nederland Merck Sharp & Dohme BV Tel: 0800 9999000 (+31 23 5153153) medicalinfo.nl@merck.com Eesti Merck Sharp & Dohme OÜ Tel.: +372 6144 200 msdeesti@merck.com Norge MSD (Norge) AS Tlf: +47 32 20 73 00 msdnorge@msd.no Ελλάδα MSD Α.Φ.Β.Ε.Ε. Τηλ: +30 210 98 97 300 dpoc_greece @merck.com Österreich Merck Sharp & Dohme Ges.m.b.H. Tel: +43 (0) 1 26 044 msd-medizin@merck.com España Merck Sharp & Dohme de España, S.A. Tel: +34 91 321 06 00 msd_info@merck.com Polska MSD Polska Sp. z o.o. Tel: +48 22 549 51 00 msdpolska@merck.com France MSD France Tél: + 33-(0)1 80 46 40 40 Portugal Merck Sharp & Dohme, Lda Tel: +351 21 4465700 clic@merck.com Hrvatska Merck Sharp & Dohme d.o.o. Tel: + 385 1 6611 333 croatia_info@merck.com România Merck Sharp & Dohme Romania S.R.L. Tel: +40 21 529 2900 msdromania@merck.com 140 Ireland Merck Sharp & Dohme Ireland (Human Health) Limited Tel: +353 (0)1 2998700 medinfo_ireland@merck.com Slovenija Merck Sharp & Dohme, inovativna zdravila d.o.o. Tel: +386 1 5204 201 msd.slovenia@merck.com Ísland Vistor hf. Sími: + 354 535 7000 Slovenská republika Merck Sharp & Dohme, s. r. o. Tel: +421 2 58282010 dpoc_czechslovak@merck.com Italia MSD Italia S.r.l. Tel: +39 06 361911 medicalinformation.it@merck.com Suomi/Finland MSD Finland Oy Puh/Tel: +358 (0)9 804 650 info@msd.fi Κύπρος Merck Sharp & Dohme Cyprus Limited Τηλ.: 800 00 673 (+357 22866700) cyprus_info@merck.com Sverige Merck Sharp & Dohme (Sweden) AB Tel: +46 77 5700488 medicinskinfo@merck.com Latvija SIA Merck Sharp & Dohme Latvija Tel: +371 67364224 msd_lv@merck.com United Kingdom Merck Sharp & Dohme Limited Tel: +44 (0) 1992 467272 medicalinformationuk@merck.com This leaflet was last revised in MM/YYYY Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu. 141 ANNEX TO THE PACKAGE LEAFLET How to use the ViraferonPeg pre-filled pen The following instructions explain how to use the pre-filled pen to inject yourself. Please read the instructions carefully and follow them step by step. Your healthcare provider will instruct you on how to give the injections. Do not attempt to administer an injection until you are sure you understand how to use the pre-filled pen. Each pre-filled pen is for single use only. Getting ready  Find a well-lit, clean flat work surface such as a table.  Take the pre-filled pen out of the refrigerator. Look at the date printed on the carton after EXP to make sure that the expiration date has not passed. Do not use if the expiration date has passed.  Remove the pre-filled pen from the carton.  Lay the pre-filled pen on a flat clean surface and wait until it reaches room temperature (but not more than 25oC). This may take up to 20 minutes.  Wash your hands well with soap and warm water. Keep your work area, your hands, and the injection site clean to decrease the risk of infection. You will need the following supplies that are included in the package: - a pre-filled pen (CLEARCLICK) - a needle ("Push-On Needle") - 2 alcohol swabs 1. Mix  Hold the pre-filled pen upright with the dial on the bottom.  Turn the dial to number 1 (see Figure 1). You may hear a "click" sound. Window Dial Device body Needle shield "Push-On Needle" 142 Figure 1  DO NOT SHAKE TO MIX. Gently turn the pre-filled pen up-side-down two times to mix (see Figure 2). Figure 2  Look in the window. The solution should be clear and colourless before use. Some bubbles may be present, but this is normal. Do not use if it is discoloured or if particles are present. 2. Add needle  Turn the dial to number 2 (see Figure 3). You may hear a "click" sound. Figure 3  Wipe the top of the pre-filled pen where the needle is going to be attached with an alcohol swab (see Figure 4). Figure 4 143  Remove the yellow paper from the needle cap before attaching the needle ("Push-On Needle") to the pre-filled pen (see Figure 5), Figure 5  Support the pre-filled pen in upright position and push the needle straight down firmly (see Figure 6). You might hear a soft sound when pushing on the needle. Figure 6  Remove the needle cap. You may see some liquid trickle out of the needle (see Figure 7). This is normal. Figure 7 3. Dial dose  Turn the dial to your prescribed dose (see Figure 8). You may hear clicking sounds as you dial. Note: The needle shield will automatically SNAP UP as you dial (see Figure 9). You may dial up or down to any dose prior to injection. Figure 8 Figure 9 SNAP! 144 You are ready to inject  Choose an injection site on your stomach area (abdomen) or thigh. Avoid your belly button (navel) and waistline. If you are very thin, you should only use the thigh for injection. You should use a different place each time you give yourself an injection. Do not inject ViraferonPeg into an area where the skin is irritated, red, bruised, infected, or has scars, stretch marks, or lumps.  Wipe the injection site with a new alcohol swab. Let the skin air dry.  Pinch a fold of loose skin in the area you have cleaned for injection.  Press the pre-filled pen against the skin as shown in Figure 10. The shield will automatically glide back to allow the needle to inject the medicine.  Hold the pre-filled pen against the skin for 15 seconds. Note: The pre-filled pen will make a clicking sound for up to 10 seconds – depending on your dose. Additional 5 seconds ensures complete dose delivery. Note: Once the pre-filled pen is removed from the skin, the needle shield will lock in place. Figure 10: Thigh injection Disposal of the injection materials The pre-filled pen, needle and all injection materials are intended for single use and must be discarded after the injection. Dispose of the used pre-filled pen safely in a closed container. Ask your healthcare provider or pharmacist for an appropriate container. 15 SEC SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what viraferonpeg is and what it is used for', 'Section_Content': "the active substance in this medicine is a protein called peginterferon alfa-2b, which belongs to the class of medicines called interferons. interferons are made by your body's immune system to help fight infections and severe diseases. this medicine is injected into your body to work with your immune system. this medicine is used for the treatment of chronic hepatitis c, a viral infection of the liver. adults the combination of this medicine, ribavirin and boceprevir is recommended for use for some types of chronic hepatitis c virus infection (also called hcv infection) in adults 18 years of age and older. it may be used in adults who have not been previously treated for hcv infection or who have previously used medicines called interferons and pegylated interferons. the combination of this medicine and ribavirin is recommended for adults 18 years of age and older who have not previously been treated with these medicines. this includes adults also infected with clinically stable hiv (human immunodeficiency virus). the combination can also be used to treat adults who have already failed treatment with an interferon alpha or peginterferon alpha in combination with ribavirin or interferon alpha alone. if you have a medical condition making use of ribavirin dangerous or if you already have had a problem taking it, your doctor will likely prescribe this medicine alone. if you have any further questions on the use of this medicine, ask your doctor or pharmacist. children and adolescents this medicine is used in combination with ribavirin in children 3 years of age and older and adolescents who have not been treated previously for chronic hepatitis c.", 'Entity_Recognition': [{'Text': 'viraferonpeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a protein called peginterferon alfa', 'Type': 'TREATMENT', 'BeginOffset': 41, 'EndOffset': 76}, {'Id': 2, 'BeginOffset': 128, 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{'Title': '2. what you need to know before you use viraferonpeg', 'Section_Content': 'do not use viraferonpeg you should tell your doctor before starting treatment if you, or the child you are caring for: - are allergic to peginterferon alfa-2b or any of the other ingredients of this medicine (listed in section 6). - are allergic to any interferon. - have had severe heart problems. - have heart disease that has not been well controlled during the past 6 months. - have severe medical conditions that leave you very weak. - have autoimmune hepatitis or any other problem with your immune system. - are taking medicine that suppresses (weakens) your immune system. - have advanced, uncontrolled liver disease (other than hepatitis c). - have thyroid disease that is not well controlled with medicines. - have epilepsy, a condition that causes convulsions (seizures, or "fits"). - are being treated with telbivudine (see section "other medicines and viraferonpeg"). you must not use viraferonpeg if any of the conditions above should apply to you, or the child you are caring for. in addition, children and adolescents must not use this medicine if they have had serious nervous or mental problems, such as severe depression or thoughts of suicide. reminder: please also read the "do not take" section of the package leaflet for ribavirin and boceprevir before using them in combination with this medicine. warnings and precautions seek medical help immediately in case of a severe allergic reaction (such as difficulty in breathing, wheezing, or hives). talk to your doctor before taking this medicine if you, or the child you are caring for: - have had a severe nervous or mental disorder or have a history of substance abuse (e.g. alcohol or drugs). the use of this medicine in children and adolescents with existence of or history of severe psychiatric conditions is not allowed (see section "do not use viraferonpeg" above). - are being treated for a mental illness or had treatment in the past for any other nervous or mental disorder, including depression (such as feelings of sadness, dejection) or suicidal or homicidal behaviour (see section 4 "possible side effects"). - have ever had a heart attack or a heart problem. - have kidney disease, your doctor may prescribe a lower than usual dose and monitor your kidney blood values regularly during treatment. if this medicine is used in combination with ribavirin, your doctor should monitor you, or the child you are caring for more carefully for a decrease in red blood cell count. - have cirrhosis or other liver problems (other than hepatitis c). - develop symptoms associated with a cold or other respiratory infection, such as fever, cough, or any difficulty in breathing. - are diabetic or have high blood pressure, your doctor may ask you, or the child you are caring for to have an eye examination. - have had any serious illness affecting breathing or blood. - have the skin disorders, psoriasis or sarcoidosis, which may become worse while you are using this medicine. - are planning to become pregnant, discuss this with your doctor before starting to use this medicine. - have received an organ transplant, either kidney or liver, interferon treatment may increase the risk of rejection. be sure to discuss this with your doctor. - if you are also being treated for hiv (see section "other medicines and viraferonpeg"). - have a current or previous infection with the hepatitis b virus, since your doctor may want to monitor you more closely. reminder: please read the "warnings and precautions" section of the package leaflet for ribavirin before using it in combination with this medicine. teeth and mouth problems have been reported in patients receiving this medicine in combination with ribavirin. you may develop gum disease, which could lead to loss of teeth. you may develop a dry mouth or vomiting, both of which can damage your teeth. it is important to brush your teeth thoroughly twice a day, rinse your mouth out if you vomit, and have regular dental check-ups. during treatment, some patients may experience eye problems, or loss of vision in rare instances. your doctor should carry out an eye examination before starting your treatment. in case of any changes in vision, you must tell your doctor and have a prompt and complete eye examination. if you have a medical condition that may lead to future eye problems (e.g. diabetes or high blood pressure), you should receive regular eye exams during therapy. if your eye disorder becomes more severe or if you develop new eye disorders, your treatment will be discontinued. while being treated with viraferonpeg, your doctor may advise to drink extra fluids to help prevent low blood pressure. your doctor will test your blood before you begin therapy and throughout the treatment to make sure that the therapy you are getting is safe and effective. children and adolescents this medicine is not recommended for use in patients under the age of 3 years. other medicines and viraferonpeg please tell your doctor or pharmacist if you, or the child you are caring for: - are taking or have recently taken any other medicines or vitamins/nutritional supplements, including medicines obtained without a prescription. - are infected with both human immunodeficiency virus (hiv-positive) and hepatitis c virus (hcv) and are being treated with an anti-hiv medicine(s) [nucleoside reverse transcriptase inhibitor (nrti), and/or highly active anti-retroviral therapy (haart)]. your doctor will monitor you for signs and symptoms of these conditions. o taking this medicine in combination with ribavirin and an anti-hiv medicine(s) may increase the risk of lactic acidosis, liver failure, and blood abnormalities: reduction in number of red blood cells, white blood cells and blood clotting cells called platelets. patients with advanced liver disease receiving haart may be at increased risk of worsening liver function, therefore adding treatment with this medicine alone or in combination with ribavirin may increase their risk. o with zidovudine or stavudine, it is not certain if ribavirin will change the way these medicines work. therefore, your blood will be checked regularly to be sure that the hiv infection is not getting worse. if it gets worse, your doctor will decide whether or not your ribavirin treatment needs to be changed. additionally, patients treated with this medicine and ribavirin combination therapy and zidovudine could be at increased risk of developing anaemia (low number of red blood cells). therefore the use of zidovudine with this medicine and ribavirin combination therapy is not recommended. reminder: please read the "other medicines" section of the package leaflet for ribavirin before using it in combination with this medicine. - are taking telbivudine. if you take telbivudine with this medicine or any type of injectable interferon product, your risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations in the arms and/or legs) is higher. these events may also be more severe. therefore, you must not take this medicine at the same time as telbivudine. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. pregnancy in studies in pregnant animals, interferons have sometimes caused miscarriage. the effect of this medicine on human pregnancy is not known. girls or women of childbearing potential need to use effective birth control during the treatment with this medicine. ribavirin can be very damaging to an unborn baby. therefore, you and your partner must take special precautions in sexual activity if there is any chance for pregnancy to occur: - if you are a girl or a woman of childbearing age who is taking ribavirin: you must have a negative pregnancy test before treatment, each month during treatment, and for the 4 months after treatment is stopped. you must use an effective birth control during the time you are taking ribavirin and for 4 months after stopping treatment. this should be discussed with your doctor. - if you are a man who is taking ribavirin: do not have sex with a pregnant woman unless you use a condom. if your female partner is not pregnant but is of childbearing age, she must be tested for pregnancy each month during treatment and for the 7 months after treatment has stopped. you or your partner must use an effective birth control during the time you are taking ribavirin and for 7 months after stopping treatment. this should be discussed with your doctor. breast-feeding it is not known whether this medicine is present in human milk. therefore, you should not breast-feed an infant if you are taking this medicine. ask your doctor for advice. reminder: please read the "pregnancy and breast-feeding" section of the package leaflet for ribavirin before using it in combination with this medicine. driving and using machines do not drive or operate any tools or machines if you feel tired, sleepy or confused while taking this medicine. viraferonpeg contains sucrose this medicine contains sucrose. if you have an intolerance to some sugars, contact your doctor before taking this medicine. this medicine contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially "sodium-free".', 'Entity_Recognition': [{'Text': 'viraferonpeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'viraferonpeg', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 23}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 68, 'EndOffset': 77}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 125, 'EndOffset': 133}, {'Id': 6, 'BeginOffset': 137, 'EndOffset': 155, 'Score': 0.8027617931365967, 'Text': 'peginterferon alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 194, 'EndOffset': 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{'Title': '3. how to use viraferonpeg', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. general information about taking this medicine your doctor has determined the correct dose of this medicine based on how much you, or the child you are caring for weighs. if necessary, the dose may be changed during treatment. this medicine is intended for subcutaneous use. this means that it is injected through a short injection needle into the fatty tissue just under the skin. if you are injecting this medicine yourself, you will be instructed how to prepare and give the injection. detailed instructions for subcutaneous administration are provided at the end of this leaflet (see section "how to self-inject viraferonpeg"). water for injection and viraferonpeg powder are provided in separate ampoules. prepare the dose by adding water for injection to viraferonpeg powder just before you intend to inject it and use it 119 immediately. look carefully at the solution you prepared before you use it. the solution should be clear and colourless. do not use the solution if it is discoloured (changed its colour from the original) or if there are bits of particles in the solution. discard any solution that is left in the vial after you give yourself the injection. for disposal instructions, see section 5 "how to store viraferonpeg". inject this medicine once each week on the same day. injecting it at the same time of day each week will help you not to forget to take it. always use this medicine exactly as your doctor has told you. do not exceed the recommended dosage, and take it for as long as prescribed. if your doctor prescribes this medicine with ribavirin or with ribavirin and boceprevir, please read the package leaflets of ribavirin and boceprevir before you begin combination treatment. use in adults viraferonpeg in combination treatment this medicine, when given with ribavirin capsules, is usually given at a dose of 1.5 microgram per kilogram of body weight once a week. if you have kidney disease, your dose may be lower, depending upon your kidney function. use in adults viraferonpeg alone this medicine, when given alone, is usually given at a dose of 0.5 or 1.0 microgram per kilogram of body weight once a week, for 6 months to 1 year. if you have kidney disease, your dose may be lower, depending upon your kidney function. your doctor will determine the correct dose for you. use in children 3 years of age and older and adolescents viraferonpeg will be given in combination with ribavirin.the dose of viraferonpeg is determined by a calculation accounting for both height and weight. your doctor will determine the correct dose for you, or the child you are caring for. the duration of treatment is up to 1 year based on the doctor\'s judgement for you, or the child you are caring for. all patients if you are injecting this medicine yourself, please be sure that the dose that has been prescribed is clearly provided on the package of medicine you receive. if you use more viraferonpeg than you should tell your doctor or healthcare professional or the doctor or healthcare professional of the child you are caring for as soon as possible. if you forget to take viraferonpeg take/administer the dose of this medicine as soon as you remember, but only if within 1-2 days after the forgotten dose. if it is very close to your next injection, do not double the dose to make up for the forgotten dose, but continue your treatment as usual. if you are uncertain, contact your doctor or pharmacist or the doctor or pharmacist of the child you are caring for.', 'Entity_Recognition': [{'Text': 'viraferonpeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 228, 'EndOffset': 241}, {'Text': 'this medicine', 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{'Title': '5. how to store viraferonpeg', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton, after exp. store in a refrigerator (2c - 8c). use the reconstituted solution (solution you prepared by adding water for injection to the viraferonpeg powder) immediately or within 24 hours when stored in a refrigerator (2 - 8). do not use this medicine if you notice discolouration of the powder, which should be white. the reconstituted solution should be clear and colourless. do not use if it is discoloured or if bits of particles are present. viraferonpeg vials are for single use only. discard any unused material. do not throw away medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'viraferonpeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'the reconstituted solution (solution', 'Type': 'TREATMENT', 'BeginOffset': 187, 'EndOffset': 223}, {'Text': 'the viraferonpeg powder', 'Type': 'TREATMENT', 'BeginOffset': 270, 'EndOffset': 293}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 317, 'EndOffset': 319}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 376, 'EndOffset': 389}, {'Text': 'discolouration of the powder', 'Type': 'PROBLEM', 'BeginOffset': 404, 'EndOffset': 432}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 457, 'EndOffset': 483}, {'Text': 'viraferonpeg vials', 'Type': 'TREATMENT', 'BeginOffset': 585, 'EndOffset': 603}, {'Text': 'any unused material', 'Type': 'PROBLEM', 'BeginOffset': 637, 'EndOffset': 656}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what viraferonpeg contains - the active substance is peginterferon alfa-2b. viraferonpeg 50 micrograms powder and solvent for solution for injection each vial contains 50 micrograms of peginterferon alfa-2b measured on a protein basis. each vial provides 50 micrograms/0.5 ml of solution when reconstituted as recommended. viraferonpeg 80 micrograms powder and solvent for solution for injection each vial contains 80 micrograms of peginterferon alfa-2b measured on a protein basis. each vial provides 80 micrograms/0.5 ml of solution when reconstituted as recommended. viraferonpeg 100 micrograms powder and solvent for solution for injection each vial contains 100 micrograms of peginterferon alfa-2b measured on a protein basis. each vial provides 100 micrograms/0.5 ml of solution when reconstituted as recommended. viraferonpeg 120 micrograms powder and solvent for solution for injection each vial contains 120 micrograms of peginterferon alfa-2b measured on a protein basis. each vial provides 120 micrograms/0.5 ml of solution when reconstituted as recommended. viraferonpeg 150 micrograms powder and solvent for solution for injection each vial contains 150 micrograms of peginterferon alfa-2b measured on a protein basis. each vial provides 150 micrograms/0.5 ml of solution when reconstituted as recommended. - the other ingredients are: powder: disodium phosphate; anhydrous, sodium dihydrogen phosphate dihydrate; sucrose and polysorbate 80. solvent: water for injections. what viraferonpeg looks like and contents of the pack this medicine is a powder and solvent (liquid) for solution for injection. the white powder is contained in a 2 ml glass vial and the clear and colourless solvent is presented in a 2 ml glass ampoule. viraferonpeg is available in different pack sizes: - 1 vial of powder for solution for injection and 1 ampoule of solvent for injection; - 1 vial of powder for solution for injection, 1 ampoule of solvent for injection, 1 injection syringe, 2 injection needles and 1 cleansing swab; - 4 vials of powder for solution for injection and 4 ampoules of solvent for injection; - 4 vials of powder for solution for injection, 4 ampoules of solvent for injection, 4 injection syringes, 8 injection needles and 4 cleansing swabs; - 6 vials of powder for solution for injection and 6 ampoules of solvent for injection; - 12 vials of powder for solution for injection, 12 ampoules of solvent for injection, 12 injection syringes, 24 injection needles and 12 cleansing swabs. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'viraferonpeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 53, 'EndOffset': 74, 'Score': 0.9427998661994934, 'Text': 'peginterferon alfa-2b', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.9732195138931274, 'RelationshipScore': 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06E4D87BCC7C4199F765DBFDFFA818C2

https://www.ema.europa.eu/documents/product-information/iressa-epar-product-information_en.pdf

Iressa

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT IRESSA 250 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 250 mg of gefitinib. Excipients with known effect: Each tablet contains 163.5 mg of lactose (as monohydrate). Each tablet contains 3.86 mg of sodium. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablets (tablet). Tablets are brown, round, biconvex, impressed with “IRESSA 250” on one side and plain on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications IRESSA is indicated as monotherapy for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (see section 4.4). 4.2 Posology and method of administration Treatment with IRESSA should be initiated and supervised by a physician experienced in the use of anti-cancer therapies. Posology The recommended posology of IRESSA is one 250 mg tablet once a day. If a dose is missed, it should be taken as soon as the patient remembers. If it is less than 12 hours to the next dose, the patient should not take the missed dose. Patients should not take a double dose (two doses at the same time) to make up for a forgotten dose. Paediatric population The safety and efficacy of IRESSA in children and adolescents aged less than 18 years have not been established. There is no relevant use of gefitinib in the paediatric population in the indication of NSCLC. Hepatic impairment Patients with moderate to severe hepatic impairment (Child-Pugh B or C) due to cirrhosis have increased plasma concentrations of gefitinib. These patients should be closely monitored for adverse events. Plasma concentrations were not increased in patients with elevated aspartate transaminase (AST), alkaline phosphatase or bilirubin due to liver metastases (see section 5.2). Renal impairment No dose adjustment is required in patients with impaired renal function at creatinine clearance > 20 ml/min. Only limited data are available in patients with creatinine clearance  20 ml/min and caution is advised in these patients (see section 5.2). Elderly No dose adjustment is required on the basis of patient age (see section 5.2). CYP2D6 poor metabolisers No specific dose adjustment is recommended in patients with known CYP2D6 poor metaboliser genotype, but these patients should be closely monitored for adverse events (see section 5.2). Dose adjustment due to toxicity Patients with poorly tolerated diarrhoea or skin adverse reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg dose (see section 4.8). For patients unable to tolerate treatment after a therapy interruption, gefitinib should be discontinued and an alternative treatment should be considered. Method of administration The tablet may be taken orally with or without food, at about the same time each day. The tablet can be swallowed whole with some water or if dosing of whole tablets is not possible, tablets may be administered as a dispersion in water (non-carbonated). No other liquids should be used. Without crushing it, the tablet should be dropped in half a glass of drinking water. The glass should be swirled occasionally, until the tablet is dispersed (this may take up to 20 minutes). The dispersion should be drunk immediately after dispersion is complete (i.e. within 60 minutes). The glass should be rinsed with half a glass of water, which should also be drunk. The dispersion can also be administered through a naso-gastric or gastrostomy tube. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Breast-feeding (see section 4.6). 4.4 Special warnings and precautions for use When considering the use of IRESSA as a treatment for locally advanced or metastatic NSCLC, it is important that EGFR mutation assessment of the tumour tissue is attempted for all patients. If a tumour sample is not evaluable, then circulating tumour DNA (ctDNA) obtained from a blood (plasma) sample may be used. Only robust, reliable and sensitive test(s) with demonstrated utility for the determination of EGFR mutation status of tumours or ctDNA should be used to avoid false negative or false positive determinations (see section 5.1). Interstitial lung disease (ILD) Interstitial lung disease (ILD) which may be acute in onset, has been observed in 1.3% of patients receiving gefitinib, and some cases have been fatal (see section 4.8). If patients experience worsening of respiratory symptoms such as dyspnoea, cough and fever, IRESSA should be interrupted and the patient should be promptly investigated. If ILD is confirmed, IRESSA should be discontinued and the patient treated appropriately. In a Japanese pharmacoepidemiological case control study in 3,159 patients with NSCLC receiving gefitinib or chemotherapy who were followed up for 12 weeks, the following risk factors for developing ILD (irrespective of whether the patient received IRESSA or chemotherapy) were identified: smoking, poor performance status (PS ≥ 2), CT scan evidence of reduced normal lung (≤ 50%), recent diagnosis of NSCLC (< 6 months), pre-existing ILD, older age (≥ 55 years old) and concurrent cardiac disease. An increased risk of ILD on gefitinib relative to chemotherapy was seen predominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95% CI 1.9 to 7.7); thereafter the relative risk was lower (adjusted OR 2.5; 95% CI 1.1 to 5.8). Risk of mortality among patients who developed ILD on IRESSA or chemotherapy was higher in patients with the following risk factors: smoking, CT scan evidence of reduced normal lung (≤ 50%), pre-existing ILD, older age (≥ 65 years old), and extensive areas adherent to pleura (≥ 50%). Hepatotoxicity and liver impairment Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed, uncommonly presenting as hepatitis (see section 4.8). There have been isolated reports of hepatic failure which in some cases led to fatal outcomes. Therefore, periodic liver function testing is recommended. Gefitinib should be used cautiously in the presence of mild to moderate changes in liver function. Discontinuation should be considered if changes are severe. Impaired liver function due to cirrhosis has been shown to lead to increased plasma concentrations of gefitinib (see section 5.2). Interactions with other medicinal products CYP3A4 inducers may increase metabolism of gefitinib and decrease gefitinib plasma concentrations. Therefore, concomitant administration of CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or herbal preparations containing St John’s wort/Hypericum perforatum) may reduce efficacy of the treatment and should be avoided (see section 4.5). In individual patients with CYP2D6 poor metaboliser genotype, treatment with a potent CYP3A4 inhibitor might lead to increased plasma levels of gefitinib. At initiation of treatment with a CYP3A4 inhibitor, patients should be closely monitored for gefitinib adverse reactions (see section 4.5). International normalised ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin together with gefitinib (see section 4.5). Patients taking warfarin and gefitinib concomitantly should be monitored regularly for changes in prothrombin time (PT) or INR. Medicinal products that cause significant sustained elevation in gastric pH, such as proton-pump inhibitors and h2-antagonists may reduce bioavailability and plasma concentrations of gefitinib and, therefore, may reduce efficacy. Antacids if taken regularly close in time to administration of gefitinib may have a similar effect (see sections 4.5 and 5.2). Data from phase II clinical trials, where gefitinib and vinorelbine have been used concomitantly, indicate that gefitinib may exacerbate the neutropenic effect of vinorelbine. Lactose IRESSA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Sodium IRESSA contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially ‘sodium-free.’ Further precautions for use Patients should be advised to seek medical advice immediately if they experience severe or persistent diarrhoea, nausea, vomiting or anorexia as these may indirectly lead to dehydration. These symptoms should be managed as clinically indicated (see section 4.8). Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment with gefitinib should be interrupted, and if symptoms do not resolve, or if symptoms recur on reintroduction of gefitinib, permanent discontinuation should be considered. In a phase I/II trial studying the use of gefitinib and radiation in paediatric patients, with newly diagnosed brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of Central Nervous System (CNS) haemorrhages were reported from 45 patients enrolled. A further case of CNS haemorrhage has been reported in a child with an ependymoma from a trial with gefitinib alone. An increased risk of cerebral haemorrhage in adult patients with NSCLC receiving gefitinib has not been established. Gastrointestinal perforation has been reported in patients taking gefitinib. In most cases this is associated with other known risk factors, including concomitant medications such as steroids or NSAIDS, underlying history of GI ulceration, age, smoking or bowel metastases at sites of perforation. 4.5 Interaction with other medicinal products and other forms of interaction The metabolism of gefitinib is via the cytochrome P450 isoenzyme CYP3A4 (predominantly) and via CYP2D6. Active substances that may increase gefitinib plasma concentrations In vitro studies have shown that gefitinib is a substrate of p-glycoprotein (Pgp). Available data do not suggest any clinical consequences to this in vitro finding. Substances that inhibit CYP3A4 may decrease the clearance of gefitinib. Concomitant administration with potent inhibitors of CYP3A4 activity (e.g. ketoconazole, posaconazole, voriconazole, protease inhibitors, clarithromycin, telithromycin) may increase gefitinib plasma concentrations. The increase may be clinically relevant since adverse reactions are related to dose and exposure. The increase might be higher in individual patients with CYP2D6 poor metaboliser genotype. Pre-treatment with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib in healthy volunteers. In situations of concomitant treatment with potent inhibitors of CYP3A4 the patient should be closely monitored for gefitinib adverse reactions. There are no data on concomitant treatment with an inhibitor of CYP2D6 but potent inhibitors of this enzyme might cause increased plasma concentrations of gefitinib in CYP2D6 extensive metabolisers by about 2-fold (see section 5.2). If concomitant treatment with a potent CYP2D6 inhibitor is initiated, the patient should be closely monitored for adverse reactions. Active substances that may reduce gefitinib plasma concentrations Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. Concomitant medicinal products that induce CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or St John’s wort/ Hypericum perforatum) should be avoided. Pre-treatment with rifampicin (a potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83% (see section 4.4). Substances that cause significant sustained elevation in gastric pH may reduce gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. High doses of short-acting antacids may have a similar effect if taken regularly close in time to administration of gefitinib. Concomitant administration of gefitinib with ranitidine at a dose that caused sustained elevations in gastric pH ≥ 5 resulted in a reduced mean gefitinib AUC by 47% in healthy volunteers (see section 4.4 and 5.2). Active substances that may have their plasma concentrations altered by gefitinib In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. In a clinical trial in patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a 35% increase in exposure to metoprolol. Such an increase might potentially be relevant for CYP2D6 substrates with narrow therapeutic index. When the use of CYP2D6 substrates are considered in combination with gefitinib, a dose modification of the CYP2D6 substrate should be considered especially for products with a narrow therapeutic window. Gefitinib inhibits the transporter protein BCRP in vitro, but the clinical relevance of this finding is unknown. Other potential interactions INR elevations and/or bleeding events have been reported in some patients concomitantly taking warfarin (see section 4.4). 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential must be advised not to get pregnant during therapy. Pregnancy There are no data from the use of gefitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IRESSA should not be used during pregnancy unless clearly necessary. Breast-feeding It is not known whether gefitinib is secreted in human milk. Gefitinib and metabolites of gefitinib accumulated in milk of lactating rats (see section 5.3). Gefitinib is contraindicated during breast-feeding and therefore breast-feeding must be discontinued while receiving gefitinib therapy (see section 4.3). 4.7 Effects on ability to drive and use machines During treatment with gefitinib, asthenia has been reported. Therefore, patients who experience this symptom should be cautious when driving or using machines. 4.8 Undesirable effects Summary of the safety profile In the pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 IRESSA-treated patients), the most frequently reported adverse drug reactions (ADRs), occurring in more than 20% of the patients, are diarrhoea and skin reactions (including rash, acne, dry skin and pruritus). ADRs usually occur within the first month of therapy and are generally reversible. Approximately 8% of patients had a severe ADR (common toxicity criteria (CTC) grade 3 or 4). Approximately 3% of patients stopped therapy due to an ADR. Interstitial lung disease (ILD) has occurred in 1.3% of patients, often severe (CTC grade 3-4). Cases with fatal outcomes have been reported. Tabulated list of adverse reactions The safety profile presented in Table 1 is based on the gefitinib clinical development programme and postmarketed experience. Adverse reactions have been assigned to the frequency categories in Table 1 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 IRESSA-treated patients). Frequencies of occurrence of undesirable effects are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 1 Adverse reactions Adverse reactions by system organ class and frequency Metabolism and nutrition disorders Very common Anorexia mild or moderate (CTC grade 1 or 2) Eye disorders Common Conjunctivitis, blepharitis, and dry eye*, mainly mild (CTC grade 1) Uncommon Corneal erosion, reversible and sometimes in association with aberrant eyelash growth Keratitis (0.12%) Vascular disorders Common Haemorrhage, such as epistaxis and haematuria Respiratory, thoracic and mediastinal disorders Common Interstitial lung disease (1.3%), often severe (CTC grade 3-4). Cases with fatal outcomes have been reported Gastrointestinal disorders Very common Diarrhoea, mainly mild or moderate (CTC grade 1 or 2) Vomiting, mainly mild or moderate (CTC grade 1 or 2) Nausea, mainly mild (CTC grade 1) Stomatitis, predominantly mild in nature (CTC grade 1) Common Dehydration, secondary to diarrhoea, nausea, vomiting or anorexia Dry mouth*, predominantly mild (CTC grade 1) Uncommon Pancreatitis Gastrointestinal perforation Hepatobiliary disorders Very common Elevations in alanine aminotransferase, mainly mild to moderate Common Elevations in aspartate aminotransferase, mainly mild to moderate Elevations in total bilirubin, mainly mild to moderate Uncommon Hepatitis** Skin and subcutaneous tissue disorders Very common Skin reactions, mainly a mild or moderate (CTC grade 1 or 2) pustular rash, sometimes itchy with dry skin, including skin fissures, on an erythematous base Common Nail disorder Alopecia Allergic reactions (1.1%), including angioedema and urticaria Rare Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme Cutaneous vasculitis Renal and urinary disorders Common Asymptomatic laboratory elevations in blood creatinine Proteinuria Cystitis Rare Haemorrhagic cystitis General disorders and administration site conditions Very common Asthenia, predominantly mild (CTC grade 1) Common Pyrexia The frequency of adverse drug reactions relating to abnormal laboratory values is based on patients with a change from baseline of 2 or more CTC grades in the relevant laboratory parameters. *This adverse reaction can occur in association with other dry conditions (mainly skin reactions) seen with gefitinib. **This includes isolated reports of hepatic failure which in some cases led to fatal outcomes. Interstitial lung disease (ILD) In the INTEREST trial, the incidence of ILD type events was 1.4% (10) patients in the gefitinib group versus 1.1% (8) patients in the docetaxel group. One ILD-type event was fatal, and this occurred in a patient receiving gefitinib. In the ISEL trial, the incidence of ILD-type events in the overall population was approximately 1% in both treatment arms. The majority of ILD-type events reported was from patients of Asian ethnicity and the ILD incidence among patients of Asian ethnicity receiving gefitinib therapy and placebo was approximately 3% and 4% respectively. One ILD-type event was fatal, and this occurred in a patient receiving placebo. In a post-marketing surveillance study in Japan (3350 patients) the reported rate of ILD-type events in patients receiving gefitinib was 5.8%. The proportion of ILD-type events with a fatal outcome was 38.6%. In a phase III open-label clinical trial (IPASS) in 1217 patients comparing IRESSA to carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected patients with advanced NSCLC in Asia, the incidence of ILD-type events was 2.6% on the IRESSA treatment arm versus 1.4% on the carboplatin/paclitaxel treatment arm. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 4.9 Overdose There is no specific treatment in the event of overdose of gefitinib. However, in phase I clinical trials, a limited number of patients were treated with daily doses of up to 1000 mg. An increase of frequency and severity of some adverse reactions was observed, mainly diarrhoea and skin rash. Adverse reactions associated with overdose should be treated symptomatically; in particular severe diarrhoea should be managed as clinically indicated. In one study a limited number of patients were treated weekly with doses from 1500 mg to 3500 mg. In this study IRESSA exposure did not increase with increasing dose, adverse events were mostly mild to moderate in severity, and were consistent with the known safety profile of IRESSA. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors; ATC code: L01XE02 Mechanism of action and pharmacodynamic effects The epidermal growth factor (EGF) and its receptor (EGFR [HER1; ErbB1]) have been identified as key drivers in the process of cell growth and proliferation for normal and cancer cells. EGFR activating mutation within a cancer cell is an important factor in promotion of tumour cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis. Gefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosine kinase domain regardless of line of therapy. No clinically relevant activity has been shown in patients with known EGFR mutation-negative tumours. The common EGFR activating mutations (Exon 19 deletions; L858R) have robust response data supporting sensitivity to gefitinib; for example a progression free survival HR (95% CI) of 0.489 (0.336, 0.710) for gefitinib vs. doublet chemotherapy [WJTOG3405]. Gefitinib response data is more sparse in patients whose tumours contain the less common mutations; the available data indicates that G719X, L861Q and S7681 are sensitising mutations; and T790M alone or exon 20 insertions alone are resistance mechanisms. Resistance Most NSCLC tumours with sensitising EGFR kinase mutations eventually develop resistance to IRESSA treatment, with a median time to disease progression of 1 year. In about 60% of cases, resistance is associated with a secondary T790M mutation for which T790M targeted EGFR TKIs may be considered as a next line treatment option. Other potential mechanisms of resistance that have been reported following treatment with EGFR signal blocking agents include: bypass signalling such as HER2 and MET gene amplification and PIK3CA mutations. Phenotypic switch to small cell lung cancer has also been reported in 5-10% of cases. Circulating Tumour DNA (ctDNA) In the IFUM trial, mutation status was assessed in tumour and ctDNA samples derived from plasma, using the Therascreen EGFR RGQ PCR kit (Qiagen). Both ctDNA and tumour samples were evaluable for 652 patients out of 1060 screened. The objective response rate (ORR) in those patients who were tumour and ctDNA mutation positive was 77% (95% CI: 66% to 86%) and in those who were tumour only mutation positive 60% (95% CI: 44% to 74%). Table 2 Summary of baseline mutation status for tumour and ctDNA samples in all screened patients evaluable for both samples Measure Definition IFUM rate % (CI) IFUM N Sensitivity Proportion of tumour M+ that are M+ by ctDNA 65.7 (55.8, 74.7) 105 Specificity Proportion of tumour M- that are M- by ctDNA) 99.8 (99.0, 100.0) 547 These data are consistent with the pre-planned exploratory Japanese subgroup analysis in IPASS (Goto 2012). In that study ctDNA derived from serum, not plasma was used for EGFR mutation analysis using the EGFR Mutation Test Kit (DxS) (N= 86). In that study, sensitivity was 43.1%, specificity was 100%. Clinical efficacy and safety First line treatment The randomised phase III first line IPASS study was conducted in patients in Asia1 with advanced (stage IIIB or IV) NSCLC of adenocarcinoma histology who were ex-light smokers (ceased smoking > 15 years ago and smoked < 10 pack years) or never smokers (see Table 3). 1China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. Table 3 Efficacy outcomes for gefitinib versus carboplatin/paclitaxel from the IPASS study Population N Objective response rates and 95% CI for difference between treatmentsa Primary endpoint Progression free survival (PFS) a,b Overall survivala,b Overall 1217 43.0% vs 32.2% [5.3%, 16.1%] HR 0.74 [0.65, 0.85] 5.7 m vs 5.8 m p<0.0001 HR 0.90 [0.79, 1.02] 18.8 m vs 17. 4m p=0.1087 EGFR mutation-positive 261 71.2% vs 47.3% [12.0%, 34.9%] HR 0.48 [0.36, 0.64] 9.5 m vs 6.3 m p<0.0001 HR 1.00 [0.76, 1.33] 21.6 m vs 21.9 m Population N Objective response rates and 95% CI for difference between treatmentsa Primary endpoint Progression free survival (PFS) a,b Overall survivala,b EGFR mutation-negative 176 1.1% vs 23.5% [-32.5%, -13.3%] HR 2.85 [2.05, 3.98] 1.5 m vs 5.5 m p<0.0001 HR 1.18 [0.86, 1.63] 11.2 m vs 12.7 m EGFR mutation- unknown 780 43.3% vs 29.2% [7.3%, 20.6%] HR 0.68 [0.58 to 0.81] 6.6 m vs 5.8 m p<0.0001 HR 0.82 [0.70 to 0.96] 18.9 m vs. 17.2 m a Values presented are for IRESSA versus carboplatin/paclitaxel. b “m” is medians in months. Numbers in square brackets are 95% confidence intervals for HR N Number of patients randomised. HR Hazard ratio (hazard ratios <1 favour IRESSA) Quality of life outcomes differed according to EGFR mutation status. In EGFR mutation-positive patients, significantly more IRESSA-treated patients experienced an improvement in quality of life and lung cancer symptoms vs. carboplatin/paclitaxel (see Table 4). Table 4 Quality of life outcomes for gefitinib versus carboplatin/paclitaxel from the IPASS study Population N FACT-L QoL improvement ratea % LCS symptom improvement rate a % Overall 1151 (48.0% vs 40.8%) p=0.0148 (51.5% vs 48.5%) p=0.3037 EGFR mutation-positive 259 (70.2% vs 44.5%) p<0.0001 (75.6% vs 53.9%) p=0.0003 EGFR mutation-negative 169 (14.6% vs 36.3%) p=0.0021 (20.2% vs 47.5%) p=0.0002 Trial outcome index results were supportive of FACT-L and LCS results a Values presented are for IRESSA versus carboplatin/paclitaxel. N Number of patients evaluable for quality of life analyses QoL Quality of life FACT-LFunctional assessment of cancer therapy-lung LCS Lung cancer subscale In the IPASS trial, IRESSA demonstrated superior PFS, ORR, QoL and symptom relief with no significant difference in overall survival compared to carboplatin/paclitaxel in previously untreated patients, with locally advanced or metastatic NSCLC, whose tumours harboured activating mutations of the EGFR tyrosine kinase. Pretreated patients The randomised phase III INTEREST study was conducted in patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy. In the overall population, no statistically significant difference between gefitinib and docetaxel (75 mg/m2) was observed for overall survival, progression free survival and objective response rates (see Table 5). Table 5 Efficacy outcomes for gefitinib versus docetaxel from the INTEREST study Population N Objective response rates and 95% CI for difference between treatmentsa Progression free survivalab Primary endpoint overall survivalab Overall 1466 9.1% vs 7.6% [-1.5%, 4.5%] HR 1.04 [0.93,1.18] 2.2 m vs 2.7 m p=0.4658 HR 1.020 [0.905, 1.150] c 7.6 m vs 8.0 m p=0.7332 EGFR mutation-positive 44 42.1% vs 21.1% [-8.2%, 46.0%] HR 0.16 [0.05, 0.49] 7.0 m vs 4.1 m p=0.0012 HR 0.83 [0.41, 1.67] 14.2 m vs 16.6 m p=0.6043 EGFR mutation- negative 253 6.6% vs 9.8% [-10.5%, 4.4%] HR 1.24 [0.94,1.64] 1.7 m vs 2.6 m p=0.1353 HR 1.02 [0.78, 1.33] 6.4 m vs 6.0 m p=0.9131 Asiansc 323 19.7% vs 8.7% [3.1 %, 19.2%] HR 0.83 [0.64,1.08] 2.9 m vs 2.8 m p=0.1746 HR 1.04 [0.80, 1.35] 10.4 m vs 12.2 m p=0.7711 Non-Asians 1143 6.2% vs 7.3% [-4.3%, 2.0%] HR 1.12 [0.98, 1.28] 2.0 m vs 2.7 m p=0.1041 HR 1.01 [0.89, 1.14] 6.9 m vs 6.9 m p=0.9259 a Values presented are for IRESSA versus docetaxel. b “m” is medians in months. Numbers in square brackets are 96% confidence interval for overall survival HR in the overall population, or otherwise 95% confidence intervals for HR c Confidence interval entirely below non-inferiority margin of 1.154 N Number of patients randomised. HR Hazard ratio (hazard ratios <1 favour IRESSA) 14 Figures 1 and 2 Efficacy outcomes in subgroups of non-Asian patients in the INTEREST study (N patients = Number of patients randomised) Overall Survival N patients Overall EGFR Mutation+ EGFR Mutation- Never-smoker Ever-smoker Adenocarcinoma Non-adenocarcinoma Female Male 1143 27 222 133 1010 600 543 369 774 Progression-free Survival 6.2 v. 7.3 Overall 42.9 v. 20.0 EGFR Mutation+ 5.5 v. 9.1 EGFR Mutation 23.7 v. 13.3 Never-smoker 3.9 v. 6.5 Ever-smoker 9.4 v. 9.4 Adenocarcinoma 2.8 v. 5.0 Non-adenocarcinoma 9.8 v. 13.1 Female 4.4 v. 4.6 Male 1143 27 222 133 1010 600 543 369 774 N patients 0.5 1.0 1.5 2.0 Hazard Ratio (Gefitinib versus Docetaxel) and 95% CI Unadjusted analysis PP population for clinical factors ITT population for biomarker factors Hazard Ratio (Gefitinib versus Docetaxel) and 95% CI Unadjusted analysis EFR population 0.5 1.0 1.5 2.00 ORR (%) Gefitinib v. Docetaxel The randomised phase III ISEL study was conducted in patients with advanced NSCLC who had received 1 or 2 prior chemotherapy regimens and were refractory or intolerant to their most recent regimen. Gefitinib plus best supportive care was compared to placebo plus best supportive care. IRESSA did not prolong survival in the overall population. Survival outcomes differed by smoking status and ethnicity (see Table 6). 15 Table 6 Efficacy outcomes for gefitinib versus placebo from the ISEL study Population N Objective response rates and 95% CI for difference between treatmentsa Time to treatment failureab Primary endpoint overall survivalabc Overall 1692 8.0% vs 1.3% [4.7%, 8.8%] HR 0.82 [0.73, 0.92] 3.0 m vs 2.6 m p=0.0006 HR 0.89 [0.77,1.02] 5.6 m vs 5.1 m p=0.0871 EGFR mutation- positive 26 37.5% vs 0% [-15.1%, 61.4%] HR 0.79 [0.20, 3.12] 10.8 m vs 3.8m p=0.7382 HR NC NR vs 4.3 m EGFR mutation- negative 189 2.6% vs 0% [-5.6%, 7.3%] HR 1.10 [0.78, 1.56] 2.0 m vs 2.6 m p=0.5771 HR 1.16 [0.79, 1.72] 3.7 m vs 5.9 m p=0.4449 Never smoker 375 18.1% vs 0% [12.3 %, 24.0%] HR 0.55 [0.42, 0.72] 5.6 m vs 2.8 m p<0.0001 HR 0.67 [0.49, 0.92] 8.9 m vs 6.1 m p=0.0124 Ever smoker 1317 5.3% vs 1.6% [1.4%, 5.7%] HR 0.89 [0.78, 1.01] 2.7 m vs 2.6 m p=0.0707 HR 0.92 [0.79, 1.06] 5.0 m vs 4.9 m p=0.2420 Asiansd 342 12.4% vs 2.1% [4.0%, 15.8%] HR 0.69 [0.52, 0.91] 4.4 m vs 2.2 m p=0.0084 HR 0.66 [0.48, 0.91] 9.5 m vs 5.5 m p=0.0100 Non-Asians 1350 6.8% vs 1.0% [3.5%, 7.9%] HR 0.86 [0.76, 0.98] 2.9 m vs 2.7 m p=0.0197 HR 0.92 [0.80, 1.07] 5.2 m vs 5.1 m p=0.2942 a Values presented are for IRESSA versus placebo. b “m” is medians in months. Numbers in square brackets are 95% confidence intervals for HR c Stratified log-rank test for overall; otherwise cox proportional hazards model d Asian ethnicity excludes patients of Indian origin and refers to the racial origin of a patient group and not necessarily their place of birth N Number of patients randomised NC Not calculated for overall survival HR as the number of events is too few NR Not reached HR Hazard ratio (hazard ratios <1 favour IRESSA) The IFUM study was a single-arm, multicentre study conducted in Caucasian patients (n=106) with activating, sensitising EGFR mutation positive NSCLC to confirm that the activity of gefitinib is 16 similar in Caucasian and Asian populations. The ORR according to investigator review was 70% and the median PFS was 9.7 months. These data are similar to those reported in the IPASS study. EGFR mutation status and clinical characteristics Clinical characteristics of never smoker, adenocarcinoma histology, and female gender have been shown to be independent predictors of positive EGFR mutation status in a multivariate analysis of 786 Caucasian patients from gefitinib studies* (see Table 7). Asian patients also have a higher incidence of EGFR mutation-positive tumours. Table 7 Summary of multivariate logistic regression analysis to identify factors that independently predicted for the presence of EGFR mutations in 786 Caucasian patients* Factors that predicted for presence of EGFR mutation p-value Odds of EGFR mutation Positive predictive value (9.5% of the overall population are EGFR mutation-positive (M+)) Smoking status <0.0001 6.5 times higher in never smokers than ever-smokers 28/70 (40%) of never smokers are M+ 47/716 (7%) of ever smokers are M+ Histology <0.0001 4.4 times higher in adenocarcinoma than in non-adenocarcinoma 63/396 (16%) of patients with adenocarcinoma histology are M+ 12/390 (3%) of patients with non-adenocarcinoma histology are M+ Gender 0.0397 1.7 times higher in females than males 40/235 (17%) of females are M+ 35/551 (6%) of males are M+ *from the following studies: INTEREST, ISEL, INTACT 1&2, IDEAL 1&2, INVITE 5.2 Pharmacokinetic properties Absorption Following oral administration of gefitinib, absorption is moderately slow and peak plasma concentrations of gefitinib typically occur at 3 to 7 hours after administration. Mean absolute bioavailability is 59% in cancer patients. Exposure to gefitinib is not significantly altered by food. In a trial in healthy volunteers where gastric pH was maintained above pH 5, gefitinib exposure was reduced by 47%, likely due to impaired solubility of gefitinib in the stomach (see sections 4.4 and 4.5). Distribution Gefitinib has a mean steady-state volume of distribution of 1400 l indicating extensive distribution into tissue. Plasma protein binding is approximately 90%. Gefitinib binds to serum albumin and alpha 1-acid glycoprotein. In vitro data indicate that gefitinib is a substrate for the membrane transport protein P-gp. Biotransformation In vitro data indicate that CYP3A4 and CYP2D6 are the major P450 isozyme involved in the oxidative metabolism of gefitinib. 17 In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. Gefitinib shows no enzyme induction effects in animal studies and no significant inhibition (in vitro) of any other cytochrome P450 enzyme. Gefitinib is extensively metabolised in humans. Five metabolites have been fully identified in excreta and 8 metabolites in plasma. The major metabolite identified was O-desmethyl gefitinib, which is 14-fold less potent than gefitinib at inhibiting EGFR stimulated cell growth and has no inhibitory effect on tumour cell growth in mice. It is therefore considered unlikely that it contributes to the clinical activity of gefitinib. The formation of O-desmethyl gefitinib has been shown, in vitro, to be via CYP2D6. The role of CYP2D6 in the metabolic clearance of gefitinib has been evaluated in a clinical trial in healthy volunteers genotyped for CYP2D6 status. In poor metabolisers no measurable levels of O-desmethyl gefitinib were produced. The levels of exposure to gefitinib achieved in both the extensive and the poor metaboliser groups were wide and overlapping but the mean exposure to gefitinib was 2-fold higher in the poor metaboliser group. The higher average exposures that could be achieved by individuals with no active CYP2D6 may be clinically relevant since adverse effects are related to dose and exposure. Elimination Gefitinib is excreted mainly as metabolites via the faeces, with renal elimination of gefitinib and metabolites accounting for less than 4% of the administered dose. Gefitinib total plasma clearance is approximately 500 ml/min and the mean terminal half-life is 41 hours in cancer patients. Administration of gefitinib once daily results in 2- to 8-fold accumulation, with steady state exposures achieved after 7 to 10 doses. At steady state, circulating plasma concentrations are typically maintained within a 2- to 3-fold range over the 24-hour dosing interval. Special populations From analyses of population pharmacokinetic data in cancer patients, no relationships were identified between predicted steady-state trough concentration and patient age, body weight, gender, ethnicity or creatinine clearance (above 20 ml/min). Hepatic impairment In a phase I open-label study of single dose gefitinib 250 mg in patients with mild, moderate or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification), there was an increase in exposure in all groups compared with healthy controls. An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed. None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib. Gefitinib has been evaluated in a clinical trial conducted in 41 patients with solid tumours and normal hepatic function, or moderate or severe hepatic impairment (classified according to baseline Common Toxicity Criteria grades for AST, alkaline phosphatase and bilirubin) due to liver metastases. It was shown that following daily administration of 250 mg gefitinib, time to steady-state, total plasma clearance (CmaxSS) and steady-state exposure (AUC24SS) were similar for the groups with normal and 18 moderately impaired hepatic function. Data from 4 patients with severe hepatic impairment due to liver metastases suggested that steady-state exposures in these patients are also similar to those in patients with normal hepatic function. 5.3 Preclinical safety data Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to the clinical exposure levels and with possible relevance to clinical use were as follows:  Corneal epithelia atrophy and corneal translucencies  Renal papillary necrosis  Hepatocellular necrosis and eosinophilic sinusoidal macrophage infiltration Data from non-clinical (in vitro) studies indicate that gefitinib has the potential to inhibit the cardiac action potential repolarisation process (e.g. QT interval). Clinical experience has not shown a causal association between QT prolongation and gefitinib. A reduction in female fertility was observed in the rat at a dose of 20 mg/kg/day. Published studies have shown that genetically modified mice, lacking expression of EGFR, exhibit developmental defects, related to epithelial immaturity in a variety of organs including the skin, gastrointestinal tract and lung. When gefitinib was administered to rats during organogenesis, there were no effects on embryofoetal development at the highest dose (30 mg/kg/day). However, in the rabbit, there were reduced foetal weights at 20 mg/kg/day and above. There were no compound-induced malformations in either species. When administered to the rat throughout gestation and parturition, there was a reduction in pup survival at a dose of 20 mg/kg/day. Following oral administration of C-14 labelled gefitinib to lactating rats 14 days post-partum, concentrations of radioactivity in milk were 11-19 fold higher than in blood. Gefitinib showed no genotoxic potential. A 2-year carcinogenicity study in rats resulted in a small but statistically significant increased incidence of hepatocellular adenomas in both male and female rats and mesenteric lymph node haemangiosarcomas in female rats at the highest dose (10 mg/kg/day) only. The hepatocellular adenomas were also seen in a 2-year carcinogenicity study in mice, which demonstrated a small increased incidence of this finding in male mice at the mid dose, and in both male and female mice at the highest dose. The effects reached statistical significance for the female mice, but not for the males. At no-effect levels in both mice and rats there was no margin in clinical exposure. The clinical relevance of these findings is unknown. The results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicity potential. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients 19 Tablet core Lactose monohydrate Microcrystalline cellulose (E460) Croscarmellose sodium Povidone (K29-32) (E1201) Sodium laurilsulfate Magnesium stearate Tablet coating Hypromellose (E464) Macrogol 300 Titanium dioxide (E171) Yellow iron oxide (E172) Red iron oxide (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container PVC/Aluminium perforated blister containing 10 tablets or PVC/Aluminium non-perforated blister containing 10 tablets. Three blisters are combined with an aluminium foil laminate over-wrap in a carton. Pack size of 30 film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 20 8. MARKETING AUTHORISATION NUMBER(S) EU/1/09/526/001 EU/1/09/526/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 24/06/2009 Date of latest renewal: 23/04/2014 10. DATE OF REVISION OF THE TEXT Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 21 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 22 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release AstraZeneca AB Gärtunavägen SE-151 85 Södertälje Sweden AstraZeneca UK Limited Macclesfield Cheshire SK10 2NA United Kingdom The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP shall be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. 23 24 ANNEX III LABELLING AND PACKAGE LEAFLET 25 A. LABELLING 26 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT IRESSA 250 mg film-coated tablets gefitinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 250 mg gefitinib. 3. LIST OF EXCIPIENTS Contains lactose and sodium, see package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 30 film-coated tablets. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 27 Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/526/001 EU/1/09/526/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE iressa 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 28 PC: {number} SN: {number} NN: {number} 29 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER/ALUMINIUM FOIL LAMINATE FLOW WRAP 1. NAME OF THE MEDICINAL PRODUCT IRESSA 250 mg tablets gefitinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER AstraZeneca 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 30 B. PACKAGE LEAFLET 31 Package leaflet: Information for the patient IRESSA 250 mg film-coated tablets gefitinib Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor, pharmacist or nurse.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What IRESSA is and what it is used for 2. What you need to know before you take IRESSA 3. How to take IRESSA 4. Possible side effects 5. How to store IRESSA 6. Contents of the pack and other information 1. What IRESSA is and what it is used for IRESSA contains the active substance gefitinib which blocks a protein called ‘epidermal growth factor receptor’ (EGFR). This protein is involved in the growth and spread of cancer cells. IRESSA is used to treat adults with non-small cell lung cancer. This cancer is a disease in which malignant (cancer) cells form in the tissues of the lung. 2. What you need to know before you take IRESSA Do not take IRESSA  if you are allergic to gefitinib or any of the other ingredients of this medicine (listed in section 6, ‘What IRESSA contains’).  if you are breast-feeding. Warnings and precautions Talk to your doctor or pharmacist before taking IRESSA  if you have ever had any other lung problems. Some lung problems may get worse during treatment with IRESSA.  if you have ever had problems with your liver. 32 Children and adolescents IRESSA is not indicated in children and adolescents under 18 years. Other medicines and IRESSA Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. In particular, tell your doctor or pharmacist if you are taking any of the following medicines:  Phenytoin or carbamazepine (for epilepsy).  Rifampicin (for tuberculosis).  Itraconazole (for fungal infections).  Barbiturates (a type of medicine used for sleeping problems).  Herbal remedies containing St John’s wort (Hypericum perforatum, used for depression and anxiety).  Proton-pump inhibitors, H2-antagonists and antacids (for ulcers, indigestion, heartburn and to reduce acids in the stomach). These medicines may affect the way IRESSA works.  Warfarin (a so-called oral anticoagulant, to prevent blood clots). If you are taking a medicine containing this active substance, your doctor may need to do blood tests more often. If any of the above applies to you, or if you are not sure, check with your doctor or pharmacist before taking IRESSA. Pregnancy, breast-feeding and fertility Talk to your doctor before taking this medicine if you are pregnant, may become pregnant or are breast-feeding. It is recommended that you avoid becoming pregnant during treatment with IRESSA because IRESSA could harm your baby. Do not take IRESSA if you are breast-feeding for the safety of your baby. Driving and using machines If you feel weak whilst taking this medicine, take care driving or using tools or machines. IRESSA contains lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. IRESSA contains sodium This medicine contains less than 1 mmol (23 mg) of sodium per dose, that is to say it is essentially ‘sodium-free’. 3. How to take IRESSA Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.  The recommended dose is one 250 mg tablet per day.  Take the tablet at about the same time each day. 33  You can take the tablet with or without food.  Do not take antacids (to reduce the acid level of your stomach) 2 hours before or 1 hour after taking IRESSA. If you have trouble swallowing the tablet, dissolve it in half a glass of still (non-fizzy) water. Do not use any other liquids. Do not crush the tablet. Swirl the water until the tablet has dissolved. This may take up to 20 minutes. Drink the liquid straight away. To make sure that you have drunk all of the medicine, rinse the glass very well with half a glass of water and drink it. If you take more IRESSA than you should If you have taken more tablets than you should, talk to a doctor or pharmacist straight away. If you forget to take IRESSA What to do if you forget to take a tablet depends on how long it is until your next dose.  If it is 12 hours or more until your next dose: take the missed tablet as soon as you remember. Then take the next dose as usual.  If it is less than 12 hours until your next dose: skip the missed tablet. Then take the next tablet at the usual time. Do not take a double dose (two tablets at the same time) to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines this medicine can cause side effects, although not everybody gets them. Tell your doctor immediately if you notice any of the following side effects - you may need urgent medical treatment:  Allergic reaction (common), particularly if symptoms include swollen face, lips, tongue or throat, difficulty to swallow, hives, nettle rash and difficulty breathing.  Serious breathlessness, or sudden worsening breathlessness, possibly with a cough or fever. This may mean that you have an inflammation of the lungs called ‘interstitial lung disease’. This may affect about 1 in 100 patients taking IRESSA and can be life-threatening.  Severe skin reactions (rare) affecting large areas of your body. The signs may include redness, pain, ulcers, blisters, and shedding of the skin. The lips, nose, eyes and genitals may also be affected.  Dehydration (common) caused by long term or severe diarrhoea, vomiting (being sick), nausea (feeling sick) or loss of appetite.  Eye problems (uncommon), such as pain, redness, watery eyes, light sensitivity, changes in vision or ingrowing eyelashes. This may mean that you have an ulcer on the surface of the eye (cornea). 34 Tell your doctor as soon as possible if you notice any of the following side effects: Very common: side effects (may affect more than 1 in 10 people)  Diarrhoea  Vomiting  Nausea  Skin reactions such as an acne-like rash, which is sometimes itchy with dry and/or cracked skin  Loss of appetite  Weakness  Red or sore mouth  Increase of a liver enzyme known as alanine aminotransferase in a blood test; if too high, your doctor may tell you to stop taking IRESSA Common: side effects (may affect up to 1 in 10 people)  Dry mouth  Dry, red or itchy eyes  Red and sore eyelids  Nail problems  Hair loss  Fever  Bleeding (such as nose bleed or blood in your urine)  Protein in your urine (shown in a urine test)  Increase of bilirubin and the other liver enzyme known as aspartate aminotransferase in a blood test; if too high, your doctor may tell you to stop taking IRESSA  Increase of creatinine levels in a blood test (related to kidney function)  Cystitis (burning sensations during urination and frequent, urgent need to urinate) Uncommon: side effects (may affect up to 1 in 100 people)  Inflammation of the pancreas. The signs include very severe pain in the upper part of the stomach area and severe nausea and vomiting.  Inflammation of the liver. Symptoms may include a general feeling of being unwell, with or without possible jaundice (yellowing of the skin and eyes). This side effect is uncommon; however, some patients have died from this.  Gastrointestinal perforation Rare: side effects (may affect up to 1 in 1000 people)  Inflammation of the blood vessels in the skin. This may give the appearance of bruising or patches of non-blanching rash on the skin.  Haemorrhagic cystitis (burning sensations during urination and frequent, urgent need to urinate with blood in the urine). Reporting of side effects If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 35 5. How to store IRESSA Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton, blister and overwrap foil after EXP. The expiry date refers to the last day of that month. Store in the original package in order to protect from moisture. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What IRESSA contains  The active substance is gefitinib. Each tablet contains 250 mg of gefitinib.  The other ingredients (excipients) are lactose monohydrate, microcrystalline cellulose (E460), croscarmellose sodium, povidone (K29-32) (E1201), sodium laurilsulfate, magnesium stearate, hypromellose (E464), macrogol 300, titanium dioxide (E171), yellow iron oxide (E172) and red iron oxide (E172). What IRESSA looks like and contents of the pack IRESSA is a round brown tablet marked with ‘IRESSA 250’ on one side and plain on the other. IRESSA comes in blister packs of 30 tablets. The blister foil may be perforated or non-perforated. Marketing Authorisation Holder AstraZeneca AB SE-151 85 Södertälje Sweden Manufacturer AstraZeneca AB Gärtunavägen SE-151 85 Södertälje Sweden AstraZeneca UK Limited Macclesfield Cheshire SK10 2NA United Kingdom For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: 36 België/Belgique/Belgien AstraZeneca S.A./N.V. Tel: +32 2 370 48 11 Lietuva UAB AstraZeneca Lietuva Tel: +370 5 2660550 България АстраЗенека България ЕООД Тел.: +359 (2) 44 55 000 Luxembourg/Luxemburg AstraZeneca S.A./N.V. Tél/Tel: +32 2 370 48 11 Česká republika AstraZeneca Czech Republic s.r.o. Tel: +420 222 807 111 Magyarország AstraZeneca Kft. Tel.: +36 1 883 6500 Danmark AstraZeneca A/S Tlf: +45 43 66 64 62 Malta Associated Drug Co. Ltd Tel: +356 2277 8000 Deutschland AstraZeneca GmbH Tel: +49 41 03 7080 Nederland AstraZeneca BV Tel: +31 79 363 2222 Eesti AstraZeneca Tel: +372 6549 600 Norge AstraZeneca AS Tlf: +47 21 00 64 00 Ελλάδα AstraZeneca A.E. Τηλ: +30 2 106871500 Österreich AstraZeneca Österreich GmbH Tel: +43 1 711 31 0 España AstraZeneca Farmacéutica Spain, S.A. Tel: +34 91 301 91 00 Polska AstraZeneca Pharma Poland Sp. z o.o. Tel.: +48 22 245 73 00 France AstraZeneca Tél: +33 1 41 29 40 00 Portugal AstraZeneca Produtos Farmacêuticos, Lda. Tel: +351 21 434 61 00 Hrvatska AstraZeneca d.o.o. Tel: +385 1 4628 000 România AstraZeneca Pharma SRL Tel: +40 21 317 60 41 Ireland AstraZeneca Pharmaceuticals (Ireland) Ltd Tel: +353 1609 7100 Slovenija AstraZeneca UK Limited Tel: +386 1 51 35 600 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika AstraZeneca AB, o.z. Tel: +421 2 5737 7777 37 Italia AstraZeneca S.p.A. Tel: +39 02 9801 1 Suomi/Finland AstraZeneca Oy Puh/Tel: +358 10 23 010 Κύπρος Αλέκτωρ Φαρµακευτική Λτδ Τηλ: +357 22490305 Sverige AstraZeneca AB Tel: +46 8 553 26 000 Latvija SIA AstraZeneca Latvija Tel: +371 67377100 United Kingdom AstraZeneca UK Ltd Tel: +44 1582 836 836 This leaflet was last revised in {MM/YYYY} Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. This leaflet is available in all EU/EEA languages on the European Medicines Agency website. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to take iressa', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. the recommended dose is one 250 mg tablet per day. take the tablet at about the same time each day. you can take the tablet with or without food. do not take antacids (to reduce the acid level of your stomach) 2 hours before or 1 hour after taking iressa. if you have trouble swallowing the tablet, dissolve it in half a glass of still (non-fizzy) water. do not use any other liquids. do not crush the tablet. swirl the water until the tablet has dissolved. this may take up to 20 minutes. drink the liquid straight away. to make sure that you have drunk all of the medicine, rinse the glass very well with half a glass of water and drink it. if you take more iressa than you should if you have taken more tablets than you should, talk to a doctor or pharmacist straight away. if you forget to take iressa what to do if you forget to take a tablet depends on how long it is until your next dose. if it is 12 hours or more until your next dose: take the missed tablet as soon as you remember. then take the next dose as usual. if it is less than 12 hours until your next dose: skip the missed tablet. then take the next tablet at the usual time. do not take a double dose (two tablets at the same time) to make up for a forgotten dose. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'iressa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 149, 'EndOffset': 152}, {'Id': 5, 'BeginOffset': 279, 'EndOffset': 287, 'Score': 0.923595130443573, 'Text': 'antacids', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.8772916197776794}]}, {'Id': 0, 'BeginOffset': 322, 'EndOffset': 329, 'Score': 0.7807247042655945, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 331, 'EndOffset': 332}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 349, 'EndOffset': 350}, {'Id': 6, 'BeginOffset': 369, 'EndOffset': 375, 'Score': 0.4829097092151642, 'Text': 'iressa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 389, 'EndOffset': 407, 'Score': 0.5997010469436646, 'Text': 'trouble swallowing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6703850626945496}]}, {'Text': 'any other liquids', 'Type': 'TREATMENT', 'BeginOffset': 487, 'EndOffset': 504}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 599, 'EndOffset': 601}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 1026, 'EndOffset': 1028}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 1166, 'EndOffset': 1168}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 1278, 'EndOffset': 1291}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1404, 'EndOffset': 1417}]}

{'Title': '4. possible side effects', 'Section_Content': "like all medicines this medicine can cause side effects, although not everybody gets them. tell your doctor immediately if you notice any of the following side effects - you may need urgent medical treatment: allergic reaction (common), particularly if symptoms include swollen face, lips, tongue or throat, difficulty to swallow, hives, nettle rash and difficulty breathing. serious breathlessness, or sudden worsening breathlessness, possibly with a cough or fever. this may mean that you have an inflammation of the lungs called 'interstitial lung disease'. this may affect about 1 in 100 patients taking iressa and can be life-threatening. severe skin reactions (rare) affecting large areas of your body. the signs may include redness, pain, ulcers, blisters, and shedding of the skin. the lips, nose, eyes and genitals may also be affected. dehydration (common) caused by long term or severe diarrhoea, vomiting (being sick), nausea (feeling sick) or loss of appetite. eye problems (uncommon), such as pain, redness, watery eyes, light sensitivity, changes in vision or ingrowing eyelashes. this may mean that you have an ulcer on the surface of the eye (cornea). tell your doctor as soon as possible if you notice any of the following side effects: very common: side effects (may affect more than 1 in 10 people) diarrhoea vomiting nausea skin reactions such as an acne-like rash, which is sometimes itchy with dry and/or cracked skin loss of appetite weakness red or sore mouth increase of a liver enzyme known as alanine aminotransferase in a blood test; if too high, your doctor may tell you to stop taking iressa common: side effects (may affect up to 1 in 10 people) dry mouth dry, red or itchy eyes red and sore eyelids nail problems hair loss fever bleeding (such as nose bleed or blood in your urine) protein in your urine (shown in a urine test) increase of bilirubin and the other liver enzyme known as aspartate aminotransferase in a blood test; if too high, your doctor may tell you to stop taking iressa increase of creatinine levels in a blood test (related to kidney function) cystitis (burning sensations during urination and frequent, urgent need to urinate) uncommon: side effects (may affect up to 1 in 100 people) inflammation of the pancreas. the signs include very severe pain in the upper part of the stomach area and severe nausea and vomiting. inflammation of the liver. symptoms may include a general feeling of being unwell, with or without possible jaundice (yellowing of the skin and eyes). this side effect is uncommon; however, some patients have died from this. gastrointestinal perforation rare: side effects (may affect up to 1 in 1000 people) inflammation of the blood vessels in the skin. this may give the appearance of bruising or patches of non-blanching rash on the skin. haemorrhagic cystitis (burning sensations during urination and frequent, urgent need to urinate with blood in 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'inflammation', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5278971791267395}]}]}, {'Text': 'inflammation of the pancreas', 'Type': 'PROBLEM', 'BeginOffset': 2240, 'EndOffset': 2268}, {'Text': 'very severe pain', 'Type': 'PROBLEM', 'BeginOffset': 2288, 'EndOffset': 2304}, {'Id': 107, 'BeginOffset': 2330, 'EndOffset': 2342, 'Score': 0.9297047853469849, 'Text': 'stomach area', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'severe nausea', 'Type': 'PROBLEM', 'BeginOffset': 2347, 'EndOffset': 2360}, {'Id': 124, 'BeginOffset': 2365, 'EndOffset': 2373, 'Score': 0.9972720742225647, 'Text': 'vomiting', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8999088406562805}]}, {'Text': 'inflammation of the liver', 'Type': 'PROBLEM', 'BeginOffset': 2375, 'EndOffset': 2400}, {'Text': 'symptoms', 'Type': 'PROBLEM', 'BeginOffset': 2402, 'EndOffset': 2410}, {'Id': 126, 'BeginOffset': 2433, 'EndOffset': 2456, 'Score': 0.6978104114532471, 'Text': 'feeling of being unwell', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9476155042648315}]}, {'Id': 127, 'BeginOffset': 2483, 'EndOffset': 2491, 'Score': 0.9873243570327759, 'Text': 'jaundice', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9119333624839783}, {'Name': 'NEGATION', 'Score': 0.6301674842834473}]}, {'Id': 128, 'BeginOffset': 2493, 'EndOffset': 2502, 'Score': 0.5242801904678345, 'Text': 'yellowing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.48089879751205444}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9947054982185364, 'RelationshipScore': 0.9930112957954407, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 109, 'BeginOffset': 2510, 'EndOffset': 2514, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.991642951965332, 'RelationshipScore': 0.91866135597229, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 110, 'BeginOffset': 2519, 'EndOffset': 2523, 'Text': 'eyes', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 109, 'BeginOffset': 2510, 'EndOffset': 2514, 'Score': 0.9947054982185364, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 110, 'BeginOffset': 2519, 'EndOffset': 2523, 'Score': 0.991642951965332, 'Text': 'eyes', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 129, 'BeginOffset': 2531, 'EndOffset': 2542, 'Score': 0.7842364311218262, 'Text': 'side effect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6219052076339722}]}, {'Id': 130, 'BeginOffset': 2584, 'EndOffset': 2588, 'Score': 0.9923601746559143, 'Text': 'died', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8302910923957825}]}, {'Id': 131, 'BeginOffset': 2600, 'EndOffset': 2628, 'Score': 0.8117012977600098, 'Text': 'gastrointestinal perforation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5538903474807739}]}, {'Id': 132, 'BeginOffset': 2635, 'EndOffset': 2647, 'Score': 0.945707380771637, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6219331622123718}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 2666, 'EndOffset': 2667}, {'Id': 151, 'BeginOffset': 2671, 'EndOffset': 2675, 'Score': 0.38798272609710693, 'Text': '1000', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.8780302405357361, 'RelationshipScore': 0.6992045044898987, 'RelationshipType': 'OVERLAP', 'Id': 133, 'BeginOffset': 2684, 'EndOffset': 2696, 'Text': 'inflammation', 'Category': 'MEDICAL_CONDITION', 'Traits': []}]}, {'Text': 'inflammation of the blood vessels in the skin', 'Type': 'PROBLEM', 'BeginOffset': 2684, 'EndOffset': 2729}, {'Id': 134, 'BeginOffset': 2763, 'EndOffset': 2771, 'Score': 0.9834448099136353, 'Text': 'bruising', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8009558320045471}]}, {'Text': 'non-blanching rash on the skin', 'Type': 'PROBLEM', 'BeginOffset': 2786, 'EndOffset': 2816}, {'Id': 137, 'BeginOffset': 2818, 'EndOffset': 2839, 'Score': 0.665891706943512, 'Text': 'haemorrhagic cystitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5810104012489319}]}, {'Text': 'burning sensations during urination', 'Type': 'PROBLEM', 'BeginOffset': 2841, 'EndOffset': 2876}, {'Id': 140, 'BeginOffset': 2919, 'EndOffset': 2937, 'Score': 0.564578115940094, 'Text': 'blood in the urine', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7275029420852661}]}, {'Id': 141, 'BeginOffset': 2953, 'EndOffset': 2965, 'Score': 0.9563587307929993, 'Text': 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{'Title': '5. how to store iressa', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton, blister and overwrap foil after exp. the expiry date refers to the last day of that month. store in the original package in order to protect from moisture. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'iressa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'blister', 'Type': 'PROBLEM', 'BeginOffset': 137, 'EndOffset': 144}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 427, 'EndOffset': 441}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what iressa contains the active substance is gefitinib. each tablet contains 250 mg of gefitinib. the other ingredients (excipients) are lactose monohydrate, microcrystalline cellulose (e460), croscarmellose sodium, povidone (k29-32) (e1201), sodium laurilsulfate, magnesium stearate, hypromellose (e464), macrogol 300, titanium dioxide (e171), yellow iron oxide (e172) and red iron oxide (e172). what iressa looks like and contents of the pack iressa is a round brown tablet marked with 'iressa 250' on one side and plain on the other. iressa comes in blister packs of 30 tablets. the blister foil may be perforated or non-perforated.", 'Entity_Recognition': [{'Text': 'iressa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 45, 'EndOffset': 54, 'Score': 0.9916983842849731, 'Text': 'gefitinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.9016662836074829, 'RelationshipScore': 0.999527096748352, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 61, 'EndOffset': 67, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9737865328788757, 'RelationshipScore': 0.5403481125831604, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 77, 'EndOffset': 83, 'Text': '250 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 77, 'EndOffset': 80}, {'Id': 3, 'BeginOffset': 87, 'EndOffset': 96, 'Score': 0.9951010346412659, 'Text': 'gefitinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.9016662836074829, 'RelationshipScore': 0.9226983785629272, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 61, 'EndOffset': 67, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9737865328788757, 'RelationshipScore': 0.9991758465766907, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 77, 'EndOffset': 83, 'Text': '250 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'lactose monohydrate, microcrystalline cellulose', 'Type': 'TREATMENT', 'BeginOffset': 137, 'EndOffset': 184}, {'Id': 6, 'BeginOffset': 193, 'EndOffset': 214, 'Score': 0.9955785870552063, 'Text': 'croscarmellose sodium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 216, 'EndOffset': 224, 'Score': 0.8563566207885742, 'Text': 'povidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'k29', 'Type': 'TEST', 'BeginOffset': 226, 'EndOffset': 229}, {'Id': 8, 'BeginOffset': 243, 'EndOffset': 263, 'Score': 0.9993706345558167, 'Text': 'sodium laurilsulfate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 265, 'EndOffset': 283, 'Score': 0.9955653548240662, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 285, 'EndOffset': 297, 'Score': 0.9881430268287659, 'Text': 'hypromellose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 306, 'EndOffset': 318, 'Score': 0.7594585418701172, 'Text': 'macrogol 300', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 320, 'EndOffset': 336, 'Score': 0.9979088306427002, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 345, 'EndOffset': 362, 'Score': 0.4155787527561188, 'Text': 'yellow iron oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 374, 'EndOffset': 388, 'Score': 0.9725320339202881, 'Text': 'red iron oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the pack iressa', 'Type': 'TREATMENT', 'BeginOffset': 436, 'EndOffset': 451}, {'Text': "'iressa", 'Type': 'TREATMENT', 'BeginOffset': 488, 'EndOffset': 495}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 496, 'EndOffset': 499}, {'Text': 'iressa', 'Type': 'TREATMENT', 'BeginOffset': 537, 'EndOffset': 543}, {'Text': 'blister packs', 'Type': 'TREATMENT', 'BeginOffset': 553, 'EndOffset': 566}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 570, 'EndOffset': 572}, {'Text': 'the blister foil', 'Type': 'TREATMENT', 'BeginOffset': 582, 'EndOffset': 598}, {'Text': 'perforated', 'Type': 'PROBLEM', 'BeginOffset': 606, 'EndOffset': 616}, {'Text': 'non-perforated', 'Type': 'PROBLEM', 'BeginOffset': 620, 'EndOffset': 634}]}

8EE3C9FA484FF1EE8B88FB996A647522

https://www.ema.europa.eu/documents/product-information/inomax-epar-product-information_en.pdf

INOmax

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT INOmax 400 ppm mol/mol medicinal gas, compressed 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Nitric oxide (NO) 400 ppm mol/mol. A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC. A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15oC. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Medicinal gas, compressed. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications INOmax, in conjunction with ventilatory support and other appropriate active substances, is indicated:  for the treatment of newborn infants ≥ 34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation.  as part of the treatment of peri- and post-operative pulmonary hypertension in adults and newborn infants, infants and toddlers, children and adolescents, ages 0-17 years in conjunction to heart surgery, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation. 4.2 Posology and method of administration Persistent Pulmonary Hypertension in the Newborn (PPHN) Prescription of nitric oxide should be supervised by a physician experienced in neonatal intensive care. Prescription should be limited to those neonatal units that have received adequate training in the use of a nitric oxide delivery system. INOmax should only be delivered according to a neonatologist’s prescription. INOmax should be used in ventilated newborn infants expected to require support >24 hours. INOmax should be used only after respiratory support has been optimised. This includes optimising tidal volume/pressures and lung recruitment (surfactant, high frequency ventilation, and positive end expiratory pressure). Pulmonary hypertension associated with heart surgery Prescription of nitric oxide should be supervised by a physician experienced in cardiothoracic anaesthesia & intensive care. Prescription should be limited to those cardio-thoracic units that have received adequate training in the use of a nitric oxide delivery system. INOmax should only be delivered according to an anaesthetist’s or intensive care physician’s prescription. Posology 3 Persistent Pulmonary Hypertension in the Newborn (PPHN) The maximum recommended dose of INOmax is 20 ppm and this dose should not be exceeded. In the pivotal clinical trials, the starting dose was 20 ppm. Starting as soon as possible and within 4-24 hours of therapy, the dose should be weaned to 5 ppm provided that arterial oxygenation is adequate at this lower dose. Inhaled nitric oxide therapy should be maintained at 5 ppm until there is improvement in the neonate’s oxygenation such that the FiO2 (fraction of inspired oxygen) < 0.60. Treatment can be maintained up to 96 hours or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from INOmax therapy. The duration of therapy is variable, but typically less than four days. In cases of failure to respond to inhaled nitric oxide, see section 4.4. Weaning Attempts to wean INOmax should be made after the ventilator support is substantially decreased or after 96 hours of therapy. When the decision is made to discontinue inhaled nitric oxide therapy, the dose should be reduced to 1 ppm for 30 minutes to one hour. If there is no change in oxygenation during administration of INOmax at 1 ppm, the FiO2 should be increased by 10 %, the INOmax is discontinued, and the neonates monitored closely for signs of hypoxaemia. If oxygenation falls >20 %, INOmax therapy should be resumed at 5 ppm and discontinuation of INOmax therapy should be reconsidered after 12 to 24 hours. Infants who cannot be weaned off INOmax by 4 days should undergo careful diagnostic work-up for other diseases. Pulmonary hypertension associated with heart surgery INOmax should be used only after conservative support has been optimised. In clinical trials INOmax has been given in addition to other standard treatment regimes in the peri-operative setting, including inotropic and vasoactive medicinal products. INOmax should be administered under close monitoring of haemodynamics and oxygenation. Newborn infants, infants and toddlers, children and adolescents, ages 0-17 years The starting dose of inhaled nitric oxide is 10 ppm(part per million) of inhaled gas. The dose may be increased up to 20 ppm if the lower dose has not provided sufficient clinical effects. The lowest effective dose should be administered and the dose should be weaned down to 5 ppm provided that the pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose. Clinical data supporting the suggested dose in the age range 12-17 years is limited. Adults The starting dose of inhaled nitric oxide is 20 ppm (part per million) of inhaled gas. The dose may be increased up to 40 ppm if the lower dose has not provided sufficient clinical effects. The lowest effective dose should be administered and the dose should be weaned down to 5 ppm provided that the pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose. The effects of inhaled nitric oxide are rapid, decrease in pulmonary artery pressure and improved oxygenation is seen within 5-20 minutes. In case of insufficient response the dose may be titrated after a minimum of 10 minutes. Consideration should be given to discontinuation of treatment if no beneficial physiological effects are apparent after a 30-minute trial of therapy. Treatment may be initiated at any time point in the peri-operative course to lower pulmonary pressure. In clinical studies treatment was often initiated before separation from Cardio Pulmonary Bypass. Inhaled NO has been given for time periods up to 7 days in the peri-operative setting, but common treatment times are 24 -48 hours. Weaning Attempts to wean INOmax should be commenced as soon as the haemodynamics have stabilised in conjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide 4 therapy should be performed in a stepwise manner. The dose should be incrementally reduced to 1 ppm for 30 minutes with close observation of systemic and central pressure, and then turned off. Weaning should be attempted at least every 12 hours when the patient is stable on a low dose of INOmax. Too rapid weaning from inhaled nitric oxide therapy carries the risk of a re-bound increase in pulmonary artery pressure with subsequent circulatory instability. Paediatric population The safety and efficacy of INOmax in premature infants less than 34 weeks of gestation has not yet been established. Currently available data are described in section 5.1 but no recommendation or posology can be made. Method of administration For endotracheopulmonary use. Nitric oxide is delivered to the patient via mechanical ventilation after dilution with an oxygen/air mixture using an approved (CE-marked) nitric oxide delivery system. Before initiation of therapy, during set-up, secure that the device setting is in agreement with the cylinder gas concentration. The delivery system must provide a constant inhaled INOmax concentration irrespective of the ventilator. With a continuous flow neonatal ventilator, this may be achieved by infusing a low flow of INOmax into the inspiratory limb of the ventilator circuit. Intermittent flow neonatal ventilation may be associated with spikes in nitric oxide concentration. The nitric oxide delivery system for intermittent flow ventilation should be adequate to avoid spikes in nitric oxide concentration. The inspired INOmax concentration must be measured continuously in the inspiratory limb of the circuit near the patient. The nitrogen dioxide (NO2) concentration and FiO2 must also be measured at the same site using calibrated and approved (CE-marked) monitoring equipment. For patient safety, appropriate alarms must be set for INOmax (± 2 ppm of the prescribed dose), NO2 (1 ppm), and FiO2 (± 0.05). The INOmax gas cylinder pressure must be displayed to allow timely gas cylinder replacement without inadvertent loss of therapy and backup gas cylinders must be available to provide timely replacement. INOmax therapy must be available for manual ventilation such as suctioning, patient transport, and resuscitation. In the event of a system failure or a wall-outlet power failure, a backup battery power supply and reserve nitric oxide delivery system should be available. The power supply for the monitoring equipment should be independent of the delivery device function. The upper limit of exposure (mean exposure) to nitric oxide for personnel defined by worker's legislation is 25 ppm for 8 hours (30 mg/m3) in most countries and the corresponding limit for NO2 is 2-3 ppm (4-6 mg/m3). Training in administration The key elements that need to be covered in training hospital personnel are as follows. Correct set-up and connections - Connections to the gas cylinder and to the ventilator patient breathing circuit Operation - Pre-use check list procedure (a series of steps required immediately prior to each patient initiation to ensure that the system is working properly and that the system is purged of NO2) - Setting the device for the correct concentration of nitric oxide to be administered - Setting the NO, NO2 and O2 monitors for high and low alarm limits - Using the manual backup delivery system - Procedures for correctly switching gas cylinders and purging system - Troubleshooting alarms 5 - NO, NO2 and O2 monitor calibration - Monthly system performance check-up procedures Monitoring formation of methaemoglobin (MetHb) Neonates and infants are known to have diminished MetHb reductase activity compared to adults. Methaemoglobin level should be measured within one hour after initiation of INOmax therapy, using an analyser which can reliably distinguish between foetal haemoglobin and methaemoglobin. If it is > 2.5 %, the INOmax dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered. Although it is unusual for the methaemoglobin level to increase significantly if the first level is low, it is prudent to repeat methaemoglobin measurements every one to two days. In adults undergoing heart surgery, methaemoglobin level should be measured within one hour of the initiation of INOmax therapy. If the fraction of methaemoglobin rises to a level that potentially compromises adequate oxygen delivery, the INOmax dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered. Monitoring formation of nitrogen dioxide (NO2) Immediately prior to each patient initiation, proper procedure must be applied to purge the system of NO2. The NO2 concentration should be maintained as low as possible and always < 0.5 ppm. If the NO2 is > 0.5 ppm, the delivery system should be assessed for malfunction, the NO2 analyser should be recalibrated, and the INOmax and/or FiO2 should be reduced if possible. If there is an unexpected change in INOmax concentration, the delivery system should be assessed for malfunction and the analyser should be recalibrated. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Neonates known to be dependent on right-to-left, or significant left-to-right, shunting of blood. 4.4 Special warnings and precautions for use Inadequate response If it is judged that clinical response is inadequate at 4-6 hours after starting INOmax, the following should be considered. For patients who are to be referred to another hospital, to prevent worsening of their condition on acute discontinuation of INOmax, the availability of nitric oxide during transport should be assured. Rescue, such as Extra Corporeal Membrane Oxygenation (ECMO) where available, should be considered based on continued deterioration or failure to improve, defined by criteria based on local circumstances. Special patient populations In clinical trials, no efficacy has been demonstrated with the use of inhaled nitric oxide in patients with congenital diaphragmatic hernia. Treatment with inhaled nitric oxide might aggravate cardiac insufficiency in a situation with left-to- right shunting. This is due to unwanted pulmonary vasodilation caused by inhaled nitric oxide, resulting in a further increase of already existing pulmonary hyperperfusion thus potentially giving raise to forward or backward failure. It, therefore, is recommended that prior to the administration of nitric oxide, pulmonary artery catheterisation or echocardiographic examination of central haemodynamics be performed. Inhaled nitric oxide should be used with caution in patients with complex heart defect, where high pressure in the pulmonary artery is of importance for maintaining circulation. 6 Inhaled nitric oxide should also be used with caution in patients with compromised left ventricular function and elevated baseline pulmonary capillary pressure (PCWP) as they may be at an increased risk of developing cardiac failure (e.g. pulmonary oedema). Discontinuation of therapy The INOmax dose should not be discontinued abruptly as it may result in an increase in pulmonary artery pressure (PAP) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation and elevation in PAP may also occur in neonates with no apparent response to INOmax. Weaning from inhaled nitric oxide should be performed with caution. For patients transported to other facilities for additional treatment, who need to continue with inhaled nitric oxide, arrangements should be made to ensure the continuous supply of inhaled nitric oxide during transportation. The physician should have access at the bedside to a reserve nitric oxide delivery system. Formation of methaemoglobin A large portion of nitric oxide for inhalation is absorbed systemically. The end medicinal products of nitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate. The concentrations of methaemoglobin in the blood should be monitored, see section 4.2. Formation of NO2 NO2 rapidly forms in gas mixtures containing nitric oxide and O2, and nitric oxide may in this way cause airway inflammation and damage. The dose of nitric oxide should be reduced if the concentration of nitrogen dioxide exceeds 0.5 ppm. Effects on platelets Animal models have shown that nitric oxide may interact with haemostasis, resulting in an increased bleeding time. Data in adult humans are conflicting, and there has been no increase in bleeding complications in randomised controlled trials in term and near-term neonates with hypoxic respiratory failure. Regular monitoring of haemostasis and measurement of bleeding time is recommended during the administration of INOmax for more than 24 hours to patients with functional or quantitative platelet anomalies, a low coagulation factor or receiving anticoagulation treatment. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. A clinically significant interaction with other medicinal products used in the treatment of hypoxic respiratory failure cannot be excluded based on the available data. There may be an additive effect with INOmax on the risk of developing methaemoglobinemia with nitric oxide donor substances, including sodium nitroprusside and nitroglycerin. INOmax has been safely administered with tolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation. The combined used with other vasodilators (e.g. sildenafil) is not extensively studied. Available data suggest additive effects on central circulation, pulmonary artery pressure and right ventricular performance. Inhaled nitric oxide combination with other vasodilators acting by the cGMP or cAMP systems should be done with caution. There is an increased risk of methaemoglobin formation if substances with a known tendency to increase methaemoglobin concentrations are administered concomitantly with nitric oxide (e.g. alkyl nitrates and sulphonamides). Substances known to cause increased methaemoglobin levels should thus be used with caution during therapy with inhaled nitric oxide. Prilocaine, whether administered as oral, parenteral, or topical formulations may cause methaemoglobinaemia. Care must be taken when INOmax is given at the same time as medicinal products containing prilocaine. In the presence of oxygen, nitric oxide is rapidly oxidised to derivatives which are toxic to the bronchial epithelium and alveolo-capillary membrane. Nitrogen dioxide (NO2) is the main substance formed, and may cause airway inflammation and damage. There are also animal data suggesting an 7 increased susceptibility to airway infections upon exposure to low levels of NO2. During treatment with nitric oxide, the NO2 concentration should be < 0.5 ppm in the nitric oxide dose range < 20 ppm. If at any time the NO2 concentration exceeds 1 ppm, the nitric oxide dose should immediately be reduced. See section 4.2 for information on monitoring for NO2. 4.6 Fertility, pregnancy and lactation There are no adequate data from the use of nitric oxide in pregnant women. The potential risk for humans is unknown. It is unknown whether nitric oxide is excreted in human milk. INOmax should not be used during pregnancy or breastfeeding. No fertility studies have been performed. 4.7 Effects on ability to drive and use machines Not relevant. 4.8 Undesirable effects Summary of safety profile Abrupt discontinuation of the administration of inhaled nitric oxide may cause rebound reaction; decrease in oxygenation and increase in central pressure and subsequent decrease in systemic blood pressure. Rebound reaction is the most commonly adverse reaction in association with the clinical use of INOmax. The rebound may be seen early as well as late during therapy. In one clinical study (NINOS), treatment groups were similar with respect to the incidence and severity of intracranial haemorrhage, Grade IV haemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary haemorrhage, or gastrointestinal haemorrhage. Tabulated list of adverse reactions The table below presents adverse reactions (ADRs) that have been reported with the use of INOmax from either the CINRGI trial of 212 neonates or post marketing experience in neonates (<1 months of age)). The displayed frequency categories use the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). 8 System organ class Very common Common Uncommon Rare Very rare Not known Blood and lymphatic system disorders Thrombo- cytopeniaa - Methaemoglobi naemiaa - - - Cardiac disorders - - - - - Bradycardiab (following abrupt discontinuation of therapy) Vascular disorders - Hypotensiona,b, d - - - - Respiratory, thoracic and mediastinal disorders - Atelectasisa - - - Hypoxiab,d Dyspnoeac Chest Discomfortc Dry throatc Nervous system disorders - - - - - Headachec Dizzinessc a: Identified from the clinical trial b: Identified from Post Marketing experience c: Identified from Post-Marketing experience, experienced by healthcare personnel following accidental exposure d: Post Marketing Safety Surveillance (PMSS) data, effects associated with acute withdrawal of the medicinal product, and /or delivery system failures. Rapid rebound reactions such as intensified pulmonary vasoconstriction and hypoxia after sudden withdrawal of inhaled nitric oxide therapy has been described, precipitating cardiovascular collapse. Description of selected adverse reactions Inhaled nitric oxide therapy may cause an increase in methaemoglobin. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V 4.9 Overdose Overdose with INOmax will be manifest by elevations in methaemoglobin and NO2. Elevated NO2 may cause acute lung injury. Elevations in methaemoglobinaemia reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels > 3 ppm or methaemoglobin levels > 7 % were treated by reducing the dose of, or discontinuing, INOmax. Methaemoglobinaemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation. 5. PHARMACOLOGICAL PROPERTIES http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other respiratory system products, ATC code R07AX01. Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the haeme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3’,5’-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide produces selective pulmonary vasodilation. INOmax appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios. Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, INOmax can improve oxygenation (as indicated by significant increases in PaO2). The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of aetiologies. In the NINOS trial, 235 neonates with hypoxic respiratory failure were randomised to receive 100 % O2 with (n=114) or without (n=121) nitric oxide most with an initial concentration of 20 ppm with weaning as possible to lower doses with a median duration of exposure of 40 hours. The objective of this double-blind, randomised, placebo controlled trial was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO). Neonates with less than a full response at 20 ppm were evaluated for a response to 80 ppm nitric oxide or control gas. The combined incidence of death and/or initiation of ECMO (the prospectively defined primary endpoint) showed a significant advantage for the nitric oxide treated group (46 % vs. 64 %, p=0.006). Data further suggested a lack of additional benefit for the higher dose of nitric oxide. The adverse events collected occurred at similar incidence rates in both groups. Follow-up exams at 18-24 months of age were similar between the two groups with respect to mental, motor, audiologic, and neurologic evaluations. In the CINRGI trial, 186 term- and near-term neonates with hypoxic respiratory failure and without lung hypoplasia were randomised to receive either INOmax (n=97) or nitrogen gas (placebo; n=89) with an initial dose of 20 ppm weaning to 5 ppm in 4 to 24 hours with median duration of exposure of 44 hours. The prospectively defined primary endpoint was the receipt of ECMO. Significantly fewer neonates in the INOmax group required ECMO compared to the control group (31 % vs. 57 %, p<0.001). The INOmax group had significantly improved oxygenation as measured by PaO2, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with INOmax, 2(2 %) were withdrawn from study drug due to methaemoglobin levels >4 %. The frequency and number of adverse events were similar in the two study groups. In patients undergoing heart surgery, an increase in pulmonary artery pressure due to pulmonary vaso- constriction is frequently seen. Inhaled nitric oxide has been shown to selectively reduce pulmonary vascular resistance and reduce the increased pulmonary artery pressure. This may increase the right ventricular ejection fraction. These effects in turn lead to improved blood circulation and oxygenation in the pulmonary circulation. In the INOT27 trial, 795 preterm infants (GA<29 weeks) with hypoxic respiratory failure were randomised to receive either INOmax (n=395) in a dose of 5 ppm or nitrogen (placebo n=400), beginning within the first 24 hours of life and treated for at least 7 days, up to 21 days. The primary outcome, of the combined efficacy endpoints of death or BPD at 36 weeks GA, was not significantly 10 different between groups, even with adjustment for gestational age as a covariate (p = 0.40), or with birth weight as a covariate (p = 0.41). The overall occurrence of intraventricular haemorrhage was 114 (28.9 %) among the iNO treated as compared to 91 (22.9 %) among the control neonates. The overall number of death at week 36 was slightly higher in the iNO group; 53/395 (13.4 %) as compared to control 42/397 (10.6 %). The INOT25 trial, studying the effects of iNO in hypoxic preterm neonates, did not show improvement in alive without BPD. No difference in the incidence of IVH or death was however observed in this study. The BALLR1 study, also evaluating the effects of iNO in preterm neonates, but initiating iNO at 7 days and in a dose of 20 ppm, found a significant increase in neonates alive without BPD at gestational week 36, 121 (45 % vs. 95 (35.4 %) p<0.028. No signs of any increase adverse effects were noted in this study. Nitric oxide chemically reacts with oxygen to form nitrogen dioxide. Nitric oxide has an unpaired electron, which makes the molecule reactive. In biological tissue, nitric oxide may form peroxynitrite with superoxide (O2-), an unstable compound which may cause tissue damage through further redox reactions. In addition, nitric oxide has affinity to metalloproteins and may also react with SH-groups in protein forming nitrosyl compounds. The clinical significance of the chemical reactivity of nitric oxide in tissue is unknown. Studies show that nitric oxide exhibits pulmonary pharmacodynamic effects at intra-airway concentrations as low as 1 ppm. The European Medicines Agency has waived the obligation to submit the results of studies with INOmax in all subsets of the paediatric population in persistent pulmonary hypertension and other pulmonary heart disease. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties The pharmacokinetics of nitric oxide has been studied in adults. Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with haemoglobin that is 60 % to 100 % oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhaemoglobin to produce methaemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhaemoglobin to transiently form nitrosylhaemoglobin, which is converted to nitrogen oxides and methaemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhaemoglobin to produce methaemoglobin and nitrate. Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate. Methaemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. Methaemoglobin concentrations increase during the first 8 hours of nitric oxide exposure. The mean methaemoglobin levels remained below 1 % in the placebo group and in the 5 ppm and 20 ppm INOmax groups, but reached approximately 5 % in the 80 ppm INOmax group. Methaemoglobin levels > 7 % were attained only in patients receiving 80 ppm, where they comprised 35 % of the group. The average time to reach peak methaemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients; but one patient did not exceed 7 % until 40 hours. Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for > 70 % of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration. 5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Acute toxicity is related to anoxia resulting from elevated methaemoglobin levels. 11 Nitric oxide is genotoxic in some test systems. No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 h/day for up to two years. Higher exposures have not been investigated. No reproduction toxicity studies have been conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Nitrogen 6.2 Incompatibilities In the presence of oxygen NO rapidly forms NO2, see section 4.5. 6.3 Shelf life 3 years 6.4 Special precautions for storage All regulations concerning handling of pressure vessels must be followed. Store gas cylinders indoors in well-ventilated rooms or outdoors in ventilated sheds where they are protected from rain and direct sunlight. Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. Storage in the pharmacy department The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas cylinders. Storage in the medical department The gas cylinder should be put in an equipped site with appropriate material in order to hold the gas cylinder vertically. Transport of gas cylinders The gas cylinders should be transported with appropriate material in order to protect them from risks of shocks and falls. During inter- or within-hospital transfers of patients treated with INOmax, the gas cylinders should be fixedly stowed away in order to hold the gas cylinders vertically and to avoid the risk of fall or untimely modifying output. A particular attention should be also turned to the fastening of the pressure regulator so as to avoid the risks of accidental failures. 6.5 Nature and contents of container Pack sizes: 12 A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel. A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel. A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel. A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel. 6.6 Special precautions for disposal and other handling Instructions for use/handling INOmax When connecting an INOmax cylinder to the delivery system, always secure that the cylinder concentration is of the same concentration for which the system is configured. In order to avoid all incidents, the following instructions should be absolutely respected. - the good condition of the material should be checked before use - the gas cylinders should be fixedly stowed away in order to avoid untimely fall - the valve should be fully open when used but not be opened with violence - a defective valve should neither be used nor be repaired. Return to distributor / manufacturer - a gas cylinder whose valve is not protected by a cap or a shell should not be used - a specific connection, with a 30 mm thread which is designated for medical use, complying with ISO 5145 and a pressure regulator which admits a pressure at least equal to 1.5 the maximum operating pressure (155 bar) of the gas cylinder should be used - the pressure regulator should be purged by the nitrogen-nitric oxide mixture before each new use in order to preclude nitrogen dioxide inhalation - the pressure regulator should not be tightened with pliers, at the risk of crushing the gasket All equipment, including connectors, tubing, and circuits, used in the delivery of nitric oxide must be made of materials compatible with the gas. From a corrosion point of view the supply system can be divided into two zones: 1) From the gas cylinder valve to the humidifier (dry gas) and 2) From the humidifier to outlet (moist gas which may contain NO2). Tests show that dry nitric oxide mixtures can be used with most materials. However, the presence of nitrogen dioxide and moisture creates an aggressive atmosphere. Among metallic construction materials, only stainless steel can be recommended. Tested polymers which can be used in nitric oxide administration systems include polyethylene (PE) and polypropylene (PP). Butyl rubber, polyamide, and polyurethane should not be used. Polytrifluorochloroethylene, hexafluoropropene-vinyliden copolymer and polytetraflourethylene have been used extensively with pure nitric oxide and other corrosive gases. They were considered so inert that testing was not required. The installation of a nitric oxide pipeline system with supply station of gas cylinders, fixed network and terminal units is forbidden. There is in general no need for scavenging of excess gas, the work place ambient air quality should however be considered and trace concentrations of NO or NO2/NOx must not exceed set national occupational exposure limits. Accidental exposure to INOmax in hospital staff has been associated with adverse events (see section 4.8). Cylinders equipped with a standard valve hand-wheel cannot be used with the INOmax DSIR delivery system. 13 Instruction for disposal of gas cylinder When the gas cylinder is empty, it should not be discarded. Empty gas cylinders will be collected by the supplier. 7. MARKETING AUTHORISATION HOLDER Linde Healthcare AB Rättarvägen 3 169 68 Solna Sweden 8. MARKETING AUTHORISATION NUMBER(S) EU/1/01/194/001, EU/1/01/194/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 01/08/2001 Date of last renewal: 01/06/2006 10. DATE OF REVISION OF THE TEXT MM/YYYY Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 14 1. NAME OF THE MEDICINAL PRODUCT INOmax 800 ppm mol/mol medicinal gas, compressed 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Nitric oxide (NO) 800 ppm mol/mol. A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC. A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15oC. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Medicinal gas, compressed. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications INOmax, in conjunction with ventilatory support and other appropriate active substances, is indicated:  for the treatment of newborn infants ≥ 34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation.  as part of the treatment of peri- and post-operative pulmonary hypertension in adults and newborn infants, infants and toddlers, children and adolescents, ages 0-17 years in conjunction to heart surgery, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation. 4.2 Posology and method of administration Persistent Pulmonary Hypertension in the Newborn (PPHN) Prescription of nitric oxide should be supervised by a physician experienced in neonatal intensive care. Prescription should be limited to those neonatal units that have received adequate training in the use of a nitric oxide delivery system. INOmax should only be delivered according to a neonatologist’s prescription. INOmax should be used in ventilated newborn infants expected to require support >24 hours. INOmax should be used only after respiratory support has been optimised. This includes optimising tidal volume/pressures and lung recruitment (surfactant, high frequency ventilation, and positive end expiratory pressure). Pulmonary hypertension associated with heart surgery Prescription of nitric oxide should be supervised by a physician experienced in cardiothoracic anaesthesia & intensive care. Prescription should be limited to those cardio-thoracic units that have received adequate training in the use of a nitric oxide delivery system. INOmax should only be delivered according to an anaesthetist’s or intensive care physician’s prescription. Posology Persistent Pulmonary Hypertension in the Newborn (PPHN) 15 The maximum recommended dose of INOmax is 20 ppm and this dose should not be exceeded. In the pivotal clinical trials, the starting dose was 20 ppm. Starting as soon as possible and within 4-24 hours of therapy, the dose should be weaned to 5 ppm provided that arterial oxygenation is adequate at this lower dose. Inhaled nitric oxide therapy should be maintained at 5 ppm until there is improvement in the neonate’s oxygenation such that the FiO2 (fraction of inspired oxygen) < 0.60. Treatment can be maintained up to 96 hours or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from INOmax therapy. The duration of therapy is variable, but typically less than four days. In cases of failure to respond to inhaled nitric oxide, see section 4.4. Weaning Attempts to wean INOmax should be made after the ventilator support is substantially decreased or after 96 hours of therapy. When the decision is made to discontinue inhaled nitric oxide therapy, the dose should be reduced to 1 ppm for 30 minutes to one hour. If there is no change in oxygenation during administration of INOmax at 1 ppm, the FiO2 should be increased by 10 %, the INOmax is discontinued, and the neonates monitored closely for signs of hypoxaemia. If oxygenation falls >20 %, INOmax therapy should be resumed at 5 ppm and discontinuation of INOmax therapy should be reconsidered after 12 to 24 hours. Infants who cannot be weaned off INOmax by 4 days should undergo careful diagnostic work-up for other diseases. Pulmonary hypertension associated with heart surgery INOmax should be used only after conservative support has been optimised. In clinical trials INOmax has been given in addition to other standard treatment regimes in the peri-operative setting, including inotropic and vasoactive medicinal products. INOmax should be administered under close monitoring of haemodynamics and oxygenation. Newborn infants, infants and toddlers, children and adolescents, ages 0-17 years The starting dose of inhaled nitric oxide is 10 ppm(part per million) of inhaled gas. The dose may be increased up to 20 ppm if the lower dose has not provided sufficient clinical effects. The lowest effective dose should be administered and the dose should be weaned down to 5 ppm provided that the pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose. Clinical data supporting the suggested dose in the age range 12-17 years is limited. Adults The starting dose of inhaled nitric oxide is 20 ppm (part per million) of inhaled gas. The dose may be increased up to 40 ppm if the lower dose has not provided sufficient clinical effects. The lowest effective dose should be administered and the dose should be weaned down to 5 ppm provided that the pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose. The effects of inhaled nitric oxide are rapid, decrease in pulmonary artery pressure and improved oxygenation is seen within 5-20 minutes. In case of insufficient response the dose may be titrated after a minimum of 10 minutes. Consideration should be given to discontinuation of treatment if no beneficial physiological effects are apparent after a 30-minute trial of therapy. Treatment may be initiated at any time point in the peri-operative course to lower pulmonary pressure. In clinical studies treatment was often initiated before separation from Cardio Pulmonary Bypass. Inhaled NO has been given for time periods up to 7 days in the peri-operative setting, but common treatment times are 24 -48 hours. Weaning Attempts to wean INOmax should be commenced as soon as the haemodynamics have stabilised in conjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide 16 therapy should be performed in a stepwise manner. The dose should be incrementally reduced to 1 ppm for 30 minutes with close observation of systemic and central pressure, and then turned off. Weaning should be attempted at least every 12 hours when the patient is stable on a low dose of INOmax. Too rapid weaning from inhaled nitric oxide therapy carries the risk of a re-bound increase in pulmonary artery pressure with subsequent circulatory instability. Paediatric population The safety and efficacy of INOmax in premature infants less than 34 weeks of gestation has not yet been established. Currently available data are described in section 5.1 but no recommendation or posology can be made. Method of administration For endotracheopulmonary use. Nitric oxide is delivered to the patient via mechanical ventilation after dilution with an oxygen/air mixture using an approved (CE-marked) nitric oxide delivery system. Before initiation of therapy, during set-up, secure that the device setting is in agreement with the cylinder gas concentration. The delivery system must provide a constant inhaled INOmax concentration irrespective of the ventilator. With a continuous flow neonatal ventilator, this may be achieved by infusing a low flow of INOmax into the inspiratory limb of the ventilator circuit. Intermittent flow neonatal ventilation may be associated with spikes in nitric oxide concentration. The nitric oxide delivery system for intermittent flow ventilation should be adequate to avoid spikes in nitric oxide concentration. The inspired INOmax concentration must be measured continuously in the inspiratory limb of the circuit near the patient. The nitrogen dioxide (NO2) concentration and FiO2 must also be measured at the same site using calibrated and approved (CE-marked) monitoring equipment. For patient safety, appropriate alarms must be set for INOmax (± 2 ppm of the prescribed dose), NO2 (1 ppm), and FiO2 (± 0.05). The INOmax gas cylinder pressure must be displayed to allow timely gas cylinder replacement without inadvertent loss of therapy and backup gas cylinders must be available to provide timely replacement. INOmax therapy must be available for manual ventilation such as suctioning, patient transport, and resuscitation. In the event of a system failure or a wall-outlet power failure, a backup battery power supply and reserve nitric oxide delivery system should be available. The power supply for the monitoring equipment should be independent of the delivery device function. The upper limit of exposure (mean exposure) to nitric oxide for personnel defined by worker's legislation is 25 ppm for 8 hours (30 mg/m3) in most countries and the corresponding limit for NO2 is 2-3 ppm (4-6 mg/m3). Training in administration The key elements that need to be covered in training hospital personnel are as follows. Correct set-up and connections - Connections to the gas cylinder and to the ventilator patient breathing circuit Operation - Pre-use check list procedure (a series of steps required immediately prior to each patient initiation to ensure that the system is working properly and that the system is purged of NO2) - Setting the device for the correct concentration of nitric oxide to be administered - Setting the NO, NO2 and O2 monitors for high and low alarm limits - Using the manual backup delivery system - Procedures for correctly switching gas cylinders and purging system - Troubleshooting alarms 17 - NO, NO2 and O2 monitor calibration - Monthly system performance check-up procedures Monitoring formation of methaemoglobin (MetHb) Neonates and infants are known to have diminished MetHb reductase activity compared to adults. Methaemoglobin level should be measured within one hour after initiation of INOmax therapy, using an analyser which can reliably distinguish between foetal haemoglobin and methaemoglobin. If it is > 2.5 %, the INOmax dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered. Although it is unusual for the methaemoglobin level to increase significantly if the first level is low, it is prudent to repeat methaemoglobin measurements every one to two days. In adults undergoing heart surgery, methaemoglobin level should be measured within one hour of the initiation of INOmax therapy. If the fraction of methaemoglobin rises to a level that potentially compromises adequate oxygen delivery, the INOmax dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered. Monitoring formation of nitrogen dioxide (NO2) Immediately prior to each patient initiation, proper procedure must be applied to purge the system of NO2. The NO2 concentration should be maintained as low as possible and always < 0.5 ppm. If the NO2 is > 0.5 ppm, the delivery system should be assessed for malfunction, the NO2 analyser should be recalibrated, and the INOmax and/or FiO2 should be reduced if possible. If there is an unexpected change in INOmax concentration, the delivery system should be assessed for malfunction and the analyser should be recalibrated. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Neonates known to be dependent on right-to-left, or significant left-to-right, shunting of blood. 4.4 Special warnings and precautions for use Inadequate response If it is judged that clinical response is inadequate at 4-6 hours after starting INOmax, the following should be considered. For patients who are to be referred to another hospital, to prevent worsening of their condition on acute discontinuation of INOmax, the availability of nitric oxide during transport should be assured. Rescue, such as Extra Corporeal Membrane Oxygenation (ECMO) where available, should be considered based on continued deterioration or failure to improve, defined by criteria based on local circumstances. Special patient populations In clinical trials, no efficacy has been demonstrated with the use of inhaled nitric oxide in patients with congenital diaphragmatic hernia. Treatment with inhaled nitric oxide might aggravate cardiac insufficiency in a situation with left-to- right shunting. This is due to unwanted pulmonary vasodilation caused by inhaled nitric oxide, resulting in a further increase of already existing pulmonary hyperperfusion thus potentially giving raise to forward or backward failure. It, therefore, is recommended that prior to the administration of nitric oxide, pulmonary artery catheterisation or echocardiographic examination of central haemodynamics be performed. Inhaled nitric oxide should be used with caution in patients with complex heart defect, where high pressure in the pulmonary artery is of importance for maintaining circulation. 18 Inhaled nitric oxide should also be used with caution in patients with compromised left ventricular function and elevated baseline pulmonary capillary pressure (PCWP) as they may be at an increased risk of developing cardiac failure (e.g. pulmonary oedema). Discontinuation of therapy The INOmax dose should not be discontinued abruptly as it may result in an increase in pulmonary artery pressure (PAP) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation and elevation in PAP may also occur in neonates with no apparent response to INOmax. Weaning from inhaled nitric oxide should be performed with caution. For patients transported to other facilities for additional treatment, who need to continue with inhaled nitric oxide, arrangements should be made to ensure the continuous supply of inhaled nitric oxide during transportation. The physician should have access at the bedside to a reserve nitric oxide delivery system. Formation of methaemoglobin A large portion of nitric oxide for inhalation is absorbed systemically. The end medicinal products of nitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate. The concentrations of methaemoglobin in the blood should be monitored, see section 4.2. Formation of NO2 NO2 rapidly forms in gas mixtures containing nitric oxide and O2, and nitric oxide may in this way cause airway inflammation and damage. The dose of nitric oxide should be reduced if the concentration of nitrogen dioxide exceeds 0.5 ppm. Effects on platelets Animal models have shown that nitric oxide may interact with haemostasis, resulting in an increased bleeding time. Data in adult humans are conflicting, and there has been no increase in bleeding complications in randomised controlled trials in term and near-term neonates with hypoxic respiratory failure. Regular monitoring of haemostasis and measurement of bleeding time is recommended during the administration of INOmax for more than 24 hours to patients with functional or quantitative platelet anomalies, a low coagulation factor or receiving anticoagulation treatment. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. A clinically significant interaction with other medicinal products used in the treatment of hypoxic respiratory failure cannot be excluded based on the available data. There may be an additive effect with INOmax on the risk of developing methaemoglobinemia with nitric oxide donor substances, including sodium nitroprusside and nitroglycerin. INOmax has been safely administered with tolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation. The combined used with other vasodilators (e.g. sildenafil) is not extensively studied. Available data suggest additive effects on central circulation, pulmonary artery pressure and right ventricular performance. Inhaled nitric oxide combination with other vasodilators acting by the cGMP or cAMP systems should be done with caution. There is an increased risk of methaemoglobin formation if substances with a known tendency to increase methaemoglobin concentrations are administered concomitantly with nitric oxide (e.g. alkyl nitrates and sulphonamides). Substances known to cause increased methaemoglobin levels should thus be used with caution during therapy with inhaled nitric oxide. Prilocaine, whether administered as oral, parenteral, or topical formulations may cause methaemoglobinaemia. Care must be taken when INOmax is given at the same time as medicinal products containing prilocaine. In the presence of oxygen, nitric oxide is rapidly oxidised to derivatives which are toxic to the bronchial epithelium and alveolo-capillary membrane. Nitrogen dioxide (NO2) is the main substance formed, and may cause airway inflammation and damage. There are also animal data suggesting an 19 increased susceptibility to airway infections upon exposure to low levels of NO2. During treatment with nitric oxide, the NO2 concentration should be < 0.5 ppm in the nitric oxide dose range < 20 ppm. If at any time the NO2 concentration exceeds 1 ppm, the nitric oxide dose should immediately be reduced. See section 4.2 for information on monitoring for NO2. 4.6 Fertility, pregnancy and lactation There are no adequate data from the use of nitric oxide in pregnant women. The potential risk for humans is unknown. It is unknown whether nitric oxide is excreted in human milk. INOmax should not be used during pregnancy or breastfeeding. No fertility studies have been performed. 4.7 Effects on ability to drive and use machines Not relevant. 4.8 Undesirable effects Summary of safety profile Abrupt discontinuation of the administration of inhaled nitric oxide may cause rebound reaction; decrease in oxygenation and increase in central pressure and subsequent decrease in systemic blood pressure. Rebound reaction is the most commonly adverse reaction in association with the clinical use of INOmax. The rebound may be seen early as well as late during therapy. In one clinical study (NINOS), treatment groups were similar with respect to the incidence and severity of intracranial haemorrhage, Grade IV haemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary haemorrhage, or gastrointestinal haemorrhage. Tabulated list of adverse reactions The table below presents adverse reactions (ADRs) that have been reported with the use of INOmax from either the CINRGI trial of 212 neonates or post marketing experience in neonates (<1 months of age). The displayed frequency categories use the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). 20 System organ class Very common Common Uncommon Rare Very rare Not known Blood and lymphatic system disorders Thrombo- cytopeniaa - Methaemoglobi naemiaa - - - Cardiac disorders - - - - - Bradycardiab (following abrupt discontinuation of therapy) Vascular disorders - Hypotensiona,b, d - - - - Respiratory, thoracic and mediastinal disorders - Atelectasisa - - - Hypoxiab,d Dyspnoeac Chest Discomfortc Dry throatc Nervous system disorders - - - - - Headachec Dizzinessc a: Identified from the clinical trial b: Identified from Post-Marketing experience c: Identified from Post-Marketing experience, experienced by healthcare personnel following accidental exposure d: Post Marketing Safety Surveillance (PMSS) data, effects associated with acute withdrawal of the medicinal product, and /or delivery system failures. Rapid rebound reactions such as intensified pulmonary vasoconstriction and hypoxia after sudden withdrawal of inhaled nitric oxide therapy has been described, precipitating cardiovascular collapse. Description of selected adverse reactions Inhaled nitric oxide therapy may cause an increase in methaemoglobin. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V 4.9 Overdose Overdose with INOmax will be manifest by elevations in methaemoglobin and NO2. Elevated NO2 may cause acute lung injury. Elevations in methaemoglobinaemia reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels > 3 ppm or methaemoglobin levels > 7 % were treated by reducing the dose of, or discontinuing, INOmax. Methaemoglobinaemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 21 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other respiratory system products, ATC code R07AX01. Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the haeme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3’,5’-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide produces selective pulmonary vasodilation. INOmax appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios. Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, INOmax can improve oxygenation (as indicated by significant increases in PaO2). The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of aetiologies. In the NINOS trial, 235 neonates with hypoxic respiratory failure were randomised to receive 100 % O2 with (n=114) or without (n=121) nitric oxide most with an initial concentration of 20 ppm with weaning as possible to lower doses with a median duration of exposure of 40 hours. The objective of this double-blind, randomised, placebo controlled trial was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO). Neonates with less than a full response at 20 ppm were evaluated for a response to 80 ppm nitric oxide or control gas. The combined incidence of death and/or initiation of ECMO (the prospectively defined primary endpoint) showed a significant advantage for the nitric oxide treated group (46 % vs. 64 %, p=0.006). Data further suggested a lack of additional benefit for the higher dose of nitric oxide. The adverse events collected occurred at similar incidence rates in both groups. Follow-up exams at 18-24 months of age were similar between the two groups with respect to mental, motor, audiologic, and neurologic evaluations. In the CINRGI trial, 186 term- and near-term neonates with hypoxic respiratory failure and without lung hypoplasia were randomised to receive either INOmax (n=97) or nitrogen gas (placebo; n=89) with an initial dose of 20 ppm weaning to 5 ppm in 4 to 24 hours with median duration of exposure of 44 hours. The prospectively defined primary endpoint was the receipt of ECMO. Significantly fewer neonates in the INOmax group required ECMO compared to the control group (31 % vs. 57 %, p<0.001). The INOmax group had significantly improved oxygenation as measured by PaO2, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with INOmax, 2(2 %) were withdrawn from study drug due to methaemoglobin levels >4 %. The frequency and number of adverse events were similar in the two study groups. In patients undergoing heart surgery, an increase in pulmonary artery pressure due to pulmonary vaso- constriction is frequently seen. Inhaled nitric oxide has been shown to selectively reduce pulmonary vascular resistance and reduce the increased pulmonary artery pressure. This may increase the right ventricular ejection fraction. These effects in turn lead to improved blood circulation and oxygenation in the pulmonary circulation. In the INOT27 trial, 795 preterm infants (GA<29 weeks) with hypoxic respiratory failure were randomised to receive either INOmax (n=395) in a dose of 5 ppm or nitrogen (placebo n=400), beginning within the first 24 hours of life and treated for at least 7 days, up to 21 days. The primary 22 outcome, of the combined efficacy endpoints of death or BPD at 36 weeks GA, was not significantly different between groups, even with adjustment for gestational age as a covariate (p = 0.40), or with birth weight as a covariate (p = 0.41). The overall occurrence of intraventricular haemorrhage was 114 (28.9 %) among the iNO treated as compared to 91 (22.9 %) among the control neonates. The overall number of death at week 36 was slightly higher in the iNO group; 53/395 (13.4 %) as compared to control 42/397 (10.6 %). The INOT25 trial, studying the effects of iNO in hypoxic preterm neonates, did not show improvement in alive without BPD. No difference in the incidence of IVH or death was however observed in this study. The BALLR1 study, also evaluating the effects of iNO in preterm neonates, but initiating iNO at 7 days and in a dose of 20 ppm, found a significant increase in neonates alive without BPD at gestational week 36, 121 (45 % vs. 95 (35.4 %) p<0.028. No signs of any increase adverse effects were noted in this study. Nitric oxide chemically reacts with oxygen to form nitrogen dioxide. Nitric oxide has an unpaired electron, which makes the molecule reactive. In biological tissue, nitric oxide may form peroxynitrite with superoxide (O2-), an unstable compound which may cause tissue damage through further redox reactions. In addition, nitric oxide has affinity to metalloproteins and may also react with SH-groups in protein forming nitrosyl compounds. The clinical significance of the chemical reactivity of nitric oxide in tissue is unknown. Studies show that nitric oxide exhibits pulmonary pharmacodynamic effects at intra-airway concentrations as low as 1 ppm. The European Medicines Agency has waived the obligation to submit the results of studies with INOmax in all subsets of the paediatric population in persistent pulmonary hypertension and other pulmonary heart disease. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties The pharmacokinetics of nitric oxide has been studied in adults. Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with haemoglobin that is 60 % to 100 % oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhaemoglobin to produce methaemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhaemoglobin to transiently form nitrosylhaemoglobin, which is converted to nitrogen oxides and methaemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhaemoglobin to produce methaemoglobin and nitrate. Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate. Methaemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. Methaemoglobin concentrations increase during the first 8 hours of nitric oxide exposure. The mean methaemoglobin levels remained below 1 % in the placebo group and in the 5 ppm and 20 ppm INOmax groups, but reached approximately 5 % in the 80 ppm INOmax group. Methaemoglobin levels > 7 % were attained only in patients receiving 80 ppm, where they comprised 35 % of the group. The average time to reach peak methaemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients; but one patient did not exceed 7 % until 40 hours. Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for > 70 % of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration. 5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Acute toxicity is related to anoxia resulting from elevated methaemoglobin levels. 23 Nitric oxide is genotoxic in some test systems.. No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 h/day for up to two years. Higher exposures have not been investigated. No reproduction toxicity studies have been conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Nitrogen 6.2 Incompatibilities In the presence of oxygen NO rapidly forms NO2, see section 4.5. 6.3 Shelf life 3 years 6.4 Special precautions for storage All regulations concerning handling of pressure vessels must be followed. Store gas cylinders indoors in well-ventilated rooms or outdoors in ventilated sheds where they are protected from rain and direct sunlight. Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. Storage in the pharmacy department The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas cylinders. Storage in the medical department The gas cylinder should be put in an equipped site with appropriate material in order to hold the gas cylinder vertically. Transport of gas cylinders The gas cylinders should be transported with appropriate material in order to protect them from risks of shocks and falls. During inter- or within-hospital transfers of patients treated with INOmax, the gas cylinders should be fixedly stowed away in order to hold the gas cylinders vertically and to avoid the risk of fall or untimely modifying output. A particular attention should be also turned to the fastening of the pressure regulator so as to avoid the risks of accidental failures. 6.5 Nature and contents of container Pack sizes: 24 A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel. A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel. A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel. A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel. 6.6 Special precautions for disposal and other handling Instructions for use/handling INOmax When connecting an INOmax cylinder to the delivery system, always secure that the cylinder concentration is of the same concentration for which the system is configured. In order to avoid all incidents, the following instructions should be absolutely respected. - the good condition of the material should be checked before use - the gas cylinders should be fixedly stowed away in order to avoid untimely fall - the valve should be fully open when used but not be opened with violence - a defective valve should neither be used nor be repaired. Return to distributor / manufacturer - a gas cylinder whose valve is not protected by a cap or a shell should not be used - a specific connection, with a 30 mm thread which is designated for medical use, complying with ISO 5145 and a pressure regulator which admits a pressure at least equal to 1.5 the maximum operating pressure (155 bar) of the gas cylinder should be used - the pressure regulator should be purged by the nitrogen-nitric oxide mixture before each new use in order to preclude nitrogen dioxide inhalation - the pressure regulator should not be tightened with pliers, at the risk of crushing the gasket All equipment, including connectors, tubing, and circuits, used in the delivery of nitric oxide must be made of materials compatible with the gas. From a corrosion point of view the supply system can be divided into two zones: 1) From the gas cylinder valve to the humidifier (dry gas) and 2) From the humidifier to outlet (moist gas which may contain NO2). Tests show that dry nitric oxide mixtures can be used with most materials. However, the presence of nitrogen dioxide and moisture creates an aggressive atmosphere. Among metallic construction materials, only stainless steel can be recommended. Tested polymers which can be used in nitric oxide administration systems include polyethylene (PE) and polypropylene (PP). Butyl rubber, polyamide, and polyurethane should not be used. Polytrifluorochloroethylene, hexafluoropropene-vinyliden copolymer and polytetraflourethylene have been used extensively with pure nitric oxide and other corrosive gases. They were considered so inert that testing was not required. The installation of a nitric oxide pipeline system with supply station of gas cylinders, fixed network and terminal units is forbidden. There is in general no need for scavenging of excess gas, the work place ambient air quality should however be considered and trace concentrations of NO or NO2/NOx must not exceed set national occupational exposure limits. Accidental exposure to INOmax in hospital staff has been associated with adverse events (see section 4.8). Cylinders equipped with a standard valve hand-wheel cannot be used with the INOmax DSIR delivery system. 25 Instruction for disposal of gas cylinder When the gas cylinder is empty, it should not be discarded. Empty gas cylinders will be collected by the supplier. 7. MARKETING AUTHORISATION HOLDER Linde Healthcare AB Rättarvägen 3 169 68 Solna Sweden 8. MARKETING AUTHORISATION NUMBER(S) EU/1/01/194/003, EU/1/01/194/004 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 01/08/2001 Date of last renewal: 01/06/2006 10. DATE OF REVISION OF THE TEXT MM/YYYY Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 26 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 27 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Linde France Zone Industrielle de Limay Porcheville 3 avenue Ozanne 78440 Porcheville France B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION Periodic Safety Update Reports The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time • Additional risk minimisation measures Prior to launch of the new indication of the product in each Member State, the Marketing Authorisation Holder shall agree the content and format of the educational material with the national competent authority. The Marketing Authorisation Holder (MAH) should ensure that, at launch of the new indication, all Healthcare Professionals who are expected to use and/or prescribe INOmax as part of the treatment of peri- or post- operative pulmonary hypertension in adults and children in conjunction to heart surgery are provided with an Educational pack. 28 The educational pack should contain the following:  Summary of Product Characteristics and Patient Information Leaflet for INOmax  Educational material for Healthcare Professionals The educational material should include information on the following key elements:  The risk of rebound effect and the precautions to take when discontinuing the treatment  The risk of abrupt discontinuation of INOmax therapy in the event of critical failure of the delivery system and how to prevent it  The monitoring of Methaemoglobin level  The monitoring of NO2 formation  The potential risk of bleeding and haemostasis disorders  The potential risks if used in combination with other vasodilators which act on cGMP or cAMP 29 ANNEX III LABELLING AND PACKAGE LEAFLET 30 A. LABELLING 31 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 2 litres gas cylinder 1. NAME OF THE MEDICINAL PRODUCT INOmax 400 ppm mol/mol medicinal gas, compressed Nitric oxide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Nitric oxide (NO) 400 ppm mol/mol. 3. LIST OF EXCIPIENTS Also contains nitrogen. 4. PHARMACEUTICAL FORM AND CONTENTS Medicinal gas, compressed A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Endotracheopulmonary use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Ensure that the parent or guardian has read and is aware of the indications and cautions presented in the package leaflet prior to administration to their baby. 8. EXPIRY DATE EXP 32 9. SPECIAL STORAGE CONDITIONS All regulations concerning handling of pressure vessels must be followed. Store gas cylinders vertically in well-ventilated rooms. Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Do not discard used gas cylinders. All gas cylinders should be returned to the supplier for disposal. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Linde Healthcare AB Rättarvägen 3 169 68 Solna Sweden 12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/01/194/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE Not applicable. 33 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA Not applicable. 34 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 10 litres gas cylinder 1. NAME OF THE MEDICINAL PRODUCT INOmax 400 ppm mol/mol medicinal gas, compressed Nitric oxide. 2. STATEMENT OF ACTIVE SUBSTANCE(S) Nitric oxide (NO) 400 ppm mol/mol. 3. LIST OF EXCIPIENTS Also contains nitrogen. 4. PHARMACEUTICAL FORM AND CONTENTS Medicinal gas, compressed A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15oC. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Endotracheopulmonary use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Ensure that the parent or guardian has read and is aware of the indications and cautions presented in the package leaflet prior to administration to their baby. 8. EXPIRY DATE EXP 35 9. SPECIAL STORAGE CONDITIONS All regulations concerning handling of pressure vessels must be followed. Store gas cylinders vertically in well-ventilated rooms. Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Do not discard used gas cylinders. All gas cylinders should be returned to the supplier for disposal. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Linde Healthcare AB Rättarvägen 3 169 68 Solna Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/01/194/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE Not applicable. 36 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA Not applicable. 37 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 2 litres gas cylinder 1. NAME OF THE MEDICINAL PRODUCT INOmax 800 ppm mol/mol medicinal gas, compressed Nitric oxide 2. STATEMENT OF ACTIVE SUBSTANCE(S) Nitric oxide (NO) 800 ppm mol/mol. 3. LIST OF EXCIPIENTS Also contains nitrogen. 4. PHARMACEUTICAL FORM AND CONTENTS Medicinal gas, compressed A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Endotracheopulmonary use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Ensure that the parent or guardian has read and is aware of the indications and cautions presented in the package leaflet prior to administration to their baby. 8. EXPIRY DATE EXP 38 9. SPECIAL STORAGE CONDITIONS All regulations concerning handling of pressure vessels must be followed. Store gas cylinders vertically in well-ventilated rooms. Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Do not discard used gas cylinders. All gas cylinders should be returned to the supplier for disposal. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Linde Healthcare AB Rättarvägen 3 169 68 Solna Sweden 12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/01/194/003 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE Not applicable. 39 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA Not applicable. 40 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 10 litres gas cylinder 1. NAME OF THE MEDICINAL PRODUCT INOmax 800 ppm mol/mol medicinal gas, compressed Nitric oxide. 2. STATEMENT OF ACTIVE SUBSTANCE(S) Nitric oxide (NO) 800 ppm mol/mol. 3. LIST OF EXCIPIENTS Also contains nitrogen. 4. PHARMACEUTICAL FORM AND CONTENTS Medicinal gas, compressed A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15oC. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Endotracheopulmonary use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Ensure that the parent or guardian has read and is aware of the indications and cautions presented in the package leaflet prior to administration to their baby. 8. EXPIRY DATE EXP 41 9. SPECIAL STORAGE CONDITIONS All regulations concerning handling of pressure vessels must be followed. Store gas cylinders vertically in well-ventilated rooms. Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Do not discard used gas cylinders. All gas cylinders should be returned to the supplier for disposal. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Linde Healthcare AB Rättarvägen 3 169 68 Solna Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/01/194/004 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE Not applicable. 42 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA Not applicable. 43 B. PACKAGE LEAFLET 44 Package leaflet: Information for the user INOmax 400 ppm mol/mol medicinal gas, compressed Nitric oxide Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor - If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4 What is in this leaflet: 1. What INOmax is and what it is used for 2. What you need to know before you begin a treatment with INOmax 3. How INOmax is given 4. Possible side effects 5. How to store INOmax 6. Contents of the pack and other information 1. What INOmax is and what it is used for INOmax contains nitric oxide, a gas used for the treatment of  newborn babies with lung failure associated with high blood pressure in the lungs, a condition known as hypoxic respiratory failure. When inhaled, this gas mixture can improve the flow of blood through the lungs, which may help to increase the amount of oxygen that reaches your baby’s blood.  newborn babies, babies, children, teenagers 0-17 years and adults with high blood pressure in the lungs, connected with heart surgery. This gas mixture can improve heart function and increase the flow of blood through the lungs, which may help to increase the amount of oxygen that reaches the blood. 2. What you need to know before you begin a treatment with INOmax Do not use INOmax - If you (as the patient) or your child (as the patient) are allergic (hypersensitive) to nitric oxide or any other ingredients of INOmax. (see section 6 ‘further information’ where the full list of ingredients is provided). - If you have been told that you (as the patient) or your child (as the patient) have an abnormal circulation within the heart. Warnings and precautions Inhaled nitric oxide may not always be effective and thus other therapies may be considered necessary for you or your child. Inhaled nitric oxide may influence the oxygen carrying capacity of the blood. This will be monitored by blood samples and if required the dose of inhaled nitric oxide must be reduced. 45 Nitric oxide may react with oxygen forming nitrogen dioxide that may cause airway irritation. Your or your child’s doctor will undertake monitoring of nitrogen dioxide and in case of elevated values the INOmax therapy will be adjusted, decreased accordingly. Inhaled nitric oxide may have a mild but influence on the platelets (components that help the blood to clot) of you or your child and any signs of bleeding and or haematoma should be observed. If you see any signs or symptoms that may be associated to bleeding you should directly inform the doctor. No effect of inhaled nitric oxide has been documented in newborn babies with a malformation where the diaphragm is not fully complete, so called ‘congenital diaphragmatic hernia’. In newborn babies with special malformations of the heart, ‘what doctors calls congenital heart defects’ inhaled nitric oxide may cause a worsening of the circulation. Children INOmax should not be used in preterm baby < 34 weeks of gestational age. Other medicines and INOmax The doctor will decide when to treat you or your child with INOmax and with other medicines, and will carefully supervise the treatment. Please tell your doctor if you (as the patient) or your child (as the patient) are taking or have recently taken or used any other medicines, including medicines obtained without a prescription. Some medicines can affect the ability of blood to carry oxygen. These include prilocaine (a local anaesthetic used for pain relief in association to minor painful procedures e.g. suturing, and minor surgical or diagnostic procedures) or glyceryl trinitrate (used to treat chest pain). Your doctor will take care to check that the blood can carry enough oxygen when you are taking these medicines. Pregnancy and breastfeeding INOmax is not recommended for use during pregnancy and breastfeeding. Tell your doctor before treatment with INOmax if you are pregnant, think you could be pregnant or are breastfeeding Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Not relevant. INOmax contains Nitrogen 3. How to use INOmax Your doctor will decide the correct dose of INOmax and will administer INOmax to you or your child’s lungs through a system designed for delivering this gas. This delivery system will ensure that the correct amount of nitric oxide is delivered by diluting INOmax with an oxygen/air mixture immediately before giving it to you. For you or your child’s safety, the delivery systems intended for administration of INOmax are fitted with devices that constantly measure the amount of nitric oxide, oxygen and nitrogen dioxide (a chemical formed when nitric oxide and oxygen are mixed) being delivered to the lungs. Your doctor will decide how long you or your child should be treated with INOmax. 46 INOmax is given in dose of 10 to 20 ppm, (maximal dose 20 ppm in children and 40 ppm in adults) part per million of the gas that you or your child inhale. The lowest effective dose will be sought. Therapy is usually required for about 4 days in newborn infants with lung failure associated with high blood pressure in the lungs. In children and adults with high blood pressure in the lungs, connected with heart surgery, INOmax is usually given for 24-48 hours. However, therapy with INOmax may last longer. If you or your child receive more INOmax than you should Too much of inhaled nitric oxide may influence the oxygen carrying capacity of the blood. This will be monitored by blood samples and if required the INOmax dose will be decreased and the administration of medicines such as vitamin C, methylene blue, or eventually blood transfusion, in order to improve the oxygen carrying capacity, may be considered. If you stop using INOmax Treatment with INOmax should not be stopped suddenly. Low blood pressure or a rebound increase in pressure in the lungs has been known to occur if treatment with INOmax is stopped suddenly without first lowering the dose. At the end of treatment, the doctor will slowly lower the amount of INOmax being given to you or your child, so that the circulation in the lungs is able to adjust to oxygen/air without INOmax. Thus it may take a day or two before you or your child is off INOmax therapy. If you have any other questions on the use of this medicine, ask your doctor. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The doctor will examine you or your child closely for all side effects. Side effects that are very commonly seen (affects more than 1 user in 10) in association with INOmax therapy include:  Low platelet count. Side effects that are commonly seen (affects more than 1 user in 100) in association with INOmax therapy include:  low blood pressure, airless or collapsed lung. Side effects that may be seen, but uncommonly (affects between 1 user in 100 and 1 user in 1000) are:  increase in methaemoglobin, thus reduced oxygen carrying capacity. Side effects that may be seen but the frequency is not known (frequency cannot be estimated from the available data) are:  Bradycardia (low cardiac frequency) or too low amount of oxygen in the blood (oxygen desaturation/hypoxemia) due to sudden withdrawal of the treatment,  Headache, dizziness, dry throat or shortness of breath following accidental ambient air exposure to nitric oxide (e.g. leakage from equipment or cylinder). You should directly inform the personnel if you experience headache while being in close proximity to your child receiving INOmax. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, even after you or your child leave the hospital, please tell your doctor. Reporting of side effects 47 If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store INOmax Keep this medicine out of the sight and reach of children Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month. INOmax therapy should only be used and handled by hospital personnel.  INOmax cylinders should be stored secured in order to avoid falling and thus potentially causing harm.  INOmax should be used and administered only by personnel specially trained in the use and handling of INOmax. All regulations concerning handling of pressurised gas cylinders must be followed. Storage is supervised by the specialists at the hospital. Gas cylinders are to be stored in well-ventilated rooms or in ventilated sheds where they are protected from rain and direct sunlight. Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. Storage in the pharmacy department The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas cylinders. Storage in the medical department The gas cylinder should be put in an equipped site with appropriate material in order to hold the cylinder vertically. When the gas cylinder is empty, do not discard. Empty gas cylinders will be collected by the supplier. 6. Contents of the pack and other information What INOmax contains The active substance in INOmax is nitric oxide 400 ppm mol/mol. A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC. A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15oC. The other ingredient is nitrogen. What INOmax looks like and contents of the pack Medicinal gas, compressed A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 48 outlet connection and a standard valve hand-wheel. A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel. A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel. A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel. INOmax is available in 2 litre and 10 litre aluminium gas cylinder. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder Linde Healthcare AB Rättarvägen 3 169 68 Solna Sweden Manufacturer Linde France Z.I. Limay Porcheville 3 avenue Ozanne 78440 Porcheville France For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Linde Gas Belgium N.V. Westvaartdijk 85 B-1850 Grimbergen Tél/Tel.: +32 70 233 826 info.healthcare.be@linde.com Lietuva UAB "AGA" Didlaukio g. 69 LT-08300, Vilnius Tel.: +370 2787787 administracija@lt.aga.com България Linde Healthcare AB SE-181 81 Lidingö Sweden Tel: +46 8 7311000 Luxembourg/Luxemburg Linde Gas Belgium N.V. Westvaartdijk 85 B-1850 Grimbergen Tél/Tel.: +32 70 233 826 info.healthcare.be@linde.com Česká republika Linde Gas a.s. U Technoplynu 1324 198 00 Praha 9 Tel: +420 800 121 121 info.cz@linde.com Magyarország Linde Gáz Magyarország Zrt. Illatos út 11/A. H-1097 Budapest Tel.: +361 347 4843 healthcare@hu.linde-gas.com Danmark Linde Healthcare AGA A/S Malta Linde Healthcare AB 49 Vermlandsgade 55 DK-2300 Copenhagen S Tlf: + 45 70 104 103 Healthcare@dk.aga.com SE-181 81 Lidingö Sweden Tel: +46 8 7311000 Deutschland Linde Gas Therapeutics GmbH Mittenheimer Straße 62 85764 Oberschleißheim Tel: +49 89 37000-0 medizinische.gase@de.linde-gas.com Nederland Linde Gas Therapeutics Benelux B.V. De Keten 7 NL-5651 GJ Eindhoven Tel: +31 40 282 58 25 info.healthcare.nl@linde.com Eesti AS Eesti AGA Pärnu mnt. 141 EE - 11314 Tallinn Tel: +372 650 4500 aga@aga.ee Norge AGA AS, Linde Healthcare Postboks 13 Nydalen N-0409 Oslo Tlf. +47 23177200 healthcare@no.aga.com Ελλάδα ΛΙΝΤΕ ΕΛΛΑΣ ΜΟΝ ΕΠΕ Θέση Τρύπιο Λιθάρι GR-19600 Μάνδρα Αττικής Τηλ: 0030 211-1045500-510 healthcare@gr.linde-gas.com Österreich Linde Healthcare Linde Gas GmbH Modecenterstr.17/ Objekt 1/3.OG A-1110 Wien Tel: +43(0)50.4273-2200 Fax: +43(0)50.4273-2260 healthcare@at.linde-gas.com España Abelló Linde, S.A. C/ Bailén 105 E-08009 (Barcelona) Tel: +34 900 941 857 / +34 902 426 462 hospitalcare@es.linde-gas.com Polska Linde Gaz Polska Sp. z o.o. ul. prof. Michała Życzkowskiego 17 31-864 Krakow Tel.: 0 801 142 748 / +48 (12) 643 92 00 healthcare@pl.linde-gas.com France Linde France - Activité médicale - Linde Healthcare 3 avenue Ozanne Z.I. Limay-Porcheville 78440 Porcheville Tél:+33 810 421 000 infotherapies@linde.com Portugal Linde Portugal, Lda. Av. Infante D. Henrique Lotes 21-24 P-1800-217 Lisboa Tel: + 351 218 310 420 linde.portugal@pt.linde-gas.com Hrvatska Linde plin d.o.o. Kalinovac 2/a 47000 Karlovac Croatia Tel. +385 47 609 200 tg.info@hr.linde-gas.com România Linde Gaz România SRL str. Avram Imbroane nr. 9 Timisoara 300136 - RO Tel: +40 256 300 700 healthcare@ro.linde-gas.com Ireland INO Therapeutics UK Slovenija Linde plin d.o.o., Celje 50 301 Cornforth Drive, Sittingbourne Research Centre, Kent Science Park, Sittingbourne Kent ME9 8PX - UK. Tel: +44 1795 411552 ukcsc@inotherapy.co.uk Bukovžlak 65/b SI-3000 CELJE Tel: + 386 (0)3 42 60 746 prodaja@si.linde-gas.com Ísland Linde Healthcare Breiðhöfða 11 IS-110 Reykjavik Sími: + 354 577 3030 healthcare@is.aga.com Slovenská republika Linde Gas k.s. Tuhovská 3 SK-831 06 Bratislava Tel: +421 2 49 10 25 16 healthcare.sk@linde.com Italia LINDE MEDICALE S.r.L Via Guido Rossa 3 I-20010 Arluno (MI) Tel : +39 02 903731/800 985 597 Suomi/Finland Oy AGA Ab, Linde Healthcare Itsehallintokuja 6 FIN-02600 Espoo Puh/Tel: + 358 10 2421 hctilaus@fi.aga.com Κύπρος Linde Hadjikyriakos Gas Ltd Λεωφόρος Λεμεσού 260, 2029 Στρόβολος Λευκωσία, Κύπρος. Τηλ. 77772828 ή +357-22482330 info@cy.linde-gas.com Sverige AGA Gas AB, Linde Healthcare SE-181 81 Lidingö Tel: + 46 8 7311800/020 790 151 healthcare@se.aga.com Latvija AGA SIA, Katrïnas St 5 Riga, LV-1045 Tel: +371 80005005 aga.ksc@lv.aga.com United Kingdom INO Therapeutics UK 301 Cornforth Drive, Sittingbourne Research Centre, Kent Science Park, Sittingbourne Kent ME9 8PX - UK. Tel: +44 1795 411552 ukcsc@inotherapy.co.uk This leaflet was last revised in MM/YYYY. Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. 51 PACKAGE LEAFLET: INFORMATION FOR THE USER INOmax 800 ppm mol/mol medicinal gas, compressed Nitric oxide Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor - If you get any of the side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What INOmax is and what it is used for 2. What you need to know before you begin a treatment with INOmax 3. How INOmax is given 4. Possible side effects 5. How to store INOmax 6. Contents of the pack and other information 1. WHAT INOmax IS AND WHAT IT IS USED FOR INOmax contains nitric oxide, a gas used for the treatment of  newborn babies with lung failure associated with high blood pressure in the lungs, a condition known as hypoxic respiratory failure. When inhaled, this gas mixture can improve the flow of blood through the lungs, which may help to increase the amount of oxygen that reaches your baby’s blood.  newborn babies, babies, children, teenagers 0-17 years and adults with high blood pressure in the lungs, connected with heart surgery. This gas mixture can improve heart function and increase the flow of blood through the lungs, which may help to increase the amount of oxygen that reaches the blood. 2. What you need to know before you begin a treatment with INOmax Do not use INOmax - If you (as the patient) or your child (as the patient) are allergic (hypersensitive) to nitric oxide or any other ingredients of INOmax. (see section 6 ‘further information’ where the full list of ingredients is provided). - If you have been told that you (as the patient) or your child (as the patient) have an abnormal circulation within the heart. Warnings and precautions Inhaled nitric oxide may not always be effective and thus other therapies may be considered necessary for you or your child. Inhaled nitric oxide may influence the oxygen carrying capacity of the blood. This will be monitored by blood samples and if required the dose of inhaled nitric oxide must be reduced. 52 Nitric oxide may react with oxygen forming nitrogen dioxide that may cause airway irritation. Your or your child’s doctor will undertake monitoring of nitrogen dioxide and in case of elevated values the INOmax therapy will be adjusted, decreased accordingly. Inhaled nitric oxide may have a mild but influence on the platelets (components that help the blood to clot) of you or your child and any signs of bleeding and or haematoma should be observed. If you see any signs or symptoms that may be associated to bleeding you should directly inform the doctor. No effect of inhaled nitric oxide has been documented in newborn babies with a malformation where the diaphragm is not fully complete, so called ‘congenital diaphragmatic hernia’. In newborn babies with special malformations of the heart, ‘what doctors calls congenital heart defects’ inhaled nitric oxide may cause a worsening of the circulation. Children INOmax should not be used in preterm baby < 34 weeks of gestational age. Other medicines and INOmax The doctor will decide when to treat you or your child with INOmax and with other medicines, and will carefully supervise the treatment. Please tell your doctor if you (as the patient) or your child (as the patient) are taking or have recently taken or used any other medicines, including medicines obtained without a prescription. Some medicines can affect the ability of blood to carry oxygen. These include prilocaine (a local anaesthetic used for pain relief in association to minor painful procedures e.g. suturing, and minor surgical or diagnostic procedures) or glyceryl trinitrate (used to treat chest pain). Your doctor will take care to check that the blood can carry enough oxygen when you are taking these medicines. Pregnancy and breastfeeding INOmax is not recommended for use during pregnancy and breastfeeding. Tell your doctor before treatment with INOmax if you are pregnant, think you could be pregnant or are breastfeeding Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Not relevant. INOmax contains Nitrogen 3. How to use INOmax Your doctor will decide the correct dose of INOmax and will administer INOmax to you or your child’s lungs through a system designed for delivering this gas. This delivery system will ensure that the correct amount of nitric oxide is delivered by diluting INOmax with an oxygen/air mixture immediately before giving it to you. For you or your child’s safety, the delivery systems intended for administration of INOmax are fitted with devices that constantly measure the amount of nitric oxide, oxygen and nitrogen dioxide (a chemical formed when nitric oxide and oxygen are mixed) being delivered to the lungs. Your doctor will decide how long you or your child should be treated with INOmax. 53 INOmax is given in dose of 10 to 20 ppm, (maximal dose 20 ppm in children and 40 ppm in adults) part per million of the gas that you or your child inhale. The lowest effective dose will be sought. Therapy is usually required for about 4 days in newborn infants with lung failure associated with high blood pressure in the lungs. In children and adults with high blood pressure in the lungs, connected with heart surgery, INOmax is usually given for 24-48 hours. However, therapy with INOmax may last longer. If you or your child receive more INOmax than you should Too much of inhaled nitric oxide may influence the oxygen carrying capacity of the blood. This will be monitored by blood samples and if required the INOmax dose will be decreased and the administration of medicines such as vitamin C, methylene blue, or eventually blood transfusion, in order to improve the oxygen carrying capacity, may be considered. If you stop using INOmax Treatment with INOmax should not be stopped suddenly. Low blood pressure or a rebound increase in pressure in the lungs has been known to occur if treatment with INOmax is stopped suddenly without first lowering the dose. At the end of treatment, the doctor will slowly lower the amount of INOmax being given to you or your child, so that the circulation in the lungs is able to adjust to oxygen/air without INOmax. Thus it may take a day or two before you or your child is off INOmax therapy. If you have any other questions on the use of this medicine, ask your doctor. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The doctor will examine you or your child closely for all side effects. Side effects that are very commonly seen (affects more than 1 user in 10) in association with INOmax therapy include:  Low platelet count. Side effects that are commonly seen (affects more than 1 user in 100) in association with INOmax therapy include:  low blood pressure, airless or collapsed lung. Side effects that may be seen, but uncommonly (affects between 1 user in 100 and 1 user in 1000) are:  increase in methaemoglobin, thus reduced oxygen carrying capacity. Side effects that may be seen but the frequency is not known (frequency cannot be estimated from the available data) are:  Bradycardia (low cardiac frequency) or too low amount of oxygen in the blood (oxygen desaturation/hypoxemia) due to sudden withdrawal of the treatment  Headache, dizziness, dry throat or shortness of breath following accidental ambient air exposure to nitric oxide (e.g. leakage from equipment or cylinder). You should directly inform the personnel if you experience headache while being in close proximity to your child receiving INOmax. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, even after you or your child leave the hospital, please tell your doctor. 54 Reporting of side effects If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store INOmax Keep this medicine out of the sight and reach of children Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month. INOmax therapy should only be used and handled by hospital personnel.  INOmax cylinders should be stored secured in order to avoid falling and thus potentially causing harm.  INOmax should be used and administered only by personnel specially trained in the use and handling of INOmax. All regulations concerning handling of pressurised gas cylinders must be followed. Storage is supervised by the specialists at the hospital. Gas cylinders are to be stored in well-ventilated rooms or in ventilated sheds where they are protected from rain and direct sunlight. Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. Storage in the pharmacy department The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas cylinders. Storage in the medical department The gas cylinder should be put in an equipped site with appropriate material in order to hold the cylinder vertically. When the gas cylinder is empty, do not discard. Empty gas cylinders will be collected by the supplier. 6. contents of the pack and other information What INOmax contains The active substance in INOmax is nitric oxide 800 ppm mol/mol. A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC. A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15oC. The other ingredient is nitrogen. What INOmax looks like and contents of the pack Medicinal gas, compressed A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 55 a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel. A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel. A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel. A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel. INOmax is available in 2 litre and 10 litre aluminium gas cylinder. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder Linde Healthcare AB Rättarvägen 3 169 68 Solna Sweden Manufacturer Linde France Z.I. Limay Porcheville 3 avenue Ozanne 78440 Porcheville France For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Linde Gas Belgium N.V. Westvaartdijk 85 B-1850 Grimbergen Tél/Tel.: +32 70 233 826 info.healthcare.be@linde.com Lietuva UAB "AGA" Didlaukio g. 69 LT-08300, Vilnius Tel.: +370 2787787 administracija@lt.aga.com България Linde Healthcare AB SE-181 81 Lidingö Sweden Tel: +46 8 7311000 Luxembourg/Luxemburg Linde Gas Belgium N.V. Westvaartdijk 85 B-1850 Grimbergen Tél/Tel.: +32 70 233 826 info.healthcare.be@linde.com Česká republika Linde Gas a.s. U Technoplynu 1324 198 00 Praha 9 Tel: +420 800 121 121 info.cz@linde.com Magyarország Linde Gáz Magyarország Zrt. Illatos út 11/A. H-1097 Budapest Tel.: +361 347 4843 healthcare@hu.linde-gas.com Danmark Malta 56 Linde Healthcare AGA A/S Vermlandsgade 55 DK-2300 Copenhagen S Tlf: + 45 70 104 103 Healthcare@dk.aga.com Linde Healthcare AB SE-181 81 Lidingö Sweden Tel: +46 8 7311000 Deutschland Linde Gas Therapeutics GmbH Mittenheimer Straße 62 85764 Oberschleißheim Tel: +49 89 37000-0 medizinische.gase@de.linde-gas.com Nederland Linde Gas Therapeutics Benelux B.V. De Keten 7 NL-5651 GJ Eindhoven Tel: +31 40 282 58 25 info.healthcare.nl@linde.com Eesti AS Eesti AGA Pärnu mnt. 141 EE - 11314 Tallinn Tel: +372 650 4500 aga@aga.ee Norge AGA AS, Linde Healthcare Postboks 13 Nydalen N-0409 Oslo Tlf. +47 23177200 healthcare@no.aga.com Ελλάδα ΛΙΝΤΕ ΕΛΛΑΣ ΜΟΝ ΕΠΕ Θέση Τρύπιο Λιθάρι GR-19600 Μάνδρα Αττικής Τηλ: 0030 211-1045500-510 healthcare@gr.linde-gas.com Österreich Linde Healthcare Linde Gas GmbH Modecenterstr.17/ Objekt 1/3.OG A-1110 Wien Tel: +43(0)50.4273-2200 Fax: +43(0)50.4273-2260 healthcare@at.linde-gas.com España Abelló Linde, S.A. C/ Bailén 105 E-08009 (Barcelona) Tel: +34 900 941 857 / +34 902 426 462 hospitalcare@es.linde-gas.com Polska Linde Gaz Polska Sp. z o.o. ul. prof. Michała Życzkowskiego 17 31-864 Krakow Tel.: 0 801 142 748 / +48 (12) 643 92 00 healthcare@pl.linde-gas.com France Linde France - Activité médicale - Linde Healthcare 3 avenue Ozanne Z.I. Limay-Porcheville 78440 Porcheville Tél: +33 810 421 000 infotherapies@linde.com Portugal Linde Portugal, Lda. Av. Infante D. Henrique Lotes 21-24 P-1800-217 Lisboa Tel: + 351 218 310 420 linde.portugal@pt.linde-gas.com Hrvatska Linde plin d.o.o. Kalinovac 2/a 47000 Karlovac Croatia Tel. +385 47 609 200 tg.info@hr.linde-gas.com România Linde Gaz România SRL str. Avram Imbroane nr. 9 Timisoara 300136 - RO Tel: +40 256 300 700 healthcare@ro.linde-gas.com Ireland Slovenija 57 INO Therapeutics UK 301 Cornforth Drive, Sittingbourne Research Centre, Kent Science Park, Sittingbourne Kent ME9 8PX - UK. Tel: +44 1795 411552 ukcsc@inotherapy.co.uk Linde plin d.o.o., Celje Bukovžlak 65/b SI-3000 CELJE Tel: + 386 (0)3 42 60 746 prodaja@si.linde-gas.com Ísland Linde Healthcare Breiðhöfða 11 IS-110 Reykjavik Sími: + 354 577 3030 healthcare@is.aga.com Slovenská republika Linde Gas k.s. Tuhovská 3 SK-831 06 Bratislava Tel: +421 2 49 10 25 16 healthcare.sk@linde.com Italia LINDE MEDICALE S.r.L Via Guido Rossa 3 I-20010 Arluno (MI) Tel : +39 02 903731/800 985 597 Suomi/Finland Oy AGA Ab, Linde Healthcare Itsehallintokuja 6 FIN-02600 Espoo Puh/Tel: + 358 10 2421 hctilaus@fi.aga.com Κύπρος Linde Hadjikyriakos Gas Ltd Λεωφόρος Λεμεσού 260, 2029 Στρόβολος Λευκωσία, Κύπρος. Τηλ. 77772828 ή +357-22482330 info@cy.linde-gas.com Sverige AGA Gas AB, Linde Healthcare SE-181 81 Lidingö Tel: + 46 8 7311800/020 790 151 healthcare@se.aga.com Latvija AGA SIA, Katrïnas St 5 Riga, LV-1045 Tel: +371 80005005 aga.ksc@lv.aga.com United Kingdom INO Therapeutics UK 301 Cornforth Drive, Sittingbourne Research Centre, Kent Science Park, Sittingbourne Kent ME9 8PX - UK. Tel: +44 1795 411552 ukcsc@inotherapy.co.uk This leaflet was last revised in MM/YYYY. Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what inomax is and what it is used for', 'Section_Content': "inomax contains nitric oxide, a gas used for the treatment of newborn babies with lung failure associated with high blood pressure in the lungs, a condition known as hypoxic respiratory failure. when inhaled, this gas mixture can improve the flow of blood through the lungs, which may help to increase the amount of oxygen that reaches your baby's blood. newborn babies, babies, children, teenagers 0-17 years and adults with high blood pressure in the lungs, connected with heart surgery. this gas mixture can improve heart function and increase the flow of blood through the lungs, which may help to increase the amount of oxygen that reaches the blood.", 'Entity_Recognition': [{'Text': 'inomax', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 7, 'BeginOffset': 0, 'EndOffset': 6, 'Score': 0.7533961534500122, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 16, 'EndOffset': 28, 'Score': 0.966358482837677, 'Text': 'nitric oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a gas', 'Type': 'TEST', 'BeginOffset': 30, 'EndOffset': 35}, {'Text': 'the treatment of newborn babies', 'Type': 'TREATMENT', 'BeginOffset': 45, 'EndOffset': 76}, {'Id': 9, 'BeginOffset': 82, 'EndOffset': 94, 'Score': 0.7416406273841858, 'Text': 'lung failure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9287715554237366}]}, {'Text': 'high blood pressure in the lungs', 'Type': 'PROBLEM', 'BeginOffset': 111, 'EndOffset': 143}, {'Id': 11, 'BeginOffset': 166, 'EndOffset': 193, 'Score': 0.7080720663070679, 'Text': 'hypoxic respiratory failure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9407062530517578}]}, {'Text': 'this gas mixture', 'Type': 'TREATMENT', 'BeginOffset': 209, 'EndOffset': 225}, {'Id': 2, 'BeginOffset': 268, 'EndOffset': 273, 'Score': 0.9651250243186951, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 13, 'BeginOffset': 316, 'EndOffset': 322, 'Score': 0.7143920063972473, 'Text': 'oxygen', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'high blood pressure in the lungs', 'Type': 'PROBLEM', 'BeginOffset': 426, 'EndOffset': 458}, {'Id': 14, 'BeginOffset': 475, 'EndOffset': 488, 'Score': 0.6770845055580139, 'Text': 'heart surgery', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Text': 'this gas mixture', 'Type': 'TREATMENT', 'BeginOffset': 490, 'EndOffset': 506}, {'Id': 5, 'BeginOffset': 519, 'EndOffset': 524, 'Score': 0.963986873626709, 'Text': 'heart', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 6, 'BeginOffset': 577, 'EndOffset': 582, 'Score': 0.9827227592468262, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 15, 'BeginOffset': 625, 'EndOffset': 631, 'Score': 0.8086786270141602, 'Text': 'oxygen', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}]}

{'Title': '2. what you need to know before you begin a treatment with inomax', 'Section_Content': "do not use inomax - if you (as the patient) or your child (as the patient) are allergic (hypersensitive) to nitric oxide or any other ingredients of inomax. (see section 6 'further information' where the full list of ingredients is provided). - if you have been told that you (as the patient) or your child (as the patient) have an abnormal circulation within the heart. warnings and precautions inhaled nitric oxide may not always be effective and thus other therapies may be considered necessary for you or your child. inhaled nitric oxide may influence the oxygen carrying capacity of the blood. this will be monitored by blood samples and if required the dose of inhaled nitric oxide must be reduced. nitric oxide may react with oxygen forming nitrogen dioxide that may cause airway irritation. your or your child's doctor will undertake monitoring of nitrogen dioxide and in case of elevated values the inomax therapy will be adjusted, decreased accordingly. inhaled nitric oxide may have a mild but influence on the platelets (components that help the blood to clot) of you or your child and any signs of bleeding and or haematoma should be observed. if you see any signs or symptoms that may be associated to bleeding you should directly inform the doctor. no effect of inhaled nitric oxide has been documented in newborn babies with a malformation where the diaphragm is not fully complete, so called 'congenital diaphragmatic hernia'. in newborn babies with special malformations of the heart, 'what doctors calls congenital heart defects' inhaled nitric oxide may cause a worsening of the circulation. children inomax should not be used in preterm baby < 34 weeks of gestational age. other medicines and inomax the doctor will decide when to treat you or your child with inomax and with other medicines, and will carefully supervise the treatment. please tell your doctor if you (as the patient) or your child (as the patient) are taking or have recently taken or used any other medicines, including medicines obtained without a prescription. some medicines can affect the ability of blood to carry oxygen. these include prilocaine (a local anaesthetic used for pain relief in association to minor painful procedures e.g. suturing, and minor surgical or diagnostic procedures) or glyceryl trinitrate (used to treat chest pain). your doctor will take care to check that the blood can carry enough oxygen when you are taking these medicines. pregnancy and breastfeeding inomax is not recommended for use during pregnancy and breastfeeding. tell your doctor before treatment with inomax if you are pregnant, think you could be pregnant or are breastfeeding ask your doctor or pharmacist for advice before taking any medicine. driving and using machines not relevant. inomax contains nitrogen", 'Entity_Recognition': [{'Text': 'inomax', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 11, 'EndOffset': 17, 'Score': 0.983574628829956, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.8493889570236206}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 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{'Title': '3. how inomax is given', 'Section_Content': "your doctor will decide the correct dose of inomax and will administer inomax to you or your child's lungs through a system designed for delivering this gas. this delivery system will ensure that the correct amount of nitric oxide is delivered by diluting inomax with an oxygen/air mixture immediately before giving it to you. for you or your child's safety, the delivery systems intended for administration of inomax are fitted with devices that constantly measure the amount of nitric oxide, oxygen and nitrogen dioxide (a chemical formed when nitric oxide and oxygen are mixed) being delivered to the lungs. your doctor will decide how long you or your child should be treated with inomax. inomax is given in dose of 10 to 20 ppm, (maximal dose 20 ppm in children and 40 ppm in adults) part per million of the gas that you or your child inhale. the lowest effective dose will be sought. therapy is usually required for about 4 days in newborn infants with lung failure associated with high blood pressure in the lungs. in children and adults with high blood pressure in the lungs, connected with heart surgery, inomax is usually given for 24-48 hours. however, therapy with inomax may last longer. if you or your child receive more inomax than you should too much of inhaled nitric oxide may influence the oxygen carrying capacity of the blood. this will be monitored by blood samples and if required the inomax dose will be decreased and the administration of medicines such as vitamin c, methylene blue, or eventually blood transfusion, in order to improve the oxygen carrying capacity, may be considered. if you stop using inomax treatment with inomax should not be stopped suddenly. low blood pressure or a rebound increase in pressure in the lungs has been known to occur if treatment with inomax is stopped suddenly without first lowering the dose. at the end of treatment, the doctor will slowly lower the amount of inomax being given to you or your child, so that the circulation in the lungs is able to adjust to oxygen/air without inomax. thus it may take a day or two before you or your child is off inomax therapy. if you have any other questions on the use of this medicine, ask your doctor.", 'Entity_Recognition': [{'Text': 'inomax', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 8, 'BeginOffset': 44, 'EndOffset': 50, 'Score': 0.9663011431694031, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 71, 'EndOffset': 77, 'Score': 0.9659562110900879, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 0, 'BeginOffset': 101, 'EndOffset': 106, 'Score': 0.8057452440261841, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'this gas', 'Type': 'TEST', 'BeginOffset': 148, 'EndOffset': 156}, {'Text': 'this delivery system', 'Type': 'TREATMENT', 'BeginOffset': 158, 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'administration of inomax', 'Type': 'TREATMENT', 'BeginOffset': 393, 'EndOffset': 417}, {'Text': 'devices', 'Type': 'TREATMENT', 'BeginOffset': 434, 'EndOffset': 441}, {'Id': 13, 'BeginOffset': 480, 'EndOffset': 492, 'Score': 0.9619142413139343, 'Text': 'nitric oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 494, 'EndOffset': 500, 'Score': 0.3965602219104767, 'Text': 'oxygen', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 505, 'EndOffset': 521, 'Score': 0.9475253820419312, 'Text': 'nitrogen dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'nitric oxide', 'Type': 'TREATMENT', 'BeginOffset': 546, 'EndOffset': 558}, {'Id': 36, 'BeginOffset': 563, 'EndOffset': 569, 'Score': 0.7314882278442383, 'Text': 'oxygen', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 604, 'EndOffset': 609, 'Score': 0.9407329559326172, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 16, 'BeginOffset': 685, 'EndOffset': 691, 'Score': 0.9721720218658447, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 693, 'EndOffset': 699, 'Score': 0.9031803607940674, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 720, 'EndOffset': 722}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 726, 'EndOffset': 728}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 748, 'EndOffset': 750}, {'Text': '40', 'Type': 'NUMBER', 'BeginOffset': 771, 'EndOffset': 773}, {'Text': 'therapy', 'Type': 'TREATMENT', 'BeginOffset': 890, 'EndOffset': 897}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 928, 'EndOffset': 929}, {'Id': 30, 'BeginOffset': 959, 'EndOffset': 971, 'Score': 0.8543919324874878, 'Text': 'lung failure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9702385663986206}]}, {'Text': 'high blood pressure in the lungs', 'Type': 'PROBLEM', 'BeginOffset': 988, 'EndOffset': 1020}, {'Text': 'high blood pressure in the lungs', 'Type': 'PROBLEM', 'BeginOffset': 1050, 'EndOffset': 1082}, {'Id': 37, 'BeginOffset': 1099, 'EndOffset': 1112, 'Score': 0.5808632373809814, 'Text': 'heart surgery', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Id': 18, 'BeginOffset': 1114, 'EndOffset': 1120, 'Score': 0.6571551561355591, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 46, 'BeginOffset': 1142, 'EndOffset': 1153, 'Score': 0.7430457472801208, 'Text': '24-48 hours', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_PROCEDURE_NAME', 'Traits': [], 'Attributes': [{'Type': 'PROCEDURE_NAME', 'Score': 0.5808632373809814, 'RelationshipScore': 0.5186576843261719, 'RelationshipType': 'OVERLAP', 'Id': 37, 'BeginOffset': 1099, 'EndOffset': 1112, 'Text': 'heart surgery', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'therapy', 'Type': 'TREATMENT', 'BeginOffset': 1164, 'EndOffset': 1171}, {'Id': 19, 'BeginOffset': 1177, 'EndOffset': 1183, 'Score': 0.9789597392082214, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 20, 'BeginOffset': 1235, 'EndOffset': 1241, 'Score': 0.9467067122459412, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'inhaled nitric oxide', 'Type': 'TREATMENT', 'BeginOffset': 1270, 'EndOffset': 1290}, {'Id': 38, 'BeginOffset': 1309, 'EndOffset': 1315, 'Score': 0.3933064639568329, 'Text': 'oxygen', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 39, 'BeginOffset': 1374, 'EndOffset': 1387, 'Score': 0.6426877975463867, 'Text': 'blood samples', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'the inomax dose', 'Type': 'TREATMENT', 'BeginOffset': 1404, 'EndOffset': 1419}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 1464, 'EndOffset': 1473}, {'Id': 24, 'BeginOffset': 1482, 'EndOffset': 1491, 'Score': 0.9909706115722656, 'Text': 'vitamin c', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 25, 'BeginOffset': 1493, 'EndOffset': 1507, 'Score': 0.970711350440979, 'Text': 'methylene blue', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 47, 'BeginOffset': 1512, 'EndOffset': 1522, 'Score': 0.9999980926513672, 'Text': 'eventually', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.6116725206375122, 'RelationshipScore': 0.8848084807395935, 'RelationshipType': 'OVERLAP', 'Id': 40, 'BeginOffset': 1523, 'EndOffset': 1540, 'Text': 'blood transfusion', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 40, 'BeginOffset': 1523, 'EndOffset': 1540, 'Score': 0.6116725206375122, 'Text': 'blood transfusion', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'the oxygen carrying capacity', 'Type': 'PROBLEM', 'BeginOffset': 1562, 'EndOffset': 1590}, {'Id': 42, 'BeginOffset': 1629, 'EndOffset': 1645, 'Score': 0.5049891471862793, 'Text': 'inomax treatment', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 27, 'BeginOffset': 1651, 'EndOffset': 1657, 'Score': 0.980668306350708, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 33, 'BeginOffset': 1690, 'EndOffset': 1708, 'Score': 0.4820614457130432, 'Text': 'low blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5272634029388428}]}, {'Text': 'a rebound increase in pressure in the lungs', 'Type': 'PROBLEM', 'BeginOffset': 1712, 'EndOffset': 1755}, {'Id': 28, 'BeginOffset': 1798, 'EndOffset': 1804, 'Score': 0.9731988310813904, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 1872, 'EndOffset': 1881}, {'Id': 29, 'BeginOffset': 1926, 'EndOffset': 1932, 'Score': 0.987725555896759, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 1998, 'EndOffset': 2003, 'Score': 0.9610151648521423, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 43, 'BeginOffset': 2025, 'EndOffset': 2031, 'Score': 0.8138560652732849, 'Text': 'oxygen', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 48, 'BeginOffset': 2044, 'EndOffset': 2050, 'Score': 0.9713712930679321, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.45175039768218994}]}, {'Id': 50, 'BeginOffset': 2114, 'EndOffset': 2128, 'Score': 0.7907227873802185, 'Text': 'inomax therapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2176, 'EndOffset': 2189}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the doctor will examine you or your child closely for all side effects. side effects that are very commonly seen (affects more than 1 user in 10) in association with inomax therapy include: low platelet count. side effects that are commonly seen (affects more than 1 user in 100) in association with inomax therapy include: low blood pressure, airless or collapsed lung. side effects that may be seen, but uncommonly (affects between 1 user in 100 and 1 user in 1000) are: increase in methaemoglobin, thus reduced oxygen carrying capacity. side effects that may be seen but the frequency is not known (frequency cannot be estimated from the available data) are: bradycardia (low cardiac frequency) or too low amount of oxygen in the blood (oxygen desaturation/hypoxemia) due to sudden withdrawal of the treatment, headache, dizziness, dry throat or shortness of breath following accidental ambient air exposure to nitric oxide (e.g. leakage from equipment or cylinder). you should directly inform the personnel if you experience headache while being in close proximity to your child receiving inomax. if any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, even after you or your child leave the hospital, please tell your doctor. reporting of side effects 47 if you get any side effects, talk to your doctor or pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'inomax', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 7, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9628885388374329, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6350749135017395}]}, {'Text': 'all side effects', 'Type': 'PROBLEM', 'BeginOffset': 146, 'EndOffset': 162}, {'Id': 9, 'BeginOffset': 164, 'EndOffset': 176, 'Score': 0.9463260769844055, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6577816009521484}, {'Name': 'DIAGNOSIS', 'Score': 0.4280793368816376}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 224, 'EndOffset': 225}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 234, 'EndOffset': 236}, {'Id': 37, 'BeginOffset': 258, 'EndOffset': 272, 'Score': 0.4973618984222412, 'Text': 'inomax therapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 282, 'EndOffset': 300, 'Score': 0.7546596527099609, 'Text': 'low platelet count', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 302, 'EndOffset': 314, 'Score': 0.9171769618988037, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5313160419464111}, {'Name': 'DIAGNOSIS', 'Score': 0.5280466675758362}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 357, 'EndOffset': 358}, {'Id': 45, 'BeginOffset': 367, 'EndOffset': 370, 'Score': 0.9300724267959595, 'Text': '100', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.9171769618988037, 'RelationshipScore': 0.750521719455719, 'RelationshipType': 'OVERLAP', 'Id': 11, 'BeginOffset': 302, 'EndOffset': 314, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5313160419464111}, {'Name': 'DIAGNOSIS', 'Score': 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'BeginOffset': 536, 'EndOffset': 539}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 544, 'EndOffset': 545}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 554, 'EndOffset': 558}, {'Text': 'increase in methaemoglobin', 'Type': 'PROBLEM', 'BeginOffset': 565, 'EndOffset': 591}, {'Text': 'reduced oxygen carrying capacity', 'Type': 'PROBLEM', 'BeginOffset': 598, 'EndOffset': 630}, {'Id': 15, 'BeginOffset': 632, 'EndOffset': 644, 'Score': 0.8578701615333557, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7308620810508728}]}, {'Id': 16, 'BeginOffset': 670, 'EndOffset': 679, 'Score': 0.4498993158340454, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 754, 'EndOffset': 765, 'Score': 0.975795567035675, 'Text': 'bradycardia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5093188285827637}]}, {'Text': 'low cardiac frequency)', 'Type': 'PROBLEM', 'BeginOffset': 767, 'EndOffset': 789}, {'Id': 42, 'BeginOffset': 811, 'EndOffset': 817, 'Score': 0.7783275246620178, 'Text': 'oxygen', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'the blood (oxygen desaturation', 'Type': 'PROBLEM', 'BeginOffset': 821, 'EndOffset': 851}, {'Id': 20, 'BeginOffset': 852, 'EndOffset': 861, 'Score': 0.9912978410720825, 'Text': 'hypoxemia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.644323468208313}]}, {'Text': 'sudden withdrawal', 'Type': 'PROBLEM', 'BeginOffset': 870, 'EndOffset': 887}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 891, 'EndOffset': 904}, {'Id': 23, 'BeginOffset': 906, 'EndOffset': 914, 'Score': 0.9965896606445312, 'Text': 'headache', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9425053000450134}]}, {'Id': 24, 'BeginOffset': 916, 'EndOffset': 925, 'Score': 0.9992573857307434, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.976211428642273}]}, {'Id': 25, 'BeginOffset': 927, 'EndOffset': 937, 'Score': 0.5686794519424438, 'Text': 'dry throat', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8782304525375366}]}, {'Id': 26, 'BeginOffset': 941, 'EndOffset': 960, 'Score': 0.997257649898529, 'Text': 'shortness of breath', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9102557301521301}]}, {'Text': 'accidental ambient air exposure', 'Type': 'TREATMENT', 'BeginOffset': 971, 'EndOffset': 1002}, {'Id': 5, 'BeginOffset': 1006, 'EndOffset': 1018, 'Score': 0.39502575993537903, 'Text': 'nitric oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'leakage from equipment', 'Type': 'TREATMENT', 'BeginOffset': 1025, 'EndOffset': 1047}, {'Id': 28, 'BeginOffset': 1121, 'EndOffset': 1129, 'Score': 0.9968908429145813, 'Text': 'headache', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8529131412506104}]}, {'Id': 6, 'BeginOffset': 1185, 'EndOffset': 1191, 'Score': 0.9487281441688538, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 29, 'BeginOffset': 1207, 'EndOffset': 1219, 'Score': 0.8934488296508789, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6922032833099365}]}, {'Text': 'any side effects', 'Type': 'PROBLEM', 'BeginOffset': 1251, 'EndOffset': 1267}, {'Id': 31, 'BeginOffset': 1383, 'EndOffset': 1395, 'Score': 0.95126873254776, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7606826424598694}]}, {'Id': 46, 'BeginOffset': 1396, 'EndOffset': 1398, 'Score': 0.4126894772052765, 'Text': '47', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.95126873254776, 'RelationshipScore': 0.9190909266471863, 'RelationshipType': 'OVERLAP', 'Id': 31, 'BeginOffset': 1383, 'EndOffset': 1395, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7606826424598694}]}]}, {'Id': 32, 'BeginOffset': 1414, 'EndOffset': 1426, 'Score': 0.9297177195549011, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.776013970375061}]}, {'Id': 33, 'BeginOffset': 1499, 'EndOffset': 1511, 'Score': 0.9554259181022644, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6548197865486145}]}, {'Id': 34, 'BeginOffset': 1560, 'EndOffset': 1572, 'Score': 0.8667250275611877, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7148151993751526}]}, {'Id': 35, 'BeginOffset': 1626, 'EndOffset': 1637, 'Score': 0.3892049193382263, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6293371319770813}]}, {'Id': 36, 'BeginOffset': 1651, 'EndOffset': 1663, 'Score': 0.8602057695388794, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7482722401618958}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1719, 'EndOffset': 1732}]}

{'Title': '5. how to store inomax', 'Section_Content': 'keep this medicine out of the sight and reach of children do not use this medicine after the expiry date which is stated on the label after exp. the expiry date refers to the last day of that month. inomax therapy should only be used and handled by hospital personnel. inomax cylinders should be stored secured in order to avoid falling and thus potentially causing harm. inomax should be used and administered only by personnel specially trained in the use and handling of inomax. all regulations concerning handling of pressurised gas cylinders must be followed. storage is supervised by the specialists at the hospital. gas cylinders are to be stored in well-ventilated rooms or in ventilated sheds where they are protected from rain and direct sunlight. protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition. storage in the pharmacy department the gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas only. inside this place, a separate premise should be dedicated to the storage of nitric oxide gas cylinders. storage in the medical department the gas cylinder should be put in an equipped site with appropriate material in order to hold the cylinder vertically. when the gas cylinder is empty, do not discard. empty gas cylinders will be collected by the supplier.', 'Entity_Recognition': [{'Text': 'inomax', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 69, 'EndOffset': 82}, {'Id': 2, 'BeginOffset': 199, 'EndOffset': 213, 'Score': 0.573488175868988, 'Text': 'inomax therapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'inomax cylinders', 'Type': 'TREATMENT', 'BeginOffset': 269, 'EndOffset': 285}, {'Text': 'harm', 'Type': 'PROBLEM', 'BeginOffset': 366, 'EndOffset': 370}, {'Id': 1, 'BeginOffset': 372, 'EndOffset': 378, 'Score': 0.7298495173454285, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'inomax', 'Type': 'TREATMENT', 'BeginOffset': 474, 'EndOffset': 480}, {'Text': 'pressurised gas cylinders', 'Type': 'TREATMENT', 'BeginOffset': 521, 'EndOffset': 546}, {'Text': 'gas cylinders', 'Type': 'TREATMENT', 'BeginOffset': 623, 'EndOffset': 636}, {'Text': 'the gas cylinders', 'Type': 'TREATMENT', 'BeginOffset': 766, 'EndOffset': 783}, {'Text': 'falls', 'Type': 'PROBLEM', 'BeginOffset': 797, 'EndOffset': 802}, {'Text': 'oxidising', 'Type': 'TREATMENT', 'BeginOffset': 804, 'EndOffset': 813}, {'Text': 'flammable materials', 'Type': 'TREATMENT', 'BeginOffset': 818, 'EndOffset': 837}, {'Text': 'heat or ignition', 'Type': 'PROBLEM', 'BeginOffset': 860, 'EndOffset': 876}, {'Text': 'the gas cylinders', 'Type': 'TREATMENT', 'BeginOffset': 913, 'EndOffset': 930}, {'Text': 'medicinal gas', 'Type': 'TEST', 'BeginOffset': 999, 'EndOffset': 1012}, {'Text': 'nitric oxide gas cylinders', 'Type': 'TREATMENT', 'BeginOffset': 1095, 'EndOffset': 1121}, {'Text': 'the gas cylinder', 'Type': 'TREATMENT', 'BeginOffset': 1157, 'EndOffset': 1173}, {'Text': 'empty gas cylinders', 'Type': 'TREATMENT', 'BeginOffset': 1324, 'EndOffset': 1343}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what inomax contains the active substance in inomax is nitric oxide 400 ppm mol/mol. a 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oc. a 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15oc. the other ingredient is nitrogen. what inomax looks like and contents of the pack medicinal gas, compressed a 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific 48 outlet connection and a standard valve hand-wheel. a 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a inometer device equipped valve hand-wheel. a 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel. a 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a inometer device equipped valve hand-wheel. inomax is available in 2 litre and 10 litre aluminium gas cylinder.', 'Entity_Recognition': [{'Text': 'inomax', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 8, 'BeginOffset': 5, 'EndOffset': 11, 'Score': 0.6400688290596008, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 45, 'EndOffset': 51, 'Score': 0.9602855443954468, 'Text': 'inomax', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 55, 'EndOffset': 67, 'Score': 0.9143556952476501, 'Text': 'nitric oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.33664247393608093, 'RelationshipScore': 0.9999457597732544, 'RelationshipType': 'STRENGTH', 'Id': 11, 'BeginOffset': 68, 'EndOffset': 75, 'Text': '400 ppm', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.35812848806381226, 'RelationshipScore': 0.9999778270721436, 'RelationshipType': 'FORM', 'Id': 12, 'BeginOffset': 76, 'EndOffset': 79, 'Text': 'mol', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '400', 'Type': 'NUMBER', 'BeginOffset': 68, 'EndOffset': 71}, {'Text': 'a 2 litre gas cylinder', 'Type': 'TREATMENT', 'BeginOffset': 85, 'EndOffset': 107}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 87, 'EndOffset': 88}, {'Text': '155', 'Type': 'NUMBER', 'BeginOffset': 118, 'EndOffset': 121}, {'Text': '307', 'Type': 'NUMBER', 'BeginOffset': 142, 'EndOffset': 145}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 178, 'EndOffset': 179}, {'Text': 'a 10 litre gas cylinder', 'Type': 'TREATMENT', 'BeginOffset': 193, 'EndOffset': 216}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 195, 'EndOffset': 197}, {'Text': '155', 'Type': 'NUMBER', 'BeginOffset': 227, 'EndOffset': 230}, {'Text': '1535', 'Type': 'NUMBER', 'BeginOffset': 251, 'EndOffset': 255}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 288, 'EndOffset': 289}, {'Id': 13, 'BeginOffset': 327, 'EndOffset': 335, 'Score': 0.47797733545303345, 'Text': 'nitrogen', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a 2 litre aluminium gas cylinder', 'Type': 'TREATMENT', 'BeginOffset': 411, 'EndOffset': 443}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 413, 'EndOffset': 414}, {'Text': 'aquamarine shoulder and white body)', 'Type': 'TREATMENT', 'BeginOffset': 465, 'EndOffset': 500}, {'Text': '155', 'Type': 'NUMBER', 'BeginOffset': 528, 'EndOffset': 531}, {'Text': 'a stainless steel positive pressure (residual) valve', 'Type': 'TREATMENT', 'BeginOffset': 551, 'EndOffset': 603}, {'Text': 'a specific 48 outlet connection', 'Type': 'TREATMENT', 'BeginOffset': 609, 'EndOffset': 640}, {'Text': '48', 'Type': 'NUMBER', 'BeginOffset': 620, 'EndOffset': 622}, {'Text': 'a standard valve hand', 'Type': 'TREATMENT', 'BeginOffset': 645, 'EndOffset': 666}, {'Text': 'a 2 litre aluminium gas cylinder', 'Type': 'TREATMENT', 'BeginOffset': 674, 'EndOffset': 706}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 676, 'EndOffset': 677}, {'Text': 'aquamarine shoulder and white body)', 'Type': 'TREATMENT', 'BeginOffset': 728, 'EndOffset': 763}, {'Text': '155', 'Type': 'NUMBER', 'BeginOffset': 791, 'EndOffset': 794}, {'Text': 'a stainless steel positive pressure (residual) valve', 'Type': 'TREATMENT', 'BeginOffset': 814, 'EndOffset': 866}, {'Text': 'a specific outlet connection', 'Type': 'TREATMENT', 'BeginOffset': 872, 'EndOffset': 900}, {'Text': 'a inometer device', 'Type': 'TREATMENT', 'BeginOffset': 905, 'EndOffset': 922}, {'Id': 3, 'BeginOffset': 938, 'EndOffset': 942, 'Score': 0.4200817048549652, 'Text': 'hand', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a 10 litre aluminium gas cylinder', 'Type': 'TREATMENT', 'BeginOffset': 950, 'EndOffset': 983}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 952, 'EndOffset': 954}, {'Text': 'aquamarine shoulder and white body)', 'Type': 'TREATMENT', 'BeginOffset': 1005, 'EndOffset': 1040}, {'Text': '155', 'Type': 'NUMBER', 'BeginOffset': 1068, 'EndOffset': 1071}, {'Text': 'a stainless steel positive pressure (residual) valve', 'Type': 'TREATMENT', 'BeginOffset': 1091, 'EndOffset': 1143}, {'Text': 'a specific outlet connection', 'Type': 'TREATMENT', 'BeginOffset': 1149, 'EndOffset': 1177}, {'Id': 5, 'BeginOffset': 1199, 'EndOffset': 1203, 'Score': 0.423911988735199, 'Text': 'hand', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a 10 litre aluminium gas cylinder', 'Type': 'TREATMENT', 'BeginOffset': 1211, 'EndOffset': 1244}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 1213, 'EndOffset': 1215}, {'Text': 'aquamarine shoulder and white body)', 'Type': 'TREATMENT', 'BeginOffset': 1266, 'EndOffset': 1301}, {'Text': '155', 'Type': 'NUMBER', 'BeginOffset': 1329, 'EndOffset': 1332}, {'Text': 'a stainless steel positive pressure (residual) valve', 'Type': 'TREATMENT', 'BeginOffset': 1352, 'EndOffset': 1404}, {'Text': 'a specific outlet connection', 'Type': 'TREATMENT', 'BeginOffset': 1410, 'EndOffset': 1438}, {'Text': 'a inometer device', 'Type': 'TREATMENT', 'BeginOffset': 1443, 'EndOffset': 1460}, {'Id': 7, 'BeginOffset': 1476, 'EndOffset': 1480, 'Score': 0.5611541867256165, 'Text': 'hand', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 1511, 'EndOffset': 1512}, {'Text': '10 litre aluminium gas cylinder', 'Type': 'TREATMENT', 'BeginOffset': 1523, 'EndOffset': 1554}]}

9E4E860B31FF2ADF0758575A786C18FA

https://www.ema.europa.eu/documents/product-information/otezla-epar-product-information_en.pdf

Otezla

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Otezla 10 mg film-coated tablets Otezla 20 mg film-coated tablets Otezla 30 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Otezla 10 mg film-coated tablets Each film-coated tablet contains 10 mg of apremilast. Excipient(s) with known effect Each film-coated tablet contains 57 mg of lactose (as lactose monohydrate). Otezla 20 mg film-coated tablets Each film-coated tablet contains 20 mg of apremilast. Excipient(s) with known effect Each film-coated tablet contains 114 mg of lactose (as lactose monohydrate). Otezla 30 mg film-coated tablets Each film-coated tablet contains 30 mg of apremilast. Excipient(s) with known effect Each film-coated tablet contains 171 mg of lactose (as lactose monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Otezla 10 mg film-coated tablets Pink, diamond shaped 10 mg film-coated tablet of 8 mm length with “APR” engraved on one side and “10” on the opposite side. Otezla 20 mg film-coated tablets Brown, diamond shaped 20 mg film-coated tablet of 10 mm length with “APR” engraved on one side and “20” on the opposite side. Otezla 30 mg film-coated tablets Beige, diamond shaped 30 mg film-coated tablet of 12 mm length with “APR” engraved on one side and “30” on the opposite side. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Psoriatic arthritis Otezla, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy (see section 5.1). Psoriasis Otezla is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA). Behçet’s disease Otezla is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s disease (BD) who are candidates for systemic therapy. 4.2 Posology and method of administration Treatment with Otezla should be initiated by specialists experienced in the diagnosis and treatment of psoriasis, psoriatic arthritis or Behçet’s disease. Posology The recommended dose of apremilast is 30 mg taken orally twice daily, approximately 12 hours apart (morning and evening), with no food restrictions. An initial titration schedule is required as shown below in Table 1. No re-titration is required after initial titration. Table 1. Dose titration schedule Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 & thereafter AM AM PM AM PM AM PM AM PM AM PM 10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg 30 mg 30 mg If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time for their next dose, the missed dose should not be taken and the next dose should be taken at the regular time. During pivotal trials the greatest improvement was observed within the first 24 weeks of treatment for PsA and PSOR and within the first 12 weeks of treatment for BD. If a patient shows no evidence of therapeutic benefit after this time period, treatment should be reconsidered. The patient's response to treatment should be evaluated on a regular basis. Special populations Elderly patients No dose adjustment is required for this patient population (see sections 4.8 and 5.2). Patients with renal impairment No dose adjustment is needed in patients with mild and moderate renal impairment. The dose of apremilast should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockcroft-Gault equation). For initial dose 4 titration in this group, it is recommended that apremilast be titrated using only the AM schedule listed in Table 1 and the PM doses be skipped (see section 5.2). Patients with hepatic impairment No dose adjustment is necessary for patients with hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of apremilast in children aged 0 to 17 years have not been established. No data are available. Method of administration Otezla is for oral use. The film-coated tablets should be swallowed whole, and can be taken either with or without food. 4.3 Contraindications Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. Pregnancy (see section 4.6). 4.4 Special warnings and precautions for use Diarrhoea, nausea, and vomiting There have been post-marketing reports of severe diarrhoea, nausea, and vomiting associated with the use of apremilast. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalised. Patients 65 years of age or older may be at a higher risk of complications. If patients develop severe diarrhoea, nausea, or vomiting, discontinuation of treatment with apremilast may be necessary. Psychiatric disorders Apremilast is associated with an increased risk of psychiatric disorders such as insomnia and depression. Instances of suicidal ideation and behaviour, including suicide, have been observed in patients with or without history of depression (see section 4.8). The risks and benefits of starting or continuing treatment with apremilast should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered from new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment with apremilast. Severe renal impairment Otezla should be dose reduced to 30 mg once daily in patients with severe renal impairment (see sections 4.2 and 5.2). Underweight patients Patients who are underweight at the start of treatment should have their body weight monitored regularly. In the event of unexplained and clinically significant weight loss, these patients should be evaluated by a medical practitioner and discontinuation of treatment should be considered. 5 Lactose content Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of apremilast. Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin and St. John’s Wort) with apremilast is not recommended. Co-administration of apremilast with multiple doses of rifampicin resulted in a decrease in apremilast area-under-the-concentration time curve (AUC) and maximum serum concentration (Cmax) by approximately 72% and 43%, respectively. Apremilast exposure is decreased when administered concomitantly with strong inducers of CYP3A4 (e.g. rifampicin) and may result in reduced clinical response. In clinical studies, apremilast has been administered concomitantly with topical therapy (including corticosteroids, coal tar shampoo and salicylic acid scalp preparations) and UVB phototherapy. There was no clinically meaningful interaction between ketoconazole and apremilast. Apremilast can be co-administered with a potent CYP3A4 inhibitor such as ketoconazole. There was no pharmacokinetic interaction between apremilast and methotrexate in psoriatic arthritis patients. Apremilast can be co-administered with methotrexate. There was no pharmacokinetic interaction between apremilast and oral contraceptives containing ethinyl estradiol and norgestimate. Apremilast can be co-administered with oral contraceptives. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Pregnancy should be excluded before treatment can be initiated. Women of childbearing potential should use an effective method of contraception to prevent pregnancy during treatment. Pregnancy There are limited data about the use of apremilast in pregnant women. Apremilast is contraindicated during pregnancy (see section 4.3). Effects of apremilast on pregnancy included embryofoetal loss in mice and monkeys, and reduced foetal weights and delayed ossification in mice at doses higher than the currently recommended highest human dose. No such effects were observed when exposure in animals was at 1.3-fold the clinical exposure (see section 5.3). Breast-feeding Apremilast was detected in milk of lactating mice (see section 5.3). It is not known whether apremilast, or its metabolites, are excreted in human milk. A risk to the breastfed infant cannot be excluded, therefore apremilast should not be used during breast-feeding. Fertility No fertility data is available in humans. In animal studies in mice, no adverse effects on fertility were observed in males at exposure levels 3-fold clinical exposure and in females at exposure levels 1-fold clinical exposure. For pre-clinical fertility data, see section 5.3. 6 4.7 Effects on ability to drive and use machines Apremilast has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions with apremilast in PsA and PSOR are gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). The other most commonly reported adverse reactions include upper respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%) and are mostly mild to moderate in severity. The most commonly reported adverse drug reactions with apremilast in BD are diarrhoea (41.3%), nausea (19.2%), headache (14.4%), upper respiratory tract infection (11.5%), upper abdominal pain (8.7%), vomiting (8.7%) and back pain (7.7%) and are mostly mild to moderate in severity. The gastrointestinal adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks. Hypersensitivity reactions are uncommonly observed (see section 4.3). Tabulated list of adverse reactions The adverse reactions observed in patients treated with apremilast are listed below by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness. The adverse drug reactions were determined based on data from the apremilast clinical development programme and post-marketing experience. The frequencies of adverse drug reactions are those reported in the apremilast arms of the four Phase III studies in PsA (n = 1,945) or the two Phase III studies in PSOR (n = 1184), and in the phase III study in BD (n = 207) the highest frequency from either data pool is represented in table 2). Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from the available data). Table 2. Summary of adverse reactions in psoriatic arthritis (PsA), psoriasis (PSOR) and Behçet’s disease (BD) System Organ Class Frequency Adverse reaction Infections and infestations Very common Upper respiratory tract infectiona Common Bronchitis Nasopharyngitis* Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Common Decreased appetite* Psychiatric disorders Common InsomniaDepression Uncommon Suicidal ideation and behaviour 7 System Organ Class Frequency Adverse reaction Nervous system disorders Very common Headache*, a Common Migraine* Tension headache* Respiratory, thoracic, and mediastinal disorders Common Cough Gastrointestinal disorders Very Common Diarrhoea* Nausea* Common Vomiting* Dyspepsia Frequent bowel movements Upper abdominal pain* Gastroesophageal reflux disease Uncommon Gastrointestinal haemorrhage Skin and subcutaneous tissue disorders Uncommon RashUrticaria Not known Angioedema Musculoskeletal and connective tissue disorders Common Back pain* General disorders and administration site conditions Common Fatigue Investigations Uncommon Weight decrease *At least one of these adverse reactions was reported as serious a Frequency reported as common in PSA and PSOR Description of selected adverse reactions Psychiatric disorders In clinical studies and post-marketing experience, uncommon cases of suicidal ideation and behaviour, were reported, while completed suicide was reported post-marketing. Patients and caregivers should be instructed to notify the prescriber of any suicidal ideation (see section 4.4). Body weight loss Patient weight was measured routinely in clinical studies. The mean observed weight loss in PsA and PSOR patients treated for up to 52 weeks with apremilast was 1.99 kg. A total of 14.3% of patients receiving apremilast had observed weight loss between 5-10% while 5.7% of the patients receiving apremilast had observed weight loss greater than 10%. None of these patients had overt clinical consequences resulting from weight loss. A total of 0.1% of patients treated with apremilast discontinued due to adverse reaction of weight decreased. The mean observed weight loss in BD patients treated with apremilast for 52 weeks was 0.52 kg. A total of 11.8% of patients receving apremilast had observed weight loss between 5-10% while 3.8% of the patients receiving apremilast had observed weight loss greater than 10%. None of these patients had overt clinical consequences from weight loss. None of the patients discontinued the study due to adverse reaction of weight decreased. Please see additional warning in section 4.4 for patients who are underweight at beginning of treatment. 8 Special populations Elderly patients From post-marketing experience, elderly patients ≥ 65 years of age may be at a higher risk of complications of severe diarrhoea, nausea and vomiting (see section 4.4). Patients with hepatic impairment The safety of apremilast was not evaluated in PsA, PSOR or BD patients with hepatic impairment. Patients with renal impairment In the PsA, PSOR or BD clinical studies, the safety profile observed in patients with mild renal impairment was comparable to patients with normal renal function. The safety of apremilast was not evaluated in PsA, PSOR or BD patients with moderate or severe renal impairment in the clinical studies. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Apremilast was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg twice daily) for 4.5 days without evidence of dose limiting toxicities. In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportive care is advised. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosupressants, selective immunosuppressants, ATC code: L04AA32 Mechanism of action Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatory mediators have been implicated in psoriatic arthritis and psoriasis. Pharmacodynamic effects In clinical studies in patients with psoriatic arthritis, apremilast significantly modulated, but did not fully inhibit, plasma protein levels of IL-1α, IL-6, IL-8, MCP-1, MIP-1β, MMP-3, and TNF-α. After 40 weeks of treatment with apremilast, there was a decrease in plasma protein levels of IL-17 and IL- 23, and an increase in IL-10. In clinical studies in patients with psoriasis, apremilast decreased lesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes, including those for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22 and IL-8. 9 In clinical studies in patients with Behçet Disease treated with apremilast, there was a significant positive association between the change in plasma TNF-alpha and clinical efficacy as measured by the number of oral ulcers. Apremilast administered at doses of up to 50 mg twice daily did not prolong the QT interval in healthy subjects. Clinical efficacy and safety Psoriatic Arthritis The safety and efficacy of apremilast were evaluated in 3 multi-centre, randomised, double-blind, placebo-controlled studies (Studies PALACE 1, PALACE 2, and PALACE 3) of similar design in adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with small molecule or biologic DMARDs. A total of 1,493 patients were randomised and treated with either placebo, apremilast 20 mg or apremilast 30 mg given orally twice daily. Patients in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion (at least 2 cm in diameter) was also required in PALACE 3. Apremilast was used as a monotherapy (34.8%) or in combination with stable doses of small molecule DMARDs (65.2%). Patients received apremilast in combination with one or more of the following: methotrexate (MTX, ≤ 25 mg/week, 54.5%), sulfasalazine (SSZ, ≤ 2 g/day, 9.0%), and leflunomide (LEF; ≤ 20 mg/day, 7.4%). Concomitant treatment with biologic DMARDs, including TNF blockers, was not allowed. Patients with each subtype of PsA were enrolled in the 3 studies, including symmetric polyarthritis (62.0%), asymmetric oligoarthritis (26.9%), distal interphalangeal (DIP) joint arthritis (6.2%), arthritis mutilans (2.7%), and predominant spondylitis (2.1%). Patients with pre-existing enthesopathy (63%) or pre-existing dactylitis (42%) were enrolled. A total of 76.4% of patients were previously treated with only small-molecule DMARDs and 22.4% of patients were previously treated with biologic DMARDs, which includes 7.8% who had a therapeutic failure with a prior biologic DMARD. The median duration of PsA disease was 5 years. Based on the study design, patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at week 16. Placebo patients who were considered non- responders were re-randomised 1:1 in a blinded fashion to either apremilast 20 mg twice daily or 30 mg twice daily. At week 24, all remaining placebo-treated patients were switched to either apremilast 20 or 30 mg twice daily. Following 52 weeks of treatment, patients could continue on open label apremilast 20 mg or 30 mg within the long-term extension of the PALACE 1, PALACE 2, and PALACE 3 studies for a total duration of treatment up to 5 years (260 weeks). The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at week 16. Treatment with apremilast resulted in significant improvements in the signs and symptoms of PsA, as assessed by the ACR 20 response criteria compared to placebo at weeks 16. The proportion of patients with ACR 20/50/70 (responses in studies PALACE 1, PALACE 2 and PALACE 3, and the pooled data for studies PALACE 1, PALACE 2 and PALACE 3) for apremilast 30 mg twice daily at week 16 are shown in table 3. ACR 20/50/70 responses were maintained at week 24. Among patients who were initially randomised to apremilast 30 mg twice daily treatment, ACR 20/50/70 response rates were maintained through week 52 in the pooled studies PALACE 1, PALACE 2 and PALACE 3 (figure 1). 10 Table 3. Proportion of patients with ACR responses in studies PALACE 1, PALACE 2 and PALACE 3 and pooled studies at week 16 *p ≤ 0.01 for apremilast vs. placebo **p ≤ 0.001 for apremilast vs. placebo a N is the number of patients as randomised and treated Figure 1 Proportion of ACR 20/50/70 responders through week 52 in the pooled analysis of studies PALACE 1, PALACE 2 and PALACE 3 (NRI*) R es po ns e R at e +/ - S E (% ) 0 10 20 30 40 50 0 16 24 40 52 Endpoint ACR 20 ACR 50 ACR 70 Study Week Endpoint ACR 20 Study Week Endpoint n/m (%) ACR 20 184/497 (37.0) Study Week Endpoint n/m (%) ACR 20 196/497 (39.4) Study Week Endpoint n/m (%) ACR 20 222/497 (44.7) Study Week Endpoint n/m (%) ACR 20 209/497 (42.1) Study Week Endpoint ACR 50 Study Week Endpoint n/m (%) ACR 50 69/497 (13.9) Study Week Endpoint n/m (%) ACR 50 93/497 (18.7) Study Week Endpoint n/m (%) ACR 50 102/497 (20.5) Study Week Endpoint n/m (%) ACR 50 90/497 (18.1) Study Week Endpoint ACR 70 Study Week Endpoint n/m (%) ACR 70 15/497 ( 3.0) Study Week Endpoint n/m (%) ACR 70 33/497 ( 6.6) Study Week Endpoint n/m (%) ACR 70 44/497 ( 8.9) Study Week Endpoint n/m (%) ACR 70 38/497 ( 7.6) *NRI: None responder imputation. Subjects who discontinued early prior to the time point and subjects who did not have sufficient data for a definitive determination of response status at the time point are counted as non-responders. Among 497 patients initially randomised to apremilast 30 mg twice daily, 375 (75%) patients were still on this treatment on week 52. In these patients, ACR 20/50/70 responses at week 52 were of 57%, 25%, and 11% respectively. Among 497 patients initially randomised to apremilast 30 mg twice daily, 375 (75%) patients entered the long term extension studies, and of these, 221 patients (59%) were still on this treatment at week 260. ACR responses were maintained in the long-term open label extension studies for up to 5 years. Responses observed in the apremilast treated group were similar in patients receiving and not receiving concomitant DMARDs, including MTX. Patients previously treated with DMARDs or PALACE 1 PALACE 2 PALACE 3 POOLED Na Placebo +/- DMARDs N = 168 Apremilast 30 mg twice daily +/- DMARDs N = 168 Placebo +/- DMARDs N = 159 Apremilast 30 mg twice daily +/- DMARDs N = 162 Placebo +/- DMARDs N = 169 Apremilast 30 mg twice daily +/- DMARDs N = 167 Placebo +/- DMARDs N = 496 Apremilast 30 mg twice daily +/- DMARDs N = 497 ACR 20a Week 16 19.0% 38.1%** 18.9% 32.1%* 18.3% 40.7%** 18.8% 37.0%** ACR 50 Week 16 6.0% 16.1%* 5.0% 10.5% 8.3% 15.0% 6.5% 13.9%** ACR 70 Week 16 1.2% 4.2% 0.6% 1.2% 2.4% 3.6% 1.4% 3.0% 11 biologics who received apremilast achieved a greater ACR 20 response at week 16 than patients receiving placebo. Similar ACR responses were observed in patients with different PsA subtypes, including DIP. The number of patients with arthritis mutilans and predominant spondylitis subtypes was too small to allow meaningful assessment. In PALACE 1, PALACE 2 and PALACE 3, improvements in Disease Activity Scale (DAS) 28 C-reactive protein (CRP) and in the proportion of patients achieving a modified PsA response criteria (PsARC) were greater in the apremilast group, compared to placebo at week 16 (nominal p-value p < 0.0004, p-value ≤ 0.0017, respectively). These improvements were maintained at week 24. Among patients who remained on the apremilast treatment to which they were randomised at study start, DAS28 (CRP) score and PsARC response were maintained through week 52. At weeks 16 and 24 improvements in parameters of peripheral activity characteristic of psoriatic arthritis (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) and in the skin manifestations of psoriasis were seen in the apremilast-treated patients. Among patients who remained on the apremilast treatment to which they were randomised at study start, these improvements were maintained through week 52. The clinical responses were maintained in the same parameters of peripheral activity and in the skin manifestations of psoriasis in the open-label extension studies for up to 5 years of treatment. Physical function and health-related quality of life Apremilast-treated patients demonstrated statistically significant improvement in physical function, as assessed by the disability index of the health assessment questionnaire (HAQ-DI) change from baseline, compared to placebo at weeks 16 in PALACE 1, PALACE 2 and PALACE 3 and in the pooled studies. Improvement in HAQ-DI scores was maintained at week 24. Among patients who were initially randomised to apremilast 30 mg twice daily treatment, the change from baseline in the HAQ-DI score at week 52 was -0.333 in the apremilast 30 mg twice daily group in a pooled analysis of the open label phase of studies PALACE 1, PALACE 2 and PALACE 3. In studies PALACE 1, PALACE 2 and PALACE 3, significant improvements were demonstrated in health-related quality of life, as measured by the changes from baseline in the physical functioning (PF) domain of the Short Form Health Survey version 2 (SF-36v2), and in the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-fatigue) scores in patients treated with apremilast compared to placebo at weeks 16 and 24. Among patients who remained on the apremilast treatment, to which they were initially randomised at study start, improvement in physical function and FACIT- fatigue was maintained through week 52. Improved physical function as assessed by the HAQ-DI and the SF36v2PF domain, and the FACIT- fatigue scores were maintained in the open-label extension studies for up to 5 years of treatment. Psoriasis The safety and efficacy of apremilast were evaluated in two multicentre, randomised, double-blind, placebo-controlled studies (Studies ESTEEM 1 and ESTEEM 2) which enrolled a total of 1,257 patients with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥ 10%, Psoriasis Area and Severity Index (PASI) score ≥ 12, static Physician Global Assessment (sPGA) of ≥ 3 (moderate or severe), and who were candidates for phototherapy or systemic therapy. These studies had a similar design through week 32. In both studies, patients were randomised 2:1 to apremilast 30 mg twice daily or placebo for 16 weeks (placebo-controlled phase) and from weeks 16- 32, all patients received apremilast 30 mg twice daily (maintenance phase). During the Randomised Treatment Withdrawal Phase (weeks 32-52), patients originally randomised to apremilast who 12 achieved at least a 75% reduction in their PASI score (PASI-75) (ESTEEM 1) or a 50% reduction in their PASI score (PASI-50) (ESTEEM 2) were re-randomised at week 32 to either placebo or apremilast 30 mg twice daily. Patients who were re-randomised to placebo and who lost PASI-75 response (ESTEEM 1) or lost 50% of the PASI improvement at week 32 compared to baseline (ESTEEM 2) were retreated with apremilast 30 mg twice daily. Patients who did not achieve the designated PASI response by week 32, or who were initially randomised to placebo, remained on apremilast until week 52. The use of low potency topical corticosteroids on the face, axillae, and groin, coal tar shampoo and/or salicylic acid scalp preparations was permitted throughout the studies. In addition, at week 32, subjects who did not achieve a PASI-75 response in ESTEEM 1, or a PASI-50 response in ESTEEM 2, were permitted to use topical psoriasis therapies and/or phototherapy in addition to apremilast 30 mg twice daily treatment. Following 52 weeks of treatment, patients could continue on open-label apremilast 30 mg within the long-term extension of the ESTEEM 1 and ESTEEM 2 studies for a total duration of treatment up to 5 years (260 weeks). In both studies, the primary endpoint was the proportion of patients who achieved PASI-75 at week 16. The major secondary endpoint was the proportion of patients who achieved a sPGA score of clear (0) or almost clear (1) at week 16. The mean baseline PASI score was 19.07 (median 16.80), and the proportion of patients with sPGA score of 3 (moderate) and 4 (severe) at baseline was 70.0% and 29.8%, respectively with a mean baseline BSA involvement of 25.19% (median 21.0%). Approximately 30% of all patients had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis (including treatment failures), with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of patients had not received prior phototherapy, conventional systemic or biologic therapy. A total of 18% of patients had a history of psoriatic arthritis. The proportion of patients achieving PASI-50, -75 and -90 responses, and sPGA score of clear (0) or almost clear (1), are presented in table 4 below. Treatment with apremilast resulted in significant improvement in moderate to severe plaque psoriasis as demonstrated by the proportion of patients with PASI-75 response at week 16, compared to placebo. Clinical improvement measured by sPGA, PASI- 50 and PASI-90 responses were also demonstrated at week 16. In addition, apremilast demonstrated a treatment benefit across multiple manifestations of psoriasis including pruritus, nail disease, scalp involvement and quality of life measures. 13 Table 4. Clinical response at week 16 in studies ESTEEM 1 and ESTEEM 2 (FAS a, LOCFb) ESTEEM 1 ESTEEM 2 Placebo 30 mg twice daily APR* Placebo 30 mg twice daily APR* N 282 562 137 274 PASIc 75, n (%) 15 (5.3) 186 (33.1) 8 (5.8) 79 (28.8) sPGAd of clear or almost clear, n (%) 11 (3.9) 122 (21.7) 6 (4.4) 56 (20.4) PASI 50, n (%) 48 (17.0) 330 (58.7) 27 (19.7) 152 (55.5) PASI 90, n (%) 1 (0.4) 55 (9.8) 2 (1.5) 24 (8.8) Percent change BSAe (%) mean ± SD -6.9 ± 38.95 -47.8 ± 38.48 -6.1 ± 47.57 -48.4 ± 40.78 Change in pruritus VASf (mm), mean ± SD -7.3 ± 27.08 -31.5 ± 32.43 -12.2 ± 30.94 -33.5 ± 35.46 Change in DLQIg, mean ± SD -2.1 ± 5.69 -6.6 ± 6.66 -2.8 ± 7.22 -6.7 ± 6.95 Change in SF-36 MCS h, mean ± SD -1.02 ± 9.161 2.39 ± 9.504 0.00 ± 10.498 2.58 ± 10.129 * p < 0.0001 for apremilast vs placebo, except for ESTEEM 2 PASI 90 and Change in SF-36 MCS where p = 0.0042 and p = 0.0078, respectively. a FAS = Full Analysis Set b LOCF = Last Observation Carried Forward c PASI = Psoriasis Area and Severity Index d sPGA = Static Physician Global Assessment e BSA = Body Surface Area f VAS = Visual Analog Scale; 0 = best, 100 = worst g DLQI = Dermatology Life Quality Index; 0 = best, 30 = worst h SF-36 MCS = Medical Outcome Study Short Form 36-Item Health Survey, Mental Component Summary The clinical benefit of apremilast was demonstrated across multiple subgroups defined by baseline demographics and baseline clinical disease characteristics (including psoriasis disease duration and patients with a history of psoriatic arthritis). The clinical benefit of apremilast was also demonstrated regardless of prior psoriasis medication usage and response to prior psoriasis treatments. Similar response rates were observed across all weight ranges. Response to apremilast was rapid, with significantly greater improvements in the signs and symptoms of psoriasis, including PASI, skin discomfort/pain and pruritus, compared to placebo by week 2. In general, PASI responses were achieved by week 16 and were maintained through week 32. In both studies, the mean percent improvement in PASI from baseline remained stable during the randomised treatment withdrawal phase for patients re-randomised to apremilast at week 32 (table 5). Table 5. Persistence of effect among subjects randomised to APR 30 twice daily at week 0 and re-randomised to APR 30 twice daily at week 32 to week 52 Time Point ESTEEM 1 ESTEEM 2 Patients who achieved PASI-75 at week 32 Patients who achieved PASI-50 at week 32 Percent Change in PASI from baseline, mean (%) ± SDa Week 16 -77.7 ± 20.30 -69.7 ± 24.23 Week 32 -88 ± 8.30 -76.7 ± 13.42 Week 52 -80.5 ± 12.60 -74.4 ± 18.91 Change in DLQI from baseline, mean ± SDa Week 16 -8.3 ± 6.26 -7.8 ± 6.41 Week 32 -8.9 ± 6.68 -7.7 ± 5.92 Week 52 -7.8 ± 5.75 -7.5 ± 6.27 14 Time Point ESTEEM 1 ESTEEM 2 Patients who achieved PASI-75 at week 32 Patients who achieved PASI-50 at week 32 Proportion of subjects with Scalp Psoriasis PGA (ScPGA) 0 or 1, n/N (%)b Week 16 40/48 (83.3) 21/37 (56.8) Week 32 39/48 (81.3) 27/37 (73.0) Week 52 35/48 (72.9) 20/37 (54.1) a Includes subjects re-randomised to APR 30 twice daily at week 32 with a baseline value and a post-baseline value at the evaluated study week. b N is based on subjects with moderate or greater scalp psoriasis at baseline who were re-randomised to APR 30 twice daily at week 32. Subjects with missing data were counted as nonresponders. In study ESTEEM 1, approximately 61% of patients re-randomised to apremilast at week 32 had a PASI-75 response at week 52. Of the patients with at least a PASI-75 response who were re- randomised to placebo at week 32 during a randomised treatment withdrawal phase, 11.7% were PASI-75 responders at week 52. The median time to loss of PASI-75 response among the patients re- randomised to placebo was 5.1 weeks. In study ESTEEM 2, approximately 80.3% of patients re-randomised to apremilast at week 32 had a PASI-50 response at week 52. Of the patients with at least a PASI-50 response who were re- randomised to placebo at week 32, 24.2% were PASI-50 responders at week 52. The median time to loss of 50% of their week 32 PASI improvement was 12.4 weeks. After randomised withdrawal from therapy at week 32, approximately 70% of patients in study ESTEEM 1, and 65.6% of patients in study ESTEEM 2, regained PASI-75 (ESTEEM 1) or PASI-50 (ESTEEM 2) responses after re-initiation of apremilast treatment. Due to the study design the duration of re-treatment was variable, and ranged from 2.6 to 22.1 weeks. In study ESTEEM 1, patients randomised to apremilast at the start of the study who did not achieve a PASI-75 response at week 32 were permitted to use concomitant topical therapies and/or UVB phototherapy between weeks 32 to 52. Of these patients, 12% achieved a PASI-75 response at week 52 with apremilast plus topical and/or phototherapy treatment. In studies ESTEEM 1 and ESTEEM 2, significant improvements (reductions) in nail psoriasis, as measured by the mean percent change in Nail Psoriasis Severity Index (NAPSI) from baseline, were observed in patients receiving apremilast compared to placebo-treated patients at week 16 (p < 0.0001 and p = 0.0052, respectively). Further improvements in nail psoriasis were observed at week 32 in patients continuously treated with apremilast. In studies ESTEEM 1 and ESTEEM 2, significant improvements in scalp psoriasis of at least moderate severity (≥ 3), measured by the proportion of patients achieving Scalp Psoriasis Physician’s Global Assessment (ScPGA) of clear (0) or minimal (1) at week 16, were observed in patients receiving apremilast compared to placebo-treated patients (p < 0.0001 for both studies). The improvements were generally maintained in subjects who were re-randomised to apremilast at week 32 through week 52 (table 5). In studies ESTEEM 1 and ESTEEM 2, significant improvements in quality of life as measured by the Dermatology Life Quality Index (DLQI) and the SF-36v2MCS were demonstrated in patients receiving apremilast compared with placebo-treated patients (table 4). Improvements in DLQI were maintained through week 52 in subjects who were re-randomised to apremilast at week 32 (table 5). In addition, in study ESTEEM 1, significant improvement in the Work Limitations Questionnaire (WLQ- 25) Index was achieved in patients receiving apremilast compared to placebo. Among 832 patients initially randomised to apremilast 30 mg twice daily, 443 patients (53%) entered the open-label extension studies of ESTEEM 1 and ESTEEM 2, and of these 115 patients (26%) were still on treatment at week 260. For patients who remained on apremilast in the open label extension of 15 ESTEEM 1 and ESTEEM 2 studies, improvements were generally maintained in PASI score, affected BSA, itch, nail and quality of life measures for up to 5 years. The long-term safety of apremilast 30 mg twice daily in patients with psoriatic arthritis and psoriasis was assessed for a total duration of treatment up to 5 years. Long-term experience in open-label extension studies with apremilast was generally comparable to the 52-week studies. Behçet’s disease The safety and efficacy of apremilast were evaluated in a phase 3, multicentre, randomised, placebo- controlled study (RELIEF) in adult patients with active Behçet’s Disease (BD) with oral ulcers. Patients were previously treated with at least one non-biologic BD medication for oral ulcers and were candidates for systemic therapy. Concomitant treatment for BD was not allowed. The population studied met the International Study Group (ISG) criteria for BD with a history of skin lesions (98.6%), genital ulcers (90.3%), musculoskeletal (72.5%), ocular (17.4%), central nervous system (9.7%) or GI manifestations (9.2%), epididymitis (2.4%) and vascular involvement (1.4%). Patients with severe BD, defined as those with active major organ involvement (for ex. meningoencephalitis or pulmonary artery aneurysm) were excluded. A total of 207 BD patients were randomised 1:1 to receive either apremilast 30 mg twice daily (n = 104) or placebo (n = 103) for 12-weeks (placebo-controlled phase) and from weeks 12 to 64, all patients received apremilast 30 mg twice daily (active treatment phase). Patients ranged in age from 19 to 72 years, with a mean age of 40 years. The mean duration of BD was 6.84 years. All patients had a history of recurrent oral ulcers with at least 2 oral ulcers at screening and randomization: the mean baseline oral ulcer counts were 4.2 and 3.9 in the apremilast and placebo groups, respectively. The primary endpoint was the Area Under the Curve (AUC) for the number of oral ulcers from baseline through week 12. Secondary endpoints included other measures of oral ulcers: oral ulcer pain Visual Analog Scale (VAS), proportion of patients who are oral ulcer-free (complete response), time to onset of oral ulcer resolution, and proportion of patients achieving resolution of oral ulcers by week 6, and who remain oral ulcer free at every visit for at least 6 additional weeks during the 12-week placebo-controlled treatment phase. Other endpoints included Behçet’s Syndrome Activity Score (BSAS), BD Current Activity Form (BDCAF), including the BD Current Activity Index (BDCAI) score, the Patient’s Perception of Disease Activity, the Clinician’s Overall Perception of Disease Activity and the BD Quality of Life Questionnaire (BD QoL). Measure of oral ulcers Apremilast 30 mg twice daily resulted in significant improvement in oral ulcers as demonstrated by the AUC for the number of oral ulcers from baseline through week 12 (p < 0.0001), compared with placebo. Significant improvements in other measures of oral ulcers were demonstrated at week 12. Table 6. Clinical response of oral ulcers at week 12 in RELIEF (ITT population) Endpointa Placebo N = 103 Apremilast 30 mg BID N = 104 AUCb for the number of oral ulcers from baseline through week 12 (MI) LS Mean 222.14 LS Mean 129.54 Change from baseline in the pain of oral ulcers as measured by VASc at week 12 (MMRM) LS Mean -18.7 LS Mean -42.7 Proportion of subjects achieving resolution of oral ulcers (oral ulcer-free) by week 6, and who remain oral ulcer free at every visit for at least 6 additional weeks during the 12-week placebo- controlled treatment phase 4.9% 29.8% 16 Endpointa Placebo N = 103 Apremilast 30 mg BID N = 104 Median time (weeks) to oral ulcer resolution during the placebo- controlled treatment phase 8.1 weeks 2.1 weeks Proportion of subjects with complete oral ulcer response at week 12 (NRI) 22.3% 52.9% Proportion of subjects with partial oral ulcer responsed at week 12 (NRI) 47.6% 76.0% ITT=intent to treat; LS=least squares; MI=multiple imputation; MMRM=mixed-effects model for repeated measures; NRI=non-responder imputation; BID=twice daily. a p-value < 0.0001 for all apremilast vs. placebo b AUC = Area Under the Curve. c VAS = Visual Analog Scale; 0 = no pain, 100 = worst possible pain. d Partial oral ulcer response = number of oral ulcers reduced by ≥ 50% post baseline (Exploratory analysis); nominal p-value – < 0.0001 Among 104 patients originally randomised to apremilast 30 mg twice daily, 75 patients (approximately 72%) remained on this treatment at week 64. A significant reduction in the mean number of oral ulcers and oral ulcer pain was observed in the apremilast 30 mg twice daily treatment group compared to the placebo treatment group at every visit, as early as week 1, through week 12 for number of oral ulcers (p ≤ 0.0015) and for oral ulcer pain (p ≤ 0.0035). Among patients who were continuously treated with apremilast and remained in the study, improvements in oral ulcers and reduction of oral ulcer pain were maintained through week 64 (figures 2 and 3). Among patients originally randomised to apremilast 30 mg twice daily who remained in the study, the proportions of patients with a complete response and partial response of oral ulcers were maintained through week 64 (53.3% and 76.0% respectively). Figure 2. Mean number of oral ulcers by time point through week 64 (ITT population; DAO) ITT = Intent To Treat; DAO = Data As Observed. APR 30 BID = apremilast 30 mg twice daily. Note: Placebo or APR 30 mg BID indicates the treatment group in which patients were randomised. Placebo treatment group patients switched to APR 30 BID at week 12. The follow-up time point was 4 weeks after patients completed week 64 or 4 weeks after patients discontinued treatment before week 64. 17 Figure 3. Mean change from baseline in oral ulcer pain on a visual analog scale by time point through week 64 (ITT Population; DAO) APR 30 BID = apremilast twice daily; ITT = Intent-To-Treat; DAO = Data As Observed Note: Placebo or APR 30 mg BID indicates the treatment group in which patients were randomised. Placebo treatment group patients switched to APR 30 BID at week 12. The follow-up time point was 4 weeks after patients completed week 64 or 4 weeks after patients discontinued treatment before week 64. Improvements in overall Behçet’s disease activity Apremilast 30 mg twice daily, compared with placebo, resulted in significant reduction in overall disease activity, as demonstrated by the mean change from baseline at week 12 in the BSAS (p < 0.0001) and the BDCAF (BDCAI, Patient’s Perception of Disease Activity, and the Clinician’s Overall Perception of Disease Activity; p-values ≤ 0.0335 for all three components). Among patients originally randomised to apremilast 30 mg twice daily who remained in the study, improvements (mean change from baseline) in both the BSAS and the BDCAF were maintained at week 64.  Improvements in quality of life Apremilast 30 mg twice daily, compared with placebo, resulted in significantly greater improvement in Quality of Life (QoL) at week 12, as demonstrated by the BD QoL Questionnaire (p = 0.0003). Among patients originally randomised to apremilast 30 mg twice daily who remained in the study, improvement in BD QoL was maintained at week 64. 5.2 Pharmacokinetic properties Absorption Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2.5 hours. Apremilast pharmacokinetics are linear, with a dose-proportional increase in systemic exposure in the dose range of 10 to 100 mg daily. Accumulation is minimal when apremilast is administered once daily and approximately 53% in healthy subjects and 68% in patients with psoriasis when administered twice daily. Co-administration with food does not alter the bioavailability therefore, apremilast can be administered with or without food. 18 Distribution Human plasma protein binding of apremilast is approximately 68%. The mean apparent volume of distribution (Vd) is 87 L, indicative of extravascular distribution. Biotransformation Apremilast is extensively metabolised by both CYP and non-CYP mediated pathways including oxidation, hydrolysis, and conjugation, suggesting inhibition of a single clearance pathway is not likely to cause a marked drug-drug interaction. Oxidative metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. Apremilast is the major circulating component following oral administration. Apremilast undergoes extensive metabolism with only 3% and 7% of the administered parent compound recovered in urine and faeces, respectively. The major circulating inactive metabolite is the glucuronide conjugate of O-demethylated apremilast (M12). Consistent with apremilast being a substrate of CYP3A4, apremilast exposure is decreased when administered concomitantly with rifampicin, a strong inducer of CYP3A4. In vitro, apremilast is not an inhibitor or inducer of cytochrome P450 enzymes. Hence, apremilast co- administered with substrates of CYP enzymes is unlikely to affect the clearance and exposure of active substances that are metabolised by CYP enzymes. In vitro, apremilast is a substrate, and a weak inhibitor of P-glycoprotein (IC50 > 50 µM), however clinically relevant drug interactions mediated via P-gp are not expected to occur. In vitro, apremilast has little to no inhibitory effect (IC50 > 10 µM) on Organic Anion Transporter (OAT)1 and OAT3, Organic Cation Transporter (OCT)2, Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP) and is not a substrate for these transporters. Hence, clinically relevant drug-drug interactions are unlikely when apremilast is co- administered with drugs that are substrates or inhibitors of these transporters. Elimination The plasma clearance of apremilast is on average about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 9 hours. Following oral administration of radiolabelled apremilast, about 58% and 39% of the radioactivity is recovered in urine and faeces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and faeces, respectively. Elderly patients Apremilast was studied in young and elderly healthy subjects. The exposure in elderly subjects (65 to 85 years of age) is about 13% higher in AUC and about 6% higher in Cmax for apremilast than that in young subjects (18 to 55 years of age). There is limited pharmacokinetic data in subjects over 75 years of age in clinical trials. No dosage adjustment is necessary for elderly patients. Renal impairment There is no meaningful difference in the PK of apremilast between mild or moderate renally impaired subjects and matched healthy subjects (N = 8 each). The results support that no dose adjustment is needed in patients with mild and moderate renal impairment. Apremilast dose should be reduced to 30 mg once daily in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2 or CLcr < 30 mL/min). In 8 subjects with severe renal impairment to whom a single dose of 30 mg apremilast was administered, the AUC and Cmax of apremilast increased by approximately 89% and 42%, respectively. 19 Hepatic impairment The pharmacokinetics of apremilast and its major metabolite M12 are not affected by moderate or severe hepatic impairment. No dose adjustment is necessary for patients with hepatic impairment. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. There is no evidence of immunotoxic, dermal irritation, or phototoxic potential. Fertility and early embryonic development In a male mouse fertility study, apremilast at oral dosages of 1, 10, 25, and 50 mg/kg/day produced no effects on male fertility; the No Observed Adverse Effect Level (NOAEL) for male fertility was greater than 50 mg/kg/day 3-fold clinical exposure. In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, a prolongation of oestrous cycles and increased time to mating were observed at 20 mg/kg/day and above; despite this, all mice mated and pregnancy rates were unaffected. The No Observed Effect Level (NOEL) for female fertility was 10 mg/kg/day (1.0- fold clinical exposure). Embryo-foetal development In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, absolute and/or relative heart weights of maternal animals were increased at 20, 40, and 80 mg/kg/day. Increased numbers of early resorptions and reduced numbers of ossified tarsals were observed at 20, 40, and 80 mg/kg/day. Reduced foetal weights and retarded ossification of the supraoccipital bone of the skull were observed at 40 and 80 mg/kg/day. The maternal and developmental NOEL in the mouse was 10 mg/kg/day (1.3-fold clinical exposure). In a monkey embryo-foetal developmental toxicity study, oral dosages of 20, 50, 200, and 1000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) at dosages of 50 mg/kg/day and above; no test article-related effect in prenatal loss was observed at 20 mg/kg/day (1.4-fold clinical exposure). Pre- and post-natal development In a pre- and postnatal study, apremilast was administered orally to pregnant female mice at dosages of 10, 80 and 300 mg/kg/day from Gestation Day (GD) 6 to day 20 of lactation. Reductions in maternal body weight and weight gain, and one death associated with difficulty in delivering pups were observed at 300 mg/kg/day. Physical signs of maternal toxicity associated with delivering pups were also observed in one mouse at each of 80 and 300 mg/kg/day. Increased peri- and postnatal pup deaths and reduced pup body weights during the first week of lactation were observed at ≥ 80 mg/kg/day (≥ 4.0-fold clinical exposure). There were no apremilast-related effects on duration of pregnancy, number of pregnant mice at the end of the gestation period, number of mice that delivered a litter, or any developmental effects in the pups beyond postnatal day 7. It is likely that pup developmental effects observed during the first week of the postnatal period were related to the apremilast-related pup toxicity (decreased pup weight and viability) and/or lack of maternal care (higher incidence of no milk in the stomach of pups). All developmental effects were observed during the first week of the postnatal period; no apremilast-related effects were seen during the remaining pre- and post-weaning periods, including sexual maturation, behavioural, mating, fertility and uterine parameters. The NOEL in the mouse for maternal toxicity and F1 generation was 10 mg/kg/day (1.3- fold clinical AUC). 20 Carcinogenicity studies Carcinogenicity studies in mice and rats showed no evidence of carcinogenicity related to treatment with apremilast. Genotoxicity studies Apremilast is not genotoxic. Apremilast did not induce mutations in an Ames assay or chromosome aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to 2,000 mg/kg/day. Other studies There is no evidence of immunotoxic, dermal irritation, or phototoxic potential. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Cellulose microcrystalline Lactose monohydrate Croscarmellose sodium Magnesium stearate Film-coating Poly (vinyl alcohol) Titanium dioxide (E171) Macrogol (3350) Talc Iron oxide red (E172) The 20 mg tablets also contain iron oxide yellow (E172). The 30 mg tablets also contain iron oxide yellow (E172) and iron oxide black (E172). 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30ºC. 6.5 Nature and contents of container Otezla 10 mg, 20 mg, 30 mg film-coated tablets (initiation pack) PVC/aluminium foil blisters containing 27 film-coated tablets (4 x 10 mg, 4 x 20 mg, 19 x 30 mg). 21 Otezla 30 mg film-coated tablets PVC/aluminium foil blisters containing 14 film-coated tablets, in pack sizes of 56 tablets and 168 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) Otezla 10 mg, 20 mg, 30 mg film-coated tablets (initiation pack) EU/1/14/981/001 Otezla 30 mg film-coated tablets EU/1/14/981/002 – pack size of 56 tablets EU/1/14/981/003 – pack size of 168 tablets 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 15 January 2015 Date of latest renewal: 23 August 2019 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 22 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 23 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Celgene Distribution B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands Amgen NV Telecomlaan 5-7 1831 Diegem Belgium The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 24 ANNEX III LABELLING AND PACKAGE LEAFLET 25 A. LABELLING 26 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Wallet card containing 2-week treatment initiation pack 1. NAME OF THE MEDICINAL PRODUCT Otezla 10 mg film-coated tablets Otezla 20 mg film-coated tablets Otezla 30 mg film-coated tablets apremilast 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 10 mg, 20 mg or 30 mg of apremilast. 3. LIST OF EXCIPIENTS Contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablet Treatment initiation pack Each pack of 27 film-coated tablets for a 2 week treatment schedule contains: 4 film-coated tablets of 10 mg 4 film-coated tablets of 20 mg 19 film-coated tablets of 30 mg 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For oral use. Week 1 Week 2 Day 1 - Day 7 Day 8 - Day 14 Sun as symbol for morning dose Moon as symbol for evening dose Refer to the wallet card for daily dose QR code to be included www.otezla-eu-pil.com 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 27 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061, 4817 ZK Breda, The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/981/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Otezla 10 mg Otezla 20 mg Otezla 30 mg 28 17. UNIQUE IDENTIFIER – 2D BARCODE 2 D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 29 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister (Particulars printed directly onto the wallet card with the blank blister sealed inside) 1. NAME OF THE MEDICINAL PRODUCT Otezla 10 mg tablets Otezla 20 mg tablets Otezla 30 mg tablets apremilast 2. NAME OF THE MARKETING AUTHORISATION HOLDER Amgen 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 30 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT Otezla 30 mg film–coated tablets apremilast 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 30 mg of apremilast. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Film-coated tablet 56 film-coated tablets 168 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For oral use. QR code to be included www.otezla-eu-pil.com 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 31 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061, 4817 ZK Breda, The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/14/981/002 56 film-coated tablets EU/1/14/981/003 168 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Otezla 30 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2 D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC SN NN 32 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Otezla 30 mg tablets apremilast 2. NAME OF THE MARKETING AUTHORISATION HOLDER Amgen 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 33 B. PACKAGE LEAFLET 34 Package leaflet: Information for the patient Otezla 10 mg film-coated tablets Otezla 20 mg film-coated tablets Otezla 30 mg film-coated tablets apremilast Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Otezla is and what it is used for 2. What you need to know before you take Otezla 3. How to take Otezla 4. Possible side effects 5. How to store Otezla 6. Contents of the pack and other information 1. What Otezla is and what it is used for What Otezla is Otezla contains the active substance ‘apremilast’. This belongs to a group of medicines called phosphodiesterase 4 inhibitors, which help to reduce inflammation. What Otezla is used for Otezla is used to treat adults with the following conditions:  Active psoriatic arthritis - if you cannot use another type of medicine called ‘Disease-Modifying Antirheumatic Drugs’ (DMARDs) or when you have tried one of these medicines and it did not work.  Moderate to severe chronic plaque psoriasis - if you cannot use one of the following treatments or when you have tried one of these treatments and it did not work: - phototherapy - a treatment where certain areas of skin are exposed to ultraviolet light - systemic therapy - a treatment that affects the entire body rather than just one local area, such as ‘ciclosporin’, ‘methotrexate’ or ‘psoralen ’.  Behçet’s disease (BD) - to treat the mouth ulcers which is a common problem for people with this illness. What psoriatic arthritis is Psoriatic arthritis is an inflammatory disease of the joints, usually accompanied by psoriasis, an inflammatory disease of the skin. 35 What plaque psoriasis is Psoriasis is an inflammatory disease of the skin, which can cause red, scaly, thick, itchy, painful patches on your skin and can also affect your scalp and nails. What Behçet’s disease is Behçet’s disease is a rare type of inflammatory disease which affects many parts of the body. The most common problem is mouth ulcers. How Otezla works Psoriatic arthritis, psoriasis and Behçet’s disease are usually lifelong conditions and there is currently no cure. Otezla works by reducing the activity of an enzyme in the body called ‘phosphodiesterase 4’, which is involved in the process of inflammation. By reducing the activity of this enzyme, Otezla can help to control the inflammation associated with psoriatic arthritis, psoriasis and Behçet’s disease, and thereby reduce the signs and symptoms of these conditions. In psoriatic arthritis, treatment with Otezla results in an improvement in swollen and painful joints, and can improve your general physical function. In psoriasis, treatment with Otezla results in a reduction in psoriatic skin plaques and other signs and symptoms of the disease. In Behçet’s disease, treatment with Otezla reduces the number of mouth ulcers and can stop them completely. It can also reduce the associated pain. Otezla has also been shown to improve the quality of life in patients with psoriasis, psoriatic arthritis or Behçet’s disease. This means that the impact of your condition on daily activities, relationships and other factors should be less than it was before. 2. What you need to know before you take Otezla Do not take Otezla:  if you are allergic to apremilast or any of the other ingredients of this medicine (listed in section 6).  if you are pregnant or think you may be pregnant. Warnings and precautions Talk to your doctor or pharmacist before taking Otezla. Depression and suicidal thoughts Tell your doctor before starting Otezla if you have depression which is getting worse with thoughts of suicide. You or your caregiver should also tell your doctor straight away of any changes in behaviour or mood, feelings of depression and of any suicidal thoughts you may have after taking Otezla. Severe kidney problems If you have severe kidney problems, your dose will be different – see section 3. 36 If you are underweight Talk to your doctor while taking Otezla if you lose weight without meaning to. Gut problems If you experience severe diarrhoea, nausea, or vomiting, you should talk to your doctor. Children and adolescents Otezla has not been studied in children and adolescents, therefore it is not recommended for use in children and adolescents aged 17 years and under. Other medicines and Otezla Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription and herbal medicines. This is because Otezla can affect the way some other medicines work. Also some other medicines can affect the way Otezla works. In particular, tell your doctor or pharmacist before taking Otezla if you are taking any of the following medicines:  rifampicin – an antibiotic used for tuberculosis  phenytoin, phenobarbital and carbamazepine - medicines used in the treatment of seizures or epilepsy  St John’s Wort – a herbal medicine for mild anxiety and depression. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. There is little information about the effects of Otezla in pregnancy. You should not become pregnant while taking this medicine and should use an effective method of contraception during treatment with Otezla. It is not known if this medicine passes into human milk. You should not use Otezla while breast- feeding. Driving and using machines Otezla has no effect on the ability to drive and use machines. Otezla contains lactose Otezla contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. 3. How to take Otezla Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. 37 How much to take  When you first start taking Otezla, you will receive a ‘treatment initiation pack’ which contains all the doses as listed in the table below.  The ‘treatment initiation pack’ is clearly labelled to make sure you take the correct tablet at the correct time.  Your treatment will start at a lower dose and will gradually be increased over the first 6 days of treatment.  The ‘treatment initiation pack’ will also contain enough tablets for another 8 days at the recommended dose (days 7 to 14).  The recommended dose of Otezla is 30 mg twice a day after the titration phase is complete - one 30 mg dose in the morning and one 30 mg dose in the evening, approximately 12 hours apart, with or without food.  This is a total daily dose of 60 mg. By the end of day 6 you will have reached this recommended dose.  Once the recommended dose has been reached, you will only get the 30 mg tablet strength in your prescribed packs. You will only ever need to go through this stage of gradually increasing your dose once even if you re-start treatment. People with severe kidney problems If you have severe kidney problems then the recommended dose of Otezla is 30 mg once a day (morning dose). Your doctor will talk to you about how to increase your dose when you first start taking Otezla. How and when to take Otezla  Otezla is for oral use.  Swallow the tablets whole, preferably with water.  You can take the tablets either with or without food.  Take Otezla at about the same time each day, one tablet in the morning and one tablet in the evening. If your condition has not improved after six months of treatment, you should talk to your doctor. If you take more Otezla than you should If you take more Otezla than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack and this leaflet with you. If you forget to take Otezla  If you miss a dose of Otezla, take it as soon as you remember. If it is close to the time for your next dose, just skip the missed dose. Take the next dose at your regular time.  Do not take a double dose to make up for a forgotten dose. Day Morning Dose Evening Dose Total Daily Dose Day 1 10 mg (pink) Do not take a dose 10 mg Day 2 10 mg (pink) 10 mg (pink) 20 mg Day 3 10 mg (pink) 20 mg (brown) 30 mg Day 4 20 mg (brown) 20 mg (brown) 40 mg Day 5 20 mg (brown) 30 mg (beige) 50 mg Day 6 onwards 30 mg (beige) 30 mg (beige) 60 mg 38 If you stop taking Otezla  You should continue taking Otezla until your doctor tells you to stop.  Do not stop taking Otezla without talking to your doctor first. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects – depression and suicidal thoughts Tell your doctor straight away about any changes in behaviour or mood, feelings of depression, thoughts of suicide or suicidal behaviour (this is uncommon). Very common side effects (may affect more than 1 in 10 people)  diarrhoea  nausea  headaches, migraines or tension headaches  upper respiratory tract infections such as cold, runny nose, sinus infection Common side effects (may affect up to 1 in 10 people)  cough  back pain  vomiting  feeling tired  stomach pain  loss of appetite  frequent bowel movements  difficulty sleeping (insomnia)  indigestion or heartburn  inflammation and swelling of the tubes in your lungs (bronchitis)  common cold (nasopharyngitis)  depression Uncommon side effects (may affect up to 1 in 100 people)  rash  hives (urticaria)  weight loss  allergic reaction  bleeding in the bowel or in the stomach  suicidal ideation or behaviour Not known side effects (frequency cannot be estimated from the available data):  severe allergic reaction (may include swelling of the face, lips, mouth, tongue, or throat that may lead to difficulty breathing or swallowing) If you are 65 years of age or older, you might have a higher risk of complications of severe diarrhoea, nausea and vomiting. If your gut problems become severe, you should talk to your doctor. 39 Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Otezla  Keep this medicine out of the sight and reach of children.  Do not use this medicine after the expiry date which is stated on the blister or on the wallet or on the carton after EXP. The expiry date refers to the last day of that month.  Do not store above 30°C.  Do not use this medicine if you notice any damage or signs of tampering to the medicine packaging. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Otezla contains The active substance is apremilast.  Otezla 10 mg film-coated tablets: each film-coated tablet contains 10 mg of apremilast.  Otezla 20 mg film-coated tablets: each film-coated tablet contains 20 mg of apremilast.  Otezla 30 mg film-coated tablets: each film-coated tablet contains 30 mg of apremilast. The other ingredients in the tablet core are cellulose microcrystalline, lactose monohydrate, croscarmellose sodium and magnesium stearate.  The film-coating contains poly (vinyl alcohol), titanium dioxide (E171), macrogol (3350), talc, iron oxide red (E172).  The 20 mg film-coated tablet also contains iron oxide yellow (E172).  The 30 mg film-coated tablet also contains iron oxide yellow (E172) and iron oxide black (E172). What Otezla looks like and contents of the pack The Otezla 10 mg film-coated tablet is a pink, diamond shaped film-coated tablet with “APR” engraved on one side and “10” on the opposite side. The Otezla 20 mg film-coated tablet is a brown, diamond shaped film-coated tablet with “APR” engraved on one side and “20” on the opposite side. The Otezla 30 mg film-coated tablet is a beige, diamond shaped film-coated tablet with “APR” engraved on one side and “30” on the opposite side. Pack sizes  The treatment initiation pack is a folding wallet containing 27 film-coated tablets: 4 x 10 mg tablets, 4 x 20 mg tablets and 19 x 30 mg tablets.  The one-month standard pack contains 56 x 30 mg film-coated tablets.  The three-month standard pack contains 168 x 30 mg film-coated tablets. 40 Marketing Authorisation Holder and Manufacturer Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands Marketing Authorisation Holder Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands Manufacturer Celgene Distribution B.V. Winthontlaan 6 N 3526 KV Utrecht Netherlands Manufacturer Amgen NV Telecomlaan 5-7 1831 Diegem Belgium For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien s.a. Amgen n.v. Tel/Tél: +32 (0)2 7752711 Lietuva Amgen Switzerland AG Vilniaus filialas Tel: +370 5 219 7474 България Амджен България ЕООД Тел.: +359 (0)2 424 7440 Luxembourg/Luxemburg s.a. Amgen Belgique/Belgien Tel/Tél: +32 (0)2 7752711 Česká republika Amgen s.r.o. Tel: +420 221 773 500 Magyarország Amgen Kft. Tel.: +36 1 35 44 700 Danmark Amgen, filial af Amgen AB, Sverige Tlf: +45 39617500 Malta Amgen B.V. The Netherlands Tel: +31 (0)76 5732500 Deutschland AMGEN GmbH Tel.: +49 89 1490960 Nederland Amgen B.V. Tel: +31 (0)76 5732500 Eesti Amgen Switzerland AG Vilniaus filialas Tel: +372 586 09553 Norge Amgen AB Tel: +47 23308000 41 Ελλάδα Genesis Pharma SA Τηλ: +30 210 8771500 Österreich Amgen GmbH Tel: +43 (0)1 50 217 España Amgen S.A. Tel: +34 93 600 18 60 Polska Amgen Biotechnologia Sp. z o.o. Tel.: +48 22 581 3000 France Amgen S.A.S. Tél: +33 (0)9 69 363 363 Portugal Amgen Biofarmacêutica, Lda. Tel: +351 21 4220606 Hrvatska Amgen d.o.o. Tel: +385 (0)1 562 57 20 România Genesis Biopharma România SRL Tel: +40 21 403 4074 Ireland Amgen Ireland Limited Tel: +353 1 8527400 Slovenija AMGEN zdravila d.o.o. Tel: +386 (0)1 585 1767 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Amgen Slovakia s.r.o. Tel: +421 2 321 114 49 Italia Amgen S.r.l. Tel: +39 02 6241121 Suomi/Finland Amgen AB, sivuliike Suomessa/Amgen AB, filial i Finland Puh/Tel: +358 (0)9 54900500 Kύπρος Genesis Pharma (Cyprus) Ltd Τηλ: +357 22765735 Sverige Amgen AB Tel: +46 (0)8 6951100 Latvija Amgen Switzerland AG Rīgas filiāle Tel: +371 257 25888 United Kingdom Amgen Limited Tel: +44 (0)1223 420305 This leaflet was last revised in Other sources of information Detailed and updated information on this medicine is available by scanning the QR code on the outer packaging with a smartphone. The same information is also available on the following URL: www.otezla-eu-pil.com. Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take otezla', 'Section_Content': "do not take otezla: if you are allergic to apremilast or any of the other ingredients of this medicine (listed in section 6). if you are pregnant or think you may be pregnant. warnings and precautions talk to your doctor or pharmacist before taking otezla. depression and suicidal thoughts tell your doctor before starting otezla if you have depression which is getting worse with thoughts of suicide. you or your caregiver should also tell your doctor straight away of any changes in behaviour or mood, feelings of depression and of any suicidal thoughts you may have after taking otezla. severe kidney problems if you have severe kidney problems, your dose will be different see section 3. if you are underweight talk to your doctor while taking otezla if you lose weight without meaning to. gut problems if you experience severe diarrhoea, nausea, or vomiting, you should talk to your doctor. children and adolescents otezla has not been studied in children and adolescents, therefore it is not recommended for use in children and adolescents aged 17 years and under. other medicines and otezla tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. this includes medicines obtained without a prescription and herbal medicines. this is because otezla can affect the way some other medicines work. also some other medicines can affect the way otezla works. in particular, tell your doctor or pharmacist before taking otezla if you are taking any of the following medicines: rifampicin an antibiotic used for tuberculosis phenytoin, phenobarbital and carbamazepine - medicines used in the treatment of seizures or epilepsy st john's wort a herbal medicine for mild anxiety and depression. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. there is little information about the effects of otezla in pregnancy. you should not become pregnant while taking this medicine and should use an effective method of contraception during treatment with otezla. it is not known if this medicine passes into human milk. you should not use otezla while breast- feeding. driving and using machines otezla has no effect on the ability to drive and use machines. otezla contains lactose otezla contains lactose (a type of sugar). if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.", 'Entity_Recognition': [{'Text': 'otezla', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 3, 'BeginOffset': 12, 'EndOffset': 18, 'Score': 0.9590954780578613, 'Text': 'otezla', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.604983389377594}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 31, 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{'Title': '3. how to take otezla', 'Section_Content': "always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. how much to take when you first start taking otezla, you will receive a 'treatment initiation pack' which contains all the doses as listed in the table below. the 'treatment initiation pack' is clearly labelled to make sure you take the correct tablet at the correct time. your treatment will start at a lower dose and will gradually be increased over the first 6 days of treatment. the 'treatment initiation pack' will also contain enough tablets for another 8 days at the recommended dose (days 7 to 14). the recommended dose of otezla is 30 mg twice a day after the titration phase is complete - one 30 mg dose in the morning and one 30 mg dose in the evening, approximately 12 hours apart, with or without food. this is a total daily dose of 60 mg. by the end of day 6 you will have reached this recommended dose. once the recommended dose has been reached, you will only get the 30 mg tablet strength in your prescribed packs. you will only ever need to go through this stage of gradually increasing your dose once even if you re-start treatment. people with severe kidney problems if you have severe kidney problems then the recommended dose of otezla is 30 mg once a day (morning dose). your doctor will talk to you about how to increase your dose when you first start taking otezla. how and when to take otezla otezla is for oral use. swallow the tablets whole, preferably with water. you can take the tablets either with or without food. take otezla at about the same time each day, one tablet in the morning and one tablet in the evening. if your condition has not improved after six months of treatment, you should talk to your doctor. if you take more otezla than you should if you take more otezla than you should, talk to a doctor or go to a hospital straight away. take the medicine pack and this leaflet with you. if you forget to take otezla if you miss a dose of otezla, take it as soon as you remember. if it is close to the time for your next dose, just skip the missed dose. take the next dose at your regular time. do not take a double dose to make up for a forgotten dose. day morning dose evening dose total daily dose day 1 10 mg (pink) do not take a dose 10 mg day 2 10 mg (pink) 10 mg (pink) 20 mg day 3 10 mg (pink) 20 mg (brown) 30 mg day 4 20 mg (brown) 20 mg (brown) 40 mg day 5 20 mg (brown) 30 mg (beige) 50 mg day 6 onwards 30 mg (beige) 30 mg (beige) 60 mg 38 if you stop taking otezla you should continue taking otezla until your doctor tells you to stop. do not stop taking otezla without talking to your doctor first. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.", 'Entity_Recognition': [{'Text': 'otezla', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects depression and suicidal thoughts tell your doctor straight away about any changes in behaviour or mood, feelings of depression, thoughts of suicide or suicidal behaviour (this is uncommon). very common side effects (may affect more than 1 in 10 people) diarrhoea nausea headaches, migraines or tension headaches upper respiratory tract infections such as cold, runny nose, sinus infection common side effects (may affect up to 1 in 10 people) cough back pain vomiting feeling tired stomach pain loss of appetite frequent bowel movements difficulty sleeping (insomnia) indigestion or heartburn inflammation and swelling of the tubes in your lungs (bronchitis) common cold (nasopharyngitis) depression uncommon side effects (may affect up to 1 in 100 people) rash hives (urticaria) weight loss allergic reaction bleeding in the bowel or in the stomach suicidal ideation or behaviour not known side effects (frequency cannot be estimated from the available data): severe allergic reaction (may include swelling of the face, lips, mouth, tongue, or throat that may lead to difficulty breathing or swallowing) if you are 65 years of age or older, you might have a higher risk of complications of severe diarrhoea, nausea and vomiting. if your gut problems become severe, you should talk to your doctor. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'otezla', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 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allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 893, 'EndOffset': 922}, {'Text': 'bleeding in the bowel', 'Type': 'PROBLEM', 'BeginOffset': 923, 'EndOffset': 944}, {'Text': 'the stomach suicidal ideation', 'Type': 'PROBLEM', 'BeginOffset': 951, 'EndOffset': 980}, {'Id': 67, 'BeginOffset': 1004, 'EndOffset': 1016, 'Score': 0.8512343168258667, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8586574792861938}]}, {'Id': 68, 'BeginOffset': 1018, 'EndOffset': 1027, 'Score': 0.49455660581588745, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.49359214305877686}]}, {'Text': 'severe allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 1074, 'EndOffset': 1098}, {'Text': 'swelling of the face, lips, mouth, tongue, or throat', 'Type': 'PROBLEM', 'BeginOffset': 1112, 'EndOffset': 1164}, {'Id': 71, 'BeginOffset': 1182, 'EndOffset': 1202, 'Score': 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problems', 'Type': 'PROBLEM', 'BeginOffset': 1346, 'EndOffset': 1363}, {'Id': 76, 'BeginOffset': 1424, 'EndOffset': 1436, 'Score': 0.9432429671287537, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8026196956634521}]}, {'Id': 77, 'BeginOffset': 1452, 'EndOffset': 1464, 'Score': 0.9159954190254211, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7696986198425293}]}, {'Id': 78, 'BeginOffset': 1535, 'EndOffset': 1547, 'Score': 0.9484518766403198, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6539139747619629}]}, {'Id': 79, 'BeginOffset': 1596, 'EndOffset': 1608, 'Score': 0.8524872064590454, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.706152081489563}]}, {'Id': 80, 'BeginOffset': 1662, 'EndOffset': 1673, 'Score': 0.35049691796302795, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6257410645484924}]}, {'Id': 81, 'BeginOffset': 1687, 'EndOffset': 1699, 'Score': 0.8497077226638794, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7426379323005676}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1755, 'EndOffset': 1768}]}

{'Title': '5. how to store otezla', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister or on the wallet or on the carton after exp. the expiry date refers to the last day of that month. do not store above 30. do not use this medicine if you notice any damage or signs of tampering to the medicine packaging. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'otezla', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 71, 'EndOffset': 84}, {'Text': 'the blister', 'Type': 'PROBLEM', 'BeginOffset': 126, 'EndOffset': 137}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 256, 'EndOffset': 259}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 271, 'EndOffset': 284}, {'Text': 'any damage', 'Type': 'PROBLEM', 'BeginOffset': 299, 'EndOffset': 309}, {'Text': 'the medicine packaging', 'Type': 'TREATMENT', 'BeginOffset': 335, 'EndOffset': 357}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what otezla contains the active substance is apremilast. otezla 10 mg film-coated tablets: each film-coated tablet contains 10 mg of apremilast. otezla 20 mg film-coated tablets: each film-coated tablet contains 20 mg of apremilast. otezla 30 mg film-coated tablets: each film-coated tablet contains 30 mg of apremilast. the other ingredients in the tablet core are cellulose microcrystalline, lactose monohydrate, croscarmellose sodium and magnesium stearate. the film-coating contains poly (vinyl alcohol), titanium dioxide (e171), macrogol (3350), talc, iron oxide red (e172). the 20 mg film-coated tablet also contains iron oxide yellow (e172). the 30 mg film-coated tablet also contains iron oxide yellow (e172) and iron oxide black (e172). what otezla looks like and contents of the pack the otezla 10 mg film-coated tablet is a pink, diamond shaped film-coated tablet with "apr" engraved on one side and "10" on the opposite side. the otezla 20 mg film-coated tablet is a brown, diamond shaped film-coated tablet with "apr" engraved on one side and "20" on the opposite side. the otezla 30 mg film-coated tablet is a beige, diamond shaped film-coated tablet with "apr" engraved on one side and "30" on the opposite side. pack sizes the treatment initiation pack is a folding wallet containing 27 film-coated tablets: 4 x 10 mg tablets, 4 x 20 mg tablets and 19 x 30 mg tablets. the one-month standard pack contains 56 x 30 mg film-coated tablets. the three-month standard pack contains 168 x 30 mg film-coated tablets.', 'Entity_Recognition': [{'Text': 'otezla', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 3, 'BeginOffset': 5, 'EndOffset': 11, 'Score': 0.9169083833694458, 'Text': 'otezla', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 45, 'EndOffset': 55, 'Score': 0.5882656574249268, 'Text': 'apremilast', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.6955565810203552, 'RelationshipScore': 0.9984675049781799, 'RelationshipType': 'FORM', 'Id': 7, 'BeginOffset': 70, 'EndOffset': 74, 'Text': 'film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7538915276527405, 'RelationshipScore': 0.9968616962432861, 'RelationshipType': 'FORM', 'Id': 8, 'BeginOffset': 75, 'EndOffset': 89, 'Text': 'coated tablets', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.2932320535182953, 'RelationshipScore': 0.9939988851547241, 'RelationshipType': 'FORM', 'Id': 9, 'BeginOffset': 91, 'EndOffset': 100, 'Text': 'each film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.8506167531013489, 'RelationshipScore': 0.8321945667266846, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 101, 'EndOffset': 114, 'Text': 'coated tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.3531412184238434, 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'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.2932320535182953, 'RelationshipScore': 0.9926421046257019, 'RelationshipType': 'FORM', 'Id': 9, 'BeginOffset': 91, 'EndOffset': 100, 'Text': 'each film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.8506167531013489, 'RelationshipScore': 0.5792691707611084, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 101, 'EndOffset': 114, 'Text': 'coated tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 64, 'EndOffset': 66}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 124, 'EndOffset': 126}, {'Id': 12, 'BeginOffset': 133, 'EndOffset': 143, 'Score': 0.5051588416099548, 'Text': 'apremilast', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.6955565810203552, 'RelationshipScore': 0.7338343262672424, 'RelationshipType': 'FORM', 'Id': 7, 'BeginOffset': 70, 'EndOffset': 74, 'Text': 'film', 'Category': 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36D957BB334DB6054C51CE128D9E6B08

https://www.ema.europa.eu/documents/product-information/equidacent-epar-product-information_en.pdf

Equidacent

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Equidacent 25 mg/mL concentrate for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of concentrate contains 25 mg of bevacizumab*. Each vial of 4 mL of concentrate contains 100 mg of bevacizumab. Each vial of 16 mL of concentrate contains 400 mg of bevacizumab. For dilution and other handling recommendations, see section 6.6. *Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese Hamster Ovary cells. Excipient(s) with known effect Each vial of 4 mL of concentrate contains 191 mg sorbitol (E420). Each vial of 16 mL of concentrate contains 764 mg sorbitol (E420). For the full list of excipients see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion. Clear to opalescent, colourless to pale brownish-yellowish solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum. Bevacizumab in combination with paclitaxel is indicated for first-line treatment of adult patients with metastatic breast cancer. For further information as to human epidermal growth factor receptor 2 (HER2) status, please refer to section 5.1. Bevacizumab in combination with capecitabine is indicated for first-line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline- containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Equidacent in combination with capecitabine. For further information as to HER2 status, please refer to section 5.1. Bevacizumab, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. 3 Bevacizumab, in combination with erlotinib, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations (see section 5.1). Bevacizumab in combination with interferon alfa-2a is indicated for first-line treatment of adult patients with advanced and/or metastatic renal cell cancer. Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer (see section 5.1). Bevacizumab, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel, is indicated for treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. Bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix (see section 5.1). 4.2 Posology and method of administration Equidacent must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products. Posology Metastatic carcinoma of the colon or rectum (mCRC) The recommended dose of Equidacent, administered as an intravenous infusion, is either 5 mg/kg or 10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity. Metastatic breast cancer (mBC) The recommended dose of Equidacent is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity. Non-small cell lung cancer (NSCLC) First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy Equidacent is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Equidacent as a single agent until disease progression. The recommended dose of Equidacent is 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses (see section 5.1). 4 It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity. First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with erlotinib EGFR mutation testing should be performed prior to initiation of treatment with the combination of Equidacent and erlotinib. It is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations. The recommended dose of Equidacent when used in addition to erlotinib is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. It is recommended that the treatment with Equidacent in addition to erlotinib is continued until disease progression. For the posology and method of administration of erlotinib, please refer to the full erlotinib prescribing information. Advanced and/or metastatic renal cell cancer (mRCC) The recommended dose of Equidacent is 10 mg/kg of body weight given once every 2 weeks as an intravenous infusion. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity. Epithelial ovarian, fallopian tube and primary peritoneal cancer Front-line treatment: Equidacent is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Equidacent as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier. The recommended dose of Equidacent is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. Treatment of platinum-sensitive recurrent disease: Equidacent is administered in combination with either carboplatin and gemcitabine for 6 cycles and up to 10 cycles or in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Equidacent as single agent until disease progression. The recommended dose of Equidacent is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. Cervical cancer Equidacent is administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin or paclitaxel and topotecan. The recommended dose of Equidacent is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity (see section 5.1). Special populations Elderly: No dose adjustment is required in the elderly. 5 Renal impairment: The safety and efficacy have not been studied in patients with renal impairment (see section 5.2). Hepatic impairment: The safety and efficacy have not been studied in patients with hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of bevacizumab in children less than 18 years old have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made. There is no relevant use of bevacizumab in the paediatric population in the indications for treatment of cancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney. Method of administration Equidacent is for intravenous use. The initial dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. It should not be administered as an intravenous push or bolus. Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended as described in section 4.4. Precautions to be taken before handling or administering the medicinal product For instructions on dilution of the medicinal product before administration, see section 6.6. Equidacent infusions should not be administered or mixed with glucose solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 4.3 Contraindications • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies. • Pregnancy (see section 4.6). 4.4 Special warnings and precautions for use In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file. Gastrointestinal (GI) perforations and Fistulae (see section 4.8) Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation when treated with bevacizumab. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with Equidacent and all patients with GI perforation had a history of prior radiation. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation. GI-vaginal Fistulae in study GOG-0240 6 Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab are at increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with GI-vaginal fistulae had a history of prior radiation. Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae. Non-GI Fistulae (see section 4.8) Patients may be at increased risk for the development of fistulae when treated with bevacizumab. Permanently discontinue Equidacent in patients with tracheoesophageal (TE) fistula or any grade 4 fistula [US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI- CTCAE v.3)]. Limited information is available on the continued use of bevacizumab in patients with other fistulae. In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Equidacent should be considered. Wound healing complications (see section 4.8) Bevacizumab may adversely affect the wound healing process. Serious wound healing complications, including anastomotic complications, with a fatal outcome have been reported. Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing complications during therapy, treatment should be withheld until the wound is fully healed. Therapy should be withheld for elective surgery. Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with bevacizumab. This condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Equidacent therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated. Hypertension (see section 4.8) An increased incidence of hypertension was observed in bevacizumab-treated patients. Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should be adequately controlled before starting Equidacent treatment. There is no information on the effect of bevacizumab in patients with uncontrolled hypertension at the time of initiating therapy. Monitoring of blood pressure is generally recommended during therapy. In most cases hypertension was controlled adequately using standard antihypertensive treatment appropriate for the individual situation of the affected patient. The use of diuretics to manage hypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen. Equidacent should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy. Posterior Reversible Encephalopathy Syndrome (PRES) (see section 4.8) There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are consistent with PRES, a rare neurologic disorder, which can present with the following signs and symptoms among others: seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of Equidacent. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known. Proteinuria (see section 4.8) 7 Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with bevacizumab. There is evidence suggesting that all grade (US National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE v.3]) proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patients treated with bevacizumab. Therapy should be permanently discontinued in patients who develop nephrotic syndrome (NCI-CTCAE v.3). Arterial thromboembolism (see section 4.8) In clinical trials, the incidence of arterial thromboembolic reactions including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients receiving bevacizumab in combination with chemotherapy compared to those who received chemotherapy alone. Patients receiving bevacizumab plus chemotherapy, with a history of arterial thromboembolism, diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolic reactions during therapy. Caution should be taken when treating these patients with Equidacent. Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions. Venous thromboembolism (see section 4.8) Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism under bevacizumab treatment. Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab in combination with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events. Equidacent should be discontinued in patients with life-threatening (grade 4) thromboembolic reactions, including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions ≤ grade 3 need to be closely monitored (NCI-CTCAE v.3). Haemorrhage Patients treated with bevacizumab have an increased risk of haemorrhage, especially tumour- associated haemorrhage. Equidacent should be discontinued permanently in patients who experience grade 3 or 4 bleeding during bevacizumab therapy (NCI-CTCAE v.3) (see section 4.8). Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patients has not been prospectively evaluated in randomised clinical trials (see section 4.8). Patients should be monitored for signs and symptoms of CNS bleeding, and Equidacent treatment discontinued in cases of intracranial bleeding. There is no information on the safety profile of bevacizumab in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting bevacizumab treatment, as such patients were excluded from clinical trials. Therefore, caution should be exercised before initiating therapy in these patients. However, patients who developed venous thrombosis while receiving therapy did not appear to have an increased rate of grade 3 or above bleeding when treated with a full dose of warfarin and bevacizumab concomitantly (NCI-CTCAE v.3). Pulmonary haemorrhage/haemoptysis 8 Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/haemoptysis (> 2.5 mL of red blood) should not be treated with bevacizumab. Aneurysms and artery dissections The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Equidacent, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. Congestive heart failure (CHF) (see section 4.8) Reactions consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with bevacizumab. Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were present. In patients in AVF3694g who received treatment with anthracyclines and who had not received anthracyclines before, no increased incidence of all grade CHF was observed in the anthracycline + bevacizumab group compared to the treatment with anthracyclines only. CHF grade 3 or higher reactions were somewhat more frequent among patients receiving bevacizumab in combination with chemotherapy than in patients receiving chemotherapy alone. This is consistent with results in patients in other studies of metastatic breast cancer who did not receive concurrent anthracycline treatment (NCI-CTCAE v.3) (see section 4.8). Neutropenia and infections (see section 4.8) Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy alone. This has mainly been seen in combination with platinum- or taxane-based therapies in the treatment of NSCLC, mBC, and in combination with paclitaxel and topotecan in persistent, recurrent, or metastatic cervical cancer. Hypersensitivity reactions/infusion reactions (see section 4.8) Patients may be at risk of developing infusion/hypersensitivity reactions. Close observation of the patient during and following the administration of bevacizumab is recommended as expected for any infusion of a therapeutic humanised monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted. Osteonecrosis of the jaw (ONJ) (see section 4.8) Cases of ONJ have been reported in cancer patients treated with bevacizumab, the majority of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when bevacizumab and intravenous bisphosphonates are administered simultaneously or sequentially. Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with Equidacent. In patients who have previously received or are receiving intravenous bisphosphonates invasive dental procedures should be avoided, if possible. 9 Intravitreal use Equidacent is not formulated for intravitreal use. Eye disorders Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intravitreal use of bevacizumab compounded from vials approved for intravenous administration in cancer patients. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted in various degrees of visual loss, including permanent blindness. Systemic effects following intravitreal use A reduction of circulating VEGF concentration has been demonstrated following intravitreal anti- VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages and arterial thromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors. Ovarian failure/fertility Bevacizumab may impair female fertility (see sections 4.6 and 4.8). Therefore fertility preservation strategies should be discussed with women of childbearing potential prior to starting treatment with bevacizumab. Excipients with known effect Sorbitol This medicinal product contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Effect of antineoplastic agents on bevacizumab pharmacokinetics No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokinetics was observed based on the results of population pharmacokinetic analyses. There were neither statistically significant nor clinically relevant differences in bevacizumab clearance in patients receiving bevacizumab monotherapy compared to patients receiving bevacizumab in combination with interferon alfa-2a, erlotinib or chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/gemcitabine). Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of co- administered interferon alfa 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurement of free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn. Combination of bevacizumab and sunitinib malate In two clinical trials of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia (MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) and sunitinib malate (50 mg daily) combination. 10 MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, and thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms were observed in some of these patients. All of these findings were reversible upon discontinuation of bevacizumab and sunitinib malate (see Hypertension, Proteinuria, PRES in section 4.4). Combination with platinum- or taxane-based therapies (see sections 4.4 and 4.8) Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed mainly in patients treated with platinum- or taxane-based therapies in the treatment of NSCLC and mBC. Radiotherapy The safety and efficacy of concomitant administration of radiotherapy and bevacizumab has not been established. EGFR monoclonal antibodies in combination with bevacizumab chemotherapy regimens No interaction studies have been performed. EGFR monoclonal antibodies should not be administered for the treatment of mCRC in combination with bevacizumab-containing chemotherapy. Results from the randomised phase III studies, PACCE and CAIRO-2, in patients with mCRC suggest that the use of anti-EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination with bevacizumab plus chemotherapy, is associated with decreased PFS and/or OS, and with increased toxicity compared with bevacizumab plus chemotherapy alone. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Pregnancy There are no clinical trial data on the use of bevacizumab in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). IgGs are known to cross the placenta, and bevacizumab is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to cause serious birth defects when administered during pregnancy. In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.8). Equidacent is contraindicated in pregnancy (see section 4.3). Breast-feeding It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and bevacizumab could harm infant growth and development (see section 5.3), women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of bevacizumab. Fertility Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility (see section 5.3). In a phase III trial in the adjuvant treatment of patients with colon cancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After discontinuation of 11 bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of the treatment with bevacizumab on fertility are unknown. 4.7 Effects on ability to drive and use machines Bevacizumab has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with bevacizumab use (see table 1 in section 4.8). If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate. 4.8 Undesirable effects Summary of the safety profile The overall safety profile of bevacizumab is based on data from over 5,700 patients with various malignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinical trials. The most serious adverse reactions were: • Gastrointestinal perforations (see section 4.4). • Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non- small cell lung cancer patients (see section 4.4). • Arterial thromboembolism (see section 4.4). The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab were hypertension, fatigue or asthenia, diarrhoea and abdominal pain. Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with bevacizumab therapy are likely to be dose-dependent. Tabulated list of adverse reactions The adverse reactions listed in this section fall into the following frequency categories: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Tables 1 and 2 list adverse reactions associated with the use of bevacizumab in combination with different chemotherapy regimens in multiple indications. Table 1 provides all adverse reactions by frequency that were determined to have a causal relationship with bevacizumab through: • comparative incidences noted between clinical trial treatment arms (with at least a 10% difference compared to the control arm for NCI-CTCAE grade 1-5 reactions or at least a 2% difference compared to the control arm for NCI-CTCAE grade 3-5 reactions), • post-authorisation safety studies, • spontaneous reporting, • epidemiological studies/non-interventional or observational studies, • or through an evaluation of individual case reports. Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE grade 3-5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe. Post-marketing adverse reactions are included in both tables 1 and 2, where applicable. Detailed information about these post-marketing reactions are provided in table 3. 12 Adverse reactions are added to the appropriate frequency category in the tables below according to the highest incidence seen in any indication. Within each frequency category, adverse reactions are presented in the order of decreasing seriousness. Some of the adverse reactions are reactions commonly seen with chemotherapy; however, bevacizumab may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel and paronychia with erlotinib. Table 1. Adverse reactions by frequency System organ class Very common Common Uncommon Rare Very rare Frequency not known Infections and infestations Sepsis, Abscessb,d, Cellulitis, Infection, Urinary tract infection Necrotising fasciitisa Blood and lymphatic system disorders Febrile neutropenia, Leucopenia, Neutropeniab Thrombocytopeni a Anaemia, Lymphopenia Immune system disorders Hypersensitivity, Infusion reactionsa,b,d Metabolism and nutrition disorders Anorexia Hypomagnesaemi a Hyponatraemia Dehydration Nervous system disorders Peripheral sensory neuropathyb, Dysarthria, Headache, Dysguesia Cerebrovascular accident, Syncope, Somnolence Posterior reversible encephalopath y syndromea,b,d Hypertensive encephalo- pathya Eye disorders Eye disorder, Lacrimation increased Cardiac disorders Congestive heart failureb,d, Supraventricular tachycardia Vascular disorders Hypertensionb,d, Thromboembolis m (venous)b,d Thromboembolis m (arterial)b,d, Haemorrhageb,d, Deep vein thrombosis Renal thrombotic microangiopathya, b Aneurysms and artery dissections Respiratory, thoracic and mediastinal disorders Dyspnoea, Rhinitis, Epistaxis, Cough Pulmonary haemorrhage/ Haemoptysisb,d, Pulmonary embolism, Hypoxia, Dysphoniaa Pulmonary hypertensiona, Nasal septum perforationa Gastrointestinal disorders Rectal haemorrhage, Stomatitis, Constipation, Diarrhoea, Nausea, Vomiting, Abdominal pain Gastrointestinal perforationb,d, Intestinal perforation, Ileus, Intestinal obstruction, Recto-vaginal fistulaed,e, Gastrointestinal Gastrointestinal ulcera 13 System organ class Very common Common Uncommon Rare Very rare Frequency not known disorder, Proctalgia Hepatobiliary disorders Gallbladder perforationa,b Skin and subcutaneous tissue disorders Wound healing complicationsb,d, Exfoliative dermatitis, Dry skin, Skin discolouration Palmar-plantar erythrodysaesthesi a syndrome Musculoskeleta l and connective tissue disorders Arthralgia, Myalgia Fistulab,d, Muscular weakness, Back pain Osteonecrosis of the jawa,b, Non- mandibular osteonecrosisa,f Renal and urinary disorders Proteinuriab,d Reproductive system and breast disorders Ovarian failureb,c,d Pelvic pain Congenital, familial, and genetic disorders Foetal abnormalitiesa,b General disorders and administration site conditions Asthenia, Fatigue, Pyrexia, Pain, Mucosal inflammation Lethargy Investigations Weight decreased When events were noted as both all grade and grade 3-5 adverse drug reactions in clinical trials, the highest frequency observed in patients has been reported. Data are unadjusted for the differential time on treatment. a For further information please refer to table 3 “Adverse reactions reported in post-marketing setting”. b Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions). c Based on a substudy from NSABP C-08 with 295 patients. d For additional information refer below within section "Description of selected serious adverse reactions". e Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category. f Observed in paediatric population only. Table 2. Severe adverse reactions by frequency System organ class Very common Common Uncommon Rare Very rare Frequency not known Infections and infestations Sepsis, Cellulitis, Abscessa,b, Infection, Urinary tract infection Necrotising fasciitisc Blood and lymphatic Febrile neutropenia, Leucopenia, Anaemia, Lymphopenia 14 System organ class Very common Common Uncommon Rare Very rare Frequency not known system disorders Neutropeniaa, Thrombocytop enia Immune system disorders Hypersensitivity, Infusion reactionsa,b,c Metabolism and nutrition disorders Dehydration, Hyponatraemia Nervous system disorders Peripheral sensory neuropathya Cerebrovascular accident, Syncope, Somnolence, Headache Posterior reversible encephalopathy syndromea,b,c, Hypertensive encephalopathyc Cardiac disorders Congestive heart failurea,b, Supraventricular tachycardia Vascular disorders Hypertensiona,b Thromboemboli sm arteriala,b, Haemorrhagea,b, Thromboemboli sm (venous)a,b, Deep vein thrombosis Renal thrombotic microangiopathy b,c Aneurysms and artery dissections Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage/ Haemoptysisa,b, Pulmonary embolism, Epistaxis, Dyspnoea, Hypoxia Pulmonary hypertensionc, Nasal septum perforationc Gastro- intestinal disorders Diarrhoea, Nausea, Vomiting, Abdominal pain Intestinal perforation, Ileus, Intestinal obstruction, Recto-vaginal fistulaec,d, Gastrointestinal disorder, Stomatitis, Proctalgia Gastrointestinal perforationa,b, Gastrointestinal ulcerc, Rectal haemorrhage Hepatobiliary disorders Gallbladder perforationb,c Skin and subcutaneous tissue disorders Wound healing complicationsa,b, Palmar-plantar erythro- dysaesthesia syndrome Musculo- skeletal and Fistulaa,b, Myalgia, Osteonecrosis of the jawb,c 15 System organ class Very common Common Uncommon Rare Very rare Frequency not known connective tissue disorders Arthralgia, Muscular weakness, Back pain Renal and urinary disorders Proteinuriaa,b Reproductive system and breast disorders Pelvic pain Ovarian failurea,b Congenital, familial, and genetic disorder Foetal abnormalitiesa,c General disorders and administratio n site conditions Asthenia, Fatigue Pain, Lethargy, Mucosal inflammation Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE grade 3-5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe. These clinically significant adverse reactions were reported in clinical trials but the grade 3-5 reactions did not meet the threshold of at least a 2% difference compared to the control arm. Table 2 also includes clinically significant adverse reactions that were observed only in the post-marketing setting, therefore, the frequency and NCI-CTCAE grade is not known. These clinically significant reactions have therefore been included in table 2 within the column entitled “Frequency not known”. a Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions). b For additional information refer below within section "Description of selected serious adverse reactions". c For further information please refer to table 3 “Adverse reactions reported in post-marketing setting”. d Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category. Description of selected serious adverse reactions Gastrointestinal (GI) perforations and Fistulae (see section 4.4) Bevacizumab has been associated with serious cases of gastrointestinal perforation. Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in patients with non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breast cancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG- 0240), GI perforations (all grade) were reported in 3.2% of patients, all of whom had a history of prior pelvic radiation. 16 The occurrence of those events varied in type and severity, ranging from free air seen on the plain abdominal X-ray, which resolved without treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases underlying intra-abdominal inflammation was present, either from gastric ulcer disease, tumour necrosis, diverticulitis, or chemotherapy-associated colitis. Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents between 0.2%-1% of all bevacizumab-treated patients. In bevacizumab clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported less commonly in patients with other types of cancer. GI-vaginal Fistulae in study GOG-0240 In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI- vaginal fistulae was 8.3% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with bevacizumab + chemotherapy was higher in patients with recurrence within the field of prior radiation (16.7%) compared with patients with no prior radiation and/or no recurrence inside the field of prior radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies. Non-GI Fistulae (see section 4.4) Bevacizumab use has been associated with serious cases of fistulae including reactions resulting in death. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-240), 1.8% of bevacizumab-treated patients and 1.4% of control patients were reported to have had non- gastrointestinal vaginal, vesical, or female genital tract fistulae. Uncommon (≥ 0.1% to < 1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract (e.g. bronchopleural and biliary fistulae) were observed across various indications. Fistulae have also been reported in post-marketing experience. Reactions were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of bevacizumab, with most reactions occurring within the first 6 months of therapy. Wound healing (see section 4.4) As bevacizumab may adversely impact wound healing, patients who had major surgery within the last 28 days were excluded from participation in phase III clinical trials. In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk of post- operative bleeding or wound healing complications observed in patients who underwent major surgery 28-60 days prior to starting bevacizumab. An increased incidence of post-operative bleeding or wound healing complication occurring within 60 days of major surgery was observed if the patient was being treated with bevacizumab at the time of surgery. The incidence varied between 10% (4/40) and 20% (3/15). Serious wound healing complications, including anastomotic complications, have been reported, some of which had a fatal outcome. 17 In locally recurrent and metastatic breast cancer trials, grade 3-5 wound healing complications were observed in up to 1.1% of patients receiving bevacizumab compared with up to 0.9% of patients in the control arms (NCI-CTCAE v.3). In clinical trials of ovarian cancer, grade 3-5 wound healing complications were observed in up to 1.8% of patients in the bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3). Hypertension (see section 4.4) In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all grades) ranged up to 42.1% in the bevacizumab-containing arms compared with up to 14% in the control arms. The overall incidence of NCI-CTC grade 3 and 4 hypertension in patients receiving bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with bevacizumab and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy alone. In study JO25567, all grade hypertension was observed in 77.3% of the patients who received bevacizumab in combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFR activating mutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was 60.0% in patients treated with bevacizumab in combination with erlotinib compared to 11.7% in patients treated with erlotinib alone. There were no grade 4 or 5 hypertension events. Hypertension was generally adequately controlled with oral anti-hypertensives such as angiotensin- converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation of bevacizumab treatment or hospitalisation. Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal. The risk of bevacizumab-associated hypertension did not correlate with the patients’ baseline characteristics, underlying disease or concomitant therapy. Posterior reversible encephalopathy syndrome (see section 4.4) There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are consistent with PRES, a rare neurological disorder. Presentation may include seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. The clinical presentation of PRES is often nonspecific, and therefore the diagnosis of PRES requires confirmation by brain imaging, preferably MRI. In patients developing PRES, early recognition of symptoms with prompt treatment of specific symptoms including control of hypertension (if associated with severe uncontrolled hypertension) is recommended in addition to discontinuation of bevacizumab therapy. Symptoms usually resolve or improve within days after treatment discontinuation, although some patients have experienced some neurologic sequelae. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known. Across clinical trials, 8 cases of PRES have been reported. Two of the eight cases did not have radiological confirmation via MRI. Proteinuria (see section 4.4) In clinical trials, proteinuria has been reported within the range of 0.7% to 54.7% of patients receiving bevacizumab. Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up 18 to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of Equidacent therapy. In most clinical trials urine protein levels of ≥ 2g/24 hrs led to stopping treatment with bevacizumab until recovery to < 2g/24 hrs. Haemorrhage (see section 4.4) In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 grade 3-5 bleeding reactions ranged from 0.4% to 6.9% in bevacizumab-treated patients, compared with up to 4.5% of patients in the chemotherapy control group. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG- 0240), grade 3-5 bleeding reactions have been reported in up to 8.3% of patients treated with bevacizumab in combination with paclitaxel and topotecan compared with up to 4.6% of patients treated with paclitaxel and topotecan. The haemorrhagic reactions that have been observed in clinical trials were predominantly tumour- associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e.g. epistaxis). Tumour-associated haemorrhage (see section 4.4) Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials in patients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cell histology, treatment with antirheumatic/anti-inflammatory substances, treatment with anticoagulants, prior radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy. The only variables that showed statistically significant correlations with bleeding were bevacizumab therapy and squamous cell histology. Patients with NSCLC of known squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from subsequent phase III trials, while patients with unknown tumour histology were included. In patients with NSCLC excluding predominant squamous histology, all grade reactions were seen with a frequency of up to 9.3% when treated with bevacizumab plus chemotherapy compared with up to 5% in the patients treated with chemotherapy alone. Grade 3-5 reactions have been observed in up to 2.3% of patients treated with bevacizumab plus chemotherapy as compared with < 1% with chemotherapy alone (NCI-CTCAE v.3). Major or massive pulmonary haemorrhage/haemoptysis can occur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in a fatal outcome. Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in colorectal cancer patients, and have been assessed as tumour-associated haemorrhages. Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including cases of central nervous system (CNS) bleeding in patients with CNS metastases (see section 4.4). The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has not been prospectively evaluated in randomised clinical trials. In an exploratory retrospective analysis of data from 13 completed randomised trials in patients with various tumour types, 3 patients out of 91 (3.3%) with brain metastases experienced CNS bleeding (all grade 4) when treated with bevacizumab, compared to 1 case (grade 5) out of 96 patients (1%) that were not exposed to bevacizumab. In two subsequent studies in patients with treated brain metastases (which included around 800 patients), one case of grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim safety analysis (NCI-CTCAE v.3). Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of bevacizumab- treated patients. These were most commonly NCI-CTCAE v.3 grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any changes in the bevacizumab 19 treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous haemorrhage (e.g. epistaxis) may be dose-dependent. There have also been less common reactions of minor mucocutaneous haemorrhage in other locations, such as gingival bleeding or vaginal bleeding. Thromboembolism (see section 4.4) Arterial thromboembolism: An increased incidence of arterial thromboembolic reactions was observed in patients treated with bevacizumab across indications, including cerebrovascular accidents, myocardial infarction, transient ischaemic attacks, and other arterial thromboembolic reactions. In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the bevacizumab-containing arms compared with up to 2.1% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving bevacizumab compared to 0.5% in patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were reported in up to 2.7% of patients treated with bevacizumab in combination with chemotherapy compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in up to 1.4% of patients treated with bevacizumab in combination with chemotherapy compared to up to 0.7% of patients treated with chemotherapy alone. In one clinical trial evaluating bevacizumab in combination with 5-fluorouracil/folinic acid, AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan were included. In this trial arterial thromboembolic reactions were observed in 11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy control group. Venous thromboembolism: The incidence of venous thromboembolic reactions in clinical trials was similar in patients receiving bevacizumab in combination with chemotherapy compared to those receiving the control chemotherapy alone. Venous thromboembolic reactions include deep venous thrombosis, pulmonary embolism and thrombophlebitis. In clinical trials across indications, the overall incidence of venous thromboembolic reactions ranged from 2.8% to 17.3% of bevacizumab-treated patients compared with 3.2% to 15.6% in the control arms. Grade 3-5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% of patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated with chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervical cancer). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 venous thromboembolic events have been reported in up to 15.6% of patients treated with bevacizumab in combination with paclitaxel and cisplatin compared with up to 7.0% of patients treated with paclitaxel and cisplatin. Patients who have experienced a venous thromboembolic reaction may be at higher risk for a recurrence if they receive bevacizumab in combination with chemotherapy versus chemotherapy alone. Congestive heart failure (CHF) In clinical trials with bevacizumab, congestive heart failure (CHF) was observed in all cancer indications studied to date, but occurred predominantly in patients with metastatic breast cancer. In four phase III trials (AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breast cancer CHF grade 3 (NCI-CTCAE v.3) or higher was reported in up to 3.5% of patients treated with bevacizumab in combination with chemotherapy compared with up to 0.9% in the control arms. For patients in study AVF3694g who received anthracyclines concomitantly with bevacizumab, the 20 incidences of grade 3 or higher CHF for the respective bevacizumab and control arms were similar to those in the other studies in metastatic breast cancer: 2.9% in the anthracycline + bevacizumab arm and 0% in the anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all grade CHF were similar between the anthracycline + bevacizumab (6.2%) and the anthracycline + placebo arms (6.0%). Most patients who developed CHF during mBC trials showed improved symptoms and/or left ventricular function following appropriate medical therapy. In most clinical trials of bevacizumab, patients with pre-existing CHF of NYHA (New York Heart Association) II-IV were excluded, therefore, no information is available on the risk of CHF in this population. Prior anthracyclines exposure and/or prior radiation to the chest wall may be possible risk factors for the development of CHF. An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large B- cell lymphoma when receiving bevacizumab with a cumulative doxorubicin dose greater than 300 mg/m2. This phase III clinical trial compared rituximab/cyclophosphamide/doxorubicin/ vincristine/prednisone (R-CHOP) plus bevacizumab to R-CHOP without bevacizumab. While the incidence of CHF was, in both arms, above that previously observed for doxorubicin therapy, the rate was higher in the R-CHOP plus bevacizumab arm. These results suggest that close clinical observation with appropriate cardiac assessments should be considered for patients exposed to cumulative doxorubicin doses greater than 300 mg/m2 when combined with bevacizumab. Hypersensitivity reactions/infusion reactions (see section 4.4 and Post-marketing experience below) In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in patients receiving bevacizumab in combination with chemotherapy than with chemotherapy alone. The incidence of these reactions in some clinical trials of bevacizumab is common (up to 5% in bevacizumab-treated patients). Infections From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG- 0240), grade 3-5 infections have been reported in up to 24% of patients treated with bevacizumab in combination with paclitaxel and topotecan compared with up to 13% of patients treated with paclitaxel and topotecan. Ovarian failure/fertility (see sections 4.4 and 4.6) In NSABP C-08, a phase III trial of bevacizumab in adjuvant treatment of patients with colon cancer, the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test, has been evaluated in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable women. Long term effects of the treatment with bevacizumab on fertility are unknown. Laboratory abnormalities Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with Equidacent treatment. Across clinical trials, the following grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in patients treated with bevacizumab with at least a 2% difference compared to the 21 corresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased international normalised ratio (INR). Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 times baseline level), both with and without proteinuria, are associated with the use of bevacizumab. The observed increase in serum creatinine was not associated with a higher incidence of clinical manifestations of renal impairment in patients treated with bevacizumab. Other special populations Elderly patients In randomised clinical trials, age > 65 years was associated with an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen in patients over 65 were grade 3-4 leucopenia and thrombocytopenia (NCI-CTCAE v.3); and all grade neutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged ≤ 65 years when treated with bevacizumab (see sections 4.4 and 4.8 under Thromboembolism). In one clinical trial, the incidence of hypertension of grade ≥ 3 was two fold higher in patients aged > 65 years than in the younger age group (< 65 years). In a study of platinum-resistant recurrent ovarian cancer patients, alopecia, mucosal inflammation, peripheral sensory neuropathy, proteinuria and hypertension were also reported and occurred at a rate at least 5% higher in the CT + BV arm for bevacizumab-treated patients ≥ 65 years of age compared with bevacizumab-treated patients aged < 65 years. No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing complications, congestive heart failure, and haemorrhage was observed in elderly patients (> 65 years) receiving bevacizumab as compared to those aged ≤ 65 years treated with bevacizumab. Paediatric population The safety and efficacy of bevacizumab in children less than 18 years old have not been established. In study BO25041 of bevacizumab added to post-operative radiation therapy (RT) with concomitant and adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial, cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed in other tumour types in adults treated with bevacizumab. In study BO20924 of bevacizumab with current standard of care in metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma, the safety profile of bevacizumab-treated children was comparable with that observed in adults treated with bevacizumab. Equidacent is not approved for use in patients under the age of 18 years. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years treated with bevacizumab. Post-marketing experience Table 3. Adverse reactions reported in post-marketing setting System organ class (SOC) Reactions (frequency*) Infections and infestations Necrotising fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation (rare) (see also section 4.4) Immune system disorders Hypersensitivity reactions and infusion reactions (not known); with the following possible co-manifestations: dyspnoea/difficulty breathing, flushing/redness/rash, hypotension or hypertension, oxygen 22 System organ class (SOC) Reactions (frequency*) desaturation, chest pain, rigors and nausea/vomiting (see also section 4.4 and Hypersensitivity reactions/infusion reactions above) Nervous system disorders Hypertensive encephalopathy (very rare) (see also section 4.4 and Hypertension in section 4.8) Posterior Reversible Encephalopathy Syndrome (PRES) (rare) (see also section 4.4) Vascular disorders Renal thrombotic microangiopathy, which may be clinically manifested as proteinuria (not known) with or without concomitant sunitinib use. For further information on proteinuria see section 4.4 and Proteinuria in section 4.8 Respiratory, thoracic and mediastinal disorders Nasal septum perforation (not known) Pulmonary hypertension (not known) Dysphonia (common) Gastrointestinal disorders Gastrointestinal ulcer (not known) Hepatobiliary disorders Gall bladder perforation (not known) Musculoskeletal and connective tissue disorders Cases of osteonecrosis of the jaw (ONJ) have been reported in patients treated with bevacizumab, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also section 4.4) Cases of non-mandibular osteonecrosis have been observed in bevacizumab-treated paediatric patients (see section 4.8, Paediatric population) Congenital, familial, and genetic disorder Cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.6) * If specified, the frequency has been derived from clinical trial data. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The highest dose tested in humans (20 mg/kg of body weight, intravenous every 2 weeks) was associated with severe migraine in several patients. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents, other antineoplastic agents, monoclonal antibodies, ATC code: L01X C07. Equidacent is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Mechanism of action Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/ 23 regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth. Pharmacodynamic effects Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer in nude mice resulted in extensive anti-tumour activity in human cancers, including colon, breast, pancreas and prostate. Metastatic disease progression was inhibited and microvascular permeability was reduced. Clinical efficacy Metastatic carcinoma of the colon or rectum (mCRC) The safety and efficacy of the recommended dose (5 mg/kg of body weight every two weeks) in metastatic carcinoma of the colon or rectum were studied in three randomised, active-controlled clinical trials in combination with fluoropyrimidine-based first-line chemotherapy. Bevacizumab was combined with two chemotherapy regimens: • AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/folinic acid (IFL) for a total of 4 weeks of each 6 week-cycle (Saltz regimen). • AVF0780g: In combination with bolus 5-fluorouracil/folinic acid (5-FU/FA) for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen). • AVF2192g: In combination with bolus 5-FU/FA for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecan treatment. Three additional studies with bevacizumab have been conducted in mCRC patients: first-line (NO16966), second-line with no previous bevacizumab treatment (E3200), and second-line with previous bevacizumab treatment following disease progression in first-line (ML18147). In these studies, bevacizumab was administered at the following dosing regimens in combination with FOLFOX-4 (5-FU/LV/oxaliplatin), XELOX (capecitabine/oxaliplatin), and fluoropyrimidine/irinotecan and fluoropyrimidine/oxaliplatin: • NO16966: bevacizumab 7.5 mg/kg of body weight every 3 weeks in combination with oral capecitabine and intravenous oxaliplatin (XELOX) or bevacizumab 5 mg/kg every 2 weeks in combination with leucovorin plus 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4). • E3200: bevacizumab 10 mg/kg of body weight every 2 weeks in combination with leucovorin and 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4) in bevacizumab-naïve patients. • ML18147: bevacizumab 5.0 mg/kg of body weight every 2 weeks or bevacizumab 7.5 mg/kg of body weight every 3 weeks in combination with fluoropyrimidine/irinotecan or fluoropyrimidine/oxaliplatin in patients with disease progression following first-line treatment with bevacizumab. Use of irinotecan- or oxaliplatin-containing regimen was switched depending on first-line usage of either oxaliplatin or irinotecan. AVF2107g This was a phase III randomised, double-blind, active-controlled clinical trial evaluating bevacizumab in combination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum. Eight hundred and thirteen patients were randomised to receive IFL + placebo (Arm 1) or IFL + bevacizumab (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus 5-FU/FA + bevacizumab (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once safety of bevacizumab with the IFL regimen was established and considered acceptable. All treatments were continued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an ECOG performance status of 0, 43% had a value of 1 and 0.4% had a value of 2. 15.5% had received prior radiotherapy and 28.4% prior chemotherapy. 24 The primary efficacy variable of the trial was overall survival. The addition of bevacizumab to IFL resulted in statistically significant increases in overall survival, progression-free survival and overall response rate (see table 4). The clinical benefit, as measured by overall survival, was seen in all pre- specified patient subgroups, including those defined by age, sex, performance status, location of primary tumour, number of organs involved and duration of metastatic disease. The efficacy results of bevacizumab in combination with IFL-chemotherapy are displayed in table 4. Table 4. Efficacy results for trial AVF2107g AVF2107g Arm 1 IFL + placebo Arm 2 IFL + bevacizumaba Number of patients 411 402 Overall survival Median time (months) 15.6 20.3 95% CI 14.29-16.99 18.46-24.18 Hazard ratiob 0.660 (p-value = 0.00004) Progression-free survival Median time (months) 6.2 10.6 Hazard ratio 0.54 (p-value < 0.0001) Overall response rate Rate (%) 34.8 44.8 (p-value = 0.0036) a 5 mg/kg every 2 weeks. b Relative to control arm. Among the 110 patients randomised to Arm 3 (5-FU/FA + bevacizumab) prior to discontinuation of this arm, the median overall survival was 18.3 months and the median progression-free survival was 8.8 months. AVF2192g This was a phase II randomised, double-blind, active-controlled clinical trial evaluating the efficacy and safety of bevacizumab in combination with 5-FU/FA as first-line treatment for metastatic colorectal cancer in patients who were not optimal candidates for first-line irinotecan treatment. One hundred and five patients were randomised to 5-FU/FA + placebo arm and 104 patients to 5-FU/FA + bevacizumab (5 mg/kg every 2 weeks) arm. All treatments were continued until disease progression. The addition of bevacizumab 5 mg/kg every two weeks to 5-FU/FA resulted in higher objective response rates, significantly longer progression-free survival, and a trend in longer survival as compared to 5-FU/FA chemotherapy alone. AVF0780g This was a phase II randomised, active-controlled, open-labelled clinical trial investigating bevacizumab in combination with 5-FU/FA as first-line treatment of metastatic colorectal cancer. The median age was 64 years. 19% of the patients had received prior chemotherapy and 14% prior radiotherapy. Seventy-one patients were randomised to receive bolus 5-FU/FA or 5-FU/FA + bevacizumab (5 mg/kg every 2 weeks). A third group of 33 patients received bolus 5-FU/FA + bevacizumab (10 mg/kg every 2 weeks). Patients were treated until disease progression. The primary endpoints of the trial were objective response rate and progression-free survival. The addition of bevacizumab 5 mg/kg every two weeks to 5-FU/FA resulted in higher objective response rates, longer progression-free survival, and a trend in longer survival, compared with 5-FU/FA chemotherapy alone (see table 5). These efficacy data are consistent with the results from trial AVF2107g. 25 The efficacy data from trials AVF0780g and AVF2192g investigating bevacizumab in combination with 5-FU/FA chemotherapy are summarised in table 5. Table 5. Efficacy results for trials AVF0780g and AVF2192g AVF0780g AVF2192g 5-FU/FA 5-FU/FA + bevacizumaba 5-FU/FA + bevacizumabb 5-FU/FA + placebo 5-FU/FA + bevacizumab Number of patients 36 35 33 105 104 Overall survival Median time (months) 13.6 17.7 15.2 12.9 16.6 95% CI 10.35 - 16.95 13.63 - 19.32 Hazard ratioc - 0.52 1.01 0.79 p-value 0.073 0.978 0.16 Progression-free survival Median time (months) 5.2 9.0 7.2 5.5 9.2 Hazard ratio 0.44 0.69 0.5 p-value - 0.0049 0.217 0.0002 Overall response rate Rate (percent) 16.7 40.0 24.2 15.2 26 95% CI 7.0 - 33.5 24.4 - 57.8 11.7 - 42.6 9.2 - 23.9 18.1 - 35.6 p-value 0.029 0.43 0.055 Duration of response Median time (months) NR 9.3 5.0 6.8 9.2 25-75 percentile (months) 5.5 - NR 6.1 - NR 3.8 - 7.8 5.59 - 9.17 5.88 - 13.01 a 5 mg/kg every 2 weeks. b 10 mg/kg every 2 weeks. c Relative to control arm. NR = Not Reached. NO16966 This was a phase III randomised, double-blind (for bevacizumab), clinical trial investigating bevacizumab 7.5 mg/kg in combination with oral capecitabine and IV oxaliplatin (XELOX), administered on a 3-weekly schedule; or bevacizumab 5 mg/kg in combination with leucovorin with 5-fluorouracil bolus, followed by 5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule. The trial contained two parts: an initial unblinded 2-arm part (Part I) in which patients were randomised to two different treatment groups (XELOX and FOLFOX- 4) and a subsequent 2 x 2 factorial 4-arm part (Part II) in which patients were randomised to four treatment groups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + bevacizumab, FOLFOX-4 + bevacizumab). In Part II, treatment assignment was double-blind with respect to bevacizumab. Approximately 350 patients were randomised into each of the 4 trial arms in the Part II of the trial. 26 Table 6. Treatment regimens in trial NO16966 (mCRC) Treatment Starting dose Schedule FOLFOX-4 or FOLFOX-4 + bevacizumab Oxaliplatin Leucovorin 5-Fluorouracil 85 mg/m2 IV 2 h 200 mg/m2 IV 2 h 400 mg/m2 IV bolus, 600 mg/m2 IV 22 h Oxaliplatin on day 1 Leucovorin on day 1 and 2 5-fluorouracil IV bolus/infusion, each on days 1 and 2 Placebo or bevacizumab 5 mg/kg IV 30-90 min Day 1, prior to FOLFOX-4, every 2 weeks XELOX or XELOX + bevacizumab Oxaliplatin Capecitabine 130 mg/m2 IV 2 h 1,000 mg/m2 oral bid Oxaliplatin on day 1 Capecitabine oral bid for 2 weeks (followed by 1 week off treatment) Placebo or bevacizumab 7.5 mg/kg IV 30-90 min Day 1, prior to XELOX, q 3 weeks 5-Fluorouracil: IV bolus injection immediately after leucovorin The primary efficacy parameter of the trial was the duration of progression-free survival. In this trial, there were two primary objectives: to show that XELOX was non-inferior to FOLFOX-4 and to show that bevacizumab in combination with FOLFOX-4 or XELOX chemotherapy was superior to chemotherapy alone. Both co-primary objectives were met: • Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival and overall survival in the eligible per-protocol population. • Superiority of the bevacizumab-containing arms versus the chemotherapy alone arms in the overall comparison was demonstrated in terms of progression-free survival in the ITT population (Table 7). Secondary PFS analyses, based on ‘on-treatment’-based response assessments, confirmed the significantly superior clinical benefit for patients treated with bevacizumab (analyses shown in table 7), consistent with the statistically significant benefit observed in the pooled analysis. Table 7. Key efficacy results for the superiority analysis (ITT population, trial NO16966) Endpoint (months) FOLFOX-4 or XELOX + placebo (n = 701) FOLFOX-4 or XELOX + bevacizumab (n = 699) P-value Primary endpoint Median PFS** 8.0 9.4 0.0023 Hazard ratio (97.5% CI)a 0.83 (0.72-0.95) Secondary endpoints Median PFS (on treatment)** 7.9 10.4 < 0.0001 Hazard ratio (97.5% CI) 0.63 (0.52-0.75) Overall response rate (invest. assessment)** 49.2% 46.5% Median overall survival* 19.9 21.2 0.0769 Hazard ratio (97.5% CI) 0.89 (0.76-1.03) * Overall survival analysis at clinical cut-off 31 January 2007. ** Primary analysis at clinical cut-off 31 January 2006. a Relative to control arm. In the FOLFOX treatment subgroup, the median PFS was 8.6 months in placebo and 9.4 months in bevacizumab-treated patients, HR = 0.89, 97.5% CI = [0.73; 1.08]; p-value = 0.1871, the 27 corresponding results in the XELOX treatment subgroup being 7.4 vs. 9.3 months, HR = 0.77, 97.5% CI = [0.63; 0.94]; p-value = 0.0026. The median overall survival was 20.3 months in placebo and 21.2 months in bevacizumab-treated patients in the FOLFOX treatment subgroup, HR = 0.94, 97.5% CI = [0.75; 1.16]; p-value = 0.4937, the corresponding results in the XELOX, treatment subgroup being 19.2 vs. 21.4 months, HR = 0.84, 97.5% CI = [0.68; 1.04]; p-value = 0.0698. ECOG E3200 This was a phase III randomised, active-controlled, open-label trial investigating bevacizumab 10 mg/kg in combination with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule in previously-treated patients (second-line) with advanced colorectal cancer. In the chemotherapy arms, the FOLFOX-4 regimen used the same doses and schedule as shown in table 6 for trial NO16966. The primary efficacy parameter of the trial was overall survival, defined as the time from randomisation to death from any cause. Eight hundred and twenty-nine patients were randomised (292 FOLFOX-4, 293 bevacizumab + FOLFOX-4 and 244 bevacizumab monotherapy). The addition of bevacizumab to FOLFOX-4 resulted in a statistically significant prolongation of survival. Statistically significant improvements in progression-free survival and objective response rate were also observed (see table 8). Table 8. Efficacy results for trial E3200 E3200 FOLFOX-4 FOLFOX-4 + bevacizumaba Number of patients 292 293 Overall survival Median (months) 10.8 13.0 95% CI 10.12 - 11.86 12.09 - 14.03 Hazard ratiob 0.751 (p-value = 0.0012) Progression-free survival Median (months) 4.5 7.5 Hazard ratio 0.518 (p-value < 0.0001) Objective response rate Rate 8.6% 22.2% (p-value < 0.0001) a 10 mg/kg every 2 weeks. b Relative to control arm. No significant difference was observed in the duration of overall survival between patients who received bevacizumab monotherapy compared to patients treated with FOLFOX-4. Progression-free survival and objective response rate were inferior in the bevacizumab monotherapy arm compared to the FOLFOX-4 arm. ML18147 This was a phase III randomised, controlled, open-label trial investigating bevacizumab 5.0 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks in combination with fluoropyrimidine-based chemotherapy versus fluoropyrimidine-based chemotherapy alone in patients with mCRC who have progressed on a first-line bevacizumab-containing regimen. Patients with histologically confirmed mCRC and disease progression were randomised 1:1 within 3 months after discontinuation of bevacizumab first-line therapy to receive 28 fluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy (chemotherapy switched depending on first-line chemotherapy) with or without bevacizumab. Treatment was given until progressive disease or unacceptable toxicity. The primary outcome measure was overall survival defined as the time from randomisation until death from any cause. A total of 820 patients were randomised. The addition of bevacizumab to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of survival in patients with mCRC who have progressed on a first-line bevacizumab-containing regimen (ITT = 819) (see table 9). Table 9. Efficacy results for study ML18147 (ITT population) ML18147 Fluoropyrimidine/irinotecan or Fluoropyrimidine/oxaliplatin based chemotherapy Fluoropyrimidine/irinotecan or Fluoropyrimidine/oxaliplatin based chemotherapy + bevacizumaba Number of patients 410 409 Overall survival Median (months) 9.8 11.2 Hazard ratio (95% confidence interval) 0.81 (0.69, 0.94) (p-value = 0.0062) Progression-free survival Median (months) 4.1 5.7 Hazard ratio (95% confidence interval) 0.68 (0.59, 0.78) (p-value < 0.0001) Objective response rate (ORR) Patients included in analysis 406 404 Rate 3.9% 5.4% (p-value = 0.3113) a 5.0 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. Statistically significant improvements in progression-free survival were also observed. Objective response rate was low in both treatment arms and the difference was not significant. Study E3200 used a 5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-naïve patients, while study ML18147 used a 2.5 mg/kg/week equivalent dose of bevacizumab in bevacizumab- pretreated patients. A cross-trial comparison of the efficacy and safety data is limited by differences between these studies, most notably in patient populations, previous bevacizumab exposure and chemotherapy regimens. Both the 5 mg/kg/week and 2.5 mg/kg/week equivalent doses of bevacizumab provided a statistically significant benefit with regards to OS (HR 0.751 in study E3200; HR 0.81 in study ML18147) and PFS (HR 0.518 in study E3200; HR 0.68 in study ML18147). In terms of safety, there was a higher overall incidence of grade 3-5 AEs in study E3200 relative to study ML18147. Metastatic breast cancer (mBC) Two large phase III trials were designed to investigate the treatment effect of bevacizumab in combination with two individual chemotherapy agents, as measured by the primary endpoint of PFS. A clinically meaningful and statistically significant improvement in PFS was observed in both trials. Summarised below are PFS results for the individual chemotherapy agents included in the indication: • Study E2100 (paclitaxel) • Median PFS increase 5.6 months, HR 0.421 (p < 0.0001, 95% CI 0.343; 0.516) • Study AVF3694g (capecitabine) 29 • Median PFS increase 2.9 months, HR 0.69 (p = 0.0002, 95% CI 0.56; 0.84) Further details of each study and the results are provided below. ECOG E2100 Trial E2100 was an open-label, randomised, active-controlled, multicentre clinical trial evaluating bevacizumab in combination with paclitaxel for locally recurrent or metastatic breast cancer in patients who had not previously received chemotherapy for locally recurrent and metastatic disease. Patients were randomised to paclitaxel alone (90 mg/m2 / IV over 1-hour once weekly for three out of four weeks) or in combination with bevacizumab (10 mg/kg IV infusion every two weeks). Prior hormonal therapy for the treatment of metastatic disease was allowed. Adjuvant taxane therapy was allowed only if it was completed at least 12 months prior to trial entry. Of the 722 patients in the trial, the majority of patients had HER2-negative disease (90%), with a small number of patients with unknown (8%) or confirmed HER2-positive status (2%), who had previously been treated with or were considered unsuitable for trastuzumab therapy. Furthermore, 65% of patients had received adjuvant chemotherapy including 19% prior taxanes and 49% prior anthracyclines. Patients with central nervous system metastases, including previously-treated or resected brain lesions, were excluded. In trial E2100, patients were treated until disease progression. In situations where early discontinuation of chemotherapy was required, treatment with bevacizumab as a single agent continued until disease progression. The patient characteristics were similar across the trial arms. The primary endpoint of this trial was progression-free survival (PFS), based on trial investigators’ assessment of disease progression. In addition, an independent review of the primary endpoint was also conducted. The results of this trial are presented in table 10. Table 10. Trial E2100 efficacy results Progression-free survival Investigator assessment* IRF assessment Paclitaxel (n = 354) Paclitaxel/ bevacizumab (n = 368) Paclitaxel (n = 354) Paclitaxel/ bevacizumab (n = 368) Median PFS (months) 5.8 11.4 5.8 11.3 HR (95% CI) 0.421 (0.343; 0.516) 0.483 (0.385; 0.607) p-value < 0.0001 < 0.0001 Response rates (for patients with measurable disease) Investigator assessment IRF assessment Paclitaxel (n = 273) Paclitaxel/ bevacizumab (n = 252) Paclitaxel (n = 243) Paclitaxel/ bevacizumab (n = 229) % pts with objective response 23.4 48.0 22.2 49.8 p-value < 0.0001 < 0.0001 * Primary analysis Overall survival Paclitaxel (n = 354) Paclitaxel/ bevacizumab (n = 368) Median OS (months) 24.8 26.5 HR (95% CI) 0.869 (0.722; 1.046) p-value 0.1374 30 The clinical benefit of bevacizumab as measured by PFS was seen in all pre-specified subgroups tested (including disease-free interval, number of metastatic sites, prior receipt of adjuvant chemotherapy and oestrogen receptor (ER) status). AVF3694g Study AVF3694g was a Phase III, multicentre, randomised, placebo-controlled trial designed to evaluate the efficacy and safety of bevacizumab in combination with chemotherapy compared to chemotherapy plus placebo as first-line treatment for patients with HER2-negative metastatic or locally recurrent breast cancer. Chemotherapy was chosen at the investigator's discretion prior to randomisation in a 2:1 ratio to receive either chemotherapy plus bevacizumab or chemotherapy plus placebo. The choices of chemotherapy included capecitabine, taxane (protein-bound paclitaxel, docetaxel), and anthracycline- based agents (doxorubicin/ cyclophosphamide, epirubicin/ cyclophosphamide, 5-fluorouracil/ doxorubicin/ cyclophosphamide, 5-fluorouracil/epirubicin/cyclophosphamide) given every three weeks (q3w). Bevacizumab or placebo was administered at a dose of 15 mg/kg q3w. This study included a blinded treatment phase, an optional open-label post-progression phase, and a survival follow-up phase. During the blinded treatment phase, patients received chemotherapy and medicinal product (bevacizumab or placebo) every 3 weeks until disease progression, treatment- limiting toxicity, or death. On documented disease progression, patients who entered the optional open-label phase could receive open-label bevacizumab together with a wide-range of second line therapies. Statistical analyses were performed independently for 1) patients who received capecitabine in combination with bevacizumab or placebo; 2) patients who received taxane-based or anthracycline- based chemotherapy in combination with bevacizumab or placebo. The primary endpoint of the study was PFS by investigator assessment. In addition, the primary endpoint was also assessed by an independent review committee (IRC). The results of this study from the final protocol defined analyses for progression free survival and response rates for the independently powered capecitabine cohort of Study AVF3694g are presented in table 11. Results from an exploratory overall survival analysis which include an additional 7 months of follow-up (approximately 46% of patients had died) are also presented. The percentage of patients who received bevacizumab in the open-label phase was 62.1% in the capecitabine + placebo arm and 49.9% in the capecitabine + bevacizumab arm. 31 Table 11 Efficacy results for study AVF3694g: – Capecitabinea and Bevacizumab/Placebo (Cap + bevacizumab/Pl) Progression-free survivalb Investigator Assessment IRC Assessment Cap + Pl (n=206) Cap + bevacizumab (n=409) Cap + Pl (n=206) Cap + bevacizumab (n=409) Median PFS (months) 5.7 8.6 6.2 9.8 Hazard ratio vs placebo arm (95% CI) 0.69 (0.56; 0.84) 0.68 (0.54; 0.86) p-value 0.0002 0.0011 Response rate (for patients with measurable disease)b Cap + Pl (n=161) Cap + bevacizumab (n=325) % pts with objective response 23.6 35.4 p-value 0.0097 Overall survivalb HR (95% CI) 0.88 (0.69; 1.13) p-value (exploratory) 0.33 a 1000 mg/m2 oral twice daily for 14 days administered every 3 weeks b Stratified analysis included all progression and death events except those where non-protocol therapy (NPT) was initiated prior to documented progression; data from those patients were censored at the last tumour assessment prior to starting NPT. An unstratified analysis of PFS (investigator assessed) was performed that did not censor for non- protocol therapy prior to disease progression. The results of these analyses were very similar to the primary PFS results. Non-small cell lung cancer (NSCLC) First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy The safety and efficacy of bevacizumab, in addition to platinum-based chemotherapy, in the first-line treatment of patients with non-squamous non-small cell lung cancer (NSCLC), was investigated in trials E4599 and BO17704. An overall survival benefit has been demonstrated in trial E4599 with a 15 mg/kg/q3wk dose of bevacizumab. Trial BO17704 has demonstrated that both 7.5 mg/kg/q3wk and 15 mg/kg/q3wk bevacizumab doses increase progression-free survival and response rate. E4599 E4599 was an open-label, randomised, active-controlled, multicentre clinical trial evaluating bevacizumab as first-line treatment of patients with locally advanced (stage IIIB with malignant pleural effusion), metastatic or recurrent NSCLC other than predominantly squamous cell histology. Patients were randomised to platinum-based chemotherapy (paclitaxel 200 mg/m2) and carboplatin AUC = 6.0, both by IV infusion (PC) on day 1 of every 3-week cycle for up to 6 cycles or PC in combination with bevacizumab at a dose of 15 mg/kg IV infusion day 1 of every 3-week cycle. After completion of six cycles of carboplatin-paclitaxel chemotherapy or upon premature discontinuation of chemotherapy, patients on the bevacizumab + carboplatin-paclitaxel arm continued to receive bevacizumab as a single agent every 3 weeks until disease progression. 878 patients were randomised to the two arms. During the trial, of the patients who received trial treatment, 32.2% (136/422) of patients received 7- 12 administrations of bevacizumab and 21.1% (89/422) of patients received 13 or more administrations of bevacizumab. 32 The primary endpoint was duration of survival. Results are presented in table 12. Table 12. Efficacy results for trial E4599 Arm 1 Carboplatin/ Paclitaxel Arm 2 Carboplatin/ Paclitaxel + bevacizumab 15 mg/kg q 3 weeks Number of patients 444 434 Overall survival Median (months) 10.3 12.3 Hazard ratio 0.80 (p = 0.003) 95% CI (0.69; 0.93) Progression-free survival Median (months) 4.8 6.4 Hazard ratio 0.65 (p < 0.0001) 95% CI (0.56; 0.76) Overall response rate Rate (percent) 12.9 29.0 (p < 0.0001) In an exploratory analysis, the extent of bevacizumab benefit on overall survival was less pronounced in the subgroup of patients who did not have adenocarcinoma histology. BO17704 Trial BO17704 was a randomised, double-blind phase III trial of bevacizumab in addition to cisplatin and gemcitabine versus placebo, cisplatin and gemcitabine in patients with locally advanced (stage IIIB with supraclavicular lymph node metastases or with malignant pleural or pericardial effusion), metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy. The primary endpoint was progression-free survival, secondary endpoints for the trial included the duration of overall survival. Patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m2 intravenous infusion on day 1 and gemcitabine 1,250 mg/m2 intravenous infusion on days 1 and 8 of every 3-week cycle for up to 6 cycles (CG) with placebo or CG with bevacizumab at a dose of 7.5 or 15 mg/kg IV infusion day 1 of every 3-week cycle. In the bevacizumab-containing arms, patients could receive bevacizumab as a single agent every 3 weeks until disease progression or unacceptable toxicity. Trial results show that 94% (277 / 296) of eligible patients went on to receive single agent bevacizumab at cycle 7. A high proportion of patients (approximately 62%) went on to receive a variety of non- protocol specified anti-cancer therapies, which may have impacted the analysis of overall survival. The efficacy results are presented in table 13. Table 13. Efficacy results for trial BO17704 Cisplatin/Gemcitabine + placebo Cisplatin/Gemcitabine + bevacizumab 7.5 mg/kg q 3 weeks Cisplatin/Gemcitabine + bevacizumab 15 mg/kg q 3 weeks Number of patients 347 345 351 Progression-free survival Median (months) 6.1 6.7 (p = 0.0026) 6.5 (p = 0.0301) Hazard ratio 0.75 [0.62; 0.91] 0.82 [0.68; 0.98] 33 Cisplatin/Gemcitabine + placebo Cisplatin/Gemcitabine + bevacizumab 7.5 mg/kg q 3 weeks Cisplatin/Gemcitabine + bevacizumab 15 mg/kg q 3 weeks Best overall response ratea 20.1% 34.1% (p < 0.0001) 30.4% (p = 0.0023) a patients with measurable disease at baseline Overall survival Median (months) 13.1 13.6 (p = 0.4203) 13.4 (p = 0.7613) Hazard ratio 0.93 [0.78; 1.11] 1.03 [0.86, 1.23] First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with erlotinib JO25567 Study JO25567 was a randomised, open-label, multi-centre phase II study conducted in Japan to evaluate the efficacy and safety of bevacizumab used in addition to erlotinib in patients with non- squamous NSCLC with EGFR activating mutations (exon 19 deletion or exon 21 L858R mutation) who had not received prior systemic therapy for stage IIIB/IV or recurrent disease. The primary endpoint was progression-free survival (PFS) based on independent review assessment. Secondary endpoints included overall survival, response rate, disease control rate, duration of response, and safety. EGFR mutation status was determined for each patient prior to patient screening and 154 patients were randomised to receive either erlotinib + bevacizumab (erlotinib 150 mg oral daily + bevacizumab [15 mg/kg IV every 3 weeks]) or erlotinib monotherapy (150 mg oral daily) until disease progression (PD) or unacceptable toxicity. In the absence of PD, discontinuation of one component of study treatment in the erlotinib + bevacizumab arm did not lead to discontinuation of the other component of study treatment as specified in the study protocol. The efficacy results of the study are presented in table 14. Table 14. Efficacy results for study JO25567 Erlotinib N = 77# Erlotinib + bevacizumab N = 75# PFS^ (months) Median 9.7 16.0 HR (95% CI) 0.54 (0.36; 0.79) p-value 0.0015 Overall response rate Rate (n) 63.6% (49) 69.3% (52) p-value 0.4951 Overall survival* (months) Median 47.4 47.0 HR (95% CI) 0.81 (0.53; 1.23) p-value 0.3267 # A total of 154 patients (ECOG Performance Status 0 or 1) were randomised. However two of the randomised patients discontinued the study before receiving any study treatment. ^ Blinded independent review (protocol-defined primary analysis). * Exploratory analysis: final OS analysis at clinical cut off on 31 October 2017, approx. 59% of patients had died. CI, confidence interval; HR, Hazard ratio from unstratified Cox regression analysis; NR, not reached. 34 Advanced and/or metastatic renal cell cancer (mRCC) Bevacizumab in combination with interferon alfa-2a for the first-line treatment of advanced and/ or metastatic renal cell cancer (BO17705) This was a phase III randomised double-blind trial conducted to evaluate the efficacy and safety of bevacizumab in combination with interferon (IFN) alfa-2a versus IFN alfa-2a alone as first-line treatment in mRCC. The 649 randomised patients (641 treated) had Karnofsky Performance Status (KPS) of ≥ 70%, no CNS metastases and adequate organ function. Patients were nephrectomised for primary renal cell carcinoma. Bevacizumab 10 mg/kg was given every 2 weeks until disease progression. IFN alfa-2a was given up to 52 weeks or until disease progression at a recommended starting dose of 9 MIU three times a week, allowing a dose reduction to 3 MIU three times a week in 2 steps. Patients were stratified according to country and Motzer score and the treatment arms were shown to be well balanced for the prognostic factors. The primary endpoint was overall survival, with secondary endpoints for the trial including progression-free survival. The addition of bevacizumab to IFN alfa-2a significantly increased PFS and objective tumour response rate. These results have been confirmed through an independent radiological review. However, the increase in the primary endpoint of overall survival by 2 months was not significant (HR = 0.91). A high proportion of patients (approximately 63% IFN/placebo; 55% bevacizumab/IFN) received a variety of non-specified post-trial anti-cancer therapies, including antineoplastic agents, which may have impacted the analysis of overall survival. The efficacy results are presented in table 15. Table 15. Efficacy results for trial BO17705 BO17705 Placebo + IFNa BVb + IFNa Number of patients 322 327 Progression-free survival Median (months) 5.4 10.2 Hazard ratio 95% CI 0.63 0.52, 0.75 (p-value < 0.0001) Objective response rate (%) in patients with measurable disease N 289 306 Placebo + IFNa BVb + IFNa Response rate 12.8% 31.4% (p-value < 0.0001) a Interferon alfa-2a 9 MIU 3x/week. b Bevacizumab 10 mg/kg q 2 wk. Overall survival Median (months) 21.3 23.3 Hazard ratio 95% CI 0.91 0.76, 1.10 (p-value 0.3360) An exploratory multivariate Cox regression model using backward selection indicated that the following baseline prognostic factors were strongly associated with survival independent of treatment: gender, white blood cell count, platelets, body weight loss in the 6 months prior to trial entry, number of metastatic sites, sum of longest diameter of target lesions, Motzer score. Adjustment for these baseline factors resulted in a treatment hazard ratio of 0.78 (95% CI [0.63; 0.96], p = 0.0219), 35 indicating a 22% reduction in the risk of death for patients in the bevacizumab + IFN alfa-2a arm compared to IFN alfa-2a arm. Ninety-seven (97) patients in the IFN alfa-2a arm and 131 patients in the bevacizumab arm reduced the dose of IFN alfa-2a from 9 MIU to either 6 or 3 MIU three times a week as pre-specified in the protocol. Dose reduction of IFN alfa-2a did not appear to affect the efficacy of the combination of bevacizumab and IFN alfa-2a based on PFS event free rates over time, as shown by a subgroup analysis. The 131 patients in the bevacizumab + IFN alfa-2a arm who reduced and maintained the IFN alfa-2a dose at 6 or 3 MIU during the trial, exhibited at 6, 12 and 18 months PFS event free rates of 73, 52 and 21% respectively, as compared to 61, 43 and 17% in the total population of patients receiving bevacizumab + IFN alfa-2a. AVF2938 This was a randomised, double-blind, phase II clinical trial investigating bevacizumab 10 mg/kg in a 2 weekly schedule with the same dose of bevacizumab in combination with 150 mg daily erlotinib, in patients with metastatic clear cell RCC. A total of 104 patients were randomised to treatment in this trial, 53 to bevacizumab 10 mg/kg every 2 weeks plus placebo and 51 to bevacizumab 10 mg/kg every 2 weeks plus erlotinib 150 mg daily. The analysis of the primary endpoint showed no difference between the bevacizumab + placebo arm and the bevacizumab + erlotinib arm (median PFS 8.5 versus 9.9 months). Seven patients in each arm had an objective response. The addition of erlotinib to bevacizumab did not result in an improvement in OS (HR = 1.764; p = 0.1789), duration of objective response (6.7 vs. 9.1 months) or time to symptom progression (HR = 1.172; p = 0.5076). AVF0890 This was a randomised phase II trial conducted to compare the efficacy and safety of bevacizumab versus placebo. A total of 116 patients were randomised to receive bevacizumab 3 mg/kg every 2 weeks (n = 39), 10 mg/kg every 2 weeks; (n = 37), or placebo (n = 40). An interim analysis showed there was a significant prolongation of the time to progression of disease in the 10 mg/kg group as compared with the placebo group (hazard ratio, 2.55; p < 0.001). There was a small difference, of borderline significance, between the time to progression of disease in the 3 mg/kg group and that in the placebo group (hazard ratio, 1.26; p = 0.053). Four patients had objective (partial) response, and all of these had received the 10 mg/kg dose bevacizumab; the ORR for the 10 mg/kg dose was 10%. Epithelial ovarian, fallopian tube and primary peritoneal cancer Front-line treatment of ovarian cancer The safety and efficacy of bevacizumab in the front-line treatment of patients with epithelial ovarian, fallopian tube or primary peritoneal cancer were studied in two phase III trials (GOG-0218 and BO17707) that evaluated the effect of the addition of bevacizumab to carboplatin and paclitaxel compared to the chemotherapy regimen alone. GOG-0218 The GOG-0218 study was a phase III multicentre, randomised, double-blind, placebo-controlled, three arm study evaluating the effect of adding bevacizumab to an approved chemotherapy regimen (carboplatin and paclitaxel) in patients with advanced (stages IIIB, IIIC and IV according to FIGO staging version dated 1988) epithelial ovarian, fallopian tube or primary peritoneal cancer. Patients who had received prior therapy with bevacizumab or prior systemic anti-cancer therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study. A total of 1,873 patients were randomised in equal proportions to the following three arms: • CPP arm: Five cycles of placebo (started cycle 2) in combination with carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 15 months of therapy 36 • CPB15 arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination with carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 15 months of therapy • CPB15+ arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination with carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by continued use of bevacizumab (15 mg/kg q3w) as single agent for a total of up to 15 months of therapy. The majority of patients included in the study were white (87% in all three arms); the median age was 60 years in CPP and CPB15 arms and 59 years in CPB15+ arm; and 29% of patients in CPP or CPB15 and 26% in CPB15+ were over 65 years of age. Overall approximately 50% of patients had a GOG PS of 0 at baseline, 43% a GOG PS score of 1, and 7% a GOG PS score of 2. Most patients had EOC (82% in CPP and CPB15, 85% in CPB15+) followed by PPC (16% in CPP, 15% in CPB15, 13% in CPB15+) and FTC (1% in CPP, 3% in CPB15, 2% in CPB15+). The majority of patients had serous adenocarcinoma histologic type (85% in CPP and CPB15, 86% in CPB15+). Overall approximately 34% of patients were FIGO stage III optimally debulked with gross residual disease, 40% stage III suboptimally debulked, and 26% were stage IV patients. The primary endpoint was PFS based on investigator’s assessment of disease progression based on radiological scans or CA-125 levels, or symptomatic deterioration per protocol. In addition, a pre- specified analysis of the data censoring for CA-125 progression events was conducted, as well as an independent review of PFS as determined by radiological scans. The trial met its primary objective of PFS improvement. Compared to patients treated with chemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who received bevacizumab at a dose of 15 mg/kg q3w in combination with chemotherapy and continued to receive bevacizumab alone (CPB15+), had a clinically meaningful and statistically significant improvement in PFS. In patients who only received bevacizumab in combination with chemotherapy and did not continue to receive bevacizumab alone (CPB15), no clinically meaningful benefit in PFS was observed. The results of this study are summarised in table 16. Table 16. Efficacy results from study GOG-0218 Progression-free survival1 CPP (n = 625) CPB15 (n = 625) CPB15+ (n = 623) Median PFS (months) 10.6 11.6 14.7 Hazard ratio (95% CI)2 0.89 (0.78, 1.02) 0.70 (0.61, 0.81) p-value3,4 0.0437 < 0.0001 Objective response rate5 CPP (n = 396) CPB15 (n = 393) CPB15+ (n = 403) % pts with objective response 63.4 66.2 66.0 p-value 0.2341 0.2041 Overall survival6 CPP (n = 625) CPB15 (n = 625) CPB15+ (n = 623) Median OS (months) 40.6 38.8 43.8 Hazard ratio (95% CI)2 1.07 (0.91, 1.25) 0.88 (0.75, 1.04) p-value3 0.2197 0.0641 37 1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor censored for NPT prior to disease progression) with data cut-off date of 25 February, 2010. 2 Relative to the control arm; stratified hazard ratio. 3 One-sided log-rank p-value. 4 Subject to a p-value boundary of 0.0116. 5 Patients with measurable disease at baseline. 6 Final overall survival analysis performed when 46.9% of the patients had died. Pre-specified PFS analyses were conducted, all with a cut-off date of 29 September 2009. The results of these pre-specified analyses are as follows: • The protocol-specified analysis of investigator assessed PFS (without censoring for CA-125 progression or non-protocol therapy [NPT]) shows a stratified hazard ratio of 0.71 (95% CI: 0.61-0.83, 1-sided log-rank p-value < 0.0001) when CPB15+ is compared with CPP, with a median PFS of 10.4 months in the CPP arm and 14.1 months in the CPB15+ arm. • The primary analysis of investigator assessed PFS (censoring for CA-125 progressions and NPT) shows a stratified hazard ratio of 0.62 (95% CI: 0.52-0.75, 1-sided log-rank p-value < 0.0001) when CPB15+ is compared with CPP, with a median PFS of 12.0 months in the CPP arm and 18.2 months in the CPB15+ arm. • The analysis of PFS as determined by the independent review committee (censoring for NPT) shows a stratified hazard ratio of 0.62 (95% CI: 0.50-0.77, 1-sided log-rank p-value < 0.0001) when CPB15+ is compared with CPP, with a median PFS of 13.1 in the CPP arm and 19.1 months in the CPB15+ arm. PFS subgroup analyses by disease stage and debulking status are summarised in table 17. These results demonstrate robustness of the analysis of PFS as shown in table 16. 38 Table 17. PFS1 results by disease stage and debulking status from study GOG-0218 Randomised patients stage III optimally debulked disease2,3 CPP (n = 219) CPB15 (n = 204) CPB15+ (n = 216) Median PFS (months) 12.4 14.3 17.5 Hazard ratio (95% CI)4 0.81 0.66 (0.62, 1.05) (0.50, 0.86) Randomised patients with stage III suboptimally debulked disease3 CPP (n = 253) CPB15 (n = 256) CPB15+ (n = 242) Median PFS (months) 10.1 10.9 13.9 Hazard ratio (95% CI)4 0.93 0.78 (0.77, 1.14) (0.63, 0.96) Randomised patients with stage IV disease CPP (n = 153) CPB15 (n = 165) CPB15+ (n = 165) Median PFS (months) 9.5 10.4 12.8 Hazard ratio (95% CI)4 0.90 0.64 (0.70, 1.16) (0.49, 0.82) 1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor censored for NPT prior to disease progression) with data cut-off date of 25 February, 2010. 2 With gross residual disease. 3 3.7% of the overall randomised patient population had stage IIIB disease. 4 Relative to the control arm. BO17707 (ICON7) BO17707 was a phase III, two-arm, multicentre, randomised, controlled, open-label study comparing the effect of adding bevacizumab to carboplatin plus paclitaxel in patients with FIGO stage I or IIA (grade 3 or clear cell histology only; n = 142), or FIGO stage IIB-IV (all grades and all histological types, n = 1,386) epithelial ovarian, fallopian tube or primary peritoneal cancer following surgery (NCI-CTCAE v.3). FIGO staging version dated 1988 was used in this trial. Patients who had received prior therapy with bevacizumab or prior systemic anti-cancer therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study. A total of 1,528 patients were randomised in equal proportions to the following two arms: • CP arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks duration. • CPB7.5+ arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks plus bevacizumab (7.5 mg/kg q3w) for up to 12 months (bevacizumab was started at cycle 2 of chemotherapy if treatment was initiated within 4 weeks of surgery or at cycle 1 if treatment was initiated more than 4 weeks after surgery). The majority of patients included in the study were white (96%), the median age was 57 years in both treatment arms, 25% of patients in each treatment arm were 65 years of age or over, and approximately 50% of patients had an ECOG PS of 1; 7% of patients in each treatment arm had an ECOG PS of 2. The majority of patients had EOC (87.7%) followed by PPC (6.9%) and FTC (3.7%) or a mixture of the three origins (1.7%). Most patients were FIGO stage III (both 68%) followed by FIGO stage IV (13% and 14%), FIGO stage II (10% and 11%) and FIGO stage I (9% and 7%). The majority of the patients in each treatment arm (74% and 71%) had poorly differentiated (grade 3) primary tumours at baseline. The incidence of each histologic sub-type of EOC was similar between the treatment arms; 69% of patients in each treatment arm had serous adenocarcinoma histologic type. 39 The primary endpoint was PFS as assessed by the investigator using RECIST. The trial met its primary objective of PFS improvement. Compared to patients treated with chemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who received bevacizumab at a dose of 7.5 mg/kg q3w in combination with chemotherapy and continued to receive bevacizumab for up to 18 cycles had a statistically significant improvement in PFS. The results of this study are summarised in table 18. Table 18. Efficacy results from study BO17707 (ICON7) Progression-free survival CP (n = 764) CPB7.5+ (n = 764) Median PFS (months)2 16.9 19.3 Hazard ratio [95% CI]2 0.86 [0.75; 0.98] (p-value = 0.0185) Objective response rate1 CP (n = 277) CPB7.5+ (n = 272) Response rate 54.9% 64.7% (p-value = 0.0188) Overall survival3 CP (n = 764) CPB7.5+ (n = 764) Median (months) 58.0 57.4 Hazard ratio [95% CI] 0.99 [0.85; 1.15] (p-value = 0.8910) 1 In patients with measurable disease at baseline. 2 Investigator assessed PFS analysis with data cut-off date of 30 November 2010. 3 Final overall survival analysis performed when 46.7% of the patients had died with data cut-off date of 31 March 2013. The primary analysis of investigator assessed PFS with a data cut-off date of 28 February 2010 shows an unstratified hazard ratio of 0.79 (95% CI: 0.68-0.91, 2-sided log-rank p-value 0.0010) with a median PFS of 16.0 months in the CP arm and 18.3 months in the CPB7.5+ arm. PFS subgroup analyses by disease stage and debulking status are summarised in table 19. These results demonstrate robustness of the primary analysis of PFS as shown in table 18. Table 19. PFS1 results by disease stage and debulking status from study BO17707 (ICON7) Randomised patients stage III optimally debulked disease2,3 CP (n = 368) CPB7.5+ (n = 383) Median PFS (months) 17.7 19.3 Hazard ratio (95% CI)4 0.89 (0.74, 1.07) Randomised patients with stage III suboptimally debulked disease3 CP (n = 154) CPB7.5+ (n = 140) Median PFS (months) 10.1 16.9 Hazard ratio (95% CI)4 0.67 (0.52, 0.87) Randomised patients with stage IV disease CP CPB7.5+ 40 (n = 97) (n = 104) Median PFS (months) 10.1 13.5 Hazard ratio (95% CI)4 0.74 (0.55, 1.01) 1 Investigator assessed PFS analysis with data cut-off date of 30 November 2010. 2 With or without gross residual disease. 3 5.8% of the overall randomised patient population had stage IIIB disease. 4 Relative to the control arm. Recurrent ovarian cancer The safety and efficacy of bevacizumab in the treatment of recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer was studied in phase III trials (AVF4095g and GOG-0213) with different patient populations and chemotherapy regimens. • AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatin and gemcitabine followed by bevacizumab as a single agent in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. • GOG-0213 evaluated the efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. AVF4095g The safety and efficacy of bevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment, was studied in a phase III randomised, double-blind, placebo-controlled trial (AVF4095g). The study compared the effect of adding bevacizumab to carboplatin and gemcitabine chemotherapy and continuing bevacizumab as a single agent to progression, to carboplatin and gemcitabine alone. Only patients with histologically documented ovarian, primary peritoneal, or fallopian tube carcinoma that had recurred > 6 months after platinum-based chemotherapy and who had not received chemotherapy in the recurrent setting and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents were included in the study. A total of 484 patients with measurable disease were randomised 1:1 to either: • Carboplatin (AUC 4, day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8) and concurrent placebo every 3 weeks for 6 and up to 10 cycles followed by placebo (every 3 weeks) alone until disease progression or unacceptable toxicity. • Carboplatin (AUC 4, day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8) and concurrent bevacizumab (15 mg/kg day 1) every 3 weeks for 6 and up to 10 cycles followed by bevacizumab (15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival based on investigator assessment using modified RECIST 1.0. Additional endpoints included objective response, duration of response, overall survival and safety. An independent review of the primary endpoint was also conducted. The results of this study are summarised in table 20. 41 Table 20. Efficacy results from study AVF4095g Progression-free survival Investigator assessment IRC assessment Placebo + C/G (n = 242) Bevacizumab + C/G (n = 242) Placebo + C/G (n = 242) Bevacizumab + C/G (n = 242) Not censored for NPT Median PFS (months) 8.4 12.4 8.6 12.3 Hazard ratio (95% CI) 0.524 [0.425, 0.645] 0.480 [0.377, 0.613] p-value < 0.0001 < 0.0001 Censored for NPT Median PFS (months) 8.4 12.4 8.6 12.3 Hazard ratio (95% CI) 0.484 [0.388, 0.605] 0.451 [0.351, 0.580] p-value < 0.0001 < 0.0001 Objective response rate Investigator assessment IRC assessment Placebo + C/G (n = 242) Bevacizumab + C/G (n = 242) Placebo + C/G (n = 242) Bevacizumab + C/G (n = 242) % pts with objective response 57.4% 78.5% 53.7% 74.8% p-value < 0.0001 < 0.0001 Overall survival Placebo + C/G (n = 242) Bevacizumab + C/G (n = 242) Median OS (months) 32.9 33.6 Hazard ratio (95% CI) 0.952 [0.771, 1.176] p-value 0.6479 PFS subgroup analyses depending on recurrence since last platinum therapy are summarised in table 21. Table 21. Progression-free survival by time from last platinum therapy to recurrence Investigator assessment Time from last platinum therapy to recurrence Placebo + C/G (n = 242) Bevacizumab + C/G (n = 242) 6 - 12 months (n = 202) Median 8.0 11.9 Hazard ratio (95% CI) 0.41 (0.29-0.58) > 12 months (n = 282) Median 9.7 12.4 Hazard ratio (95% CI) 0.55 (0.41-0.73) GOG-0213 GOG-0213, a phase III randomised controlled open label trial, studied the safety and efficacy of bevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting. There was no exclusion criterion for prior anti-angiogenic therapy. The study 42 evaluated the effect of adding bevacizumab to carboplatin+paclitaxel and continuing bevacizumab as a single agent until disease progression or unacceptable toxicity compared to carboplatin+paclitaxel alone. A total of 673 patients were randomised in equal proportions to the following two treatment arms: • CP arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) every 3 weeks for 6 and up to 8 cycles. • CPB arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) and concurrent bevacizumab (15 mg/kg) every 3 weeks for 6 and up to 8 cycles, followed by bevacizumab (15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity. Most patients in both the CP arm (80.4%) and the CPB arm (78.9%) were white. The median age was 60.0 years in the CP arm and 59.0 years in the CPB arm. The majority of patients (CP: 64.6%; CPB: 68.8%) were in the age category < 65 years. At baseline, most patients in both treatment arms had a GOG PS of 0 (CP: 82.4%: CPB; 80.7%) or 1 (CP: 16.7%: CPB; 18.1%). A GOG PS of 2 at baseline was reported in 0.9% of patients in the CP arm and in 1.2% of patients in the CPB arm. The primary efficacy endpoint was overall survival (OS). The main secondary efficacy endpoint was progression-free survival (PFS). Results are presented in table 22. Table 22. Efficacy results1,2 from study GOG-0213 Primary endpoint Overall survival (OS) CP (n = 336) CPB (n = 337) Median OS (months) 37.3 42.6 Hazard ratio (95% CI) (eCRF)a 0.823 [CI: 0.680, 0.996] p-Value 0.0447 Hazard ratio (95% CI) (registration form)b 0.838 [CI: 0.693, 1.014] p-value 0.0683 Secondary endpoint Progression-free survival (PFS) CP (n = 336) CPB (n = 337) Median PFS (months) 10.2 13.8 Hazard ratio (95% CI) 0.613 [CI: 0.521, 0.721] p-value < 0.0001 1 Final analysis 2 Tumour assessments and response evaluations were determined by the investigators using the GOG RECIST criteria (Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228Y247). a Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status Yes/No (Yes = randomised to undergo cytoreduction or randomised to not undergo cytoreduction; No = not a candidate or did not consent to cytoreduction). b stratified by the duration of treatment free-interval prior to enrolling onto this study per the registration form, and secondary surgical debulking status Yes/No. 43 The trial met its primary objective of OS improvement. Treatment with bevacizumab at 15 mg/kg every 3 weeks in combination with chemotherapy (carboplatin and paclitaxel) for 6 and up to 8 cycles, followed by bevacizumab until disease progression or unacceptable toxicity resulted, when data were derived from eCRF, in a clinically meaningful and statistically significant improvement in OS compared to treatment with carboplatin and paclitaxel alone. Cervical cancer GOG-0240 The efficacy and safety of bevacizumab in combination with chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) in the treatment for patients with persistent, recurrent or metastatic carcinoma of the cervix was evaluated in study GOG-0240, a randomised, four-arm, open label, multi-centre phase III trial. A total of 452 patients were randomised to receive either: • Paclitaxel 135 mg/m2 IV over 24 hours on day 1 and cisplatin 50 mg/m2 IV on day 2, every 3 weeks (q3w); or Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and cisplatin 50 mg/m2 IV on day 2 (q3w); or Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and cisplatin 50 mg/m2 IV on day 1 (q3w) • Paclitaxel 135 mg/m2 IV over 24 hours on day 1 and cisplatin 50 mg/m2 IV on day 2 plus bevacizumab 15 mg/kg IV on day 2 (q3w); or Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and cisplatin 50 mg/m2 IV on day 2 plus bevacizumab 15 mg/kg IV on day 2 (q3w); or Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and cisplatin 50 mg/m2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 (q3w) • Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1-3 (q3w) • Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1-3 plus bevacizumab 15 mg/kg IV on day 1 (q3w) Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix which was not amenable to curative treatment with surgery and/or radiation therapy and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. The median age was 46.0 years (range: 20-83) in the chemo alone group and 48.0 years (range: 22-85) in the chemo + bevacizumab group; with 9.3% of patients in the chemo alone group and 7.5% of patients in the chemo + bevacizumab group over the age of 65 years. Of the 452 patients randomised at baseline, the majority of patients were white (80.0% in the chemo alone group and 75.3% in the chemo + bevacizumab group), had squamous cell carcinoma (67.1% in the chemo alone group and 69.6% in the chemo + bevacizumab group), had persistent/recurrent disease (83.6% in the chemo alone group and 82.8% in the chemo + bevacizumab group), had 1-2 metastatic sites (72.0% in the chemo alone group and 76.2% in the chemo + bevacizumab group), had lymph node involvement (50.2% in the chemo alone group and 56.4% in the chemo + bevacizumab group), and had a platinum free interval ≥ 6 months (72.5% in the chemo alone group and 64.4% in the chemo + bevacizumab group). The primary efficacy endpoint was overall survival. Secondary efficacy endpoints included progression-free survival and objective response rate. Results from the primary analysis and the follow-up analysis are presented by bevacizumab treatment and by trial treatment in table 23 and 24, respectively. 44 Table 23. Efficacy results from study GOG-0240 by bevacizumab treatment Chemotherapy (n = 225) Chemotherapy + bevacizumab (n = 227) Primary endpoint Overall survival - Primary analysis6 Median (months)1 12.9 16.8 Hazard ratio [95% CI] 0.74 [0.58, 0.94] (p-value5 = 0.0132) Overall survival - Follow-up analysis7 Median (months)1 13.3 16.8 Hazard ratio [95% CI] 0.76 [0.62, 0.94] (p-value5,8 = 0.0126) Secondary endpoints Progression-free survival - Primary analysis6 Median PFS (months)1 6.0 8.3 Hazard ratio [95% CI] 0.66 [0.54, 0.81] (p-value5 < 0.0001) Best overall response - Primary analysis6 Responders (response rate2) 76 (33.8%) 103 (45.4%) 95% CI for response rates3 [27.6%, 40.4%] [38.8%, 52.1%] Difference in response rates 11.60% 95% CI for difference in response rates4 [2.4%, 20.8%] p-value (Chi-squared test) 0.0117 1 Kaplan-Meier estimates. 2 Patients and percentage of patients with best overall response of confirmed CR or PR; percentage calculated on patients with measurable disease at baseline. 3 95% CI for one sample binomial using Pearson-Clopper method. 4 Approximate 95% CI for difference of two rates using Hauck-Anderson method. 5 log-rank test (stratified). 6 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final analysis. 7 Follow-up analysis was performed with a data cut-off date of 07 March 2014. 8 p-value displayed for descriptive purpose only. 45 Table 24. Overall survival results from study GOG-0240 by trial treatment Treatment comparison Other factor Overall survival - Primary analysis1 Hazard ratio (95% CI) Overall survival - Follow-up analysis2 Hazard ratio (95% CI) Bevacizumab vs. No bevacizumab Cisplatin + Paclitaxel 0.72 (0.51, 1.02) (17.5 vs.14.3 months; p = 0.0609) 0.75 (0.55, 1.01) (17.5 vs.15.0 months; p = 0.0584) Topotecan + Paclitaxel 0.76 (0.55, 1.06) (14.9 vs. 11.9 months; p = 0.1061) 0.79 (0.59, 1.07) (16.2 vs. 12.0 months; p = 0.1342) Topotecan + Paclitaxel vs. Cisplatin + Paclitaxel Bevacizumab 1.15 (0.82, 1.61) (14.9 vs. 17.5 months; p = 0.4146) 1.15 (0.85, 1.56) (16.2 vs. 17.5 months; p = 0.3769) No bevacizumab 1.13 (0.81, 1.57) (11.9 vs.14.3 months; p = 0.4825) 1.08 (0.80, 1.45) (12.0 vs. 15.0 months; p = 0.6267) 1 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final analysis. 2 Follow-up analysis was performed with a data cut-off date of 07 March 2014; all p-values are displayed for descriptive purpose only. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies, in all subsets of the paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum, lung carcinoma (small cell and non-small cell carcinoma), kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney), ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and cervix and corpus uteri carcinoma. High-grade glioma Anti-tumour activity was not observed in two earlier studies among a total of 30 children aged > 3 years old with relapsed or progressive high-grade glioma when treated with bevacizumab and irinotecan (CPT 11). There is insufficient information to determine the safety and efficacy of bevacizumab in children with newly diagnosed high-grade glioma.  In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontine high-grade glioma (including 8 with glioblastoma [WHO grade IV], 9 with anaplastic astrocytoma [grade III] and 1 with anaplastic oligodendroglioma [grade III]) were treated with bevacizumab (10 mg/kg) two weeks apart and then with bevacizumab in combination with CPT-11 (125-350 mg/m2) once every two weeks until progression. There were no objective (partial or complete) radiological responses (MacDonald criteria). Toxicity and adverse reactions included arterial hypertension and fatigue as well as CNS ischaemia with acute neurological deficit.  In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsed or progressive high-grade glioma (3 with WHO grade IV, 9 with grade III) were treated with bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) every 2 weeks. There were no complete responses and 2 partial responses (MacDonald criteria). In a randomised phase II study (BO25041) a total of 121 patients aged ≥ 3 years to < 18 years with newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) 46 were treated with post-operative radiation therapy (RT) and adjuvant temozolomide (T) with and without bevacizumab: 10 mg/kg every 2 weeks IV. The study did not meet its primary endpoint of demonstrating a significant improvement of event free survival (EFS) (Central Radiology Review Committee (CRRC)-assessed) when bevacizumab was added to the RT/T arm compared with RT/T alone (HR = 1.44; 95% CI: 0.90, 2.30). These results were consistent with those from various sensitivity analyses and in clinically relevant subgroups. The results for all secondary endpoints (investigator assessed EFS, and ORR and OS) were consistent in showing no improvement associated with the addition of bevacizumab to the RT/T arm compared with the RT/T arm alone. Addition of bevacizumab to RT/T did not demonstrate clinical benefit in study BO25041 in 60 evaluable children patients with newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) (see section 4.2 for information on paediatric use). Soft tissue sarcoma In a randomised phase II study (BO20924) a total of 154 patients aged ≥ 6 months to < 18 years with newly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma were treated with standard of care (Induction IVADO/IVA+/- local therapy followed by maintenance vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a total duration of treatment of approximately 18 months. At the time of the final primary analysis, the primary endpoint of EFS by independent central review did not show a statistically significant difference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72). The difference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the two treatment arms in the few patients who had evaluable tumour at baseline and had a confirmed response prior to receiving any local therapy: 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the chemo arm and 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the BV + chemo arm. The secondary endpoint of overall survival was not mature. Until mature OS results and safety data are available no definitive conclusion can be drawn on the benefit/risk balance. Addition of bevacizumab to standard of care did not demonstrate clinical benefit in clinical trial BO20924, in 71 evaluable children (from age 6 months to less than 18 years old) patients with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma (see section 4.2 for information on paediatric use). The incidence of adverse events, including grade ≥ 3 adverse events and serious adverse events, was similar between the two treatment arms. No adverse events leading to death occurred in either treatment arm; all deaths were attributed to disease progression. Bevacizumab addition to multimodal standard of care treatment seemed to be tolerated in this paediatric population. 5.2 Pharmacokinetic properties The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solid tumours. In all clinical trials, bevacizumab was administered as an IV infusion. The rate of infusion was based on tolerability, with an initial infusion duration of 90 minutes. The pharmacokinetics of bevacizumab was linear at doses ranging from 1 to 10 mg/kg. Distribution The typical value for central volume (Vc) was 2.73 L and 3.28 L for female and male patients respectively, which is in the range that has been described for IgGs and other monoclonal antibodies. The typical value for peripheral volume (Vp) was 1.69 L and 2.35 L for female and male patients respectively, when bevacizumab is co-administered with anti-neoplastic agents. After correcting for body weight, male patients had a larger Vc (+ 20%) than female patients. Biotransformation 47 Assessment of bevacizumab metabolism in rabbits following a single IV dose of 125I-bevacizumab indicated that its metabolic profile was similar to that expected for a native IgG molecule which does not bind VEGF. The metabolism and elimination of bevacizumab is similar to endogenous IgG i.e. primarily via proteolytic catabolism throughout the body, including endothelial cells, and does not rely primarily on elimination through the kidneys and liver. Binding of the IgG to the FcRn receptor results in protection from cellular metabolism and the long terminal half-life. Elimination The value for clearance is, on average, equal to 0.188 and 0.220 L/day for female and male patients, respectively. After correcting for body weight, male patients had a higher bevacizumab clearance (+ 17%) than females. According to the two-compartmental model, the elimination half-life is 18 days for a typical female patient and 20 days for a typical male patient. Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab clearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster in subjects with higher tumour burden when compared with a typical patient with median values of albumin and tumour burden. Pharmacokinetics in special populations The population pharmacokinetics were analysed in adult and paediatric patients to evaluate the effects of demographic characteristics. In adults the results showed no significant difference in the pharmacokinetics of bevacizumab in relation to age. Renal impairment No trials have been conducted to investigate the pharmacokinetics of bevacizumab in renally impaired patients since the kidneys are not a major organ for bevacizumab metabolism or excretion. Hepatic impairment No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients with hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion. Paediatric population The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents and young adults (7 months to 21 years, 5.9 to 125 kg) across 4 clinical studies using a population pharmacokinetic model. The pharmacokinetic results show that the clearance and volume of distribution of bevacizumab were comparable between paediatric and young adult patients when normalised by body weight, with exposure trending lower as body weight decreased. Age was not associated with the pharmacokinetics of bevacizumab when body weight was taken into account. The pharmacokinetics of bevacizumab was well characterised by the paediatric population PK model for 70 paediatric patients in study BO20924 (1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in study BO25041 (1 to 17 years; 11.2 to 82.3 kg). In study BO20924, bevacizumab exposure was generally lower compared to a typical adult patient at the same dose. In study BO25041, bevacizumab exposure was similar compared to a typical adult at the same dose. In both studies, bevacizumab exposure trended lower as body weight decreased. 5.3 Preclinical safety data In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed in young animals with open growth plates, at bevacizumab average serum concentrations below the expected human therapeutic average serum concentrations. In rabbits, bevacizumab was shown to 48 inhibit wound healing at doses below the proposed clinical dose. Effects on wound healing were shown to be fully reversible. Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not been performed. No specific studies in animals have been conducted to evaluate the effect on fertility. An adverse effect on female fertility can however be expected as repeat dose toxicity studies in animals have shown inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea and associated decrease in ovarian and uterus weight as well as a decrease in the number of menstrual cycles. Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased incidence of specific gross and skeletal foetal malformations. Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted in average serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every 2 weeks. Information on foetal malformations observed in the post-marketing setting are provided in sections 4.6 and 4.8. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium L-glutamate Sorbitol (E420) Polysorbate 80 Hydrochloric acid (for pH-adjustment) Water for injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. A concentration dependent degradation profile of bevacizumab was observed when diluted with glucose solutions (5%). 6.3 Shelf life Unopened vial 3 years Diluted medicinal product Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C to 30°C in sodium chloride 9 mg/mL (0.9%) solution for injection. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. 49 Keep the vial in the outer carton in order to protect from light. For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 4 mL solution in a vial (Type I glass) with a stopper (butyl rubber) containing 100 mg of bevacizumab. 16 mL solution in a vial (Type I glass) with a stopper (butyl rubber) containing 400 mg of bevacizumab. Pack of 1 vial. 6.6 Special precautions for disposal and other handling Equidacent should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared solution. The necessary amount of bevacizumab should be withdrawn and diluted to the required administration volume with sodium chloride 9 mg/mL (0.9%) solution for injection. The concentration of the final bevacizumab solution should be kept within the range of 1.4 mg/mL to 16.5 mg/mL. In the majority of the occasions the necessary amount of Equidacent can be diluted with 0.9% sodium chloride solution for injection to a total volume of 100 mL. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. No incompatibilities between Equidacent and polyvinyl chloride or polyolefin bags or infusion sets have been observed. Equidacent is for single-use only, as the product contains no preservatives. Any unused medicinal product or waste material should be disposed in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Centus Biotherapeutics Europe Limited South Bank House, Barrow Street Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1472/001 EU/1/20/1472/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA): http://www.ema.europa.eu. http://www.ema.europa.eu./ 50 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 51 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Kyowa Kirin Co., Ltd. Takasaki Plant, 100-1 Hagiwara-machi, Takasaki, Gunma, 370-0013, Japan Name and address of the manufacturer responsible for batch release Geryon Pharma Ireland Limited Skybridge House, Corballis Road North, Dublin Airport, Swords, Co. Dublin, K67 P6K2, Ireland B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 52 ANNEX III LABELLING AND PACKAGE LEAFLET 53 A. LABELLING 54 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Equidacent 25 mg/mL concentrate for solution for infusion bevacizumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 100 mg bevacizumab. 3. LIST OF EXCIPIENTS Contains: sodium L-glutamate, sorbitol (E420), polysorbate 80, hydrochloric acid, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion. 1 vial of 4 mL 100 mg/4 mL 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use after dilution Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original carton in order to protect from light. 55 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Centus Biotherapeutics Europe Limited South Bank House, Barrow Street Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1472/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER - 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 56 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Equidacent 25 mg/mL sterile concentrate bevacizumab IV 2. METHOD OF ADMINISTRATION IV after dilution 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 100 mg/4 mL 6. OTHER 57 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Equidacent 25 mg/mL concentrate for solution for infusion bevacizumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 400 mg bevacizumab. 3. LIST OF EXCIPIENTS Contains: sodium L-glutamate, sorbitol (E420), polysorbate 80, hydrochloric acid, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion. 1 vial of 16 mL 400 mg/16 mL 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use after dilution Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original carton in order to protect from light. 58 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Centus Biotherapeutics Europe Limited South Bank House, Barrow Street Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1472/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER - 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 59 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Equidacent 25 mg/mL sterile concentrate bevacizumab IV 2. METHOD OF ADMINISTRATION IV after dilution 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 400 mg/16 mL 6. OTHER 60 B. PACKAGE LEAFLET 61 Package leaflet: Information for the user Equidacent 25 mg/mL concentrate for solution for infusion bevacizumab This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor, pharmacist or nurse.  If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Equidacent is and what it is used for 2. What you need to know before you use Equidacent 3. How to use Equidacent 4. Possible side effects 5. How to store Equidacent 6. Contents of the pack and other information 1. What Equidacent is and what it is used for Equidacent contains the active substance bevacizumab, which is a humanised monoclonal antibody (a type of protein that is normally made by the immune system to help defend the body from infection and cancer).  Bevacizumab binds selectively to a protein called human vascular endothelial growth factor (VEGF), which is found on the lining of blood and lymph vessels in the body.  The VEGF protein causes blood vessels to grow within tumours, these blood vessels provide the tumour with nutrients and oxygen.  Once bevacizumab is bound to VEGF, tumour growth is prevented by blocking the growth of the blood vessels which provide the nutrients and oxygen to the tumour. Advanced cancer in the large bowel Equidacent is a medicine used for the treatment of adult patients with advanced cancer in the large bowel, i.e., in the colon or rectum. Equidacent will be administered in combination with chemotherapy treatment containing a fluoropyrimidine medicine. Breast cancer which has spread (metastatic) Equidacent is also used for the treatment of adult patients with metastatic breast cancer. When used for patients with breast cancer, it will be administered with a chemotherapy medicinal product called paclitaxel or capecitabine. Advanced non-small cell lung cancer Equidacent is also used for the treatment of adult patients with advanced non-small cell lung cancer. Equidacent will be administered together with a chemotherapy regimen containing platinum. Equidacent is also used for the treatment of adult patients with advanced non-small cell lung cancer when cancer cells have specific mutations of a protein called epidermal growth factor receptor (EGFR). Equidacent will be administered in combination with erlotinib. 62 Advanced kidney cancer Equidacent is also used for treatment of adult patients with advanced kidney cancer. When used for patients with kidney cancer, it will be administered with another type of medicine called interferon. Advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer Equidacent is also used for the treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. When used for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, it will be administered in combination with carboplatin and paclitaxel. When used for those adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer whose disease has come back at least 6 months after the last time they were treated with a chemotherapy regimen containing a platinum agent, Equidacent will be administered in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel. Cervical cancer which does not go away, comes back or has spread Equidacent is also used for the treatment of adult patients with persistent, recurrent or metastatic cervical cancer. Equidacent will be administered in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy. 2. What you need to know before you use Equidacent Do not use Equidacent if:  you are allergic (hypersensitive) to bevacizumab or to any of the other ingredients of this medicine (listed in section 6).  you are allergic (hypersensitive) to Chinese hamster ovary (CHO) cell products or to other recombinant human or humanised antibodies.  you are pregnant. Warnings and precautions Talk to your doctor, pharmacist or nurse before using Equidacent:  It is possible that Equidacent may increase the risk of developing holes in the gut wall. If you have conditions causing inflammation inside the abdomen (e.g. diverticulitis, stomach ulcers, colitis associated with chemotherapy), please discuss this with your doctor.  Equidacent may increase the risk of developing an abnormal connection or passageway between two organs or vessels. The risk of developing connections between the vagina and any parts of the gut can increase if you have persistent, recurrent or metastatic cervical cancer.  Equidacent can increase the risk of bleeding or increase the risk of problems with wound healing after surgery. If you are going to have an operation, if you have had major surgery within the last 28 days or if you still have an unhealed wound following surgery, you should not receive this medicine.  Equidacent may increase the risk of developing serious infections of the skin or deeper layers under the skin, especially if you had holes in the gut wall or problems with wound healing.  Equidacent can increase the incidence of high blood pressure. If you have high blood pressure which is not well controlled with blood pressure medicines, please consult your doctor as it is important to make sure that your blood pressure is under control before starting Equidacent treatment.  If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall. 63  Equidacent increases the risk of having protein in your urine especially if you already have high blood pressure.  The risk of developing blood clots in your arteries (a type of blood vessel) can increase if you are over 65 years old, if you have diabetes, or if you have had previous blood clots in your arteries. Please talk to your doctor since blood clots can lead to heart attack and stroke.  Equidacent can also increase the risk of developing blood clots in your veins (a type of blood vessel).  This medicine may cause bleeding, especially tumour-related bleeding. Please consult your doctor if you or your family tend to suffer from bleeding problems or you are taking medicines to thin the blood for any reason.  It is possible that Equidacent may cause bleeding in and around your brain. Please discuss this with your doctor if you have metastatic cancer affecting your brain.  It is possible that Equidacent can increase the risk of bleeding in your lungs, including coughing or spitting blood. Please discuss with your doctor if you noticed this previously.  Equidacent can increase the risk of developing a weak heart. It is important that your doctor knows if you have ever received anthracyclines (for example doxorubicin, a specific type of chemotherapy used to treat some cancers) or had radiotherapy to your chest, or if you have heart disease.  This medicine may cause infections and a decreased number of your neutrophils (a type of blood cell important for your protection against bacteria).  It is possible that Equidacent can cause hypersensitivity and/or infusion reactions (reactions related to your injection of the medicine). Please let your doctor, pharmacist or nurse know if you have previously experienced problems after injections, such as dizziness/feeling of fainting, breathlessness, swelling or skin rash.  A rare neurological side effect named posterior reversible encephalopathy syndrome (PRES) has been associated with Equidacent treatment. If you have headache, vision changes, confusion or seizure with or without high blood pressure, please contact your doctor. Please consult your doctor, even if these above statements were only applicable to you in the past. Before you are given Equidacent or while you are being treated with Equidacent:  if you have or have had pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth tell your doctor and dentist immediately.  if you need to undergo an invasive dental treatment or dental surgery, tell your dentist that you are being treated with Equidacent, in particular when you are also receiving or have received an injection of bisphosphonate into your blood. You may be advised to have a dental check-up before you start treatment with Equidacent. Children and adolescents Equidacent use is not recommended in children and adolescents under the age of 18 years because the safety and benefit have not been established in these patient populations. 64 Death of bone tissue (osteonecrosis) in bones other than the jaw have been reported in patients under 18 years old when treated with bevacizumab. Other medicines and Equidacent Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. Combinations of Equidacent with another medicine called sunitinib malate (prescribed for renal and gastrointestinal cancer) may cause severe side effects. Discuss with your doctor to make sure that you do not combine these medicine. Tell your doctor if you are using platinum- or taxane-based therapies for lung or metastatic breast cancer. These therapies in combination with Equidacent may increase the risk of severe side effects. Please tell your doctor if you have recently received, or are receiving, radiotherapy. Pregnancy, breast-feeding and fertility You must not use this medicine if you are pregnant. Equidacent may cause damage to your unborn baby as it may stop the formation of new blood vessels.  Your doctor should advise you about using contraception during treatment with Equidacent and for at least 6 months after the last dose of Equidacent. Tell your doctor straight away if you are pregnant, become pregnant during treatment with this medicine, or plan to become pregnant in the near future. You must not breast-feed your baby during treatment with Equidacent and for at least 6 months after the last dose of Equidacent, as this medicine may interfere with the growth and development of your baby. Equidacent may impair female fertility. Please consult your doctor for more information. Ask your doctor, pharmacist or nurse for advice before taking any medicine. Driving and using machines Equidacent has not been shown to reduce your ability to drive or to use any tools or machines. However, sleepiness and fainting have been reported with Equidacent use. If you experience symptoms that affect your vision or concentration, or your ability to react, do not drive or use machines until symptoms disappear. Equidacent contains sorbitol Each Equidacent vial of 4 mL of concentrate contains 191 mg sorbitol and each Equidacent vial of 16 mL of concentrate contains 764 mg sorbitol. Sorbitol is a source of fructose. If you have hereditary fructose intolerance (HFI), a rare genetic disorder, you must not receive this medicine. Patients with HFI cannot break down fructose, which may cause serious side effects. You must tell your doctor before receiving this medicine if you have HFI. Important information about some of the ingredients of Equidacent This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium- free’. 3. How to use Equidacent 65 Dosage and frequency of administration The dose of Equidacent needed depends on your body weight and the kind of cancer to be treated.  The recommended dose is 5 mg, 7.5 mg, 10 mg or 15 mg per kilogram of your body weight. Your doctor will prescribe a dose of Equidacent that is right for you.  You will be treated with Equidacent once every 2 or 3 weeks.  The number of infusions that you receive will depend on how you are responding to treatment - you should continue to receive this medicine until Equidacent fails to stop your tumour growing. Your doctor will discuss this with you. Method and route of administration Equidacent is a concentrate for solution for infusion. Depending on the dose prescribed for you, some or all of the contents of the Equidacent vial will be diluted with sodium chloride solution before use. A doctor or nurse will give you this diluted Equidacent solution by intravenous infusion (a drip into your vein).  The first infusion will be given to you over 90 minutes.  If this is well-tolerated the second infusion may be given over 60 minutes.  Later infusions may be given to you over 30 minutes. The administration of Equidacent should be temporarily discontinued  if you develop severe high blood pressure requiring treatment with blood pressure medicines,  if you have problems with wound healing following surgery,  if you undergo surgery. The administration of Equidacent should be permanently discontinued if you develop  severe high blood pressure which cannot be controlled by blood pressure medicines; or a sudden severe rise in blood pressure,  presence of protein in your urine accompanied by swelling of your body,  a hole in your gut wall,  an abnormal tube-like connection or passage between the windpipe and the gullet, between internal organs and skin, between the vagina and any parts of the gut or between other tissues that are not normally connected (fistula), and are judged by your doctor to be severe,  serious infections of the skin or deeper layers under the skin,  a blood clot in your arteries,  a blood clot in the blood vessels of your lungs,  any severe bleeding. If too much Equidacent is given  you may develop a severe migraine. If this happens you should talk to your doctor, pharmacist or nurse immediately. If a dose of Equidacent is missed  your doctor will decide when you should be given your next dose of Equidacent. You should discuss this with your doctor. If you stop treatment with Equidacent Stopping your treatment with Equidacent may stop the effect on tumour growth. Do not stop treatment with Equidacent unless you have discussed this with your doctor. 66 If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. The side effects listed below were seen when Equidacent was given together with chemotherapy. This does not necessarily mean that these side effects were strictly caused by Equidacent. Allergic reactions If you have an allergic reaction, tell your doctor or a member of the medical staff straight away. The signs may include: difficulty in breathing or chest pain. You could also experience redness or flushing of the skin or a rash, chills and shivering, feeling sick (nausea) or being sick (vomiting). You should seek help immediately if you suffer from any of the below mentioned side effects. Severe side effects, which may be very common (may affect more than 1 in 10 people), include:  high blood pressure,  feeling of numbness or tingling in hands or feet,  decreased number of cells in the blood, including white cells that help to fight against infections (this may be accompanied by fever), and cells that help the blood to clot,  feeling weak and having no energy,  tiredness,  diarrhoea, nausea, vomiting and abdominal pain. Severe side effects, which may be common (may affect up to 1 in 10 people), include:  perforation of the gut,  bleeding, including bleeding in the lungs in patients with non-small cell lung cancer,  blocking of the arteries by a blood clot,  blocking of the veins by a blood clot,  blocking of the blood vessels of the lungs by a blood clot,  blocking of the veins of the legs by a blood clot,  heart failure,  problems with wound healing after surgery,  redness, peeling, tenderness, pain, or blistering on the fingers or feet,  decreased number of red cells in the blood,  lack of energy,  stomach and intestinal disorder,  muscle and joint pain, muscular weakness,  dry mouth in combination with thirst and/or reduced or darkened urine,  inflammation of the moist lining of mouth and gut, lungs and air passages, reproductive, and urinary tracts,  sores in the mouth and the tube from the mouth to the stomach, which may be painful and cause difficulty swallowing,  pain, including headache, back pain and pain in the pelvis and anal regions,  localised pus collection,  infection, and in particular infection in the blood or bladder,  reduced blood supply to the brain or stroke,  sleepiness,  nose bleed, 67  increase in heart rate (pulse),  blockage in the gut or bowel,  abnormal urine test (protein in the urine),  shortness of breath or low levels of oxygen in the blood,  infections of the skin or deeper layers under the skin,  fistula: abnormal tube-like connection between internal organs and skin or other tissues that are not normally connected, including connections between vagina and the gut in patients with cervical cancer. Severe side effects of unknown frequency (frequency cannot be estimated from the available data), include:  serious infections of the skin or deeper layers under the skin, especially if you had holes in the gut wall or problems with wound healing,  allergic reactions (the signs may include difficulty breathing, facial redness, rash, low blood pressure or high blood pressure, low oxygen in your blood, chest pain, or nausea/vomiting),  a negative effect on a woman’s ability to have children (see the paragraphs below the list of side effects for further recommendations),  a brain condition with symptoms including seizures (fits), headache, confusion, and changes in vision (Posterior Reversible Encephalopathy Syndrome or PRES),  symptoms that suggest changes in normal brain function (headaches, vision changes, confusion, or seizures), and high blood pressure,  an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections),  clogging of a very small blood vessel(s) in the kidney,  abnormally high blood pressure in the blood vessels of the lungs which makes the right side of the heart work harder than normal,  a hole in the cartilage wall separating the nostrils of the nose,  a hole in the stomach or intestines,  an open sore or hole in the lining of the stomach or small intestine (the signs may include abdominal pain, feeling bloated, black tarry stools or blood in your stools (faeces) or blood in your vomit),  bleeding from the lower part of the large bowel,  lesions in the gums with an exposed jaw bone that does not heal and may be associated with pain and inflammation of the surrounding tissue (see the paragraphs below the list of side effects for further recommendations),  hole in the gall bladder (symptoms and signs may include abdominal pain, fever, and nausea/vomiting). You should seek help as soon as possible if you suffer from any of the below mentioned side effects. Very common (may affect more than 1 in 10 people) side effects, which were not severe, include:  constipation,  loss of appetite,  fever,  problems with the eyes (including increased production of tears),  changes in speech,  change in the sense of taste,  runny nose,  dry skin, flaking and inflammation of the skin, change in skin colour,  loss of body weight,  nose bleeds. Common (may affect up to 1 in 10 people) side effects, which were not severe, include:  voice changes and hoarseness. 68 Patients older than 65 years have an increased risk of experiencing the following side effects:  blood clot in the arteries which can lead to a stroke or a heart attack,  reduction in the number of white cells in the blood, and cells that help the blood clot,  diarrhoea,  sickness,  headache,  fatigue,  high blood pressure. Equidacent may also cause changes in laboratory tests carried out by your doctor. These include a decreased number of white cells in the blood, in particular neutrophils (one type of white blood cell which helps protect against infections) in the blood; presence of protein in the urine; decreased blood potassium, sodium or phosphorous (a mineral); increased blood sugar; increased blood alkaline phosphatase (an enzyme); increased serum creatinine (a protein measured by a blood test to see how well your kidneys are working); decreased haemoglobin (found in red blood cells, which carry oxygen), which may be severe. Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. These could be signs and symptoms of bone damage in the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience any of them. Pre-menopausal women (women who have a menstrual cycle) may notice that their periods become irregular or are missed and may experience impaired fertility. If you are considering having children you should discuss this with your doctor before your treatment starts. Equidacent has been developed and made to treat cancer by injecting it into the bloodstream. It has not been developed or made for injection into the eye. It is therefore not authorised to be used in this way. When Equidacent is injected directly into the eye (unapproved use), the following side effects may occur:  Infection or inflammation of the eye globe,  Redness of the eye, small particles or spots in your vision (floaters), eye pain,  Seeing flashes of light with floaters, progressing to a loss of some of your vision,  Increased eye pressure,  Bleeding in the eye. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Equidacent Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the outer carton and on the vial label after the abbreviation EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2 °C – 8 °C). Do not freeze. Keep the vial in the outer carton in order to protect from light. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 69 Infusion solutions should be used immediately after dilution. Do not use Equidacent if you notice any particulate matter or discolouration prior to administration. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Equidacent contains  The active substance is bevacizumab. Each mL of concentrate contains 25 mg of bevacizumab, corresponding to 1.4 to 16.5 mg/mL when diluted as recommended. Each 4 mL vial contains 100 mg of bevacizumab, corresponding to 1.4 mg/mL when diluted as recommended. Each 16 mL vial contains 400 mg of bevacizumab, corresponding to 16.5 mg/mL when diluted as recommended.  The other ingredients are sodium L-glutamate, sorbitol (E420), polysorbate 80, hydrochloric acid and water for injections. What Equidacent looks like and contents of the pack Equidacent is a concentrate for solution for infusion. The concentrate is a clear to opalescent, colourless to pale brownish-yellowish solution in a glass vial with a rubber stopper. Each vial contains 100 mg bevacizumab in 4 mL of solution or 400 mg bevacizumab in 16 mL of solution. Each pack of Equidacent contains one vial. Marketing Authorisation Holder Centus Biotherapeutics Europe Limited South Bank House, Barrow Street Dublin 4 Ireland Manufacturer Geryon Pharma Ireland Limited Skybridge House, Corballis Road North, Dublin Airport, Swords, Co. Dublin, K67 P6K2, Ireland This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what equidacent is and what it is used for', 'Section_Content': 'equidacent contains the active substance bevacizumab, which is a humanised monoclonal antibody (a type of protein that is normally made by the immune system to help defend the body from infection and cancer). bevacizumab binds selectively to a protein called human vascular endothelial growth factor (vegf), which is found on the lining of blood and lymph vessels in the body. the vegf protein causes blood vessels to grow within tumours, these blood vessels provide the tumour with nutrients and oxygen. once bevacizumab is bound to vegf, tumour growth is prevented by blocking the growth of the blood vessels which provide the nutrients and oxygen to the tumour. advanced cancer in the large bowel equidacent is a medicine used for the treatment of adult patients with advanced cancer in the large bowel, i.e., in the colon or rectum. equidacent will be administered in combination with chemotherapy treatment containing a fluoropyrimidine medicine. breast cancer which has spread (metastatic) equidacent is also used for the treatment of adult patients with metastatic breast cancer. when used for patients with breast cancer, it will be administered with a chemotherapy medicinal product called paclitaxel or capecitabine. advanced non-small cell lung cancer equidacent is also used for the treatment of adult patients with advanced non-small cell lung cancer. equidacent will be administered together with a chemotherapy regimen containing platinum. equidacent is also used for the treatment of adult patients with advanced non-small cell lung cancer when cancer cells have specific mutations of a protein called epidermal growth factor receptor (egfr). equidacent will be administered in combination with erlotinib. advanced kidney cancer equidacent is also used for treatment of adult patients with advanced kidney cancer. when used for patients with kidney cancer, it will be administered with another type of medicine called interferon. advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer equidacent is also used for the treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. when used for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, it will be administered in combination with carboplatin and paclitaxel. when used for those adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer whose disease has come back at least 6 months after the last time they were treated with a chemotherapy regimen containing a platinum agent, equidacent will be administered in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel. cervical cancer which does not go away, comes back or has spread equidacent is also used for the treatment of adult patients with persistent, recurrent or metastatic cervical cancer. equidacent will be administered in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy.', 'Entity_Recognition': [{'Text': 'equidacent', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the active substance bevacizumab', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 52}, {'Text': 'a humanised monoclonal antibody', 'Type': 'PROBLEM', 'BeginOffset': 63, 'EndOffset': 94}, {'Id': 28, 'BeginOffset': 186, 'EndOffset': 195, 'Score': 0.870233952999115, 'Text': 'infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8586699962615967}]}, {'Id': 29, 'BeginOffset': 200, 'EndOffset': 206, 'Score': 0.9308375120162964, 'Text': 'cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9456033706665039}]}, {'Text': 'bevacizumab binds', 'Type': 'PROBLEM', 'BeginOffset': 209, 'EndOffset': 226}, {'Text': 'human 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{'Title': '2. what you need to know before you use equidacent', 'Section_Content': "do not use equidacent if: you are allergic (hypersensitive) to bevacizumab or to any of the other ingredients of this medicine (listed in section 6). you are allergic (hypersensitive) to chinese hamster ovary (cho) cell products or to other recombinant human or humanised antibodies. you are pregnant. warnings and precautions talk to your doctor, pharmacist or nurse before using equidacent: it is possible that equidacent may increase the risk of developing holes in the gut wall. if you have conditions causing inflammation inside the abdomen (e.g. diverticulitis, stomach ulcers, colitis associated with chemotherapy), please discuss this with your doctor. equidacent may increase the risk of developing an abnormal connection or passageway between two organs or vessels. the risk of developing connections between the vagina and any parts of the gut can increase if you have persistent, recurrent or metastatic cervical cancer. equidacent can increase the risk of bleeding or increase the risk of problems with wound healing after surgery. if you are going to have an operation, if you have had major surgery within the last 28 days or if you still have an unhealed wound following surgery, you should not receive this medicine. equidacent may increase the risk of developing serious infections of the skin or deeper layers under the skin, especially if you had holes in the gut wall or problems with wound healing. equidacent can increase the incidence of high blood pressure. if you have high blood pressure which is not well controlled with blood pressure medicines, please consult your doctor as it is important to make sure that your blood pressure is under control before starting equidacent treatment. if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall. equidacent increases the risk of having protein in your urine especially if you already have high blood pressure. the risk of developing blood clots in your arteries (a type of blood vessel) can increase if you are over 65 years old, if you have diabetes, or if you have had previous blood clots in your arteries. please talk to your doctor since blood clots can lead to heart attack and stroke. equidacent can also increase the risk of developing blood clots in your veins (a type of blood vessel). this medicine may cause bleeding, especially tumour-related bleeding. please consult your doctor if you or your family tend to suffer from bleeding problems or you are taking medicines to thin the blood for any reason. it is possible that equidacent may cause bleeding in and around your brain. please discuss this with your doctor if you have metastatic cancer affecting your brain. it is possible that equidacent can increase the risk of bleeding in your lungs, including coughing or spitting blood. please discuss with your doctor if you noticed this previously. equidacent can increase the risk of developing a weak heart. it is important that your doctor knows if you have ever received anthracyclines (for example doxorubicin, a specific type of chemotherapy used to treat some cancers) or had radiotherapy to your chest, or if you have heart disease. this medicine may cause infections and a decreased number of your neutrophils (a type of blood cell important for your protection against bacteria). it is possible that equidacent can cause hypersensitivity and/or infusion reactions (reactions related to your injection of the medicine). please let your doctor, pharmacist or nurse know if you have previously experienced problems after injections, such as dizziness/feeling of fainting, breathlessness, swelling or skin rash. a rare neurological side effect named posterior reversible encephalopathy syndrome (pres) has been associated with equidacent treatment. if you have headache, vision changes, confusion or seizure with or without high blood pressure, please contact your doctor. please consult your doctor, even if these above statements were only applicable to you in the past. before you are given equidacent or while you are being treated with equidacent: if you have or have had pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth tell your doctor and dentist immediately. if you need to undergo an invasive dental treatment or dental surgery, tell your dentist that you are being treated with equidacent, in particular when you are also receiving or have received an injection of bisphosphonate into your blood. you may be advised to have a dental check-up before you start treatment with equidacent. children and adolescents equidacent use is not recommended in children and adolescents under the age of 18 years because the safety and benefit have not been established in these patient populations. death of bone tissue (osteonecrosis) in bones other than the jaw have been reported in patients under 18 years old when treated with bevacizumab. other medicines and equidacent tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. combinations of equidacent with another medicine called sunitinib malate (prescribed for renal and gastrointestinal cancer) may cause severe side effects. discuss with your doctor to make sure that you do not combine these medicine. tell your doctor if you are using platinum- or taxane-based therapies for lung or metastatic breast cancer. these therapies in combination with equidacent may increase the risk of severe side effects. please tell your doctor if you have recently received, or are receiving, radiotherapy. pregnancy, breast-feeding and fertility you must not use this medicine if you are pregnant. equidacent may cause damage to your unborn baby as it may stop the formation of new blood vessels. your doctor should advise you about using contraception during treatment with equidacent and for at least 6 months after the last dose of equidacent. tell your doctor straight away if you are pregnant, become pregnant during treatment with this medicine, or plan to become pregnant in the near future. you must not breast-feed your baby during treatment with equidacent and for at least 6 months after the last dose of equidacent, as this medicine may interfere with the growth and development of your baby. equidacent may impair female fertility. please consult your doctor for more information. ask your doctor, pharmacist or nurse for advice before taking any medicine. driving and using machines equidacent has not been shown to reduce your ability to drive or to use any tools or machines. however, sleepiness and fainting have been reported with equidacent use. if you experience symptoms that affect your vision or concentration, or your ability to react, do not drive or use machines until symptoms disappear. equidacent contains sorbitol each equidacent vial of 4 ml of concentrate contains 191 mg sorbitol and each equidacent vial of 16 ml of concentrate contains 764 mg sorbitol. sorbitol is a source of fructose. if you have hereditary fructose intolerance (hfi), a rare genetic disorder, you must not receive this medicine. patients with hfi cannot break down fructose, which may cause serious side effects. you must tell your doctor before receiving this medicine if you have hfi. important information about some of the ingredients of equidacent this medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium- free'.", 'Entity_Recognition': [{'Text': 'equidacent', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 34, 'EndOffset': 42}, {'Id': 17, 'BeginOffset': 44, 'EndOffset': 58, 'Score': 0.6001881957054138, 'Text': 'hypersensitive', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 63, 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{'Title': '3. how to use equidacent', 'Section_Content': 'dosage and frequency of administration the dose of equidacent needed depends on your body weight and the kind of cancer to be treated. the recommended dose is 5 mg, 7.5 mg, 10 mg or 15 mg per kilogram of your body weight. your doctor will prescribe a dose of equidacent that is right for you. you will be treated with equidacent once every 2 or 3 weeks. the number of infusions that you receive will depend on how you are responding to treatment - you should continue to receive this medicine until equidacent fails to stop your tumour growing. your doctor will discuss this with you. method and route of administration equidacent is a concentrate for solution for infusion. depending on the dose prescribed for you, some or all of the contents of the equidacent vial will be diluted with sodium chloride solution before use. a doctor or nurse will give you this diluted equidacent solution by intravenous infusion (a drip into your vein). the first infusion will be given to you over 90 minutes. if this is well-tolerated the second infusion may be given over 60 minutes. later infusions may be given to you over 30 minutes. the administration of equidacent should be temporarily discontinued if you develop severe high blood pressure requiring treatment with blood pressure medicines, if you have problems with wound healing following surgery, if you undergo surgery. the administration of equidacent should be permanently discontinued if you develop severe high blood pressure which cannot be controlled by blood pressure medicines; or a sudden severe rise in blood pressure, presence of protein in your urine accompanied by swelling of your body, a hole in your gut wall, an abnormal tube-like connection or passage between the windpipe and the gullet, between internal organs and skin, between the vagina and any parts of the gut or between other tissues that are not normally connected (fistula), and are judged by your doctor to be severe, serious infections of the skin or deeper layers under the skin, a blood clot in your arteries, a blood clot in the blood vessels of your lungs, any severe bleeding. if too much equidacent is given you may develop a severe migraine. if this happens you should talk to your doctor, pharmacist or nurse immediately. if a dose of equidacent is missed your doctor will decide when you should be given your next dose of equidacent. you should discuss this with your doctor. if you stop treatment with equidacent stopping your treatment with equidacent may stop the effect on tumour growth. do not stop treatment with equidacent unless you have discussed this with your doctor. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'equidacent', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'administration', 'Type': 'TREATMENT', 'BeginOffset': 24, 'EndOffset': 38}, {'Text': 'equidacent', 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. if you get any side effects talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. the side effects listed below were seen when equidacent was given together with chemotherapy. this does not necessarily mean that these side effects were strictly caused by equidacent. allergic reactions if you have an allergic reaction, tell your doctor or a member of the medical staff straight away. the signs may include: difficulty in breathing or chest pain. you could also experience redness or flushing of the skin or a rash, chills and shivering, feeling sick (nausea) or being sick (vomiting). you should seek help immediately if you suffer from any of the below mentioned side effects. severe side effects, which may be very common (may affect more than 1 in 10 people), include: high blood pressure, feeling of numbness or tingling in hands or feet, decreased number of cells in the blood, including white cells that help to fight against infections (this may be accompanied by fever), and cells that help the blood to clot, feeling weak and having no energy, tiredness, diarrhoea, nausea, vomiting and abdominal pain. severe side effects, which may be common (may affect up to 1 in 10 people), include: perforation of the gut, bleeding, including bleeding in the lungs in patients with non-small cell lung cancer, blocking of the arteries by a blood clot, blocking of the veins by a blood clot, blocking of the blood vessels of the lungs by a blood clot, blocking of the veins of the legs by a blood clot, heart failure, problems with wound healing after surgery, redness, peeling, tenderness, pain, or blistering on the fingers or feet, decreased number of red cells in the blood, lack of energy, stomach and intestinal disorder, muscle and joint pain, muscular weakness, dry mouth in combination with thirst and/or reduced or darkened urine, inflammation of the moist lining of mouth and gut, lungs and air passages, reproductive, and urinary tracts, sores in the mouth and the tube from the mouth to the stomach, which may be painful and cause difficulty swallowing, pain, including headache, back pain and pain in the pelvis and anal regions, localised pus collection, infection, and in particular infection in the blood or bladder, reduced blood supply to the brain or stroke, sleepiness, nose bleed, 67 increase in heart rate (pulse), blockage in the gut or bowel, abnormal urine test (protein in the urine), shortness of breath or low levels of oxygen in the blood, infections of the skin or deeper layers under the skin, fistula: abnormal tube-like connection between internal organs and skin or other tissues that are not normally connected, including connections between vagina and the gut in patients with cervical cancer. severe side effects of unknown frequency (frequency cannot be estimated from the available data), include: serious infections of the skin or deeper layers under the skin, especially if you had holes in the gut wall or problems with wound healing, allergic reactions (the signs may include difficulty breathing, facial redness, rash, low blood pressure or high blood pressure, low oxygen in your blood, chest pain, or nausea/vomiting), a negative effect on a woman's ability to have children (see the paragraphs below the list of side effects for further recommendations), a brain condition with symptoms including seizures (fits), headache, confusion, and changes in vision (posterior reversible encephalopathy syndrome or pres), symptoms that suggest changes in normal brain function (headaches, vision changes, confusion, or seizures), and high blood pressure, an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections), clogging of a very small blood vessel(s) in the kidney, abnormally high blood pressure in the blood vessels of the lungs which makes the right side of the heart work harder than normal, a hole in the cartilage wall separating the nostrils of the nose, a hole in the stomach or intestines, an open sore or hole in the lining of the stomach or small intestine (the signs may include abdominal pain, feeling bloated, black tarry stools or blood in your stools (faeces) or blood in your vomit), bleeding from the lower part of the large bowel, lesions in the gums with an exposed jaw bone that does not heal and may be associated with pain and inflammation of the surrounding tissue (see the paragraphs below the list of side effects for further recommendations), hole in the gall bladder (symptoms and signs may include abdominal pain, fever, and nausea/vomiting). you should seek help as soon as possible if you suffer from any of the below mentioned side effects. very common (may affect more than 1 in 10 people) side effects, which were not severe, include: constipation, loss of appetite, fever, problems with the eyes (including increased production of tears), changes in speech, change in the sense of taste, runny nose, dry skin, flaking and inflammation of the skin, change in skin colour, loss of body weight, nose bleeds. common (may affect up to 1 in 10 people) side effects, which were not severe, include: voice changes and hoarseness. patients older than 65 years have an increased risk of experiencing the following side effects: blood clot in the arteries which can lead to a stroke or a heart attack, reduction in the number of white cells in the blood, and cells that help the blood clot, diarrhoea, sickness, headache, fatigue, high blood pressure. equidacent may also cause changes in laboratory tests carried out by your doctor. these include a decreased number of white cells in the blood, in particular neutrophils (one type of white blood cell which helps protect against infections) in the blood; presence of protein in the urine; decreased blood potassium, sodium or phosphorous (a mineral); increased blood sugar; increased blood alkaline phosphatase (an enzyme); increased serum creatinine (a protein measured by a blood test to see how well your kidneys are working); decreased haemoglobin (found in red blood cells, which carry oxygen), which may be severe. pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. these could be signs and symptoms of bone damage in the jaw (osteonecrosis). tell your doctor and dentist immediately if you experience any of them. pre-menopausal women (women who have a menstrual cycle) may notice that their periods become irregular or are missed and may experience impaired fertility. if you are considering having children you should discuss this with your doctor before your treatment starts. equidacent has been developed and made to treat cancer by injecting it into the bloodstream. it has not been developed or made for injection into the eye. it is therefore not authorised to be used in this way. when equidacent is injected directly into the eye (unapproved use), the following side effects may occur: infection or inflammation of the eye globe, redness of the eye, small particles or spots in your vision (floaters), eye pain, seeing flashes of light with floaters, progressing to a loss of some of your vision, increased eye pressure, bleeding in the eye. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'equidacent', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, 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'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9973680377006531, 'RelationshipScore': 0.5453539490699768, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 262, 'BeginOffset': 6362, 'EndOffset': 6365, 'Text': 'jaw', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'heaviness in the jaw', 'Type': 'PROBLEM', 'BeginOffset': 6345, 'EndOffset': 6365}, {'Id': 285, 'BeginOffset': 6370, 'EndOffset': 6390, 'Score': 0.3603097200393677, 'Text': 'loosening of a tooth', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6565470695495605}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9973680377006531, 'RelationshipScore': 0.9412950873374939, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 262, 'BeginOffset': 6362, 'EndOffset': 6365, 'Text': 'jaw', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'symptoms', 'Type': 'PROBLEM', 'BeginOffset': 6417, 'EndOffset': 6425}, {'Text': 'bone damage in the jaw (osteonecrosis', 'Type': 'PROBLEM', 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0.9266806840896606}]}, {'Id': 266, 'BeginOffset': 6957, 'EndOffset': 6960, 'Score': 0.9822377562522888, 'Text': 'eye', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 267, 'BeginOffset': 7063, 'EndOffset': 7066, 'Score': 0.9748293161392212, 'Text': 'eye', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 292, 'BeginOffset': 7099, 'EndOffset': 7111, 'Score': 0.7340672016143799, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6811304092407227}]}, {'Id': 293, 'BeginOffset': 7123, 'EndOffset': 7132, 'Score': 0.9946407079696655, 'Text': 'infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5739421248435974}]}, {'Text': 'inflammation of the eye globe', 'Type': 'PROBLEM', 'BeginOffset': 7136, 'EndOffset': 7165}, {'Text': 'redness of the eye', 'Type': 'PROBLEM', 'BeginOffset': 7167, 'EndOffset': 7185}, {'Text': 'small particles or spots in your vision (floaters)', 'Type': 'PROBLEM', 'BeginOffset': 7187, 'EndOffset': 7237}, {'Id': 299, 'BeginOffset': 7239, 'EndOffset': 7247, 'Score': 0.896190345287323, 'Text': 'eye pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9606963992118835}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.3049248158931732, 'RelationshipScore': 0.7688801884651184, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 270, 'BeginOffset': 7220, 'EndOffset': 7226, 'Text': 'vision', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'seeing flashes of light with floaters', 'Type': 'PROBLEM', 'BeginOffset': 7249, 'EndOffset': 7286}, {'Text': 'a loss of some of your vision', 'Type': 'PROBLEM', 'BeginOffset': 7303, 'EndOffset': 7332}, {'Text': 'increased eye pressure', 'Type': 'PROBLEM', 'BeginOffset': 7334, 'EndOffset': 7356}, {'Text': 'bleeding in the eye', 'Type': 'PROBLEM', 'BeginOffset': 7358, 'EndOffset': 7377}, {'Id': 305, 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'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6235925555229187}]}, {'Id': 310, 'BeginOffset': 7655, 'EndOffset': 7667, 'Score': 0.8528140187263489, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7403839826583862}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 7723, 'EndOffset': 7736}]}

{'Title': '5. how to store equidacent', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer carton and on the vial label after the abbreviation exp. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not freeze. keep the vial in the outer carton in order to protect from light. infusion solutions should be used immediately after dilution. do not use equidacent if you notice any particulate matter or discolouration prior to administration. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'equidacent', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 273, 'EndOffset': 274}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 310, 'EndOffset': 326}, {'Text': 'infusion solutions', 'Type': 'TREATMENT', 'BeginOffset': 359, 'EndOffset': 377}, {'Text': 'any particulate matter', 'Type': 'PROBLEM', 'BeginOffset': 457, 'EndOffset': 479}, {'Text': 'discolouration', 'Type': 'PROBLEM', 'BeginOffset': 483, 'EndOffset': 497}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 657, 'EndOffset': 671}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what equidacent contains the active substance is bevacizumab. each ml of concentrate contains 25 mg of bevacizumab, corresponding to 1.4 to 16.5 mg/ml when diluted as recommended. each 4 ml vial contains 100 mg of bevacizumab, corresponding to 1.4 mg/ml when diluted as recommended. each 16 ml vial contains 400 mg of bevacizumab, corresponding to 16.5 mg/ml when diluted as recommended. the other ingredients are sodium l-glutamate, sorbitol (e420), polysorbate 80, hydrochloric acid and water for injections. what equidacent looks like and contents of the pack equidacent is a concentrate for solution for infusion. the concentrate is a clear to opalescent, colourless to pale brownish-yellowish solution in a glass vial with a rubber stopper. each vial contains 100 mg bevacizumab in 4 ml of solution or 400 mg bevacizumab in 16 ml of solution. each pack of equidacent contains one vial.', 'Entity_Recognition': 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'DOSAGE', 'Score': 0.5200250148773193, 'RelationshipScore': 0.9894602298736572, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 73, 'EndOffset': 99, 'Text': 'concentrate contains 25 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.30160778760910034, 'RelationshipScore': 0.9973516464233398, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 140, 'EndOffset': 150, 'Text': '16.5 mg/ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9685809016227722, 'RelationshipScore': 0.9696649312973022, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 185, 'EndOffset': 189, 'Text': '4 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '1.4', 'Type': 'NUMBER', 'BeginOffset': 133, 'EndOffset': 136}, {'Text': '16.5', 'Type': 'NUMBER', 'BeginOffset': 140, 'EndOffset': 144}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 185, 'EndOffset': 186}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 204, 'EndOffset': 207}, {'Id': 6, 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6713FC7614B0655EA9786EAEFC31C1C6

https://www.ema.europa.eu/documents/product-information/iclusig-epar-product-information_en.pdf

Iclusig

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Iclusig 15 mg film-coated tablets Iclusig 30 mg film-coated tablets Iclusig 45 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Iclusig 15 mg film-coated tablets Each film-coated tablet contains 15 mg of ponatinib (as hydrochloride). Excipients with known effect Each film-coated tablet contains 40 mg of lactose monohydrate. Iclusig 30 mg film-coated tablets Each film-coated tablet contains 30 mg of ponatinib (as hydrochloride). Excipients with known effect Each film-coated tablet contains 80 mg of lactose monohydrate. Iclusig 45 mg film-coated tablets Each film-coated tablet contains 45 mg of ponatinib (as hydrochloride). Excipients with known effect Each film-coated tablet contains 120 mg of lactose monohydrate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Iclusig 15 mg film-coated tablets White, biconvex, round film-coated tablet that is approximately 6 mm in diameter, with "A5" debossed on one side. Iclusig 30 mg film-coated tablets White, biconvex, round film-coated tablet that is approximately 8 mm in diameter, with "C7" debossed on one side. Iclusig 45 mg film-coated tablets White, biconvex, round film-coated tablet that is approximately 9 mm in diameter, with “AP4” debossed on one side. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Iclusig is indicated in adult patients with  chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation  Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation. See sections 4.2 for the assessment of cardiovascular status prior to start of therapy and 4.4 for situations where an alternative treatment may be considered. 4.2 Posology and method of administration Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia. Haematologic support such as platelet transfusion and haematopoietic growth factors can be used during treatment if clinically indicated. Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed, including history and physical examination, and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and medical and supportive therapy for conditions that contribute to cardiovascular risk should be optimised during treatment with ponatinib. Posology The recommended starting dose is 45 mg of ponatinib once daily. For the standard dose of 45 mg once daily, a 45 mg film-coated tablet is available. Treatment should be continued as long as the patient does not show evidence of disease progression or unacceptable toxicity. Patients should be monitored for response according to standard clinical guidelines. Discontinuing ponatinib should be considered if a complete haematologic response has not occurred by 3 months (90 days). The risk of arterial occlusive events is likely to be dose-related. Reducing the dose of Iclusig to 15 mg should be considered for CP-CML patients who have achieved a major cytogenetic response taking the following factors into account in the individual patient assessment: cardiovascular risk, side effects of ponatinib therapy, time to cytogenetic response, and BCR-ABL transcript levels (see sections 4.4 and 5.1). If dose reduction is undertaken, close monitoring of response is recommended. Management of toxicities Dose modifications or interruption of dosing should be considered for the management of haematological and non-haematological toxicities. In the case of severe adverse reactions, treatment should be withheld. For patients whose adverse reactions are resolved or attenuated in severity, Iclusig may be restarted and escalation of the dose back to the daily dose used prior to the adverse reaction may be considered, if clinically appropriate. For a dose of 30 mg or 15 mg once daily, 15 mg and 30 mg film-coated tablets are available. 4 Myelosuppression Dose modifications for neutropenia (ANC* < 1.0 x 109/L) and thrombocytopenia (platelet < 50 x 109/L) that are unrelated to leukaemia are summarized in Table 1. Table 1 Dose modifications for myelosuppression ANC* < 1.0 x 109/L or platelet < 50 x 109/L First occurrence:  Iclusig should be withheld and resumed at the same dose after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L Recurrence at 45 mg:  Iclusig should be withheld and resumed at 30 mg after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L Recurrence at 30 mg:  Iclusig should be withheld and resumed at 15 mg after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L *ANC = absolute neutrophil count Arterial occlusion and venous thromboembolism In a patient suspected of developing an arterial occlusive event or a venous thromboembolism, Iclusig should be immediately interrupted. A benefit-risk consideration should guide a decision to restart Iclusig therapy (see sections 4.4 and 4.8) after the event is resolved. Hypertension may contribute to risk of arterial occlusive events. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled. Pancreatitis Recommended modifications for pancreatic adverse reactions are summarized in Table 2. Table 2 Dose modifications for pancreatitis and elevation of lipase/amylase Grade 2 pancreatitis and/or asymptomatic elevation of lipase/amylase Iclusig should be continued at the same dose Grade 3 or 4 asymptomatic elevation of lipase/amylase (> 2.0 x IULN*) only Occurrence at 45 mg:  Iclusig should be withheld and resumed at 30 mg after recovery to ≤ Grade 1 (< 1.5 x IULN) Occurrence at 30 mg:  Iclusig should be withheld and resumed at 15 mg after recovery to ≤ Grade 1 (< 1.5 x IULN) Occurrence at 15 mg:  Iclusig discontinuation should be considered Grade 3 pancreatitis Occurrence at 45 mg:  Iclusig should be withheld and resumed at 30 mg after recovery to < Grade 2 Occurrence at 30 mg:  Iclusig should be withheld and resumed at 15 mg after recovery to < Grade 2 Occurrence at 15 mg:  Iclusig discontinuation should be considered Grade 4 pancreatitis Iclusig should be discontinued *IULN = institution upper limit of normal Hepatic toxicity Dose interruption or discontinuation may be required as described in Table 3. 5 Table 3 Recommended dose modifications for hepatic toxicity Elevation of liver transaminase > 3 × ULN* Persistent grade 2 (longer than 7 days) Grade 3 or higher Occurrence at 45 mg:  Iclusig should be interrupted and hepatic function should be monitored  Iclusig should be resumed at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN), or recovery to pre-treatment grade Occurrence at 30 mg:  Iclusig should be interrupted and resumed at 15 mg after recovery to ≤ Grade 1, or recovery to pre- treatment grade Occurrence at 15 mg:  Iclusig should be discontinued Elevation of AST or ALT ≥ 3 × ULN concurrent with an elevation of bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN Iclusig should be discontinued *ULN = Upper Limit of Normal for the lab Elderly patients Of the 449 patients in the clinical study of Iclusig, 155 (35%) were ≥ 65 years of age. Compared to patients < 65 years, older patients are more likely to experience adverse reactions. Hepatic impairment Patients with hepatic impairment may receive the recommended starting dose. Caution is recommended when administering Iclusig to patients with hepatic impairment (see sections 4.4 and 5.2). Renal impairment Renal excretion is not a major route of ponatinib elimination. Iclusig has not been studied in patients with renal impairment. Patients with estimated creatinine clearance of ≥ 50 mL/min should be able to safely receive Iclusig with no dosage adjustment. Caution is recommended when administering Iclusig to patients with estimated creatinine clearance of < 50 mL/min, or end-stage renal disease. Paediatric population The safety and efficacy of Iclusig in patients less than 18 years of age have not been established. No data are available. Method of administration Iclusig is for oral use. The tablets should be swallowed whole. Patients should not crush or dissolve the tablets. Iclusig may be taken with or without food. Patients should be advised not to swallow the desiccant canister found in the bottle. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Important adverse reactions Myelosuppression Iclusig is associated with severe (National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4) thrombocytopenia, neutropenia, and anaemia. Most of the patients with grade 3 or 4 platelet count decreased, anaemia or neutropenia, developed it within the first 3 months of treatment. The frequency of these events is greater in patients with accelerated phase CML (AP-CML) or blast 6 phase CML (BP-CML)/Ph+ ALL than in chronic phase CML (CP-CML). A complete blood count should be performed every 2 weeks for the first 3 months and then monthly or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Iclusig temporarily or reducing the dose (see section 4.2). Arterial occlusion Arterial occlusions, including fatal myocardial infarction, stroke, retinal arterial occlusions associated in some cases with permanent visual impairment or vision loss, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, renal artery stenosis (associated with worsening, labile or treatment-resistant hypertension), and the need for urgent revascularization procedures have occurred in Iclusig-treated patients. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Arterial occlusion adverse events were more frequent with increasing age and in patients with history of ischaemia, hypertension, diabetes, or hyperlipidaemia. The risk of arterial occlusive events is likely to be dose-related (see sections 4.2 and 5.1). In the phase 2 trial (with a minimum of 64 months follow-up), arterial occlusive adverse reactions have occurred in 25% of patients (treatment-emergent frequencies). Some patients experienced more than 1 type of event. Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 13%, 9%, and 11% of Iclusig-treated patients, respectively. In the phase 2 trial, serious arterial occlusive adverse reactions occurred in 20% of patients (treatment-emergent frequencies). Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 10%, 7%, and 9% of Iclusig treated patients, respectively (see section 4.8). The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 351, 611, and 605 days, respectively. Iclusig should not be used in patients with a history of myocardial infarction, prior revascularization or stroke, unless the potential benefit of treatment outweighs the potential risk (see sections 4.2 and 4.8). In these patients, alternative treatment options should also be considered before starting treatment with ponatinib. Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed, including history and physical examination, and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and medical and supportive therapy for conditions that contribute to cardiovascular risk should be optimised during treatment with ponatinib. Monitoring for evidence of arterial occlusion should be performed and if decreased vision or blurred vision occurs, an ophthalmic examination (including fundoscopy) should be performed. Iclusig should be interrupted immediately in case of arterial occlusion. A benefit -risk consideration should guide a decision to restart Iclusig therapy (see sections 4.2 and 4.8). Venous thromboembolism In the phase 2 trial (with a minimum of 64 months follow-up), venous thromboembolic adverse reactions have occurred in 6% of patients (treatment-emergent frequencies). Serious venous thromboembolic adverse reactions occurred in 5% of patients (treatment-emergent frequencies) (see section 4.8). Monitoring for evidence of thromboembolism should be performed. Iclusig should be interrupted immediately in case of thromboembolism. A benefit -risk consideration should guide a decision to restart Iclusig therapy (see sections 4.2 and 4.8). 7 Retinal venous occlusions associated in some cases with permanent visual impairment or vision loss have occurred in Iclusig-treated patients. If decreased vision or blurred vision occurs, an ophthalmic examination (including fundoscopy) should be performed. Hypertension Hypertension may contribute to risk of arterial thrombotic events, including renal artery stenosis. During Iclusig treatment, blood pressure should be monitored and managed at each clinic visit and hypertension should be treated to normal. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled (see section 4.2). In the event of significant worsening, labile or treatment-resistant hypertension, treatment should be interrupted and evaluation for renal artery stenosis should be considered. Treatment-emergent hypertension (including hypertensive crisis) occurred in Iclusig-treated patients. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Aneurysms and artery dissections The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Iclusig, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. Congestive heart failure Fatal and serious heart failure or left ventricular dysfunction occurred in Iclusig-treated patients, including events related to prior vascular occlusive events. Patients should be monitored for signs or symptoms consistent with heart failure and they should be treated as clinically indicated, including interruption of Iclusig. Discontinuation of ponatinib should be considered in patients who develop serious heart failure (see sections 4.2 and 4.8). Pancreatitis and serum lipase Iclusig is associated with pancreatitis. The frequency of pancreatitis is greater in the first 2 months of use. Check serum lipase every 2 weeks for the first 2 months and then periodically thereafter. Dose interruption or reduction may be required. If lipase elevations are accompanied by abdominal symptoms, Iclusig should be withheld and patients evaluated for evidence of pancreatitis (see section 4.2). Caution is recommended in patients with a history of pancreatitis or alcohol abuse. Patients with severe or very severe hypertriglyceridemia should be appropriately managed to reduce the risk of pancreatitis. Hepatotoxicity Iclusig may result in elevation in ALT, AST, bilirubin, and alkaline phosphatase. Most patients who had an event of hepatotoxicity had their first event during the first year of treatment. Hepatic failure (including fatal outcome) has been observed. Liver function tests should be performed prior to treatment initiation and monitored periodically, as clinically indicated. Haemorrhage Severe haemorrhage, including fatalities, occurred in Iclusig-treated patients. The incidence of severe bleeding events was higher in patients with AP-CML, BP-CML and Ph+ ALL. Gastrointestinal haemorrhage and subdural hematoma were the most commonly reported grade 3/4 bleeding events. Most haemorrhagic events, but not all, occurred in patients with grade 3/4 thrombocytopenia. Iclusig should be interrupted and patients evaluated for serious or severe haemorrhage. Hepatitis B reactivation Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with Iclusig. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients 8 with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Iclusig should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8). Posterior Reversible Encephalopathy Syndrome Post-marketing cases of Posterior Reversible Encephalopathy Syndrome (PRES) have been reported in Iclusig-treated patients. PRES is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. If diagnosed, interrupt Iclusig treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of PRES. Medicinal product interactions Caution should be exercised with concurrent use of Iclusig and moderate and strong CYP3A inhibitors and moderate and strong CYP3A inducers (see section 4.5). Concomitant use of ponatinib with anti-clotting agents should be approached with caution in patients who may be at risk of bleeding events (see “Myelosuppression” and “Haemorrhage”). Formal studies of ponatinib with anti-clotting medicinal products have not been conducted. QT prolongation The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients and no clinically significant QT prolongation was observed (see section 5.1). However, a thorough QT study has not been performed; therefore a clinically significant effect on QT cannot be excluded. Special populations Hepatic impairment Patients with hepatic impairment may receive the recommended starting dose. Caution is recommended when administering Iclusig to patients with hepatic impairment (see sections 4.2 and 5.2). Renal impairment Caution is recommended in when administering Iclusig to patients with estimated creatinine clearance of < 50 mL/min or end-stage renal disease (see section 4.2). Lactose This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Substances that may increase ponatinib serum concentrations CYP3A inhibitors Ponatinib is metabolized by CYP3A4. Co-administration of a single 15 mg oral dose of Iclusig in the presence of ketoconazole (400 mg daily), a strong CYP3A inhibitor, resulted in modest increases in ponatinib systemic exposure, with ponatinib AUC0-∞ and Cmax values that were 78% and 47% higher, respectively, than those seen when ponatinib was administered alone. Caution should be exercised and a reduction of the starting dose of Iclusig to 30 mg should be considered with concurrent use of strong CYP3A inhibitors such as clarithromycin, indinavir, 9 itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit juice. Substances that may decrease ponatinib serum concentrations CYP3A inducers Co-administration of a single 45 mg dose of Iclusig in the presence of rifampin (600 mg daily), a strong CYP3A inducer, to 19 healthy volunteers, decreased the AUC0-∞ and Cmax of ponatinib by 62% and 42%, respectively, when compared to administration of ponatinib alone. Co-administration of strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John’s Wort with ponatinib should be avoided, and alternatives to the CYP3A4 inducer should be sought, unless the benefit outweighs the possible risk of ponatinib underexposure. Substances that may have their serum concentrations altered by ponatinib Transporter substrates In vitro, ponatinib is an inhibitor of P-gp and BCRP. Therefore, ponatinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) or BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine) and may increase their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when ponatinib is administered with these medicinal products. Paediatric population Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/Contraception in males and females Women of childbearing age being treated with Iclusig should be advised not to become pregnant and men being treated with Iclusig should be advised not to father a child during treatment. An effective method of contraception should be used during treatment. It is unknown whether ponatinib affects the effectiveness of systemic hormonal contraceptives. An alternative or additional method of contraception should be used. Pregnancy There are no adequate data from the use of Iclusig in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Iclusig should be used during pregnancy only when clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus. Breast-feeding It is unknown whether Iclusig is excreted in human milk. Available pharmacodynamic and toxicological data cannot exclude potential excretion in human milk. Breast-feeding should be stopped during treatment with Iclusig. Fertility No human data on the effect of ponatinib on fertility are available. In rats, treatment with ponatinib has shown effects on female fertility and male fertility was not affected (see section 5.3). The clinical relevance of these findings to human fertility is unknown. 4.7 Effects on ability to drive and use machines Iclusig has minor influence on the ability to drive and use machines. Adverse reactions such as lethargy, dizziness, and vision blurred have been associated with Iclusig. Therefore, caution should be recommended when driving or operating machines. 10 4.8 Undesirable effects Summary of the safety profile The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 CML and Ph+ ALL patients who were resistant or intolerant to prior TKI therapy including those with a BCR-ABL T315I mutation. All patients received 45 mg Iclusig once daily. Dose adjustments to 30 mg once daily or 15 mg once daily were allowed for the management of treatment toxicity. Additionally, after approximately 2 years of follow-up, all patients who were still taking a 45 mg daily dose were recommended to undergo a dose reduction, even in the absence of adverse events, in response to the continued occurrence of vascular occlusive events in the clinical trial. At the time of reporting, all ongoing patients had a minimum follow-up of 64 months. The median duration of treatment with Iclusig was 32.2 months in CP-CML patients, 19.4 months in AP-CML patients, and 2.9 months in BP-CML/Ph+ ALL patients. The median dose intensity was 28 mg/day in CP-CML patients or, 63% of the expected 45 mg dose; median dose intensity was greater in advanced disease states (32 mg/day in the AP-CML patients and 44 mg/day in the BP CML/Ph+ ALL patients). The most common serious adverse reactions >2% (treatment-emergent frequencies) were pneumonia (7.3%), pancreatitis (5.8%), abdominal pain (4.7%), atrial fibrillation (4.5%), pyrexia (4.5%), myocardial infarction (4.0%), peripheral arterial occlusive disease (3.8%), anaemia (3.8%), angina pectoris (3.3%), platelet count decreased (3.1%), febrile neutropenia (2.9%), hypertension (2.9%), coronary artery disease (2.7%), cardiac failure congestive (2.4%), cerebrovascular accident (2.4%), sepsis (2.4%), cellulitis (2.2%), acute kidney injury (2.0%), urinary tract infection (2.0%) and lipase increased (2.0%). Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 10%, 7%, and 9% of Iclusig treated patients, respectively. Serious venous occlusive reactions (treatment-emergent frequencies) occurred in 5% of patients. Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 13%, 9%, and 11% of Iclusig-treated patients, respectively. Overall arterial occlusive adverse reactions have occurred in 25% of Iclusig-treated patients from the phase 2 trial, with serious adverse reactions occurring in 20% of patients. Some patients experienced more than one type of event. Venous thromboembolic reactions (treatment-emergent frequencies) occurred in 6% of patients. The incidence of thromboembolic events is higher in patients with Ph+ ALL or BP-CML than those with AP-CML or CP-CML. No venous occlusive events were fatal. After a minimum follow-up of 64 months, the rates of adverse reactions resulting in discontinuation were 20% in CP-CML, 11% in AP-CML, 15% in BP-CML and 9% in Ph+ ALL. Tabulated list of adverse reactions Adverse reactions reported in all CML and Ph+ ALL patients are presented in Table 4. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 11 Table 4 Adverse reactions observed in CML and Ph+ ALL patients – frequency reported by incidence of treatment emergent events System organ class Frequency Adverse reactions Infections and infestations Very common upper respiratory tract infection Common pneumonia, sepsis, folliculitis, cellulitis Blood and lymphatic system disorders Very common anaemia, platelet count decreased, neutrophil count decreased Common pancytopenia, febrile neutropenia, white blood cell count decreased, lymphocyte count decreased Endocrine disorders Common hypothyroidism Metabolism and nutrition disorders Very common decreased appetite Common dehydration, fluid retention, hypocalcaemia, hyperglycaemia, hyperuricaemia, hypophosphataemia, hypertriglyceridaemia, hypokalaemia, weight decreased, hyponatraemia Uncommon tumour lysis syndrome Psychiatric disorders Very common insomnia Nervous system disorders Very common headache, dizziness Common cerebrovascular accident, cerebral infarction, neuropathy peripheral, lethargy, migraine, hyperaesthesia, hypoaesthesia, paraesthesia, transient ischaemic attack Uncommon cerebral artery stenosis, cerebral haemorrhage, haemorrhage intracranial, posterior reversible encephalopathy syndrome * Eye disorders Common vision blurred, dry eye, periorbital oedema, eyelid oedema, conjunctivitis, visual impairment Uncommon retinal vein thrombosis, retinal vein occlusion, retinal artery occlusion Cardiac disorders Common cardiac failure, myocardial infarction, cardiac failure congestive, coronary artery disease, angina pectoris, pericardial effusion, atrial fibrillation, ejection fraction decreased, acute coronary syndrome, atrial flutter Uncommon myocardial ischemia, cardiac discomfort, ischemic cardiomyopathy, arteriospasm coronary, left ventricular dysfunction, Vascular disorders Very common hypertension Common peripheral arterial occlusive disease, peripheral ischaemia, peripheral artery stenosis, intermittent claudication, deep vein thrombosis, hot flush, flushing Uncommon poor peripheral circulation, splenic infarction, embolism venous, venous thrombosis, hypertensive crisis, renal artery stenosis Not known aneurysms and artery dissections 12 System organ class Frequency Adverse reactions Respiratory, thoracic and mediastinal disorders Very common dyspnoea, cough Common pulmonary embolism, pleural effusion, epistaxis, dysphonia, pulmonary hypertension Gastrointestinal disorders Very common abdominal pain, diarrhoea, vomiting, constipation, nausea, lipase increased Common pancreatitis, blood amylase increased, gastrooesophageal reflux disease, stomatitis, dyspepsia, abdominal distension, abdominal discomfort, dry mouth, gastric haemorrhage Hepatobiliary disorders Very common alanine aminotransferase increased, aspartate aminotransferase increased Common blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased Uncommon hepatotoxicity, hepatic failure, jaundice Skin and subcutaneous tissue disorders Very common rash, dry skin, pruritus Common rash pruritic, exfoliative rash, erythema, alopecia, skin exfoliation, night sweats, hyperhidrosis, petechia, ecchymosis, pain of skin, dermatitis exfoliative, hyperkeratosis, skin hyperpigmentation Musculoskeletal and connective tissue disorders Very common bone pain, arthralgia, myalgia, pain in extremity, back pain, muscle spasms Common musculoskeletal pain, neck pain, musculoskeletal chest pain Reproductive system and breast disorders Common erectile dysfunction General disorders and administrative site conditions Very common fatigue, asthenia, oedema peripheral, pyrexia, pain Common chills, influenza like illness, non-cardiac chest pain, mass, face oedema * Spontaneous reports from post-marketing experience Description of selected adverse reactions Vascular occlusion (see section 4.2 and 4.4). Serious vascular occlusion has occurred in patients treated with Iclusig, including cardiovascular, cerebrovascular and peripheral vascular events, and venous thrombotic events. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Arterial occlusive adverse events were more frequent with increasing age and in patients with history of ischaemia, hypertension, diabetes, or hyperlipidaemia. Myelosuppression Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 thrombocytopenia, neutropenia, and anaemia was higher in patients with AP-CML and BP- CML/Ph+ ALL than in patients with CP-CML (see Table 5). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. Discontinuation due to myelosuppression was infrequent (thrombocytopenia 4%, neutropenia and anaemia < 1% each). 13 Hepatitis B reactivation Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4). Severe Cutaneous Adverse Reactions (SCARs) Severe skin reactions (such as Stevens-Johnson Syndrome) have been reported with some BCR-ABL Tyrosine Kinase Inhibitors. Patients should be warned to immediately report suspected skin reactions, especially if associated with blistering, peeling, mucosal involvement or systemic symptoms. Table 5 Incidence of clinically relevant grade 3/4* laboratory abnormalities in ≥ 2% of patients in any disease group from the Phase 2 Trial (N=449): minimum follow-up of 64 month for all ongoing patients Laboratory test All patients (N=449) (%) CP-CML (N=270) (%) AP-CML (N=85) (%) BP-CML/Ph+ ALL (N=94) (%) Haematology Thrombocytopenia (platelet count decreased) 40 35 49 46 Neutropenia (ANC decreased) 34 23 52 52 Leukopenia (WBC decreased) 25 12 37 53 Anaemia (Hgb decreased) 20 8 31 46 Lymphopenia 17 10 25 28 Biochemistry Lipase increased 14 14 13 14 Phosphorus decreased 10 10 13 9 Glucose increased 7 8 13 1 ALT increased 6 4 8 7 Sodium decreased 5 6 6 2 AST increased 4 3 5 3 Amylase increased 4 4 4 3 Potassium decreased 2 < 1 6 2 Potassium increased 2 2 1 3 Alkaline phosphatase increased 2 2 4 2 Bilirubin 1 < 1 2 1 Calcium decreased 1 < 1 2 1 ALT=alanine aminotransferase, ANC=absolute neutrophil count, AST=aspartate aminotransferase, Hgb=haemoglobin, WBC=white blood cell count. *Reported using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Isolated reports of unintentional overdose with Iclusig were reported in clinical trials. Single doses of 165 mg and an estimated 540 mg in two patients did not result in any clinically significant adverse reactions. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and asymptomatic, moderate pericardial effusion. Treatment was interrupted, the events resolved, and Iclusig was restarted at 45 mg, once daily. In the event of an overdose of Iclusig, the patient should be observed and appropriate supportive treatment given. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 14 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE24 Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon triple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL kinase. Ponatinib inhibits the tyrosine kinase activity of ABL and T315I mutant ABL with IC50 values of 0.4 and 2.0 nM, respectively. In cellular assays, ponatinib was able to overcome imatinib, dasatinib, and nilotinib resistance mediated by BCR-ABL kinase domain mutations. In preclinical mutagenesis studies, 40 nM was determined as the concentration of ponatinib sufficient to inhibit viability of cells expressing all tested BCR-ABL mutants by > 50% (including T315I) and suppress the emergence of mutant clones. In a cell-based accelerated mutagenesis assay, no mutation in BCR-ABL was detected that could confer resistance to 40 nM ponatinib. Ponatinib elicited tumour shrinkage and prolonged survival in mice bearing tumours expressing native or T315I mutant BCR-ABL. At doses of 30 mg or greater plasma steady state trough concentrations of ponatinib typically exceed 21 ng/mL (40 nM). At doses of 15 mg or greater, 32 of 34 patients (94%) demonstrated a ≥ 50% reduction of CRK-like (CRKL) phosphorylation, a biomarker of BCR-ABL inhibition, in peripheral blood mononuclear cells. Ponatinib inhibits the activity of other clinically relevant kinases with IC50 values below 20 nM and has demonstrated cellular activity against RET, FLT3, and KIT and members of the FGFR, PDGFR, and VEGFR families of kinases. Clinical efficacy and safety The safety and efficacy of Iclusig in CML and Ph+ ALL patients who were resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy were evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once-daily with the possibility of dose de-escalations and dose interruptions followed by dose resumption and re-escalation. Patients were assigned to one of six cohorts based on disease phase (CP-CML; AP-CML; or BP- CML/Ph+ ALL), resistance or intolerance (R/I) to dasatinib or nilotinib, and the presence of the T315I mutation. The trial is ongoing. Resistance in CP-CML was defined as failure to achieve either a complete haematological response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months) while on dasatinib or nilotinib. CP-CML patients who experienced a loss of response or development of a kinase domain mutation in the absence of a complete cytogenetic response or progression to AP-CML or BP-CML at any time on dasatinib or nilotinib were also considered resistant. Resistance in AP-CML and BP-CML/Ph+ ALL was defined as failure to achieve either a major haematological response (AP-CML by 3 months, BP-CML/Ph+ ALL by 1 month), loss of major haematological response (at any time), or development of kinase domain mutation in the absence of a major haematological response while on dasatinib or nilotinib. Intolerance was defined as the discontinuation of dasatinib or nilotinib due to toxicities despite optimal management in the absence of a complete cytogenetic response for CP CML patients or major haematological response for AP CML, BP CML, or Ph+ ALL patients. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PCyR). The secondary efficacy endpoints in CP-CML were complete haematological response (CHR) and major molecular response (MMR). The primary efficacy endpoint in AP-CML and BP-CML/Ph+ ALL was major haematological response (MaHR), defined as either a complete haematological response (CHR) or no evidence of leukaemia (NEL). The secondary efficacy endpoints in AP-CML and BP-CML/Ph+ ALL were MCyR and MMR. 15 For all patients, additional secondary efficacy endpoints included: confirmed MCyR, time to response, duration of response, progression free survival, and overall survival. Also, post-hoc analyses to assess the relationship of shorter-term cytogenetic (MCyR) and molecular (MMR) response outcomes with longer-term outcomes of PFS and OS, maintenance of response (MCyR and MMR) after dose reductions, and PFS and OS by Arterial Occlusive Event status were conducted. The trial enrolled 449 patients of which 444 were eligible for analysis: 267 CP-CML patients (R/I Cohort: n=203, T315I Cohort: n=64), 83 AP-CML patients (R/I Cohort: n=65, T315I Cohort: n=18), 62 BP-CML (R/I Cohort: n=38, T315I Cohort: n=24), and 32 Ph+ ALL patients (R/I Cohort: n=10, T315I Cohort: n=22). A prior MCyR or better (MCyR, MMR, or CMR) to dasatinib or nilotinib was only achieved in 26% patients with CP-CML and a prior MaHR or better (MaHR, MCyR, MMR, or CMR) was only achieved in 21%, and 24% of AP-CML, and BP-CML/Ph+ALL patients, respectively. Baseline demographic characteristics are described in Table 6 below. Table 6 Demographics and disease characteristics Patient characteristics at entry Total safety population N=449 Age Median, years (range) 59 (18 - 94) Gender, n (%) Male 238 (53%) Race, n (%) Asian 59 (13%) Black/African American 25 (6%) White 352 (78%) Other 13 (3%) ECOG Performance Status, n (%) ECOG=0 or 1 414 (92%) Disease history Median time from diagnosis to first dose, years (range) 6.09 (0.33 - 28.47) Resistant to Prior TKI Therapy a *, n (%) 374 (88%) Prior TKI therapy– number of regimens, n (%) 1 32 (7%) 2 155 (35%) ≥ 3 262 (58%) BCR-ABL mutation detected at entry, n (%)b None 198 (44%) 1 192 (43%) ≥ 2 54 (12%) a* of 427 patients reporting prior TKI therapy with dasatinib or nilotinib b Of the patients with one or more BCR-ABL kinase domain mutations detected at entry, 37 unique mutations were detected. Overall, 55% of patients had one or more BCR-ABL kinase domain mutation at entry with the most frequent being: T315I (29%), F317L (8%), E255K (4%) and E359V (4%). In 67% of CP-CML patients in the R/I cohort, no mutations were detected at study entry. Efficacy results are summarized in Table 7, Table 8, and Table 9. 16 Table 7 Efficacy of Iclusig in resistant or intolerant chronic phase CML patients Overall (N=267) Resistant or Intolerant R/I Cohort (N=203) T315I Cohort (N=64) Cytogenetic Response Major (MCyR) a % (95% CI) 55% (49-62) 51% (44-58) 70% (58-81) Complete (CCyR) % (95% CI) 46% (40-52) 40% (33-47) 66% (53-77) Major Molecular Response b % (95% CI) 40% (35-47) 35% (28-42) 58% (45-70) a Primary endpoint for CP-CML Cohorts was MCyR, which combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses. b Measured in peripheral blood. Defined as a ≤ 0.1% ratio of BCR-ABL to ABL transcripts on the International Scale (IS) (ie, ≤ 0.1% BCR-ABLIS; patients must have the b2a2/b3a2 (p210) transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR). Database cutoff date 06 February 2017. CP-CML patients who received fewer prior TKIs attained higher cytogenetic, haematological, and molecular responses. Of the CP-CML patients previously treated with one, two, three or four prior TKIs, 75% (12/16), 68% (66/97), 44% (63/142), and 58% (7/12)) achieved a MCyR while on Iclusig, respectively. Of the CP-CML patients with no mutation detected at entry, 49% (66/136) achieved a MCyR. For every BCR-ABL mutation detected in more than one CP-CML patient at entry, a MCyR was achieved following treatment with Iclusig. In CP-CML patients who achieved MCyR, the median time to MCyR was 2.8 months (range: 1.6 to 11.3 months) and in patients who achieved MMR, the median time to MMR was 5.5 months (range: 1.8 to 55.5 months). At the time of updated reporting with minimum follow-up for all ongoing patients of 64 months, the median durations of MCyR and MMR had not yet been reached. Based on the Kaplan-Meier estimates, 82% (95% CI: [74%–88%]) of CP-CML (median duration of treatment: 32.2 months) patients who achieved a MCyR are projected to maintain that response at 48 months and 61% (95% CI: [51%- 70%]) of CP-CML patients who achieved a MMR are projected to maintain that response at 36 months. The probability of all patients with CP CML maintaining MCyR and MMR did not change further when the analysis was extended out to 5 years. With a minimum follow-up of 64 months, 3.4% (9/267) of CP-CML patients experienced transformation of their disease to AP-CML or BP-CML. For CP-CML patients overall (N=267), as well as for CP-CML R/I Cohort A patients (N=203) and T315I Cohort B patients (N=64), the median OS has not yet been reached. For the overall CP-CML disease group, the probability of survival at 2, 3, 4, and 5 years is estimated as 86.0%, 81.2%, 76.9%, and 73.3%, respectively, as shown in Figure 1. 17 Figure 1- Kaplan-Meier estimates for overall survival in the CP-CML population (Treated Population) CP -CML patients who achieved MCyR or MMR response within the first year of treatment had statistically significantly improved progression-free (PFS) and overall survival (OS) compared to those patients who did not meet the treatment milestones. A MCyR at the 3-month landmark correlated strongly and statistically significantly with PFS and OS (p<0.0001 and p=0.0006, respectively). Statistical significance was achieved in the correlation of PFS and OS with a MCyR at the 12-month landmark (p=<0.0001 and p=0.0012, respectively). 18 Table 8 Efficacy of Iclusig in resistant or intolerant advanced phase CML patients Accelerated Phase CML Blast Phase CML Overall (N=83) Resistant or Intolerant Overall (N=62) Resistant or Intolerant R/I Cohort (N=65) T315I Cohort (N=18) R/I Cohort (N=38) T315I Cohort (N=24) Haematological Response Rate Majora (MaHR) % (95% CI) 57% (45-68) 57% (44-69) 56% (31-79) 31% (20–44) 32% (18–49) 29% (13–51) Completeb (CHR) % (95% CI) 51% (39-62) 49% (37-62) 56% (31-79) 21% (12-33) 24% (11-40) 17% (5-37) Major Cytogenetic Responsec % (95% CI) 39% (28-50) 34% (23-47) 56% (31-79) 23% (13-35) 18% (8-34) 29% (13-51) a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines complete haematological responses and no evidence of leukaemia. b CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils < 5% in peripheral blood, No extramedullary involvement (including no hepatomegaly or splenomegaly). c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses. Database cutoff date 06 February 2017 Table 9 Efficacy of Iclusig in resistant or intolerant Ph+ ALL patients Overall (N=32) Resistant or Intolerant R/I Cohort (N=10) T315I Cohort (N=22) Haematological Response Rate Majora (MaHR) % (95% CI) 41% (24-59) 50% (19-81) 36% (17-59) Completeb (CHR) % (95% CI) 34% (19-53) 40% (12-74) 32% (14-55) Major Cytogenetic Responsec % (95% CI) 47% (29-65) 60% (26-88) 41% (21-64) a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines complete haematological responses and no evidence of leukaemia. b CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils < 5% in peripheral blood, No extramedullary involvement (including no hepatomegaly or splenomegaly). c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses. Database cutoff date 06 February 2017 The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ ALL was 0.7 months (range: 0.4 to 5.8 months), 1.0 months (range: 0.4 to 3.7 months), and 0.7 months (range: 0.4 to 5.5 months), 19 respectively. At the time of updated reporting with minimum follow-up for all ongoing patients of 64 months, the median duration of MaHR for AP-CML (median duration of treatment: 19.4 months) BP-CML (median duration of treatment: 2.9 months), and Ph+ ALL (median duration of treatment: 2.7 months) patients was estimated as 12.9 months (range: 1.2 to 68.4 months), 6.0 months (range: 1.8 to 59.6 months), and 3.2 months (range: 1.8 to 12.8 months), respectively. For all patients in the phase 2 trial, the dose intensity-safety relationship indicated that there are significant increases in grade ≥ 3 adverse events (cardiac failure, arterial thrombosis, hypertension, thrombocytopenia, pancreatitis, neutropenia, rash, ALT increase, AST increase, lipase increase, myelosuppression, arthralgia) over the dose range of 15 to 45 mg once-daily. The analysis of the dose intensity-safety relationship in the phase 2 trial concluded that after adjusting for covariates, the overall dose intensity is significantly associated with an increased risk of vascular occlusion, with an odds ratio of approximately 1.6 for each 15 mg increase. In addition, results from logistic regression analyses of data from patients in the phase 1 trial, suggest a relationship between systemic exposure (AUC) and occurrence of arterial thrombotic events. A reduction in dose is therefore expected to reduce the risk of vascular occlusive events, however, the analysis suggested that there may be a ‘carry over’ effect of higher doses such that it might take up to several months before a dose reduction manifests in risk reduction. Other covariates that show a statistically significant association with the occurrence of vascular occlusive events in this analysis are medical history of ischemia and age. Dose reduction in CP-CML patients In the phase 2 trial, dose reductions were recommended following adverse events; in addition in October 2013 new recommendations for prospective dose reduction in all CP-CML patients in the absence of adverse events were introduced in this trial with the aim of reducing the risk of vascular occlusive events. With a minimum follow-up of 48 months, and approximately 2 years after the recommendation for prospective dose reduction, there were 110 CP-CML patients ongoing. A majority of these ongoing patients (82/110 patients; 75%) were reported to be receiving 15 mg at the last dose, while 24/110 patients (22%) were receiving 30 mg, and 4/110 (4%) were receiving 45 mg. At the time of study closure initiation (minimum follow-up of 64 months, and more than 3 years after the recommendation for prospective dose reduction), 99 CP-CML patients were ongoing and 77 (78%) of these patients received 15 mg as their last dose on study. Safety In the phase 2 trial, 86 CP-CML patients achieved MCyR at a dose of 45 mg, 45 CP-CML patients achieved MCyR after a dose reduction to 30 mg, mostly for adverse events. Vascular occlusive events occurred in 44 of these 131 patients. Most of these events occurred at the dose at which the patient achieved MCyR; fewer events occurred after dose reduction. Table 10 Vascular occlusive first adverse events in CP-CML patients who achieved MCyR at 45 mg or 30 mg (data extraction 7 April 2014) Most recent dose at onset of first vascular occlusive Event 45 mg 30 mg 15 mg Achieved MCyR at 45 mg (N=86) 19 6 0 Achieved MCyR at 30 mg (N=45) 1 13 5 The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 351, 611, and 605 days, respectively. When adjusted for exposure, the incidence of first arterial occlusive events was greatest in the first two years of follow-up and declined with decreasing daily dose intensity (following recommendation for prospective dose reduction). Factors other than dose may also contribute to this risk of arterial occlusion. 20 Efficacy Data from the phase 2 trial are available on the maintenance of response (MCyR and MMR) in all CP- CML patients who underwent dose reduction for any reason. Table 11 shows these data for patients who achieved MCyR and MMR at 45 mg; similar data are available for patients who achieved MCyR and MMR at 30 mg. The majority of patients who underwent dose reduction maintained response (MCyR and MMR) for the duration of currently available follow-up. A proportion of patients did not undergo any dose reduction, based on an individual benefit-risk assessment. Table 11 Maintenance of response in CP-CML patients who achieved MCyR or MMR at 45 mg dose (data extraction 6 February 2017) Achieved MCyR at 45 mg (N=86) Achieved MMR at 45 mg (N=63) Number of patients Maintained MCyR Number of patients Maintained MMR No dose reduction 19 13 (68%) 18 11 (61%) Dose reduction to 30 mg only 15 13 (87%) 5 3 (60%) ≥ 3 month reduction at 30 mg 12 10 (83%) 3 2 (67%) ≥ 6 month reduction at 30 mg 11 9 (82%) 3 2 (67%) ≥ 12 month reduction at 30 mg 8 7 (88%) 3 2 (67%) ≥ 18 month reduction at 30 mg 7 6 (86%) 2 2 (100%) ≥ 24 month reduction at 30 mg 6 6 (100%) 2 2 (100%) ≥ 36 month reduction at 30 mg 1 1 (100%) -- -- Any dose reduction to 15 mg 52 51 (98%) 40 36 (90%) ≥ 3 month reduction at 15 mg 49 49 (100%) 39 36 (92%) ≥ 6 month reduction at 15 mg 47 47 (100%) 37 35 (95%) ≥ 12 month reduction at 15 mg 44 44 (100%) 34 33 (97%) ≥ 18 month day reduction at 15 mg 38 38 (100%) 29 29 (100%) ≥ 24 month reduction at 15 mg 32 32 (100%) 23 23 (100%) ≥ 36 month reduction at 15 mg 8 8 (100%) 4 4 (100%) The anti-leukaemic activity of Iclusig was also evaluated in a phase 1 dose escalation study that included 65 CML and Ph+ ALL patients; the study is completed. Of 43 CP-CML patients, 31 CP-CML patients achieved a MCyR with a median duration of follow-up of 55.5 months (range: 1.7 to 91.4 months). At the time of reporting, 25 CP-CML patients were in MCyR (median duration of MCyR had not been reached). Cardiac electrophysiology The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients who received 30 mg, 45 mg, or 60 mg Iclusig once daily. Serial ECGs in triplicate were collected at baseline and at steady state to evaluate the effect of ponatinib on QT intervals. No clinically significant changes in the mean QTc interval (i.e., > 20 ms) from baseline were detected in the study. In addition, the pharmacokinetic-pharmacodynamic models show no exposure-effect relationship, with an estimated QTcF mean change of –6.4 ms (upper confidence interval –0.9 ms) at Cmax for the 60 mg group. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Iclusig in children from birth to less than 1 year in CML and Ph+ ALL. The European Medicines Agency has deferred the obligation to submit the results of studies with Iclusig in paediatric patients from 1 year to less than 18 years in CML and Ph+ ALL (see section 4.2 for information on paediatric use). 21 5.2 Pharmacokinetic properties Absorption Peak concentrations of ponatinib are observed approximately 4 hours after oral administration. Within the range of clinically relevant doses evaluated in patients (15 mg to 60 mg), ponatinib exhibited dose proportional increases in both Cmax and AUC. The geometric mean (CV%) Cmax and AUC(0-τ) exposures achieved for ponatinib 45 mg daily at steady state were 77 ng/mL (50%) and 1296 ng•hr/mL (48%), respectively. Following either a high-fat and low-fat meal, plasma ponatinib exposures (Cmax and AUC) were not different versus fasting conditions. Iclusig may be administered with or without food. Co-administration of Iclusig with a potent inhibitor of gastric acid secretion resulted in a minor reduction in ponatinib Cmax without a reduction in AUC0-∞. Distribution Ponatinib is highly bound (> 99%) to plasma proteins in vitro. The blood/plasma ratio of ponatinib is 0.96. Ponatinib is not displaced by concomitant administration of ibuprofen, nifedipine, propranolol, salicylic acid, or warfarin. At daily doses of 45 mg, the geometric mean (CV%) apparent steady state volume of distribution is 1101 L (94%) suggesting that ponatinib is extensively distributed in the extravascular space. In vitro studies suggested that ponatinib is either not a substrate or is a weak substrate for both P-gp and breast cancer resistance protein BCRP. Ponatinib is not a substrate for the human organic anion transporting polypeptides OATP1B1, OATP1B3 and the organic cation transporter OCT-1. Biotransformation Ponatinib is metabolized to an inactive carboxylic acid by esterases and/or amidases, and metabolized by CYP3A4 to an N-desmethyl metabolite that is 4 times less active than ponatinib. The carboxylic acid and the N-desmethyl metabolite comprise 58% and 2% of the circulating levels of ponatinib, respectively. At therapeutic serum concentrations, ponatinib did not inhibit OATP1B1 or OATP1B3, OCT1 or OCT2, organic anion transporters OAT1 or OAT3, or bile salt export pump (BSEP) in vitro. Therefore, clinical medicinal product interactions are unlikely to occur as a result of ponatinib-mediated inhibition of substrates for these transporters. In vitro studies indicate that clinical medicinal product interactions are unlikely to occur as a result of ponatinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A or CYP2D6. An in vitro study in human hepatocytes indicated that clinical medicinal product interactions are also unlikely to occur as a result of ponatinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, or CYP3A. Elimination Following single and multiple 45 mg doses of Iclusig, the terminal elimination half-life of ponatinib was 22 hours, and steady state conditions are typically achieved within 1 week of continuous dosing. With once-daily dosing, plasma exposures of ponatinib are increased by approximately 1.5-fold between first dose and steady state conditions. Although plasma ponatinib exposures increased to steady-state levels with continuous dosing, a population pharmacokinetic analysis predicts a limited increase in apparent oral clearance within the first two weeks of continuous dosing, which is not considered clinically relevant. Ponatinib is mainly eliminated via faeces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the faeces and approximately 5% in the urine. Unchanged ponatinib accounted for 24% and < 1% of the administered dose in faeces and urine, respectively, with the remainder of the dose comprising metabolites. Renal impairment Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined (see section 4.2). 22 Hepatic impairment A single dose of 30 mg ponatinib was administered to patients with mild, moderate, or severe hepatic impairment and to healthy volunteers with normal hepatic function. Ponatinib Cmax was comparable in patients with mild hepatic impairment and healthy volunteers with normal hepatic function. In patients with moderate or severe hepatic impairment, ponatinib Cmax and AUC0-∞ were lower and ponatinib plasma elimination half-life was longer in patients with mild, moderate, and severe hepatic impairment but not clinically significantly different than in healthy volunteers with normal hepatic function. In vitro data showed no difference in plasma protein binding in plasma samples of healthy subjects and hepatically impaired (mild, moderate and severe) subjects. Compared to healthy volunteers with normal liver function, no major differences in ponatinib PK were observed in patients with varying degrees of hepatic impairment. A reduction of the starting dose of Iclusig in patients with hepatic impairment is not necessary (see sections 4.2 and 4.4). Caution is recommended when administering Iclusig to patients with hepatic impairment (see sections 4.2 and 4.4). Iclusig has not been studied at doses above 30 mg in patients with hepatic impairment (Childs-Pugh Classes A, B & C). Intrinsic factors affecting ponatinib pharmacokinetics No specific studies have been performed to evaluate the effects of gender, age, race, and body weight on ponatinib pharmacokinetics. An integrated population pharmacokinetic analysis completed for ponatinib suggests that age may be predictive of variability for ponatinib apparent oral clearance (CL/F). Gender, race and body weight were not predictive in explaining ponatinib pharmacokinetic intersubject variability. 5.3 Preclinical safety data Iclusig has been evaluated in safety pharmacology, repeat-dose toxicity, genotoxicity, reproductive toxicity, phototoxicity and carcinogenicity studies. Ponatinib did not exhibit genotoxic properties when evaluated in the standard in vitro and in vivo systems. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use are described below. Depletion of lymphoid organs was observed in repeat-dose toxicity studies in rats and cynomolgus monkeys. The effects were shown to be reversible after withdrawal of the treatment. Hyper-/hypoplastic changes of the chondrocytes in the physis were noted in repeat-dose toxicity studies in rats. In rats, inflammatory changes accompanied by increases in neutrophils, monocytes, eosinophils, and fibrinogen levels were found in the preputial and clitoral glands following chronic dosing. Skin changes in the form of crusts, hyperkeratosis, or erythema were observed in toxicity studies in cynomolgus monkeys. Dry flaky skin was observed in toxicity studies in rats. In a study in rats, diffuse corneal edema with neutrophilic cell infiltration, and hyperplastic changes in the lenticular epithelium suggestive of a mild phototoxic reaction were observed in animals treated with 5 and 10 mg/kg ponatinib. In cynomolgus monkeys, systolic heart murmurs with no macroscopic or microscopic correlates were noted in individual animals treated with 5 and 45 mg/kg in the single dose toxicity study and at 1, 2.5 23 and 5 mg/kg in the 4-week repeat-dose toxicity study. The clinical relevance of this finding is unknown. In cynomolgus monkeys, thyroid gland follicular atrophy mostly accompanied by a reduction in T3 levels and a tendency toward increased TSH levels were observed in the 4-week repeat-dose toxicity study in cynomolgus monkeys. Ponatinib-related microscopic findings in the ovaries (increased follicular atresia) and testes (minimal germ cell degeneration) in animals treated with 5 mg/kg ponatinib were noted in repeat-dose toxicity studies in cynomolgus monkeys. Ponatinib at doses of 3, 10, and 30 mg/kg produced increases in urine output and electrolyte excretions and caused a decrease in gastric emptying in safety pharmacology studies in rats. In rats, embryo-foetal toxicity in the form of post-implantation loss, reduced foetal body weight, and multiple soft tissue and skeletal alterations were observed at maternal toxic dosages. Multiple foetal soft tissue and skeletal alterations were also observed at maternal nontoxic dosages. In a fertility study in male and female rats, female fertility parameters were reduced at dose levels corresponding to human clinical exposures. Evidence for pre- and post-implantation loss of embryos was reported in female rats and ponatinib may therefore impair female fertility. There were no effects on male rat fertility parameters. The clinical relevance of these findings on human fertility is unknown. In juvenile rats, mortality related to inflammatory effects was observed in animals treated with 3 mg/kg/day, and reductions in body weight gain were observed at doses of 0.75, 1.5 and 3 mg/kg/day during the pre-weaning and early post-weaning treatment phases. Ponatinib did not adversely affect important developmental parameters in the juvenile toxicity study. In a two-year carcinogenicity study in male and female rats, oral administration of ponatinib at 0.05, 0.1 and 0.2 mg/kg/day in males and at 0.2 and 0.4 mg/kg/day in females did not result in any tumorigenic effects. The 0.8 mg/kg/day dose in females resulted in a plasma exposure level generally lower or equivalent to the human exposure at the range of dose from 15 mg to 45 mg daily. A statistically significant increased incidence of squamous cell carcinoma of the clitoral gland was observed at that dose. The clinical relevance of this finding for humans is not known. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Lactose monohydrate Microcrystalline cellulose Sodium starch glycolate Colloidal anhydrous silica Magnesium stearate Tablet coating Talc Macrogol 4000 Poly(vinyl alcohol) Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 24 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store in the original container in order to protect from light. The bottle contains one sealed canister containing a molecular sieve desiccant. Keep the canister in the bottle. 6.5 Nature and contents of container Iclusig 15 mg film-coated tablets High density polyethylene (HDPE) bottles with screw-top closures, containing either 30, 60 or 180 film-coated tablets, together with one plastic canister containing a molecular sieve desiccant. Iclusig 30 mg film-coated tablets High density polyethylene (HDPE) bottles with screw-top closures, containing 30 film-coated tablets, together with one plastic canister containing a molecular sieve desiccant. Iclusig 45 mg film-coated tablets High density polyethylene (HDPE) bottles with screw-top closures, containing either 30 or 90 film-coated tablets, together with one plastic canister containing a molecular sieve desiccant. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Disposal No special requirements for disposal. 7. MARKETING AUTHORISATION HOLDER Incyte Biosciences Distribution B.V. Paasheuvelweg 25 1105 BP Amsterdam Netherlands 8. MARKETING AUTHORISATION NUMBER(S) Iclusig 15 mg film-coated tablets EU/1/13/839/001 EU/1/13/839/002 EU/1/13/839/005 Iclusig 30 mg film-coated tablets EU/1/13/839/006 Iclusig 45 mg film-coated tablets EU/1/13/839/003 EU/1/13/839/004 25 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 1 July 2013 Date of latest renewal: 8 February 2018 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 26 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 27 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Haupt Pharma - AMAREG GmbH Donaustaufer Strasse 378 93055 Regensburg Germany Incyte Biosciences Distribution B.V. Paasheuvelweg 25 1105 BP Amsterdam Netherlands Tjoapack Netherlands B.V. Nieuwe Donk 9 4879 AC Etten-Leur Netherlands The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 28  Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date In order to determine the optimal starting dose of Iclusig and characterise the safety and efficacy of Iclusig following dose reductions after achieving MCyR in patients with CP-CML, the MAH should conduct and submit the results of a dose- ranging study. August 2021 29 ANNEX III LABELLING AND PACKAGE LEAFLET 30 A. LABELLING 31 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING OUTER CARTON AND BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Iclusig 15 mg film-coated tablets ponatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 15 mg ponatinib (as hydrochloride). 3. LIST OF EXCIPIENTS Contains lactose. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 30 tablets 60 tablets 180 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Outer Carton: Do not swallow the desiccant canister found in the bottle. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original container in order to protect from light. 32 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Incyte Biosciences Distribution B.V. Paasheuvelweg 25 1105 BP Amsterdam Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/839/001 60 film-coated tablets EU/1/13/839/002 180 film-coated tablets EU/1/13/839/005 30 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Outer Carton: Iclusig 15 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 33 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING OUTER CARTON AND BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Iclusig 30 mg film-coated tablets ponatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 30 mg ponatinib (as hydrochloride). 3. LIST OF EXCIPIENTS Contains lactose. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 30 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Outer Carton: Do not swallow the desiccant canister found in the bottle. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original container in order to protect from light. 34 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Incyte Biosciences Distribution B.V. Paasheuvelweg 25 1105 BP Amsterdam Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/839/006 30 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Outer Carton: Iclusig 30 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 35 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING OUTER CARTON AND BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Iclusig 45 mg film-coated tablets ponatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 45 mg ponatinib (as hydrochloride). 3. LIST OF EXCIPIENTS Contains lactose. See the package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 30 tablets 90 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Outer Carton: Do not swallow the desiccant canister found in the bottle. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original container in order to protect from light. 36 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Incyte Biosciences Distribution B.V. Paasheuvelweg 25 1105 BP Amsterdam Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/839/003 30 film-coated tablets EU/1/13/839/004 90 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Outer Carton: Iclusig 45 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 37 B. PACKAGE LEAFLET 38 Package leaflet: Information for the patient Iclusig 15 mg film-coated tablets Iclusig 30 mg film-coated tablets Iclusig 45 mg film-coated tablets ponatinib This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor or pharmacist.  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.  If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Iclusig is and what it is used for 2. What you need to know before you take Iclusig 3. How to take Iclusig 4. Possible side effects 5. How to store Iclusig 6. Contents of the pack and other information 1. What Iclusig is and what it is used for Iclusig is used to treat adults with the following leukaemia types who are no longer benefiting from treatment with other medicines, or have a certain genetic difference known as a T315I mutation:  chronic myeloid leukaemia (CML): a blood cancer involving too many abnormal white blood cells in the blood and the bone marrow (where blood cells are formed).  Philadelphia-chromosome positive acute lymphoblastic leukaemia (Ph+ ALL): a type of leukaemia involving too many immature white blood cells in the blood and blood forming bone marrow. In this kind of leukaemia, some of the DNA (genetic material) has become rearranged to form an abnormal chromosome, the Philadelphia chromosome. Iclusig belongs to a group of medicines called tyrosine kinase inhibitors. In patients with CML and Ph+ ALL, changes in the DNA trigger a signal that tells the body to produce abnormal white blood cells. Iclusig blocks this signal, thereby stopping the production of these cells. 2. What you need to know before you take Iclusig Do not take Iclusig  if you are allergic to ponatinib or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor or pharmacist before taking Iclusig if you have:  a liver or pancreas disorder or reduced kidney function. Your doctor may want to take additional precautions. 39  a history of alcohol abuse  had a prior heart attack or stroke  a history of blood clots in your blood vessels  a history of renal artery stenosis (narrowing of the blood vessels to one or both kidneys)  heart problems, including heart failure, irregular heartbeats, and QT prolongation  high blood pressure  or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall  a history of bleeding issues  ever had or might now have a hepatitis B infection. This is because Iclusig could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started. Your doctor will perform:  evaluations of your heart function and the condition of your arteries and veins  a complete blood count This will be repeated every 2 weeks for the first 3 months after starting the therapy. Afterwards it is performed monthly or as indicated by the doctor.  checks of the serum protein known as lipase A serum protein called lipase will be checked every 2 weeks for the first 2 months, then periodically. A break in treatment or a decrease in dose may be required when lipase is increased.  liver tests Liver function tests will be performed periodically, as indicated by your doctor. A brain condition called posterior reversible encephalopathy syndrome (PRES) has been reported in patients treated with ponatinib. Symptoms may include sudden onset of severe headache, confusion, seizures, and vision changes. Tell your doctor straight away if you experience any of these symptoms during your treatment with ponatinib, because it could be serious. Children and adolescents Do not give this medicine to children under 18 years because no data are available in children. Other medicines and Iclusig Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. The following medicines can affect or be affected by Iclusig:  ketoconazole, itraconazole, voriconazole: medicines to treat fungal infections.  indinavir, nelfinavir, ritonavir, saquinavir: medicines to treat HIV infection.  clarithromycin, telithromycin, troleandomycin: medicines to treat bacterial infections.  nefazodone: a medicine to treat depression.  St. John’s wort: a herbal product used to treat depression.  carbamazepine: a medicine to treat epilepsy, euphoric/depressive stages and certain pain conditions.  phenobarbital, phenytoin: medicines to treat epilepsy.  rifabutin, rifampicin: medicines to treat tuberculosis or certain other infections.  digoxin: a medicine to treat heart weakness.  dabigatran: a medicine to prevent the formation of blood clots.  colchicine: a medicine to treat gout attacks.  pravastatin, rosuvastatin: medicines to lower elevated cholesterol levels.  methotrexate: a medicine to treat severe joint inflammation (rheumatoid arthritis), cancer and the skin disease psoriasis.  sulfasalazine: a medicine to treat severe bowel and rheumatic joint inflammation. Iclusig with food and drink Avoid grapefruit products such as grapefruit juice. 40 Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.  Contraceptive advice for men and women Women of childbearing age being treated with Iclusig should avoid becoming pregnant. Men receiving treatment with Iclusig are advised not to father a child during treatment. Effective contraception must be used during treatment. Only use Iclusig during pregnancy if your doctor tells you it is absolutely necessary, as potential risks exist for the unborn child.  Breast-feeding Stop breast-feeding during treatment with Iclusig. It is not known if Iclusig passes into breast milk. Driving and using machines You should take special care when driving and using machines as patients taking Iclusig may experience visual disturbance, dizziness, sleepiness, and tiredness. Iclusig contains lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. 3. How to take Iclusig Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Iclusig therapy should be prescribed by a doctor experienced in leukaemia treatment. Iclusig is available as:  a 45 mg film-coated tablet for the recommended dose.  a 15 mg film-coated tablet and a 30 mg film-coated tablet to allow for dose adjustments. The recommended starting dose is one 45 mg film-coated tablet once daily. Your doctor may reduce your dose or tell you to temporarily stop taking Iclusig if:  an appropriate response to the treatment is reached  the number of white blood cells called neutrophils is reduced.  the number of blood platelets is reduced.  a severe side effect occurs, not affecting the blood - pancreas inflammation. - increased levels of the serum proteins lipase or amylase.  you develop heart or blood vessel problems.  you have a liver disorder. Iclusig use may be resumed at the same, or a reduced dose, after the event is resolved or controlled. Your doctor may evaluate your response to the treatment at regular intervals. 41 Method of use Swallow the tablets whole, with a glass of water. The tablets can be taken with or without food. Do not crush or dissolve the tablets. Do not swallow the desiccant canister contained in the bottle. Duration of use Make sure you take Iclusig daily for as long as it is prescribed. This is a long-term treatment. If you take more Iclusig than you should Talk to your doctor immediately if this occurs. If you forget to take Iclusig Do not take a double dose to make up for a forgotten dose. Take your next dose at your regular time. If you stop taking Iclusig Do not stop taking Iclusig without your doctor’s permission. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Patients aged 65 and over are more likely to be affected by side effects. Seek medical attention immediately if you experience any of the following serious side effects. If abnormal results from blood tests are received, a doctor should be contacted immediately. Serious side effects (common: may affect up to 1 in 10 people):  lung infection (may cause breathing difficulty)  pancreas inflammation. Inform your doctor immediately if pancreas inflammation occurs. Symptoms are severe pain in the stomach and back.  fever, often with other signs of infection due to decreased number of white blood cells  heart attack (symptoms include: sudden feeling of increased heart rate, chest pain, breathlessness)  changes in blood levels: - decreased number of red blood cells (symptoms include: weakness, dizziness, fatigue) - decreased number of blood platelets (symptoms include: increased tendency to bleed or bruise) - decreased number of white blood cells called neutrophilis (symptoms include: increase tendency of infection) - increased level of the serum protein known as lipase  a heart rhythm disorder, abnormal pulse  heart failure (symptoms include: weakness, fatigue, swollen legs)  uncomfortable pressure, fullness, squeezing or pain in the centre of the chest (Angina pectoris) and chest pain not in connection with the heart  high blood pressure  narrowing of the arteries in the brain  problems of the blood vessels in the heart muscle 42  blood infection  swollen, or red area of skin that feels hot and tender (cellulitis)  dehydration  breathing difficulties  fluid in the thorax (may cause breathing difficulty)  diarrhoea  blood clot in a deep vein, sudden vein obstruction, blood clot in a blood vessel of the lung (symptoms include: hot flush, flushing, redness of the face, breathing difficulty)  stroke (symptoms include: difficulty to speak or move, sleepiness, migraine, abnormal sensations)  blood circulation problems (symptoms include: pain in the legs or arms, coldness of the extremities of the limbs)  blood clot in the main arteries carrying blood to the head or neck (carotid artery)  constipation  sodium decrease in the blood  increased tendency to bleed or bruise Other possible side effects that may occur with the following frequencies are: Very common side effects (may affect more than 1 in 10 people):  upper airway infection (may cause breathing difficulty)  decreased appetite  insomnia  headache, dizziness  cough  diarrhoea, vomiting, nausea  increased blood levels of several liver enzymes called: - alanine aminotransferase - aspartate aminotransferase  rash, dry skin, itching  pain in bones, joints, pain in muscles, back, arms or legs, muscle spasms  fatigue, accumulation of fluid in arms and/or legs, fever, pain Common side effects (may affect up to 1 in 10 people):  inflammation of hair follicles, swollen, red area of skin or underneath skin that feels hot and tender  decreased activity of thyroid gland  fluid retention  low calcium, phosphate or potassium levels in the blood  increased blood sugar or uric acid levels in the blood, high blood fat values of triglycerides  weight loss  mini stroke  nerve disorder in the arms and/or legs (often causes numbness and pain in the hands and feet)  lethargy, migraine  increased or reduced sense of touch or sensation, abnormal sensation such as prickling, tingling and itchiness  blurred vision, dry eye, infection in the eye, visual disturbance  tissue swelling in eyelid or around the eyes, caused by excess fluid  palpitation  pain in one or both legs when walking or exercising, which disappears after some minutes of rest  hot flush, flushing  nosebleed, difficulty producing voice sounds, hypertension in the lungs  increased blood levels of liver and pancreatic enzymes: - amylase - alkaline phosphatase - gamma-glutamyltransferase 43  heartburn caused by reflux of stomach juices, inflammation in the mouth, abdominal swelling or discomfort or indigestion, dry mouth  stomach bleeding (symptoms include: stomach pain, vomiting blood)  increased blood level of bilirubin - the yellow breakdown substance of the blood pigment (symptoms include: dark amber urine)  pain in skeletal system or neck  skin rash, peeling of the skin, abnormal thickening of the skin, redness, bruising, skin pain, changes in skin colour, hair loss  tissue swelling in face caused by excess fluid  night sweats, increased sweating  inability to develop or maintain an erection  chills, flu-like illness Uncommon side effects (may affect up to 1 in 100 people):  metabolic disorders caused by the break-down products of dying cancer cells  bleeding in the brain  obstruction of the blood vessels in the eye  heart problems, left sided chest pain, dysfunction of the left heart chamber  narrowing of the blood vessels, poor blood circulation, sudden increase in blood pressure  renal artery stenosis (narrowing of the blood vessels to one or both kidneys)  circulatory problems in the spleen  liver damage, jaundice (symptoms include: yellowing of the skin and eyes)  headache, confusion, seizures, and loss of vision, which may be symptoms of a brain condition known as posterior reversible encephalopathy syndrome (PRES). Not known (frequency cannot be estimated from the available data):  recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a liver infection).  troubling skin rashes involving blisters or peeling and spread across the body, and involving tiredness. Inform your doctor immediately if you experience these symptoms.  an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Iclusig Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the bottle label and carton after EXP. The expiry date refers to the last day of that month. Store in the original container in order to protect from light. The bottle contains one sealed plastic canister containing a molecular sieve desiccant. Keep the canister in the bottle. Do not swallow the desiccant canister. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 44 6. Contents of the pack and other information What Iclusig contains  The active substance is ponatinib. Each 15 mg film-coated tablet contains 15 mg ponatinib (as ponatinib hydrochloride). Each 30 mg film-coated tablet contains 30 mg ponatinib (as ponatinib hydrochloride). Each 45 mg film-coated tablet contains 45 mg ponatinib (as ponatinib hydrochloride).  The other ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, silica (colloidal anhydrous), magnesium stearate, talc, macrogol 4000, polyvinyl alcohol, titanium dioxide (E171). See section 2 “Iclusig contains lactose”. What Iclusig looks like and contents of the pack Iclusig film-coated tablets are white, round and rounded on the upper and lower side. Iclusig 15 mg film-coated tablets are approximately 6 mm in diameter with "A5" on one side. Iclusig 30 mg film-coated tablets are approximately 8 mm in diameter with "C7" on one side. Iclusig 45 mg film-coated tablets are approximately 9 mm in diameter with "AP4" on one side. Iclusig is available in plastic bottles, each containing one canister of a molecular sieve desiccant. Bottles are packed within a cardboard box. Bottles of Iclusig 15 mg contain either 30, 60 or 180 film-coated tablets. Bottles of Iclusig 30 mg contain 30 film-coated tablets. Bottles of Iclusig 45 mg contain either 30 or 90 film-coated tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder Incyte Biosciences Distribution B.V. Paasheuvelweg 25 1105 BP Amsterdam Netherlands Manufacturer Haupt Pharma Amareg GmbH Donaustaufer Str. 378 93055 Regensburg Germany Incyte Biosciences Distribution B.V. Paasheuvelweg 25 1105 BP Amsterdam Netherlands Tjoapack Netherlands B.V. Nieuwe Donk 9 4879 AC Etten-Leur Netherlands This leaflet was last revised in {MM/YYYY}. Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take iclusig', 'Section_Content': "do not take iclusig if you are allergic to ponatinib or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor or pharmacist before taking iclusig if you have: a liver or pancreas disorder or reduced kidney function. your doctor may want to take additional precautions. a history of alcohol abuse had a prior heart attack or stroke a history of blood clots in your blood vessels a history of renal artery stenosis (narrowing of the blood vessels to one or both kidneys) heart problems, including heart failure, irregular heartbeats, and qt prolongation high blood pressure or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall a history of bleeding issues ever had or might now have a hepatitis b infection. this is because iclusig could cause hepatitis b to become active again, which can be fatal in some cases. patients will be carefully checked by their doctor for signs of this infection before treatment is started. your doctor will perform: evaluations of your heart function and the condition of your arteries and veins a complete blood count this will be repeated every 2 weeks for the first 3 months after starting the therapy. afterwards it is performed monthly or as indicated by the doctor. checks of the serum protein known as lipase a serum protein called lipase will be checked every 2 weeks for the first 2 months, then periodically. a break in treatment or a decrease in dose may be required when lipase is increased. liver tests liver function tests will be performed periodically, as indicated by your doctor. a brain condition called posterior reversible encephalopathy syndrome (pres) has been reported in patients treated with ponatinib. symptoms may include sudden onset of severe headache, confusion, seizures, and vision changes. tell your doctor straight away if you experience any of these symptoms during your treatment with ponatinib, because it could be serious. children and adolescents do not give this medicine to children under 18 years because no data are available in children. other medicines and iclusig tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. the following medicines can affect or be affected by iclusig: ketoconazole, itraconazole, voriconazole: medicines to treat fungal infections. indinavir, nelfinavir, ritonavir, saquinavir: medicines to treat hiv infection. clarithromycin, telithromycin, troleandomycin: medicines to treat bacterial infections. nefazodone: a medicine to treat depression. st. john's wort: a herbal product used to treat depression. carbamazepine: a medicine to treat epilepsy, euphoric/depressive stages and certain pain conditions. phenobarbital, phenytoin: medicines to treat epilepsy. rifabutin, rifampicin: medicines to treat tuberculosis or certain other infections. digoxin: a medicine to treat heart weakness. dabigatran: a medicine to prevent the formation of blood clots. colchicine: a medicine to treat gout attacks. pravastatin, rosuvastatin: medicines to lower elevated cholesterol levels. methotrexate: a medicine to treat severe joint inflammation (rheumatoid arthritis), cancer and the skin disease psoriasis. sulfasalazine: a medicine to treat severe bowel and rheumatic joint inflammation. iclusig with food and drink avoid grapefruit products such as grapefruit juice. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. contraceptive advice for men and women women of childbearing age being treated with iclusig should avoid becoming pregnant. men receiving treatment with iclusig are advised not to father a child during treatment. effective contraception must be used during treatment. only use iclusig during pregnancy if your doctor tells you it is absolutely necessary, as potential risks exist for the unborn child. breast-feeding stop breast-feeding during treatment with iclusig. it is not known if iclusig passes into breast milk. driving and using machines you should take special care when driving and using machines as patients taking iclusig may experience visual disturbance, dizziness, sleepiness, and tiredness. iclusig contains lactose if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.", 'Entity_Recognition': [{'Text': 'iclusig', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 20, 'BeginOffset': 12, 'EndOffset': 19, 'Score': 0.2521614134311676, 'Text': 'iclusig', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 31, 'EndOffset': 39}, {'Id': 21, 'BeginOffset': 43, 'EndOffset': 52, 'Score': 0.92234206199646, 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{'Title': '3. how to take iclusig', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. iclusig therapy should be prescribed by a doctor experienced in leukaemia treatment. iclusig is available as: a 45 mg film-coated tablet for the recommended dose. a 15 mg film-coated tablet and a 30 mg film-coated tablet to allow for dose adjustments. the recommended starting dose is one 45 mg film-coated tablet once daily. your doctor may reduce your dose or tell you to temporarily stop taking iclusig if: an appropriate response to the treatment is reached the number of white blood cells called neutrophils is reduced. the number of blood platelets is reduced. a severe side effect occurs, not affecting the blood - pancreas inflammation. - increased levels of the serum proteins lipase or amylase. you develop heart or blood vessel problems. you have a liver disorder. iclusig use may be resumed at the same, or a reduced dose, after the event is resolved or controlled. your doctor may evaluate your response to the treatment at regular intervals. method of use swallow the tablets whole, with a glass of water. the tablets can be taken with or without food. do not crush or dissolve the tablets. do not swallow the desiccant canister contained in the bottle. duration of use make sure you take iclusig daily for as long as it is prescribed. this is a long-term treatment. if you take more iclusig than you should talk to your doctor immediately if this occurs. if you forget to take iclusig do not take a double dose to make up for a forgotten dose. take your next dose at your regular time. if you stop taking iclusig do not stop taking iclusig without your doctor's permission. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.", 'Entity_Recognition': [{'Text': 'iclusig', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Id': 27, 'BeginOffset': 135, 'EndOffset': 150, 'Score': 0.6749221682548523, 'Text': 'iclusig therapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'leukaemia treatment', 'Type': 'TREATMENT', 'BeginOffset': 199, 'EndOffset': 218}, {'Text': 'a 45 mg film-coated tablet', 'Type': 'TREATMENT', 'BeginOffset': 245, 'EndOffset': 271}, {'Text': '45', 'Type': 'NUMBER', 'BeginOffset': 247, 'EndOffset': 249}, {'Text': 'a 15 mg film-coated tablet', 'Type': 'TREATMENT', 'BeginOffset': 298, 'EndOffset': 324}, {'Text': '15', 'Type': 'NUMBER', 'BeginOffset': 300, 'EndOffset': 302}, {'Text': 'a 30 mg film-coated tablet', 'Type': 'TREATMENT', 'BeginOffset': 329, 'EndOffset': 355}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 331, 'EndOffset': 333}, {'Text': 'dose adjustments', 'Type': 'TREATMENT', 'BeginOffset': 369, 'EndOffset': 385}, {'Text': '45', 'Type': 'NUMBER', 'BeginOffset': 424, 'EndOffset': 426}, {'Id': 17, 'BeginOffset': 533, 'EndOffset': 540, 'Score': 0.22656728327274323, 'Text': 'iclusig', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 572, 'EndOffset': 585}, {'Text': 'white blood cells', 'Type': 'TEST', 'BeginOffset': 611, 'EndOffset': 628}, {'Text': 'neutrophils', 'Type': 'PROBLEM', 'BeginOffset': 636, 'EndOffset': 647}, {'Id': 28, 'BeginOffset': 674, 'EndOffset': 689, 'Score': 0.340131551027298, 'Text': 'blood platelets', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'a severe side effect', 'Type': 'PROBLEM', 'BeginOffset': 702, 'EndOffset': 722}, {'Text': 'the blood - 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. patients aged 65 and over are more likely to be affected by side effects. seek medical attention immediately if you experience any of the following serious side effects. if abnormal results from blood tests are received, a doctor should be contacted immediately. serious side effects (common: may affect up to 1 in 10 people): lung infection (may cause breathing difficulty) pancreas inflammation. inform your doctor immediately if pancreas inflammation occurs. symptoms are severe pain in the stomach and back. fever, often with other signs of infection due to decreased number of white blood cells heart attack (symptoms include: sudden feeling of increased heart rate, chest pain, breathlessness) changes in blood levels: - decreased number of red blood cells (symptoms include: weakness, dizziness, fatigue) - decreased number of blood platelets (symptoms include: increased tendency to bleed or bruise) - decreased number of white blood cells called neutrophilis (symptoms include: increase tendency of infection) - increased level of the serum protein known as lipase a heart rhythm disorder, abnormal pulse heart failure (symptoms include: weakness, fatigue, swollen legs) uncomfortable pressure, fullness, squeezing or pain in the centre of the chest (angina pectoris) and chest pain not in connection with the heart high blood pressure narrowing of the arteries in the brain problems of the blood vessels in the heart muscle 42 blood infection swollen, or red area of skin that feels hot and tender (cellulitis) dehydration breathing difficulties fluid in the thorax (may cause breathing difficulty) diarrhoea blood clot in a deep vein, sudden vein obstruction, blood clot in a blood vessel of the lung (symptoms include: hot flush, flushing, redness of the face, breathing difficulty) stroke (symptoms include: difficulty to speak or move, sleepiness, migraine, abnormal sensations) blood circulation problems (symptoms include: pain in the legs or arms, coldness of the extremities of the limbs) blood clot in the main arteries carrying blood to the head or neck (carotid artery) constipation sodium decrease in the blood increased tendency to bleed or bruise other possible side effects that may occur with the following frequencies are: very common side effects (may affect more than 1 in 10 people): upper airway infection (may cause breathing difficulty) decreased appetite insomnia headache, dizziness cough diarrhoea, vomiting, nausea increased blood levels of several liver enzymes called: - alanine aminotransferase - aspartate aminotransferase rash, dry skin, itching pain in bones, joints, pain in muscles, back, arms or legs, muscle spasms fatigue, accumulation of fluid in arms and/or legs, fever, pain common side effects (may affect up to 1 in 10 people): inflammation of hair follicles, swollen, red area of skin or underneath skin that feels hot and tender decreased activity of thyroid gland fluid retention low calcium, phosphate or potassium levels in the blood increased blood sugar or uric acid levels in the blood, high blood fat values of triglycerides weight loss mini stroke nerve disorder in the arms and/or legs (often causes numbness and pain in the hands and feet) lethargy, migraine increased or reduced sense of touch or sensation, abnormal sensation such as prickling, tingling and itchiness blurred vision, dry eye, infection in the eye, visual disturbance tissue swelling in eyelid or around the eyes, caused by excess fluid palpitation pain in one or both legs when walking or exercising, which disappears after some minutes of rest hot flush, flushing nosebleed, difficulty producing voice sounds, hypertension in the lungs increased blood levels of liver and pancreatic enzymes: - amylase - alkaline phosphatase - gamma-glutamyltransferase 43 heartburn caused by reflux of stomach juices, inflammation in the mouth, abdominal swelling or discomfort or indigestion, dry mouth stomach bleeding (symptoms include: stomach pain, vomiting blood) increased blood level of bilirubin - the yellow breakdown substance of the blood pigment (symptoms include: dark amber urine) pain in skeletal system or neck skin rash, peeling of the skin, abnormal thickening of the skin, redness, bruising, skin pain, changes in skin colour, hair loss tissue swelling in face caused by excess fluid night sweats, increased sweating inability to develop or maintain an erection chills, flu-like illness uncommon side effects (may affect up to 1 in 100 people): metabolic disorders caused by the break-down products of dying cancer cells bleeding in the brain obstruction of the blood vessels in the eye heart problems, left sided chest pain, dysfunction of the left heart chamber narrowing of the blood vessels, poor blood circulation, sudden increase in blood pressure renal artery stenosis (narrowing of the blood vessels to one or both kidneys) circulatory problems in the spleen liver damage, jaundice (symptoms include: yellowing of the skin and eyes) headache, confusion, seizures, and loss of vision, which may be symptoms of a brain condition known as posterior reversible encephalopathy syndrome (pres). not known (frequency cannot be estimated from the available data): recurrence (reactivation) of hepatitis b infection when you have had hepatitis b in the past (a liver infection). troubling skin rashes involving blisters or peeling and spread across the body, and involving tiredness. inform your doctor immediately if you experience these symptoms. an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections). reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national 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{'Title': '5. how to store iclusig', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle label and carton after exp. the expiry date refers to the last day of that month. store in the original container in order to protect from light. the bottle contains one sealed plastic canister containing a molecular sieve desiccant. keep the canister in the bottle. do not swallow the desiccant canister. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what iclusig contains the active substance is ponatinib. each 15 mg film-coated tablet contains 15 mg ponatinib (as ponatinib hydrochloride). each 30 mg film-coated tablet contains 30 mg ponatinib (as ponatinib hydrochloride). each 45 mg film-coated tablet contains 45 mg ponatinib (as ponatinib hydrochloride). the other ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, silica (colloidal anhydrous), magnesium stearate, talc, macrogol 4000, polyvinyl alcohol, titanium dioxide (e171). see section 2 "iclusig contains lactose". what iclusig looks like and contents of the pack iclusig film-coated tablets are white, round and rounded on the upper and lower side. iclusig 15 mg film-coated tablets are approximately 6 mm in diameter with "a5" on one side. iclusig 30 mg film-coated tablets are approximately 8 mm in diameter with "c7" on one side. iclusig 45 mg film-coated tablets are approximately 9 mm in diameter with "ap4" on one side. iclusig is available in plastic bottles, each containing one canister of a molecular sieve desiccant. bottles are packed within a cardboard box. bottles of iclusig 15 mg contain either 30, 60 or 180 film-coated tablets. bottles of iclusig 30 mg contain 30 film-coated tablets. bottles of iclusig 45 mg contain either 30 or 90 film-coated tablets. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'iclusig', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 2, 'BeginOffset': 46, 'EndOffset': 55, 'Score': 0.9861889481544495, 'Text': 'ponatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.5456987023353577, 'RelationshipScore': 0.988246500492096, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 62, 'EndOffset': 67, 'Text': '15 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7871436476707458, 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FA65F69B53B33366EDF59BA3A1938917

https://www.ema.europa.eu/documents/product-information/maviret-epar-product-information_en.pdf

Maviret

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Maviret 100 mg/40 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 100 mg glecaprevir and 40 mg pibrentasvir. Excipient with known effect Each film-coated tablet contains 7.48 mg lactose (as lactose monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Pink, oblong, biconvex, film-coated tablet of dimensions 18.8 mm x 10.0 mm, debossed on one side with ‘NXT’. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Maviret is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults and in adolescents aged 12 to <18 years (see sections 4.2, 4.4. and 5.1). 4.2 Posology and method of administration Maviret treatment should be initiated and monitored by a physician experienced in the management of patients with HCV infection. Posology Adults and adolescents aged 12 to <18 years The recommended dose of Maviret is 300 mg/120 mg (three 100 mg/40 mg tablets), taken orally, once daily at the same time with food (see section 5.2). The recommended Maviret treatment durations for HCV genotype 1, 2, 3, 4, 5, or 6 infected patients with compensated liver disease (with or without cirrhosis) are provided in Table 1 and Table 2. Table 1: Recommended Maviret treatment duration for patients without prior HCV therapy Genotype Recommended treatment duration No cirrhosis Cirrhosis GT 1, 2, 3, 4, 5, 6 8 weeks 8 weeks 3 Table 2: Recommended Maviret treatment duration for patients who failed prior therapy with peg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin Genotype Recommended treatment duration No cirrhosis Cirrhosis GT 1, 2, 4-6 8 weeks 12 weeks GT 3 16 weeks 16 weeks For patients who failed prior therapy with an NS3/4A- and/or an NS5A-inhibitor, see section 4.4. Missed dose In case a dose of Maviret is missed, the prescribed dose can be taken within 18 hours after the time it was supposed to be taken. If more than 18 hours have passed since Maviret is usually taken, the missed dose should not be taken and the patient should take the next dose per the usual dosing schedule. Patients should be instructed not to take a double dose. If vomiting occurs within 3 hours of dosing, an additional dose of Maviret should be taken. If vomiting occurs more than 3 hours after dosing, an additional dose of Maviret is not needed. Elderly No dose adjustment of Maviret is required in elderly patients (see sections 5.1 and 5.2). Renal impairment No dose adjustment of Maviret is required in patients with any degree of renal impairment including patients on dialysis (see sections 5.1 and 5.2). Hepatic impairment No dose adjustment of Maviret is required in patients with mild hepatic impairment (Child-Pugh A). Maviret is not recommended in patients with moderate hepatic impairment (Child Pugh-B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.3, 4.4, and 5.2). Liver or kidney transplant patients A 12-week treatment duration has been evaluated and is recommended in liver or kidney transplant recipients with or without cirrhosis (see section 5.1). A 16-week treatment duration should be considered in genotype 3-infected patients who are treatment experienced with peg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin. Patients with HIV-1 Co-infection Follow the dosing recommendations in Tables 1 and 2. For dosing recommendations with HIV antiviral agents, refer to section 4.5. Paediatric population No dose adjustment of Maviret is required in adolescents aged 12 to <18 years (see sections 5.1 and 5.2). The safety and efficacy of Maviret in children aged less than 12 years have not yet been established. No data are available. Method of administration For oral use. Patients should be instructed to swallow tablets whole with food and not to chew, crush or break the tablets as it may alter the bioavailability of the agents (see section 5.2). 4 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.4, and 5.2). Concomitant use with atazanavir containing products, atorvastatin, simvastatin, dabigatran etexilate, ethinyl oestradiol-containing products, strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) (see section 4.5). 4.4 Special warnings and precautions for use Hepatitis B Virus reactivation Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should, therefore, be monitored and managed according to current clinical guidelines. Hepatic impairment Maviret is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, 4.3, and 5.2). Patients who failed a prior regimen containing an NS5A- and/or an NS3/4A-inhibitor Genotype 1-infected (and a very limited number of genotype 4-infected) patients with prior failure on regimens that may confer resistance to glecaprevir/pibrentasvir were studied in the MAGELLAN-1 study (section 5.1). The risk of failure was, as expected, highest for those exposed to both classes. A resistance algorithm predictive of the risk for failure by baseline resistance has not been established. Accumulating double class resistance was a general finding for patients who failed re-treatment with glecaprevir/pibrentasvir in MAGELLAN-1. No re-treatment data is available for patients infected with genotypes 2, 3, 5 or 6. Maviret is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/or NS5A-inhibitors. Drug-drug interactions Co-administration is not recommended with several medicinal products as detailed in section 4.5. Use in diabetic patients Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabetic patients initiating direct acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct acting antiviral therapy is initiated. Lactose Maviret contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 5 4.5 Interaction with other medicinal products and other forms of interaction Potential for Maviret to affect other medicinal products Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Co-administration with Maviret may increase plasma concentrations of medicinal products that are substrates of P-gp (e.g. dabigatran etexilate, digoxin), BCRP (e.g. rosuvastatin), or OATP1B1/3 (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin). See Table 3 for specific recommendations on interactions with sensitive substrates of P-gp, BCRP, and OATP1B1/3. For other P-gp, BCRP, or OATP1B1/3 substrates, dose adjustment may be needed. Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A and uridine glucuronosyltransferase (UGT) 1A1 in vivo. Clinically significant increases in exposure were not observed for sensitive substrates of CYP3A (midazolam, felodipine) or UGT1A1 (raltegravir) when administered with Maviret. Both glecaprevir and pibrentasvir inhibit the bile salt export pump (BSEP) in vitro. Significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A6, UGT1A9, UGT1A4, UGT2B7, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K are not expected. Patients treated with vitamin K antagonists As liver function may change during treatment with Maviret, a close monitoring of International Normalised Ratio (INR) values is recommended. Potential for other medicinal products to affect Maviret Use with strong P-gp/CYP3A inducers Medicinal products that are strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) could significantly decrease glecaprevir or pibrentasvir plasma concentrations and may lead to reduced therapeutic effect of Maviret or loss of virologic response. Co-administration of such medicinal products with Maviret is contraindicated (see section 4.3). Co-administration of Maviret with medicinal products that are moderate inducers P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations (e.g. oxcarbazepine, eslicarbazepine, lumacaftor, crizotinib). Co-administration of moderate inducers is not recommended (see section 4.4). Glecaprevir and pibrentasvir are substrates of the efflux transporters P-gp and/or BCRP. Glecaprevir is also a substrate of the hepatic uptake transporters OATP1B1/3. Co-administration of Maviret with medicinal products that inhibit P-gp and BCRP (e.g. ciclosporin, cobicistat, dronedarone, itraconazole, ketoconazole, ritonavir) may slow elimination of glecaprevir and pibrentasvir and thereby increase plasma exposure of the antivirals. Medicinal products that inhibit OATP1B1/3 (e.g. elvitegravir, ciclosporin, darunavir, lopinavir) increase systemic concentrations of glecaprevir. Established and other potential medicinal product interactions Table 3 provides the least-squares mean Ratio (90% Confidence Interval) effect on concentration of Maviret and some common concomitant medicinal products. The direction of the arrow indicates the direction of the change in exposures (Cmax, AUC, and Cmin) in glecaprevir, pibrentasvir, and the co- administered medicinal product (↑ = increase (more than 25%), ↓ = decrease (more than 20%), ↔ = no change (equal to or less than 20% decrease or 25% increase)). This is not an exclusive list. 6 Table 3: Interactions between Maviret and other medicinal products Medicinal product by therapeutic areas/possible mechanism of interaction Effect on medicinal product levels Cmax AUC Cmin Clinical comments ANGIOTENSIN-II RECEPTOR BLOCKERS Losartan 50 mg single dose ↑ losartan 2.51 (2.00, 3.15) 1.56 (1.28, 1.89) -- No dose adjustment is required. ↑ losartan carboxylic acid 2.18 (1.88, 2.53) ↔ -- Valsartan 80 mg single dose (Inhibition of OATP1B1/3) ↑ valsartan 1.36 (1.17, 1.58) 1.31 (1.16, 1.49) -- No dose adjustment is required. ANTIARRHYTHMICS Digoxin 0.5 mg single dose (Inhibition of P-gp) ↑ digoxin 1.72 (1.45, 2.04) 1.48 (1.40, 1.57) -- Caution and therapeutic concentration monitoring of digoxin is recommended. ANTICOAGULANTS Dabigatran etexilate 150 mg single dose (Inhibition of P-gp) ↑ dabigatran 2.05 (1.72, 2.44) 2.38 (2.11, 2.70) -- Co-administration is contraindicated (see section 4.3). ANTICONVULSANTS Carbamazepine 200 mg twice daily (Induction of P- gp/CYP3A) ↓ glecaprevir 0.33 (0.27, 0.41) 0.34 (0.28, 0.40) -- Co-administration may lead to reduced therapeutic effect of Maviret and is contraindicated (see section 4.3). ↓ pibrentasvir 0.50 (0.42, 0.59) 0.49 (0.43, 0.55) -- Phenytoin, phenobarbital, primidone Not studied. Expected: ↓ glecaprevir and ↓ pibrentasvir ANTIMYCOBACTERIALS Rifampicin 600 mg single dose (Inhibition of OATP1B1/3) ↑ glecaprevir 6.52 (5.06, 8.41) 8.55 (7.01, 10.4) -- Co-administration is contraindicated (see section 4.3). ↔ pibrentasvir ↔ ↔ -- Rifampicin 600 mg once dailya (Induction of P- gp/BCRP/CYP3A) ↓ glecaprevir 0.14 (0.11, 0.19) 0.12 (0.09, 0.15) -- ↓ pibrentasvir 0.17 (0.14, 0.20) 0.13 (0.11, 0.15) -- ETHINYL-OESTRADIOL-CONTAINING PRODUCTS Ethinyloestradiol (EE)/Norgestimate 35 µg/250 µg once daily ↑ EE 1.31 (1.24, 1.38) 1.28 (1.23, 1.32) 1.38 (1.25, 1.52) Co-administration of Maviret with ethinyloestradiol- containing products is contraindicated due to the risk of ALT elevations (see section 4.3). No dose adjustment is required with levonorgestrel, ↑ norelgestromin ↔ 1.44 (1.34, 1.54) 1.45 (1.33, 1.58) ↑ norgestrel 1.54 (1.34, 1.76) 1.63 (1.50, 1.76) 1.75 (1.62, 1.89) EE/Levonorgestrel 20 µg/100 µg once daily ↑ EE 1.30 (1.18, 1.44) 1.40 (1.33, 1.48) 1.56 (1.41, 1.72) ↑ norgestrel 1.37 (1.23, 1.52) 1.68 (1.57, 1.80) 1.77 (1.58, 1.98) 7 norethidrone or norgestimate as contraceptive progestagen. HERBAL PRODUCTS St. John’s wort (Hypericum perforatum) (Induction of P- gp/CYP3A) Not studied. Expected: ↓ glecaprevir and ↓ pibrentasvir Co-administration may lead to reduced therapeutic effect of Maviret and is contraindicated (see section 4.3). HIV-ANTIVIRAL AGENTS Atazanavir + ritonavir 300/100 mg once dailyb ↑ glecaprevir ≥4.06 (3.15, 5.23) ≥6.53 (5.24, 8.14) ≥14.3 (9.85, 20.7) Co-administration with atazanavir is contraindicated due to the risk of ALT elevations (see section 4.3). ↑ pibrentasvir ≥1.29 (1.15, 1.45) ≥1.64 (1.48, 1.82) ≥2.29 (1.95, 2.68) Darunavir + ritonavir 800/100 mg once daily ↑ glecaprevir 3.09 (2.26, 4.20) 4.97 (3.62, 6.84) 8.24 (4.40, 15.4) Co-administration with darunavir is not recommended. ↔ pibrentasvir ↔ ↔ 1.66 (1.25, 2.21) Efavirenz/emtricitab ine/tenofovir disoproxil fumarate 600/200/300 mg once daily ↑ tenofovir ↔ 1.29 (1.23, 1.35) 1.38 (1.31, 1.46) Co-administration with efavirenz may lead to reduced therapeutic effect of Maviret and is not recommended. No clinically significant interactions are expected with tenofovir disoproxil fumarate. The effect of efavirenz/emtricitabine/tenofovir disoproxil fumarate on glecaprevir and pibrentasvir was not directly quantified within this study, but glecaprevir and pibrentasvir exposures were significantly lower than historical controls. Elvitegravir/cobicist at/emtricitabine/ tenofovir alafenamide (P-gp, BCRP, and OATP inhibition by cobicistat, OATP inhibition by elvitegravir) ↔ tenofovir ↔ ↔ ↔ No dose adjustment is required. ↑ glecaprevir 2.50 (2.08, 3.00) 3.05 (2.55, 3.64) 4.58 (3.15, 6.65) ↑ pibrentasvir ↔ 1.57 (1.39, 1.76) 1.89 (1.63, 2.19) Lopinavir/ritonavir 400/100 mg twice daily ↑ glecaprevir 2.55 (1.84, 3.52) 4.38 (3.02, 6.36) 18.6 (10.4, 33.5) Co-administration is not recommended. ↑ pibrentasvir 1.40 (1.17, 1.67) 2.46 (2.07, 2.92) 5.24 (4.18, 6.58) Raltegravir 400 mg twice daily (Inhibition of UGT1A1) ↑ raltegravir 1.34 (0.89, 1.98) 1.47 (1.15, 1.87) 2.64 (1.42, 4.91) No dose adjustment is required. HCV-ANTIVIRAL AGENTS Sofosbuvir 400 mg single dose (P-gp/BCRP inhibition) ↑ sofosbuvir 1.66 (1.23, 2.22) 2.25 (1.86, 2.72) -- No dose adjustment is required. ↑ GS-331007 ↔ ↔ 1.85 (1.67, 2.04) ↔ glecaprevir ↔ ↔ ↔ ↔ pibrentasvir ↔ ↔ ↔ 8 HMG-COA REDUCTASE INHIBITORS Atorvastatin 10 mg once daily (Inhibition of OATP1B1/3, P-gp, BCRP, CYP3A) ↑ atorvastatin 22.0 (16.4, 29.5) 8.28 (6.06, 11.3) -- Co-administration with atorvastatin and simvastatin is contraindicated (see section 4.3). Simvastatin 5 mg once daily (Inhibition of OATP1B1/3, P-gp, BCRP) ↑ simvastatin 1.99 (1.60, 2.48) 2.32 (1.93, 2.79) -- ↑ simvastatin acid 10.7 (7.88, 14.6) 4.48 (3.11, 6.46) -- Lovastatin 10 mg once daily (Inhibition of OATP1B1/3, P-gp, BCRP) ↑ lovastatin ↔ 1.70 (1.40, 2.06) -- Co-administration is not recommended. If used, lovastatin should not exceed a dose of 20 mg/day and patients should be monitored. ↑ lovastatin acid 5.73 (4.65, 7.07) 4.10 (3.45, 4.87) -- Pravastatin 10 mg once daily (Inhibition of OATP1B1/3) ↑ pravastatin 2.23 (1.87, 2.65) 2.30 (1.91, 2.76) -- Caution is recommended. Pravastatin dose should not exceed 20 mg per day and rosuvastatin dose should not exceed 5 mg per day. Rosuvastatin 5 mg once daily (Inhibition of OATP1B1/3, BCRP) ↑ rosuvastatin 5.62 (4.80, 6.59) 2.15 (1.88, 2.46) -- Fluvastatin, Pitavastatin Not studied. Expected: ↑ fluvastatin and ↑ pitavastatin Interactions with fluvastatin and pitavastatin are likely and caution is recommended during the combination. A low dose of the statin is recommended at the initiation of the DAA treatment. IMMUNOSUPPRESSANTS Ciclosporin 100 mg single dose ↑ glecaprevirc 1.30 (0.95, 1.78) 1.37 (1.13, 1.66) 1.34 (1.12, 1.60) Maviret is not recommended for use in patients requiring stable ciclosporin doses > 100 mg per day. If the combination is unavoidable, use can be considered if the benefit outweighs the risk with a close clinical monitoring. ↑ pibrentasvir ↔ ↔ 1.26 (1.15, 1.37) Ciclosporin 400 mg single dose ↑ glecaprevir 4.51 (3.63, 6.05) 5.08 (4.11, 6.29) -- ↑ pibrentasvir ↔ 1.93 (1.78, 2.09) -- Tacrolimus 1 mg single dose (CYP3A4 and P-gp inhibition) ↑ tacrolimus 1.50 (1.24, 1.82) 1.45 (1.24, 1.70) -- The combination of Maviret with tacrolimus should be used with caution. Increase of ↔ glecaprevir ↔ ↔ ↔ ↔ pibrentasvir ↔ ↔ ↔ 9 tacrolimus exposure is expected. Therefore, a therapeutic drug monitoring of tacrolimus is recommended and a dose adjustment of tacrolimus made accordingly. PROTON PUMP INHIBITORS Omeprazole 20 mg once daily (Increase gastric pH value) ↓ glecaprevir 0.78 (0.60, 1.00) 0.71 (0.58, 0.86) -- No dose adjustment is required. ↔ pibrentasvir ↔ ↔ -- Omeprazole 40 mg once daily (1 hour before breakfast) ↓ glecaprevir 0.36 (0.21, 0.59) 0.49 (0.35, 0.68) -- ↔ pibrentasvir ↔ ↔ -- Omeprazole 40 mg once daily (evening without food) ↓ glecaprevir 0.54 (0.44, 0.65) 0.51 (0.45, 0.59) -- ↔ pibrentasvir ↔ ↔ -- VITAMIN K ANTAGONISTS Vitamin K antagonists Not studied. Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Maviret. DAA=direct acting antiviral a. Effect of rifampicin on glecaprevir and pibrentasvir 24 hours after final rifampicin dose. b. Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported. c. HCV-infected transplant recipients who received a median ciclosporin dose of 100 mg per day had increased glecaprevir exposures to 2.4-fold of those not receiving ciclosporin. Additional drug-drug interaction studies were performed with the following medical products and showed no clinically significant interactions with Maviret: abacavir, amlodipine, buprenorphine, caffeine, dextromethorphan, dolutegravir, emtricitabine, felodipine, lamivudine, lamotrigine, methadone, midazolam, naloxone, norethindrone or other progestin-only contraceptives, rilpivirine, tenofovir alafenamide and tolbutamide. 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of glecaprevir or pibrentasvir in pregnant women. Studies in rats/mice with glecaprevir or pibrentasvir do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Maternal toxicity associated with embryo-foetal loss has been observed in the rabbit with glecaprevir which precluded evaluation of glecaprevir at clinical exposures in this species (see section 5.3). As a precautionary measure, Maviret use is not recommended in pregnancy. 10 Breast-feeding It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk (for details see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Maviret therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No human data on the effect of glecaprevir and/or pibrentasvir on fertility are available. Animal studies do not indicate harmful effects of glecaprevir or pibrentasvir on fertility at exposures higher than the exposures in humans at the recommended dose (see Section 5.3). 4.7 Effects on ability to drive and use machines Maviret has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The safety assessment of Maviret in subjects treated for 8, 12 or 16 weeks with compensated liver disease (with or without cirrhosis) was based on registrational Phase 2 and 3 studies which evaluated approximately 2,300 subjects. The most commonly reported adverse reactions (incidence ≥ 10%) were headache and fatigue. Less than 0.1% of subjects treated with Maviret had serious adverse reactions (transient ischaemic attack). The proportion of subjects treated with Maviret who permanently discontinued treatment due to adverse reactions was 0.1%. The type and severity of adverse reactions in subjects with cirrhosis were overall comparable to those seen in subjects without cirrhosis. Tabulated summary of adverse reactions The following adverse reactions were identified in patients treated with Maviret. The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data). Table 4: Adverse reactions identified with Maviret Frequency Adverse reactions Immune system disorders Uncommon angioedema Nervous system disorders Very common headache Gastrointestinal disorders Common diarrhoea, nausea Skin and subcutaneous tissue disorders Not known pruritus General disorders and administration site conditions Very common fatigue Common asthenia Description of selected adverse reactions Adverse reactions in subjects with severe renal impairment including subjects on dialysis 11 The safety of Maviret in subjects with chronic kidney disease (including subjects on dialysis) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or without cirrhosis) was assessed in EXPEDITION-4 (n=104) and EXPEDITION-5 (n=101). The most common adverse reactions in subjects with severe renal impairment were pruritus (17%) and fatigue (12%) in EXPEDITION-4 and pruritus (14.9%) in EXPEDITION-5. Adverse Reactions in Subjects with Liver or Kidney Transplant The safety of Maviret was assessed in 100 post-liver or -kidney transplant recipients with genotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was comparable to that observed in subjects in the Phase 2 and 3 studies. Adverse reactions observed in greater than or equal to 5% of subjects receiving Maviret for 12 weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%). Safety in HCV/HIV-1 Co-infected Subjects The overall safety profile in HCV/HIV-1 co-infected subjects (ENDURANCE-1 and EXPEDITION- 2) was comparable to that observed in HCV mono-infected subjects. Paediatric population The safety of Maviret in HCV GT1-6 infected adolescents is based on data from a Phase 2/3 open- label study in 47 subjects aged 12 years to <18 years treated with Maviret for 8 to 16 weeks (DORA- Part 1). The adverse reactions observed were comparable with those observed in clinical studies of Maviret in adults. Serum bilirubin elevations Elevations in total bilirubin of at least 2x upper limit normal (ULN) were observed in 1.3% of subjects related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubin elevations were asymptomatic, transient, and typically occurred early during treatment. Bilirubin elevations were predominantly indirect and not associated with ALT elevations. Direct hyperbilirubinemia was reported in 0.3% of subjects. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The highest documented doses administered to healthy volunteers is 1,200 mg once daily for 7 days for glecaprevir and 600 mg once daily for 10 days for pibrentasvir. Asymptomatic serum ALT elevations (>5x ULN) were observed in 1 out of 70 healthy subjects following multiple doses of glecaprevir (700 mg or 800 mg) once daily for ≥ 7 days. In case of overdose, the patient should be monitored for any signs and symptoms of toxicities (see section 4.8). Appropriate symptomatic treatment should be instituted immediately. Glecaprevir and pibrentasvir are not significantly removed by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AP57 glecaprevir and pibrentasvir Mechanism of action http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 12 Maviret is a fixed-dose combination of two pan-genotypic, direct-acting antiviral agents, glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor), targeting multiple steps in the HCV viral lifecycle. Glecaprevir Glecaprevir is a pan-genotypic inhibitor of the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. Pibrentasvir Pibrentasvir is a pan-genotypic inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies. Antiviral activity The EC50 values of glecaprevir and pibrentasvir against full-length or chimeric replicons encoding NS3 or NS5A from laboratory strains are presented in Table 5. Table 5. Activity of glecaprevir and pibrentasvir against HCV genotypes 1-6 replicon cell lines HCV Subtype Glecaprevir EC50, nM Pibrentasvir EC50, nM 1a 0.85 0.0018 1b 0.94 0.0043 2a 2.2 0.0023 2b 4.6 0.0019 3a 1.9 0.0021 4a 2.8 0.0019 5a NA 0.0014 6a 0.86 0.0028 NA = not available The in vitro activity of glecaprevir was also studied in a biochemical assay, with similarly low IC50 values across genotypes. EC50 values of glecaprevir and pibrentasvir against chimeric replicons encoding NS3 or NS5A from clinical isolates are presented in Table 6. 13 Table 6. Activity of glecaprevir and pibrentasvir against transient replicons containing NS3 or NS5A from HCV genotypes 1-6 clinical isolates HCV subtype Glecaprevir Pibrentasvir Number of clinical isolates Median EC50, nM (range) Number of clinical isolates Median EC50, nM (range) 1a 11 0.08 (0.05 – 0.12) 11 0.0009 (0.0006 – 0.0017) 1b 9 0.29 (0.20 – 0.68) 8 0.0027 (0.0014 – 0.0035) 2a 4 1.6 (0.66 – 1.9) 6 0.0009 (0.0005 – 0.0019) 2b 4 2.2 (1.4 – 3.2) 11 0.0013 (0.0011 – 0.0019) 3a 2 2.3 (0.71 – 3.8) 14 0.0007 (0.0005 – 0.0017) 4a 6 0.41 (0.31 – 0.55) 8 0.0005 (0.0003 – 0.0013) 4b NA NA 3 0.0012 (0.0005 – 0.0018) 4d 3 0.17 (0.13 – 0.25) 7 0.0014 (0.0010 – 0.0018) 5a 1 0.12 1 0.0011 6a NA NA 3 0.0007 (0.0006 – 0.0010) 6e NA NA 1 0.0008 6p NA NA 1 0.0005 NA = not available Resistance In cell culture Amino acid substitutions in NS3 or NS5A selected in cell culture or important for the inhibitor class were phenotypically characterized in replicons. Substitutions important for the HCV protease inhibitor class at positions 36, 43, 54, 55, 56, 155, 166, or 170 in NS3 had no impact on glecaprevir activity. Substitutions at amino acid position 168 in NS3 had no impact in genotype 2, while some substitutions at position 168 reduced glecaprevir susceptibility by up to 55-fold (genotypes 1, 3, 4), or reduced susceptibility by > 100-fold (genotype 6). Some substitutions at position 156 reduced susceptibility to glecaprevir (genotypes 1 to 4) by > 100-fold. Substitutions at amino acid position 80 did not reduce susceptibility to glecaprevir except for Q80R in genotype 3a, which reduced susceptibility to glecaprevir by 21-fold. Single substitutions important for the NS5A inhibitor class at positions 24, 28, 30, 31, 58, 92, or 93 in NS5A in genotypes 1 to 6 had no impact on the activity of pibrentasvir. Specifically in genotype 3a, A30K or Y93H had no impact on pibrentasvir activity. Some combinations of substitutions in genotypes 1a and 3a (including A30K+Y93H in genotype 3a) showed reductions in susceptibility to pibrentasvir. In genotype 3b replicon, the presence of naturally occurring polymorphisms K30 and M31 in NS5A reduced susceptibility to pibrentasvir by 24-fold relative to the activity of pibrentasvir in genotype 3a replicon. In clinical studies Studies in treatment-naïve and peginterferon (pegIFN), ribavirin (RBV) and/or sofosbuvir treatment- experienced subjects with or without cirrhosis Twenty two of the approximately 2,300 subjects treated with Maviret for 8, 12, or 16 weeks in registrational Phase 2 and 3 clinical studies experienced virologic failure (2 with genotype 1, 2 with genotype 2, 18 with genotype 3 infection). 14 Among the 2 genotype 1-infected subjects who experienced virologic failure, one had treatment- emergent substitutions A156V in NS3 and Q30R/L31M/H58D in NS5A, and one had Q30R/H58D (while Y93N was present at baseline and post-treatment) in NS5A. Among the 2 genotype 2-infected subjects, no treatment-emergent substitutions were observed in NS3 or NS5A (the M31 polymorphism in NS5A was present at baseline and post-treatment in both subjects). Among the 18 genotype 3-infected subjects treated with Maviret for 8, 12, or 16 weeks who experienced virologic failure, treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, or Q168L/R were observed in 11 subjects. A166S or Q168R were present at baseline and post-treatment in 5 subjects. Treatment-emergent NS5A substitutions M28G, A30G/K, L31F, P58T, or Y93H were observed in 16 subjects, and 13 subjects had A30K (n=9) or Y93H (n=5) at baseline and post- treatment. Studies in subjects with or without compensated cirrhosis who were treatment-experienced to NS3/4A protease and/or NS5A inhibitors Ten of 113 subjects treated with Maviret in the MAGELLAN-1 study for 12 or 16 weeks experienced virologic failure. Among the 10 genotype 1-infected subjects with virologic failure, treatment-emergent NS3 substitutions V36A/M, R155K/T, A156G/T/V, or D168A/T were observed in 7 subjects. Five of the 10 had combinations of V36M, Y56H, R155K/T, or D168A/E in NS3 at baseline and post-treatment. All of the genotype 1-infected virologic failure subjects had one or more NS5A substitutions L/M28M/T/V, Q30E/G/H/K/L/R, L31M, P32 deletion, H58C/D, or Y93H at baseline, with additional treatment-emergent NS5A substitutions M28A/G, P29Q/R, Q30K, H58D, or Y93H observed in 7 of the subjects at the time of failure. Effect of baseline HCV amino acid polymorphisms on treatment response A pooled analysis of treatment-naïve and pegylated interferon, ribavirin and/or sofosbuvir treatment- experienced subjects receiving Maviret in the Phase 2 and Phase 3 clinical studies was conducted to explore the association between baseline polymorphisms and treatment outcome and to describe substitutions seen upon virologic failure. Baseline polymorphisms relative to a subtype-specific reference sequence at amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 92, and 93 in NS5A were evaluated at a 15% detection threshold by next-generation sequencing. Baseline polymorphisms in NS3 were detected in 1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164), 41.9% (13/31), and 2.9% (1/34) of subjects with HCV genotype 1, 2, 3, 4, 5, and 6 infection, respectively. Baseline polymorphisms in NS5A were detected in 26.8% (225/841), 79.8% (331/415), 22.1% (136/615), 49.7% (80/161), 12.9% (4/31), and 54.1% (20/37) of subjects with HCV genotype 1, 2, 3, 4, 5, and 6 infection, respectively. Genotype 1, 2, 4, 5, and 6: Baseline polymorphisms in genotypes 1, 2, 4, 5 and 6 had no impact on treatment outcome. Genotype 3: For subjects who received the recommended regimen (n=313), baseline polymorphisms in NS5A (Y93H included) or NS3 did not have a relevant impact on treatment outcomes. All subjects (15/15) with Y93H and 77% (17/22) with A30K in NS5A at baseline achieved SVR12. The overall prevalence of A30K and Y93H at baseline was 7.0% and 4.8%, respectively. The ability to assess the impact of baseline polymorphisms in NS5A was limited among treatment-naïve subjects with cirrhosis and treatment-experienced subjects due to low prevalence of A30K (3.0%, 4/132) or Y93H (3.8%, 5/132). Cross-resistance In vitro data indicate that the majority of the resistance-associated substitutions in NS5A at amino acid positions 24, 28, 30, 31, 58, 92, or 93 that confer resistance to ombitasvir, daclatasvir, ledipasvir, elbasvir, or velpatasvir remained susceptible to pibrentasvir. Some combinations of NS5A 15 substitutions at these positions showed reductions in susceptibility to pibrentasvir. Glecaprevir was fully active against resistance-associated substitutions in NS5A, while pibrentasvir was fully active against resistance-associated substitutions in NS3. Both glecaprevir and pibrentasvir were fully active against substitutions associated with resistance to NS5B nucleotide and non-nucleotide inhibitors. Clinical efficacy and safety Table 7 summarizes clinical studies conducted with Maviret in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 infection. Table 7: Clinical studies conducted with Maviret in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 Infection Genotype (GT) Clinical study Summary of study design TN and PRS-TE subjects without cirrhosis GT1 ENDURANCE-1 a Maviret for 8 weeks (n=351) or 12 weeks (n=352) SURVEYOR-1 Maviret for 8 weeks (n=34) GT2 ENDURANCE-2 Maviret (n=202) or Placebo (n=100) for 12 weeks SURVEYOR-2b Maviret for 8 weeks (n=199) or 12 weeks (n=25) GT3 ENDURANCE-3 Maviret for 8 weeks (n=157) or 12 weeks (n=233) Sofosbuvir + daclatasvir for 12 weeks (n=115) SURVEYOR-2 Maviret for 8 weeks (TN only, n=29) or 12 weeks (n=76) or 16 weeks (TE only, n=22) GT4, 5, 6 ENDURANCE-4 Maviret for 12 weeks (n=121) ENDURANCE-5,6 Maviret for 8 weeks (n=75) SURVEYOR-1 Maviret for 12 weeks (n=32) SURVEYOR-2c Maviret for 8 weeks (n=58) GT1-6 VOYAGE-1f Maviret for 8 weeks (GT1, 2, 4, 5, and 6 and GT3 TN) (n=356) or 16 weeks (GT3 TE only) (n=6) TN and PRS-TE subjects with cirrhosis GT1, 2, 4, 5, 6 EXPEDITION-1 Maviret for 12 weeks (n=146) GT3 SURVEYOR-2d Maviret for 12 weeks (TN only, n=64) or 16 weeks (TE only, n=51) GT5, 6 ENDURANCE-5,6 Maviret for 12 weeks (n=9) GT1-6 VOYAGE-2f Maviret for 12 weeks (GT1, 2, 4, 5, and 6 and GT3 TN) (n=157) or 16 weeks (GT3 TE only) (n=3) GT1-6 EXPEDITION-8 Maviret for 8 weeks (n=343) (TN only) Subjects with CKD stage 3b, 4 and 5 with or without cirrhosis GT1-6 EXPEDITION-4 Maviret for 12 weeks (n=104) GT1-6 EXPEDITION-5 Maviret for 8 weeks (n=84) or 12 weeks (n=13) or 16 weeks (n=4) NS5A inhibitor and/or PI-experienced subjects with or without cirrhosis GT1, 4 MAGELLAN-1e Maviret for 12 weeks (n=66) or 16 weeks (n=47) HCV/HIV-1 Co-Infected Subjects with or without Cirrhosis GT1-6 EXPEDITION-2 Maviret for 8 weeks (n=137) or 12 weeks (n=16) Liver or Kidney Transplant Recipients GT1-6 MAGELLAN-2 Maviret for 12 weeks (n=100) Adolescent subjects (12 to <18 years) GT1-6 DORA (Part 1) Maviret for 8 weeks (n=44) or 16 weeks (n=3) TN=treatment naïve, PRS-TE=treatment experienced (includes previous treatment that included pegIFN (or IFN), and/or RBV and/or sofosbuvir), PI=Protease Inhibitor, CKD=chronic kidney disease a. Included 33 subjects co-infected with HIV-1. b. GT2 from SURVEYOR-2 Parts 1 and 2 - Maviret for 8 weeks (n=54) or 12 weeks (n=25); GT2 from SURVEYOR-2 Part 4 - Maviret for 8 weeks (n=145). c. GT3 without cirrhosis from SURVEYOR-2 Parts 1 and 2 - Maviret for 8 weeks (n=29) or 12 weeks (n=54); GT3 without cirrhosis from SURVEYOR-2 Part 3 - Maviret for 12 weeks (n=22) or 16 weeks (n=22). d. GT3 with cirrhosis from SURVEYOR-2 Part 2 - Maviret for 12 weeks (n=24) or 16 weeks (n=4); GT3 with cirrhosis from SURVEYOR-2 Part 3 - Maviret for 12 weeks (n=40) or 16 weeks (n=47). e. GT1, 4 from MAGELLAN-1 Part 1 - Maviret for 12 weeks (n=22); GT1, 4 from MAGELLAN-1 Part 2 - Maviret for 12 weeks (n=44) or 16 weeks (n=47). 16 f. VOYAGE-1 and VOYAGE-2 were Asian regional studies. Serum HCV RNA values were measured during the clinical studies using the Roche COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL (except for SURVEYOR-1 and SURVEYOR-2 which used the Roche COBAS TaqMan real-time reverse transcriptase-PCR (RT-PCR) assay v. 2.0 with an LLOQ of 25 IU/mL). Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the studies to determine the HCV cure rate. Clinical studies in treatment-naïve or treatment-experienced subjects with or without cirrhosis Of the 2,409 subjects with compensated liver disease (with or without cirrhosis) treated who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir, the median age was 53 years (range: 19 to 88); 73.3% were treatment-naïve, 26.7% were treatment-experienced to a combination containing either sofosbuvir, ribavirin and/or peginterferon; 40.3% were HCV genotype 1; 19.8% were HCV genotype 2; 27.8% were HCV genotype 3; 8.1% were HCV genotype 4; 3.4% were HCV genotype 5-6; 13.1% were ≥65 years; 56.6% were male; 6.2% were Black; 12.3% had cirrhosis; 4.3% had severe renal impairment or end stage renal disease; 20.0% had a body mass index of at least 30 kg per m2; 7.7% had HIV-1 coinfection and the median baseline HCV RNA level was 6.2 log10 IU/mL Table 8: SVR12 in treatment-naïve and treatment-experienceda subjects to peginterferon, ribavirin and/or sofosbuvir with genotype 1, 2, 4, 5 and 6 infection who received the recommended duration (pooled data from ENDURANCE-1b, SURVEYOR-1, -2, and EXPEDITION-1, 2b, -4 and 8) Genotype 1 Genotype 2 Genotype 4 Genotype 5 Genotype 6 SVR12 in subjects without cirrhosis 8 weeks 99.2% (470/474) 98.1% (202/206) 95.2% (59/62) 100% (2/2) 92.3% (12/13) Outcome for subjects without SVR12 On-treatment VF 0.2% (1/474) 0% (0/206) 0% (0/62) 0% (0/2) 0% (0/13) Relapsec 0% (0/471) 1.0% (2/204) 0% (0/61) 0% (0/2) 0% (0/13) Otherd 0.6% (3/474) 1.0% (2/206) 4.8% (3/62) 0% (0/2) 7.7% (1/13) SVR12 in subjects with cirrhosis 8 weeks 97.8% (226/231) 100% (26/26) 100% (13/13) 100% (1/1) 100% (9/9) 12 weeks 96.8% (30/31) 90.0% (9/10) 100% (8/8) --- 100% (1/1) Outcome for subjects without SVR12 On-treatment VF 0% (0/262) 0% (0/36) 0% (0/21) 0% (0/1) 0% (0/10) Relapsec 0.4% (1/256) 0% (0/35) 0% (0/20) 0% (0/1) 0% (0/10) Otherd 1.9%(5/262) 2.8% (1/36) 0% (0/21) 0% (0/1) 0% (0/10) VF=virologic failure a. Percent of subjects with prior treatment experience to PRS is 26%, 14%, 24%, 0%, and 13% for genotypes 1, 2, 4, 5, and 6, respectively. None of the GT5 subjects were TE-PRS, and 3 GT6 subjects were TE-PRS. b. Includes a total of 154 subjects coinfected with HIV-1 in ENDURANCE-1 and EXPEDITION-2 who received the recommended duration. c. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those who completed treatment. d. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. Of the genotype 1-, 2-, 4-, 5-, or 6-infected subjects with end stage renal disease enrolled in EXPEDITION-4, 97.8% (91/93) achieved SVR12 with no virologic failures. 17 Clinical Study in Subjects with Genotype 5 or 6 Infection ENDURANCE-5,6 was an open-label study in 84 HCV GT5 (N=23) or 6-infected (N=61) TN or TE- PRS subjects. Subjects without cirrhosis received Maviret for 8 weeks, and subjects with compensated cirrhosis received Maviret for 12 weeks. Of the 84 subjects treated, the median age was 59 years (range 24-79); 27% had HCV genotype 5, 73% had HCV genotype 6; 54% were female, 30% were White, 68% were Asian; 90% were HCV TN; 11% had compensated cirrhosis. The overall SVR12 rate was 97.6% (82/84). The SVR12 rate was 95.7% (22/23) for GT5-infected subjects and 98.4% (60/61) for GT6-infected subjects. One TN GT5-infected subject without cirrhosis experienced relapse, and one TN GT6-infected subject with compensated cirrhosis experienced on- treatment virologic failure. Subjects with Genotype 1, 2, 4, 5, or 6 Infection with Cirrhosis who received 8 weeks of Maviret The safety and efficacy of Maviret given for 8 weeks in GT 1, 2, 4, 5 or 6 treatment naïve subjects with compensated cirrhosis was evaluated in a single-arm, open-label study (EXPEDITION-8). Of the 280 subjects treated, the median age was 60 years (range: 34 to 88); 81.8% had HCV genotype 1, 10% had HCV genotype 2, 4.6% had HCV genotype 4, 0.4% had HCV genotype 5; 3.2% had HCV genotype 6; 60% were male; 9.6% were Black. The overall SVR12 rate was 98.2% (275/280). There were no virologic failures. Subjects with genotype 3 infection The efficacy of Maviret in subjects who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir with genotype 3 chronic hepatitis C infection was demonstrated in the ENDURANCE-3 (treatment-naïve without cirrhosis), EXPEDITION-8 (treatment-naïve with cirrhosis), and SURVEYOR-2 Part 3 (subjects with and without cirrhosis and/or treatment-experienced) clinical studies. ENDURANCE-3 was a partially-randomized, open-label, active-controlled study in treatment-naïve genotype 3-infected subjects. Subjects were randomized (2:1) to either Maviret for 12 weeks or the combination of sofosbuvir and daclatasvir for 12 weeks; subsequently the study included a third arm (which was non-randomized) with Maviret for 8 weeks. EXPEDITION-8 was a single-arm, open-label study in treatment-naïve subjects with compensated cirrhosis and genotype 1, 2, 3, 4, 5 or 6 infection who received Maviret for 8 weeks. SURVEYOR-2 Part 3 was an open-label study that evaluated the efficacy of Maviret in treatment-experienced genotype 3-infected subjects without cirrhosis and with compensated cirrhosis for 16-weeks. Among treatment-experienced subjects, 46% (42/91) failed a previous regimen containing sofosbuvir. Table 9: SVR12 in treatment-naïve, genotype 3-infected subjects without cirrhosis (ENDURANCE-3) SVR Maviret 8 weeks N=157 Maviret 12 weeks N=233 SOF+DCV 12 weeks N=115 94.9% (149/157) 95.3% (222/233) 96.5% (111/115) Treatment difference -1.2%; 95% confidence interval (-5.6% to 3.1%) Treatment difference -0.4%; 97.5% confidence interval (-5.4% to 4.6%) Outcome for subjects without SVR12 On-treatment VF 0.6% (1/157) 0.4% (1/233) 0% (0/115) Relapsea 3.3% (5/150) 1.4% (3/222) 0.9% (1/114) Otherb 1.3% (2/157) 3.0% (7/233) 2.6% (3/115) a. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those who completed treatment. b. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. In a pooled analysis of treatment naïve patients without cirrhosis (including Phase 2 and 3 data) where SVR12 was assessed according to the presence of baseline A30K, a numerically lower SVR12 rate 18 was achieved in patients with A30K treated for 8 weeks as compared to those treated for 12 weeks [78% (14/18) vs 93% (13/14)]. Table 10: SVR12 in genotype 3-infected subjects with or without cirrhosis (SURVEYOR-2 Part 3 and EXPEDITION-8) Treatment-naïve with cirrhosis Treatment-naïve with cirrhosis Treatment-experienced with or without cirrhosis Maviret 8 weeks (N=63) Maviret 12 weeks (N=40) Maviret 16 weeks (N=69) SVR 95.2% (60/63) 97.5% (39/40) 95.7% (66/69) Outcome for subjects without SVR12 On-treatment VF 0% (0/63) 0% (0/40) 1.4% (1/69) Relapsea 1.6% (1/62) 0% (0/39) 2.9% (2/68) Otherb 3.2% (2/63) 2.5% (1/40) 0% (0/69) SVR by cirrhosis status No Cirrhosis NA NA 95.5% (21/22) Cirrhosis 95.2% (60/63) 97.5% (39/40) 95.7% (45/47) a. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those who completed treatment. b. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. Of the genotype 3-infected subjects with end stage renal disease enrolled in EXPEDITION-4, 100% (11/11) achieved SVR12. Subjects with genotype 3b infection GT3b is a subtype reported in a relatively small number of HCV infected patients in China and a few countries in South and Southeast Asia, but rarely outside of this region. Studies VOYAGE-1 and VOYAGE-2 were conducted in China, Singapore, and South Korea in HCV genotype 1-6 subjects without cirrhosis (VOYAGE-1) or with compensated cirrhosis (VOYAGE-2) that were treatment- naïve (TN) or treatment-experienced to combinations of interferon, peg-interferon, ribavirin and/or sofosbuvir (TE-PRS). All subjects without cirrhosis or with compensated cirrhosis received 8 or 12 weeks of Maviret, respectively, except GT3 TE-PRS subjects who received 16 weeks of Maviret. The overall SVR12 rates were 97.2% (352/362) and 99.4% (159/160) in VOYAGE-1 and VOYAGE-2, respectively. Among GT3b subjects without cirrhosis, a numerically lower SVR12 rate of 58.3% (7/12) [62.5% (5/8) for TN subjects and 50% (2/4) for TE-PRS subjects] was observed compared to GT3a subjects without cirrhosis (92.9% (13/14)). Three GT3b TN subjects experienced relapse and two GT3b TE- PRS subjects experienced on-treatment virologic failure. Among subjects with compensated cirrhosis, the overall SVR12 rate for GT3b infected subjects was 87.5% (7/8) [85.7% (6/7) for TN subjects and 100% (1/1) for TE-PRS subjects] and 100% (6/6) for GT3a infected subjects. One GT3b TN subject experienced relapse. Overall SVR12 Rate from the Clinical Studies in Treatment-Naïve or Treatment-Experienced Subjects with or without Cirrhosis In subjects who are treatment-naïve (TN) or treatment-experienced to combinations of interferon, peginterferon, ribavirin and/or sofosbuvir (TE-PRS) who received the recommended duration, 97.5% (1,395/1,431) achieved SVR12 overall, while 0.2% (3/1,431) experienced on-treatment virologic failure and 0.9% (12/1,407) experienced post-treatment relapse. In TN or TE-PRS subjects with compensated cirrhosis who received the recommended duration, 97.1% (431/444) achieved SVR12 (among which 97.7% [335/343] of TN subjects achieved SVR12), while 0.2% (1/444) experienced on-treatment virologic failure and 0.9% (4/434) experienced post- treatment relapse. 19 In TN subjects without cirrhosis who received the recommended duration of 8 weeks, 97.5% (749/768) achieved SVR12, while 0.1% (1/768) experienced on-treatment virologic failure and 0.7% (5/755) experienced post-treatment relapse. In TE-PRS subjects without cirrhosis who received the recommended duration, 98.2% (215/219) achieved SVR12, while 0.5% (1/219) experienced on-treatment virologic failure and 1.4% (3/218) experienced post-treatment relapse. The presence of HIV-1 coinfection did not impact efficacy. The SVR12 rate in TN or TE-PRS HCV/HIV-1 co-infected subjects treated for 8 or 12 weeks (without cirrhosis and with compensated cirrhosis, respectively) was 98.2% (165/168) from ENDURANCE-1 and EXPEDITION-2. One subject experienced on-treatment virologic failure (0.6%, 1/168) and no subjects relapsed (0%, 0/166). Clinical Study in Liver or Kidney Transplant Recipients MAGELLAN-2 was a single-arm, open-label study in 100 post-liver or -kidney transplant HCV GT1-6 infected subjects without cirrhosis who received Maviret for 12 weeks. The study included subjects who were HCV treatment-naïve or treatment-experienced to combinations of (peg) interferon, ribavirin, and/or sofosbuvir, with the exception of GT3-infected subjects who were all treatment- naïve. Of the 100 subjects treated, the median age was 60 years (range: 39 to 78); 57% had HCV genotype 1, 13% had HCV genotype 2, 24% had HCV genotype 3, 4% had HCV genotype 4, 2% had HCV genotype 6; 75% were male; 8% were Black; 66% were HCV treatment-naïve; none had cirrhosis and 80% had a baseline fibrosis state of F0 or F1; 80% of subjects were post-liver transplant and 20% were post-kidney transplant. Immunosuppressants allowed for co-administration were ciclosporin ≤100 mg/day, tacrolimus, sirolimus, everolimus, azathioprine, mycophenolic acid, prednisone, and prednisolone. The overall SVR12 rate in post-transplant subjects was 98.0% (98/100). There was one relapse and no on-treatment virologic failure. Clinical Study in Renally Impaired Subjects EXPEDITION-5 was an open-label study in 101 HCV GT1-6 infected subjects without cirrhosis or with compensated cirrhosis and chronic kidney disease (CKD) stage 3b, 4, or 5. Subjects were either treatment-naïve or treatment-experienced to combinations of (peg) interferon, ribavirin, and/or sofosbuvir and received Maviret for 8, 12, or 16 weeks per approved treatment durations. Of the 101 subjects treated, the median age was 58 years (range 32-87); 53% had HCV genotype 1; 27% had HCV genotype 2; 15% had HCV genotype 3; 4% had HCV genotype 4; 59% were male; 73% were White; 80% were HCV treatment-naïve; 13% had cirrhosis and 65% had a baseline fibrosis state of F0 or F1; 7% were CKD stage 3b; 17% were CKD Stage 4, and 76% were CKD Stage 5 (all receiving dialysis); 84 subjects received 8 weeks of treatment, 13 subjects received 12 weeks of treatment, and 4 subjects received 16 weeks of treatment. The overall SVR12 rate was 97% (98/101). There were no virologic failures. Elderly Clinical studies of Maviret included 328 patients aged 65 and over (13.8% of the total number of subjects). The response rates observed for patients ≥ 65 years of age were similar to that of patients < 65 years of age, across treatment groups. Paediatric population DORA (Part 1) was an open-label study to evaluate safety and efficacy in adolescents aged 12 years to less than 18 years who received Maviret 300 mg/120 mg (three 100 mg/40 mg film-coated tablets), for 8, or 16 weeks. 47 subjects were enrolled in DORA (Part 1). The median age was 14 years (range: 12 to 17); 79% had HCV genotype 1, 6% had HCV genotype 2, 9% had HCV genotype 3, 6% had HCV genotype 4; 55% were female; 11% were Black; 77% were HCV treatment-naïve; 23% were 20 treatment-experienced to interferon; 4% had HIV-coinfection; none had cirrhosis; the mean weight was 59 kg (range: 32 to 109 kg). The overall SVR12 rate was 100% (47/47). No subject experienced virologic failure. The European Medicines Agency has deferred the obligation to submit the results of studies with glecaprevir/pibrentasvir in one or more subsets of the paediatric population from 3 years to less than 12 years in the treatment of chronic hepatitis C (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetic properties of the components of Maviret are provided in Table 11. Table 11: Pharmacokinetic properties of the components of Maviret in healthy adult subjects Glecaprevir Pibrentasvir Absorption Tmax (h)a 5.0 5.0 Effect of meal (relative to fasting)b ↑ 83-163% ↑ 40-53% Distribution % Bound to human plasma proteins 97.5 >99.9 Blood-to-plasma ratio 0.57 0.62 Biotransformation Metabolism secondary none Elimination Major route of elimination Biliary excretion Biliary excretion t1/2 (h) at steady-state 6 - 9 23 - 29 % of dose excreted in urinec 0.7 0 % of dose excreted in faecesc 92.1d 96.6 Transport Substrate of transporter P-gp, BCRP, and OATP1B1/3 P-gp and not excluded BCRP a. Median Tmax following single doses of glecaprevir and pibrentasvir in healthy subjects. b. Mean systemic exposure with moderate to high fat meals. c. Single dose administration of [14C]glecaprevir or [14C]pibrentasvir in mass balance studies. d. Oxidative metabolites or their byproducts accounted for 26% of radioactive dose. No glecaprevir metabolites were observed in plasma. In patients with chronic hepatitis C infection without cirrhosis, following 3 days of monotherapy with either glecaprevir 300 mg per day (N=6) or pibrentasvir 120 mg per day (N=8) alone, geometric mean AUC24 values were 13600 ng∙h/mL for glecaprevir and 459 ng∙h/mL for pibrentasvir. Estimation of the pharmacokinetic parameters using population pharmacokinetic models has inherent uncertainty due to dose non-linearity and cross interaction between glecaprevir and pibrentasvir. Based on population pharmacokinetic models for Maviret in chronic hepatitis C patients, steady-state AUC24 values for glecaprevir and pibrentasvir were 4800 and 1430 ng∙h/mL in subjects without cirrhosis (N=1804), and 10500 and 1530 ng∙h/mL in subjects with cirrhosis (N=280), respectively. Relative to healthy subjects (N=230), population estimates of AUC24, ss were similar (10% difference) for glecaprevir and 34% lower for pibrentasvir in HCV-infected patients without cirrhosis. Linearity/non-linearity Glecaprevir AUC increased in a greater than dose-proportional manner (1200 mg QD had 516-fold higher exposure than 200 mg QD) which may be related to saturation of uptake and efflux transporters. Pibrentasvir AUC increased in a greater than dose-proportional manner at doses up to 120 mg, (over 10-fold exposure increase at 120 mg QD compared to 30 mg QD), but exhibited linear 21 pharmacokinetics at doses ≥ 120 mg. The non-linear exposure increase <120 mg may be related to saturation of efflux transporters. Pibrentasvir bioavailability when coadministered with glecaprevir is 3-fold of pibrentasvir alone. Glecaprevir is affected to a lower extent by coadministration with pibrentasvir. Pharmacokinetics in special populations Race/ethnicity No dose adjustment of Maviret is required based on race or ethnicity. Gender/weight No dose adjustment of Maviret is required based on gender or body weight. Elderly No dose adjustment of Maviret is required in elderly patients. Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (12 to 88 years) analysed, age did not have a clinically relevant effect on the exposure to glecaprevir or pibrentasvir. Paediatric Population No dose adjustment of Maviret is required in adolescents 12 years and older. Exposures of glecaprevir and pibrentasvir in adolescents aged 12 to <18 years were comparable to those in adults from Phase 2/3 studies. The pharmacokinetics of glecaprevir and pibrentasvir have not been established in paediatric patients <12 years of age. Renal impairment Glecaprevir and pibrentasvir AUC were increased ≤ 56% in non-HCV infected subjects with mild, moderate, severe, or end-stage renal impairment not on dialysis compared to subjects with normal renal function. Glecaprevir and pibrentasvir AUC were similar with and without dialysis (≤ 18% difference) in dialysis-dependent non-HCV infected subjects. In population pharmacokinetic analysis of HCV-infected subjects, 86% higher glecaprevir and 54% higher pibrentasvir AUC were observed for subjects with end stage renal disease, with or without dialysis, compared to subjects with normal renal function. Larger increases may be expected when unbound concentration is considered. Overall, the changes in exposures of Maviret in HCV-infected subjects with renal impairment with or without dialysis were not clinically significant. Hepatic impairment At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir AUC was 33% higher in Child-Pugh A subjects, 100% higher in Child-Pugh B subjects, and increased to 11-fold in Child-Pugh C subjects. Pibrentasvir AUC was similar in Child-Pugh A subjects, 26% higher in Child-Pugh B subjects, and 114% higher in Child-Pugh C subjects. Larger increases may be expected when unbound concentration is considered. Population pharmacokinetic analysis demonstrated that following administration of Maviret in HCV- infected subjects with compensated cirrhosis, exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV-infected subjects. The mechanism for the differences between glecaprevir exposure in chronic Hepatitis C patients with or without cirrhosis is unknown. 5.3 Preclinical safety data Glecaprevir and pibrentasvir were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rodent micronucleus assays. Carcinogenicity studies with glecaprevir and pibrentasvir have not been conducted. 22 No effects on mating, female or male fertility, or early embryonic development were observed in rodents at up to the highest dose tested. Systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 63 and 102 times higher, respectively, than the exposure in humans at the recommended dose. In animal reproduction studies, no adverse developmental effects were observed when the components of Maviret were administered separately during organogenesis at exposures up to 53 times (rats; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures at the recommended dose of Maviret. Maternal toxicity (anorexia, lower body weight, and lower body weight gain) with some embryofoetal toxicity (increase in post-implantation loss and number of resorptions and a decrease in mean foetal body weight), precluded the ability to evaluate glecaprevir in the rabbit at clinical exposures. There were no developmental effects with either compound in rodent peri/postnatal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times, respectively, the exposure in humans at the recommended dose. Unchanged glecaprevir was the main component observed in the milk of lactating rats without effect on nursing pups. Pibrentasvir was the only component observed in the milk of lactating rats without effect on nursing pups. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Copovidone (Type K 28) Vitamin E (tocopherol) polyethylene glycol succinate Silica, colloidal anhydrous Propylene glycol monocaprylate (Type II) Croscarmellose sodium Sodium stearyl fumarate Film coating Hypromellose 2910 (E464) Lactose monohydrate Titanium dioxide Macrogol 3350 Iron oxide red (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 36 months. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container PVC/PE/PCTFE aluminium foil blister packs. Pack containing 84 (4 x 21) film-coated tablets. 23 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany 8. MARKETING AUTHORISATION NUMBER EU/1/17/1213/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 26th July 2017 10. DATE OF REVISION OF THE TEXT Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/ 24 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 25 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen GERMANY AbbVie Logistics B.V Zuiderzeelaan 53 8017 JV Zwolle NETHERLANDS B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web- portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 26 • Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date Non-interventional post-authorisation safety study (PASS): In order to evaluate the recurrence of hepatocellular carcinoma associated with Maviret, the MAH shall conduct and submit the results of a prospective safety study using data deriving from a cohort of a well-defined group of patients, based on an agreed protocol. The final study report shall be submitted by: Q2 2023 27 ANNEX III LABELLING AND PACKAGE LEAFLET 28 A. LABELLING 29 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Maviret 100 mg/40 mg film-coated tablets glecaprevir/pibrentasvir 2. STATEMENT OF ACTIVE SUBSTANCE Each film-coated tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS film-coated tablets 84 (4 x 21) film-coated tablets 5. METHOD AND ROUTE OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 30 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany 12. MARKETING AUTHORISATION NUMBER EU/1/17/1213/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE maviret 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 31 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON 1. NAME OF THE MEDICINAL PRODUCT Maviret 100 mg/40 mg film-coated tablets glecaprevir/pibrentasvir 2. STATEMENT OF ACTIVE SUBSTANCE Each film-coated tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS film-coated tablets 21 film-coated tablets 5. METHOD AND ROUTE OF ADMINISTRATION Read the package leaflet before use. Oral use Take all 3 tablets in 1 blister once daily with food 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 32 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany 12. MARKETING AUTHORISATION NUMBER EU/1/17/1213/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE maviret 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 33 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Maviret 100 mg/40 mg tablets glecaprevir/pibrentasvir 2. NAME OF THE MARKETING AUTHORISATION HOLDER AbbVie (as logo) 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 34 B. PACKAGE LEAFLET 35 Package leaflet: Information for the user Maviret 100 mg/40 mg film-coated tablets glecaprevir/pibrentasvir This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or pharmacist. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Maviret is and what it is used for 2. What you need to know before you take Maviret 3. How to take Maviret 4. Possible side effects 5. How to store Maviret 6. Contents of the pack and other information 1. What Maviret is and what it is used for Maviret is an antiviral medicine used to treat adults and adolescents (12 to less than 18 years old) with long-term (‘chronic’) hepatitis C (an infectious disease that affects the liver, caused by the hepatitis C virus). It contains the active substances glecaprevir and pibrentasvir. Maviret works by stopping the hepatitis C virus from multiplying and infecting new cells. This allows the infection to be eliminated from the body. 2. What you need to know before you take Maviret Do not take Maviret if: • you are allergic to glecaprevir, pibrentasvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet). • you have severe liver problems other than from hepatitis C. • you are taking the following medicines: • atazanavir (for HIV infection) • atorvastatin or simvastatin (to lower blood cholesterol) • carbamazepine, phenobarbital, phenytoin, primidone (normally used for epilepsy) • dabigatran etexilate (to prevent blood clots) • ethinyl oestradiol-containing medicines (such as contraception medicines, including vaginal rings and tablets) • rifampicin (for infections) • St. John’s wort (Hypericum perforatum), (herbal remedy used for mild depression). Do not take Maviret if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Maviret. 36 Warnings and precautions Talk to your doctor if you have the following because your doctor may want to check you more closely: • liver problems other than hepatitis C • current or previous infection with the hepatitis B virus • diabetes. You may need closer monitoring of your blood glucose levels and/or adjustment of your diabetes medication after starting Maviret. Some diabetic patients have experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like Maviret. Blood tests Your doctor will test your blood before, during and after your treatment with Maviret. This is so that your doctor can decide if: • you should take Maviret and for how long • your treatment has worked and you are free of the hepatitis C virus. Children Do not give this medicine to children under 12 years of age. The use of Maviret in children under 12 years of age has not yet been studied. Other medicines and Maviret Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Tell your doctor or pharmacist before taking Maviret, if you are taking any of the medicines in the table below. The doctor may need to change your dose of these medicines. Medicines you must tell your doctor about before taking Maviret Medicine Purpose of the medicine ciclosporin, tacrolimus to suppress the immune system darunavir, efavirenz, lopinavir, ritonavir for HIV infection digoxin for heart problems fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin to lower blood cholesterol warfarin and other similar medicines* to prevent blood clots *Your doctor may need to increase the frequency of your blood tests to check how well your blood can clot. If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking Maviret. Pregnancy and contraception The effects of Maviret during pregnancy are not known. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine, as the use of Maviret in pregnancy is not recommended. Contraceptive medicines that contain ethinylestradiol must not be used in combination with Maviret. Breast-feeding Talk to your doctor before taking Maviret if you are breast-feeding. It is not known whether the two medicines in Maviret pass into breast milk. Driving and using machines Maviret should not affect your ability to drive or use any tools or machines. 37 Maviret contains lactose If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor before taking this medicine. 3. How to take Maviret Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Your doctor will tell you how long you need to take Maviret for. How much to take The recommended dose for adults and adolescents (12 to <18 years old) is three tablets of Maviret 100mg/40mg taken together, once a day. Three tablets in one blister is the daily dose. How to take • Take the tablets with food. • Swallow the tablets whole. • Do not chew, crush or break the tablets as it may affect the amount of Maviret in your blood. If you are sick (vomit) after taking Maviret it may affect the amount of Maviret in your blood. This may make Maviret work less well. • If you vomit less than 3 hours after taking Maviret, take another dose. • If you vomit more than 3 hours after taking Maviret, you do not need to take another dose until your next scheduled dose. If you take more Maviret than you should If you accidentally take more than the recommended dose, contact your doctor or go to the nearest hospital straight away. Take the medicine pack with you so that you can show the doctor what you have taken. If you forget to take Maviret It is important not to miss a dose of this medicine. If you do miss a dose, work out how long it is since you should have last taken Maviret: • If you notice within 18 hours of the time you usually take Maviret take the dose as soon as possible. Then take the next dose at your usual time. • If you notice 18 hours or more after the time you usually take Maviret, wait and take the next dose at your usual time. Do not take a double dose (two doses too close together). If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor or pharmacist if you notice any of the following side effects: Very common: may affect more than 1 in 10 people • feeling very tired (fatigue) • headache Common: may affect up to 1 in 10 people • feeling sick (nausea) • diarrhoea • feeling weak or lack of energy (asthenia) 38 Uncommon: may affect up to 1 in 100 people • swelling of the face, lips, tongue, throat, abdomen, arms or legs Not known: cannot be estimated from the available data • itching Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Maviret Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blister after ‘EXP’. This medicine does not require any special storage. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Maviret contains • The active substances are glecaprevir and pibrentasvir. Each tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. • The other ingredients are: − Tablet core: copovidone (Type K 28), vitamin E polyethylene glycol succinate, silica, anhydrous colloidal, propylene glycol monocaprylate (type II), croscarmellose sodium, sodium stearyl fumarate. − Tablet film-coating: hypromellose (E464), lactose monohydrate, titanium dioxide, macrogol 3350, iron oxide red (E172). What Maviret looks like and contents of the pack Maviret tablets are pink, oblong, curved on both sides (biconvex), film-coated tablets with dimensions of 18.8 mm x 10.0 mm and debossed on one side with ‘NXT’. Maviret tablets are packed into foil blisters, each containing 3 tablets. Maviret is available in a pack of 84 tablets as 4 cartons, each containing 21 film-coated tablets. Marketing Authorisation Holder and Manufacturer AbbVie Deutschland GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien AbbVie SA Tél/Tel: +32 10 477811 Lietuva AbbVie UAB Tel: +370 5 205 3023 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 39 България АбВи ЕООД Тел.: +359 2 90 30 430 Luxembourg/Luxemburg AbbVie SA Belgique/Belgien Tél/Tel: +32 10 477811 Česká republika AbbVie s.r.o. Tel: +420 233 098 111 Magyarország AbbVie Kft. Tel.: +36 1 455 8600 Danmark AbbVie A/S Tlf: +45 72 30-20-28 Malta V.J.Salomone Pharma Limited Tel: +356 22983201 Deutschland AbbVie Deutschland GmbH & Co. KG Tel: 00800 222843 33 (gebührenfrei) Tel: +49 (0) 611 / 1720-0 Nederland AbbVie B.V. Tel: +31 (0)88 322 2843 Eesti AbbVie Biopharmaceuticals GmbH Eesti filiaal Tel: +372 623 1011 Norge AbbVie AS Tlf: +47 67 81 80 00 Ελλάδα AbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε. Τηλ: +30 214 4165 555 Österreich AbbVie GmbH Tel: +43 1 20589-0 España AbbVie Spain, S.L.U. Tel: +34 91 384 09 10 Polska AbbVie Polska Sp. z o.o. Tel.: +48 22 372 78 00 France AbbVie Tél: +33 (0)1 45 60 13 00 Portugal AbbVie, Lda. Tel: +351 (0)21 1908400 Hrvatska AbbVie d.o.o. Tel: +385 (0)1 5625 501 România AbbVie S.R.L. Tel: +40 21 529 30 35 Ireland AbbVie Limited Tel: +353 (0)1 4287900 Slovenija AbbVie Biofarmacevtska družba d.o.o. Tel: +386 (1)32 08 060 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika AbbVie s.r.o. Tel: +421 2 5050 0777 Italia AbbVie S.r.l. Tel: +39 06 928921 Suomi/Finland AbbVie Oy Puh/Tel: +358 (0)10 2411 200 Κύπρος Lifepharma (Z.A.M.) Ltd Τηλ: +357 22 34 74 40 Sverige AbbVie AB Tel: +46 (0)8 684 44 600 Latvija AbbVie SIA Tel: +371 67605000 United Kingdom AbbVie Ltd Tel: +44 (0)1628 561090 40 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. To listen to or request a copy of this leaflet in <Braille>, <large print> or <audio>, please contact the local representative of the Marketing Authorisation Holder. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what maviret is and what it is used for', 'Section_Content': "maviret is an antiviral medicine used to treat adults and adolescents (12 to less than 18 years old) with long-term ('chronic') hepatitis c (an infectious disease that affects the liver, caused by the hepatitis c virus). it contains the active substances glecaprevir and pibrentasvir. maviret works by stopping the hepatitis c virus from multiplying and infecting new cells. this allows the infection to be eliminated from the body.", 'Entity_Recognition': [{'Text': 'maviret', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 10, 'BeginOffset': 0, 'EndOffset': 7, 'Score': 0.22616110742092133, 'Text': 'maviret', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'NAME', 'Traits': []}, {'Text': 'an antiviral medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 32}, {'Id': 11, 'BeginOffset': 87, 'EndOffset': 89, 'Score': 0.9028027057647705, 'Text': '18', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'AGE', 'Traits': []}, {'Text': "long-term ('chronic') hepatitis c", 'Type': 'PROBLEM', 'BeginOffset': 106, 'EndOffset': 139}, {'Text': 'an infectious disease', 'Type': 'PROBLEM', 'BeginOffset': 141, 'EndOffset': 162}, {'Id': 0, 'BeginOffset': 180, 'EndOffset': 185, 'Score': 0.9386139512062073, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the hepatitis c virus', 'Type': 'PROBLEM', 'BeginOffset': 197, 'EndOffset': 218}, {'Text': 'the active substances glecaprevir', 'Type': 'TREATMENT', 'BeginOffset': 233, 'EndOffset': 266}, {'Id': 3, 'BeginOffset': 271, 'EndOffset': 283, 'Score': 0.9862918257713318, 'Text': 'pibrentasvir', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the hepatitis c virus', 'Type': 'PROBLEM', 'BeginOffset': 311, 'EndOffset': 332}, {'Text': 'the infection', 'Type': 'PROBLEM', 'BeginOffset': 387, 'EndOffset': 400}, {'Id': 1, 'BeginOffset': 427, 'EndOffset': 431, 'Score': 0.6674163341522217, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}]}

{'Title': '2. what you need to know before you take maviret', 'Section_Content': "do not take maviret if: you are allergic to glecaprevir, pibrentasvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet). you have severe liver problems other than from hepatitis c. you are taking the following medicines: atazanavir (for hiv infection) atorvastatin or simvastatin (to lower blood cholesterol) carbamazepine, phenobarbital, phenytoin, primidone (normally used for epilepsy) dabigatran etexilate (to prevent blood clots) ethinyl oestradiol-containing medicines (such as contraception medicines, including vaginal rings and tablets) rifampicin (for infections) st. john's wort (hypericum perforatum), (herbal remedy used for mild depression). do not take maviret if any of the above apply to you. if you are not sure, talk to your doctor or pharmacist before taking maviret. warnings and precautions talk to your doctor if you have the following because your doctor may want to check you more closely: liver problems other than hepatitis c current or previous infection with the hepatitis b virus diabetes. you may need closer monitoring of your blood glucose levels and/or adjustment of your diabetes medication after starting maviret. some diabetic patients have experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like maviret. blood tests your doctor will test your blood before, during and after your treatment with maviret. this is so that your doctor can decide if: you should take maviret and for how long your treatment has worked and you are free of the hepatitis c virus. children do not give this medicine to children under 12 years of age. the use of maviret in children under 12 years of age has not yet been studied. other medicines and maviret tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. tell your doctor or pharmacist before taking maviret, if you are taking any of the medicines in the table below. the doctor may need to change your dose of these medicines. medicines you must tell your doctor about before taking maviret medicine purpose of the medicine ciclosporin, tacrolimus to suppress the immune system darunavir, efavirenz, lopinavir, ritonavir for hiv infection digoxin for heart problems fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin to lower blood cholesterol warfarin and other similar medicines* to prevent blood clots *your doctor may need to increase the frequency of your blood tests to check how well your blood can clot. if any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking maviret. pregnancy and contraception the effects of maviret during pregnancy are not known. if you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine, as the use of maviret in pregnancy is not recommended. contraceptive medicines that contain ethinylestradiol must not be used in combination with maviret. breast-feeding talk to your doctor before taking maviret if you are breast-feeding. it is not known whether the two medicines in maviret pass into breast milk. driving and using machines maviret should not affect your ability to drive or use any tools or machines. maviret contains lactose if you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor before taking this medicine.", 'Entity_Recognition': [{'Text': 'maviret', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 32, 'EndOffset': 40}, {'Id': 2, 'BeginOffset': 44, 'EndOffset': 55, 'Score': 0.9801697134971619, 'Text': 'glecaprevir', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.4377642869949341}]}, {'Id': 3, 'BeginOffset': 57, 'EndOffset': 69, 'Score': 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{'Title': '3. how to take maviret', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. your doctor will tell you how long you need to take maviret for. how much to take the recommended dose for adults and adolescents (12 to <18 years old) is three tablets of maviret 100mg/40mg taken together, once a day. three tablets in one blister is the daily dose. how to take take the tablets with food. swallow the tablets whole. do not chew, crush or break the tablets as it may affect the amount of maviret in your blood. if you are sick (vomit) after taking maviret it may affect the amount of maviret in your blood. this may make maviret work less well. if you vomit less than 3 hours after taking maviret, take another dose. if you vomit more than 3 hours after taking maviret, you do not need to take another dose until your next scheduled dose. if you take more maviret than you should if you accidentally take more than the recommended dose, contact your doctor or go to the nearest hospital straight away. take the medicine pack with you so that you can show the doctor what you have taken. if you forget to take maviret it is important not to miss a dose of this medicine. if you do miss a dose, work out how long it is since you should have last taken maviret: if you notice within 18 hours of the time you usually take maviret take the dose as soon as possible. then take the next dose at your usual time. if you notice 18 hours or more after the time you usually take maviret, wait and take the next dose at your usual time. do not take a double dose (two doses too close together). if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'maviret', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': '18', 'Type': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor or pharmacist if you notice any of the following side effects: very common: may affect more than 1 in 10 people feeling very tired (fatigue) headache common: may affect up to 1 in 10 people feeling sick (nausea) diarrhoea feeling weak or lack of energy (asthenia) 38 uncommon: may affect up to 1 in 100 people swelling of the face, lips, tongue, throat, abdomen, arms or legs not known: cannot be estimated from the available data itching reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 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{'Title': '5. how to store maviret', 'Section_Content': "keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and blister after 'exp'. this medicine does not require any special storage. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.", 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what maviret contains the active substances are glecaprevir and pibrentasvir. each tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. the other ingredients are: − tablet core: copovidone (type k 28), vitamin e polyethylene glycol succinate, silica, anhydrous colloidal, propylene glycol monocaprylate (type ii), croscarmellose sodium, sodium stearyl fumarate. − tablet film-coating: hypromellose (e464), lactose monohydrate, titanium dioxide, macrogol 3350, iron oxide red (e172). what maviret looks like and contents of the pack maviret tablets are pink, oblong, curved on both sides (biconvex), film-coated tablets with dimensions of 18.8 mm x 10.0 mm and debossed on one side with 'nxt'. maviret tablets are packed into foil blisters, each containing 3 tablets. maviret is available in a pack of 84 tablets as 4 cartons, each containing 21 film-coated tablets.", 'Entity_Recognition': [{'Text': 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6ADFC0A7644EC15EE22DE3F3603EA17D

https://www.ema.europa.eu/documents/product-information/desloratadine-actavis-epar-product-information_en.pdf

Desloratadine Actavis

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Desloratadine Actavis 5 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 5 mg desloratadine. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Blue coloured, round, with diameter of 6 mm, biconvex, film-coated tablets with the marking ‘LT’ engraved on one side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Desloratadine Actavis is indicated in adults and adolescents aged 12 years and older for the relief of symptoms associated with: - allergic rhinitis (see section 5.1) - urticaria (see section 5.1) 4.2 Posology and method of administration Posology Adults and adolescents (12 years of age and over) The recommended dose of Desloratadine Actavis is one tablet once a day. Intermittent allergic rhinitis (presence of symptoms for less than 4 days per week or for less than 4 weeks) should be managed in accordance with the evaluation of patient’s disease history and the treatment could be discontinued after symptoms are resolved and reinitiated upon their reappearance. In persistent allergic rhinitis (presence of symptoms for 4 days or more per week and for more than 4 weeks), continued treatment may be proposed to the patients during the allergen exposure periods. Paediatric population There is limited clinical trial efficacy experience with the use of desloratadine in adolescents 12 through 17 years of age (see sections 4.8 and 5.1). The safety and efficacy of Desloratadine Actavis 5 mg film-coated tablets in children below the age of 12 years have not been established. No data are available. Method of administration Oral use. The dose can be taken with or without food. 4.3 Contraindications Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, or to loratadine. 3 4.4 Special warnings and precautions for use In the case of severe renal insufficiency, desloratadine should be used with caution (see section 5.2). Desloratadine should be administered with caution in patients with medical or familial history of seizures, and mainly young children, being more susceptible to develop new seizures under desloratadine treatment. Healthcare providers may consider discontinuing desloratadine in patients who experience a seizure while on treatment. 4.5 Interaction with other medicinal products and other forms of interaction No clinically relevant interactions were observed in clinical trials with desloratadine tablets in which erythromycin or ketoconazole were co-administered (see section 5.1). Paediatric population Interaction studies have only been performed in adults. In a clinical pharmacology trial, desloratadine tablets taken concomitantly with alcohol did not potentiate the performance impairing effects of alcohol (see section 5.1). However, cases of alcohol intolerance and intoxication have been reported during post-marketing use. Therefore, caution is recommended if alcohol is taken concomitantly. 4.6 Fertility, pregnancy and lactation Pregnancy A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no malformative nor foeto/ neonatal toxicity of desloratadine. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of desloratadine during pregnancy. Breast-feeding Desloratadine has been identified in breastfed newborns/infants of treated women. The effect of desloratadine on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from desloratadine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility There are no data available on male and female fertility. 4.7 Effects on ability to drive and use machines Desloratadine has no or negligible influence on the ability to drive and use machines based on clinical trials. Patients should be informed that most people do not experience drowsiness. Nevertheless, as there is individual variation in response to all medicinal products, it is recommended that patients are advised not to engage in activities requiring mental alertness, such as driving a car or using machines, until they have established their own response to the medicinal product. 4.8 Undesirable effects Summary of the safety profile In clinical trials in a range of indications including allergic rhinitis and chronic idiopathic urticaria, at the recommended dose of 5 mg daily, undesirable effects with desloratadine were reported in 3% of patients in excess of those treated with placebo. The most frequent of adverse reactions reported in excess of placebo were fatigue (1.2%), dry mouth (0.8%) and headache (0.6%). 4 Paediatric population In a clinical trial with 578 adolescent patients, 12 through 17 years of age, the most common adverse event was headache; this occurred in 5.9 % of patients treated with desloratadine and 6.9 % of patients receiving placebo. Tabulated list of adverse reactions The frequency of the clinical trial adverse reactions reported in excess of placebo and other undesirable effects reported during the post-marketing period are listed in the following table. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). System Organ Class Frequency Adverse reactions seen with desloratadine Metabolism and nutrition disorders Not known Increased appetite Psychiatric disorders Very rare Not known Hallucinations Abnormal behaviour, aggression Nervous system disorders Common Very rare Headache Dizziness, somnolence, insomnia, psychomotor hyperactivity, seizures Cardiac disorders Very rare Not known Tachycardia, palpitations QT prolongation Gastrointestinal disorders Common Very rare Dry mouth Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea Hepatobiliary disorders Very rare Not known Elevations of liver enzymes, increased bilirubin, hepatitis Jaundice Skin and subcutaneous tissue disorders Not known Photosensitivity Musculoskeletal and connective tissue disorders Very rare Myalgia General disorders and administration site conditions Common Very rare Not known Fatigue Hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, pruritus, rash, and urticaria) Asthenia Investigations Not known Weight increased Paediatric population Other undesirable effects reported during the post-marketing period in paediatric patients with an unknown frequency included QT prolongation, arrhythmia, bradycardia, abnormal behaviour, and aggression. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose The adverse event profile associated with overdosage, as seen during post-marketing use, is similar to that seen with therapeutic doses, but the magnitude of the effects can be higher. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 5 Treatment In the event of overdose, consider standard measures to remove unabsorbed active substance. Symptomatic and supportive treatment is recommended. Desloratadine is not eliminated by haemodialysis; it is not known if it is eliminated by peritoneal dialysis. Symptoms Based on a multiple dose clinical trial, in which up to 45 mg of desloratadine was administered (nine times the clinical dose), no clinically relevant effects were observed. Paediatric population The adverse event profile associated with overdosage, as seen during post-marketing use, is similar to that seen with therapeutic doses, but the magnitude of the effects can be higher. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06A X27 Mechanism of action Desloratadine is a non-sedating, long-acting histamine antagonist with selective peripheral H1-receptor antagonist activity. After oral administration, desloratadine selectively blocks peripheral histamine H1-receptors because the substance is excluded from entry to the central nervous system. Desloratadine has demonstrated anti-allergic properties from in vitro studies. These include inhibiting the release of pro-inflammatory cytokines such as IL-4, IL-6, IL-8, and IL-13 from human mast cells/basophils, as well as inhibition of the expression of the adhesion molecule P-selectin on endothelial cells. The clinical relevance of these observations remains to be confirmed. Clinical efficacy and safety In a multiple dose clinical trial, in which up to 20 mg of desloratadine was administered daily for 14 days, no statistically or clinically relevant cardiovascular effect was observed. In a clinical pharmacology trial, in which desloratadine was administered at a dose of 45 mg daily (nine times the clinical dose) for ten days, no prolongation of QTc interval was seen. No clinically relevant changes in desloratadine plasma concentrations were observed in multiple-dose ketoconazole and erythromycin interaction trials. Desloratadine does not readily penetrate the central nervous system. In controlled clinical trials, at the recommended dose of 5 mg daily, there was no excess incidence of somnolence as compared to placebo. Desloratadine given at a single daily dose of 7.5 mg did not affect psychomotor performance in clinical trials. In a single dose study performed in adults, desloratadine 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying. In clinical pharmacology trials, co-administration with alcohol did not increase the alcohol-induced impairment in performance or increase in sleepiness. No significant differences were found in the psychomotor test results between desloratadine and placebo groups, whether administered alone or with alcohol. In patients with allergic rhinitis, desloratadine was effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. Desloratadine effectively controlled symptoms for 24 hours. 6 Paediatric population The efficacy of desloratadine tablets has not been clearly demonstrated in trials with adolescent patients 12 through 17 years of age. In addition to the established classifications of seasonal and perennial, allergic rhinitis can alternatively be classified as intermittent allergic rhinitis and persistent allergic rhinitis according to the duration of symptoms. Intermittent allergic rhinitis is defined as the presence of symptoms for less than 4 days per week or for less than 4 weeks. Persistent allergic rhinitis is defined as the presence of symptoms for 4 days or more per week and for more than 4 weeks. Desloratadine was effective in alleviating the burden of seasonal allergic rhinitis as shown by the total score of the rhino-conjunctivitis quality of life questionnaire. The greatest amelioration was seen in the domains of practical problems and daily activities limited by symptoms. Chronic idiopathic urticaria was studied as a clinical model for urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and because chronic patients can be more easily recruited prospectively. Since histamine release is a causal factor in all urticarial diseases, desloratadine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria, as advised in clinical guidelines. In two placebo-controlled six week trials in patients with chronic idiopathic urticaria, desloratadine was effective in relieving pruritus and decreasing the size and number of hives by the end of the first dosing interval. In each trial, the effects were sustained over the 24 hour dosing interval. As with other antihistamine trials in chronic idiopathic urticaria, the minority of patients who were identified as non- responsive to antihistamines was excluded. An improvement in pruritus of more than 50% was observed in 55% of patients treated with desloratadine compared with 19% of patients treated with placebo. Treatment with desloratadine also significantly reduced interference with sleep and daytime function, as measured by a four-point scale used to assess these variables. 5.2 Pharmacokinetic properties Absorption Desloratadine plasma concentrations can be detected within 30 minutes of administration. Desloratadine is well absorbed with maximum concentration achieved after approximately 3 hours; the terminal phase half-life is approximately 27 hours. The degree of accumulation of desloratadine was consistent with its half-life (approximately 27 hours) and a once daily dosing frequency. The bioavailability of desloratadine was dose proportional over the range of 5 mg to 20 mg. In a pharmacokinetic trial in which patient demographics were comparable to those of the general seasonal allergic rhinitis population, 4% of the subjects achieved a higher concentration of desloratadine. This percentage may vary according to ethnic background. Maximum desloratadine concentration was about 3-fold higher at approximately 7 hours with a terminal phase half-life of approximately 89 hours. The safety profile of these subjects was not different from that of the general population. Distribution Desloratadine is moderately bound (83 % - 87 %) to plasma proteins. There is no evidence of clinically relevant medicine accumulation following once daily dosing of desloratadine (5 mg to 20 mg) for 14 days. Biotransformation The enzyme responsible for the metabolism of desloratadine has not been identified yet, and therefore, some interactions with other medicinal products cannot be fully excluded. Desloratadine does not inhibit CYP3A4 in vivo, and in vitro studies have shown that the medicinal product does not inhibit CYP2D6 and is neither a substrate nor an inhibitor of P-glycoprotein. Elimination 7 In a single dose trial using a 7.5 mg dose of desloratadine, there was no effect of food (high-fat, high caloric breakfast) on the disposition of desloratadine. In another study, grapefruit juice had no effect on the disposition of desloratadine. Renally impaired patients The pharmacokinetics of desloratadine in patients with chronic renal insufficiency (CRI) was compared with that of healthy subjects in one single-dose study and one multiple dose study. In the single-dose study, the exposure to desloratadine was approximately 2 and 2.5-fold greater in subjects with mild to moderate and severe CRI, respectively, than in healthy subjects. In the multiple-dose study, steady state was reached after Day 11, and compared to healthy subjects the exposure to desloratadine was ~1.5-fold greater in subjects with mild to moderate CRI and ~2.5-fold greater in subjects with severe CRI. In both studies, changes in exposure (AUC and Cmax) of desloratadine and 3-hydroxydesloratadine were not clinically relevant. 5.3 Preclinical safety data Desloratadine is the primary active metabolite of loratadine. Non-clinical studies conducted with desloratadine and loratadine demonstrated that there are no qualitative or quantitative differences in the toxicity profile of desloratadine and loratadine at comparable levels of exposure to desloratadine. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. The lack of carcinogenic potential was demonstrated in studies conducted with desloratadine and loratadine. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Microcrystalline cellulose Starch, pregelatinised Mannitol Talc Magnesium stearate Tablet coating: Hypromellose 6cP Titanium dioxide (E171) Macrogol 6000 Indigo carmine aluminum lake (E132) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage Blisters: This medicinal product does not require any special storage conditions. Bottles: 8 This medicinal product does not require any special temperature storage conditions. Keep the bottle tightly closed in order to protect from light. 6.5 Nature and contents of container OPA/Aluminium/PVC–Aluminium blisters. Pack sizes: 7, 10, 14, 20, 21, 30, 50, 90 and 100 tablets. Polyethylene bottles containing a desiccant and closed with a polyethylene cap. Pack sizes: 30 and 100 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. Reykjavíkurvegi 76-78 220 Hafnarfjörður Iceland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/11/745/001 EU/1/11/745/002 EU/1/11/745/003 EU/1/11/745/004 EU/1/11/745/005 EU/1/11/745/006 EU/1/11/745/007 EU/1/11/745/008 EU/1/11/745/009 EU/1/11/745/010 EU/1/11/745/011 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 13.01.2012 Date of latest renewal: 11.11.2016 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/ 9 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 10 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Actavis Ltd. BLB 016 Bulebel Industrial Estate Zejtun ZTN 3000 Malta or Balkanpharma-Dupnitsa AD 3 Samokovsko Shosse Str. 2600 Dupnitsa Bulgaria The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web- portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) Not applicable. 11 ANNEX III LABELLING AND PACKAGE LEAFLET 12 A. LABELLING 13 PARTICULARS TO APPEAR ON THE OUTER PACKAGING BLISTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Desloratadine Actavis 5 mg film-coated tablets desloratadine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 5 mg desloratadine. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 7 film-coated tablets 10 film-coated tablets 14 film-coated tablets 20 film-coated tablets 21 film-coated tablets 30 film-coated tablets 50 film-coated tablets 90 film-coated tablets 100 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Swallow the tablet whole with water. Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 14 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/11/745/001 7 film-coated tablets EU/1/11/745/002 10 film-coated tablets EU/1/11/745/003 14 film-coated tablets EU/1/11/745/004 20 film-coated tablets EU/1/11/745/005 21 film-coated tablets EU/1/11/745/006 30 film-coated tablets EU/1/11/745/007 50 film-coated tablets EU/1/11/745/008 90 film-coated tablets EU/1/11/745/009 100 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE desloratadine actavis 5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> <Not applicable.> 15 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA < PC: {number} SN: {number} NN: {number} > <Not applicable.> 16 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Desloratadine Actavis 5 mg tablets desloratadine 2. NAME OF THE MARKETING AUTHORISATION HOLDER [Actavis Group PTC ehf. Logo] 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 17 PARTICULARS TO APPEAR ON THE OUTER PACKAGING BOTTLE CARTON 1. NAME OF THE MEDICINAL PRODUCT Desloratadine Actavis 5 mg film-coated tablets desloratadine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 5 mg desloratadine. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 30 film-coated tablets 100 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Swallow the tablet whole with water. Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not swallow the desiccant. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Keep the bottle tightly closed in order to protect from light. 18 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/11/745/010 30 film-coated tablets EU/1/11/745/011 100 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE desloratadine actavis 5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> <Not applicable.> 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA < PC: {number} SN: {number} NN: {number} > <Not applicable.> 19 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Desloratadine Actavis 5 mg film-coated tablets desloratadine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 5 mg desloratadine. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 30 tablets 100 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Swallow the tablet whole with water. Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not swallow the desiccant. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Keep the bottle tightly closed in order to protect from light. 20 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [Actavis Group PTC ehf. Logo] 12. MARKETING AUTHORISATION NUMBER(S) EU/1/11/745/010 30 film-coated tablets EU/1/11/745/011 100 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 21 B. PACKAGE LEAFLET 22 Package leaflet: Information for the patient Desloratadine Actavis 5 mg film-coated tablets desloratadine Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Desloratadine Actavis is and what it is used for 2. What you need to know before you take Desloratadine Actavis 3. How to take Desloratadine Actavis 4. Possible side effects 5. How to store Desloratadine Actavis 6. Contents of the pack and other information 1. What Desloratadine Actavis is and what it is used for What Desloratadine Actavis is Desloratadine Actavis contains desloratadine which is an antihistamine. How Desloratadine Actavis works Desloratadine Actavis is an antiallergy medicine that does not make you drowsy. It helps control your allergic reaction and its symptoms. When Desloratadine Actavis should be used Desloratadine Actavis relieves symptoms associated with allergic rhinitis (inflammation of the nasal passages caused by an allergy, for example, hay fever or allergy to dust mites) in adults and adolescents 12 years of age and older. These symptoms include sneezing, runny or itchy nose, itchy palate, and itchy, red or watery eyes. Desloratadine Actavis is also used to relieve the symptoms associated with urticaria (a skin condition caused by an allergy). These symptoms include itching and hives. Relief of these symptoms lasts a full day and helps you to resume your normal daily activities and sleep. 2. What you need to know before you take Desloratadine Actavis Do not take Desloratadine Actavis: • if you are allergic to desloratadine, or any of the other ingredients of this medicine (listed in section 6) or to loratadine. Warnings and precautions Talk to your doctor, pharmacist or nurse before taking Desloratadine Actavis: • if you have poor kidney function. • if you have medical or familial history of seizures. 23 Use in children and adolescents Do not give this medicine to children less than 12 years of age. Other medicines and Desloratadine Actavis There are no known interactions of Desloratadine Actavis with other medicines. Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Desloratadine Actavis with food, drink and alcohol Desloratadine Actavis may be taken with or without a meal. Use caution when taking Desloratadine Actavis with alcohol. Pregnancy, breast-feeding and fertility If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Taking Desloratadine Actavis is not recommended if you are pregnant or nursing a baby. Fertility There is no data available on male/female fertility. Driving and using machines At the recommended dose, this medicine is not expected to affect your ability to drive or use machines. Although most people do not experience drowsiness, it is recommended not to engage in activities requiring mental alertness, such as driving a car or operating machinery until you have established your own response to the medicinal product. 3. How to take Desloratadine Actavis Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Adults and adolescents 12 years of age and over The recommended dose is one tablet once a day with water, with or without food. This medicine is for oral use. Swallow the tablet whole. Regarding the duration of treatment, your doctor will determine the type of allergic rhinitis you are suffering from and will determine for how long you should take Desloratadine Actavis. If your allergic rhinitis is intermittent (presence of symptoms for less than 4 days per week or for less than 4 weeks), your doctor will recommend you a treatment schedule that will depend on the evaluation of the history of your disease. If your allergic rhinitis is persistent (presence of symptoms for 4 days or more per week and for more than 4 weeks), your doctor may recommend you a longer term treatment. For urticaria, the duration of treatment may be variable from patient to patient and therefore you should follow the instructions of your doctor. If you take more Desloratadine Actavis than you should Take Desloratadine Actavis only as it is prescribed for you. No serious problems are expected with accidental overdose. However, if you take more Desloratadine Actavis than you were told to, tell your doctor, pharmacist or nurse immediately. If you forget to take Desloratadine Actavis If you forget to take your dose on time, take it as soon as possible and then go back to your regular dosing schedule. Do not take a double dose to make up for a forgotten dose. 24 If you stop taking Desloratadine Actavis If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. During the marketing of desloratadine, cases of severe allergic reactions (difficulty in breathing, wheezing, itching, hives and swelling) have been reported very rarely. If you notice any of these serious side effects, stop taking the medicine and seek urgent medical advice straight away. In clinical studies in adults, side effects were about the same as with a dummy tablet. However, fatigue, dry mouth and headache were reported more often than with a dummy tablet. In adolescents, headache was the most commonly reported side effect. In clinical studies with desloratadine, the following side effects were reported as: Common: the following may affect up to 1 in 10 people • fatigue • dry mouth • headache Adults During the marketing of desloratadine, the following side effects were reported as: Very rare: the following may affect up to 1 in 10,000 people • severe allergic reactions • rash • pounding or irregular heartbeat • fast heartbeat • stomach ache • feeling sick (nausea) • vomiting • upset stomach • diarrhoea • dizziness • drowsiness • inability to sleep • muscle pain • hallucinations • seizures • restlessness with increased body movement • liver inflammation • abnormal liver function tests Not known: frequency cannot be estimated from the available data • unusual weakness • yellowing of the skin and/or eyes • increased sensitivity of the skin to the sun, even in case of hazy sun, and to UV light, for instance to UV lights of a solarium • changes in the way the heart beats • abnormal behaviour • aggression ● weight increased ● increased appetite Children Not known: frequency cannot be estimated from the available data • slow heartbeat • abnormal behaviour • change in the way the heart beats • aggression Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 25 5. How to store Desloratadine Actavis Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton, bottle label and blister after ‘EXP’. The expiry date refers to the last day of that month. Blisters: This medicine does not require any special storage conditions. Bottles: This medicine does not require any special temperature storage conditions. Keep the bottle tightly closed in order to protect from light. Tell your pharmacist if you notice any change in the appearance of the tablets. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Desloratadine Actavis contains - The active substance is desloratadine. Each film-coated tablet (tablet) contains 5 mg desloratadine. - The other ingredients are: Tablet core: Microcrystalline cellulose, starch (pregelatinised), mannitol, talc, magnesium stearate. Tablet coating: Hypromellose 6cP, titanium dioxide (E171), macrogol 6000, indigo carmine aluminum lake (E132). What Desloratadine Actavis looks like and contents of the pack Blue coloured, round, with diameter of 6 mm, biconvex, film-coated tablets with the marking ‘LT’ engraved on one side. Desloratadine Actavis 5 mg film-coated tablets are packed in: Blister packs: 7, 10, 14, 20, 21, 30, 50, 90 or 100 tablets. Plastic bottles containing a desiccant and closed with a plastic cap: 30 or 100 tablets. Do not swallow the desiccant. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder Actavis Group PTC ehf. Reykjavíkurvegi 76-78 220 Hafnarfjörður Iceland Manufacturer Actavis Ltd. BLB 016 Bulebel Industrial Estate Zejtun ZTN 3000 Malta or 26 Balkanpharma-Dupnitsa AD 3 Samokovsko Shosse Str. 2600 Dupnitsa Bulgaria For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Aurobindo Pharma B.V. Nederland / Pays-Bas / Niederlande Tél/Tel: +31 (0)35 542 99 33 Lietuva UAB "Sicor Biotech" Tel: +370 5 266 0203 България Актавис ЕАД Teл.: +359 2 489 95 85 Luxembourg/Luxemburg Aurobindo Pharma B.V. Pays-Bas / Niederlande Tél/Tel: +31 (0)35 542 99 33 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: + 420 251 007 111 Magyarország Teva Gyógyszergyár Zrt. Tel.: +36 1 288 6400 Danmark Teva Denmark A/S Tlf: +45 44985511 Malta Actavis Ltd. Tel: +35621693533 Deutschland PUREN Pharma GmbH & Co. KG Telefon: +49 (0)89 558909 0 Nederland Aurobindo Pharma B.V. Tel: +31 (0)35 542 99 33 Eesti UAB "Sicor Biotech" Eesti filiaal Tel: +372 661 0801 Norge Teva Norway AS Tlf: +47 66 77 55 90 Ελλάδα Specifar ABEE Τηλ: +30 210 5401500 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43(0)1 97007 0 España Aurovitas Spain, S.A.U. Tfno.: +34 91 630 86 45 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel: +48 22 345 93 00 France Actavis Group PTC ehf. Islande Tél: +354 5503300 Portugal Actavis Group PTC ehf. Islândia Tel: +354 5503300 Hrvatska Pliva Hrvatska d.o.o. Tel: +385 1 37 20 000 România Teva Pharmaceuticals S.R.L Tel: +40 21 230 65 24 Ireland Actavis Ireland Limited Tel: +353 (0)21 4619040 Slovenija Pliva Ljubljana d.o.o. Tel: +386 1 58 90 390 27 Ísland Actavis Group PTC ehf. Sími: +354 550 3300 Slovenská republika TEVA Pharmaceuticals Slovakia s.r.o. Tel: +421 2 57 26 79 11 Italia Aurobindo Pharma (Italia) s.r.l. Tel: +39 0296392601 Suomi/Finland ratiopharm Oy Puh/Tel: +358 (0)20 180 5900 Κύπρος A. Potamitis Medicare Ltd Τηλ: +357 22583333 Sverige Teva Sweden AB Tel: +46 42 12 11 00 Latvija UAB "Sicor Biotech" filiāle Latvijā Tel: +371 673 23 666 United Kingdom Actavis UK Limited Tel: +44 1271 385257 This leaflet was last revised in MM/YYYY Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ Renally impaired patients The pharmacokinetics of desloratadine in patients with chronic renal insufficiency (CRI) was compared with that of healthy subjects in one single-dose study and one multiple dose study. In the single-dose study, the exposure to desloratadine was appro... Annex II A. manufacturer responsible for batch release B. Conditions or restrictions regarding supply and use C. Other conditions and requirements of the marketing authorisation D. conditions or restrictions with regard to the safe and effective use of the medicinal product ANNEX III LABELLING AND PACKAGE LEAFLET Keep out of the sight and reach of children. Keep out of the sight and reach of children. 1. NAME OF THE MEDICINAL PRODUCT 2. STATEMENT OF ACTIVE SUBSTANCE(S) 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 5. METHOD AND ROUTE(S) OF ADMINISTRATION 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE What is in this leaflet Not known: frequency cannot be estimated from the available data Reporting of side effects This leaflet was last revised in MM/YYYY

{'Title': '1. what desloratadine actavis is and what it is used for', 'Section_Content': 'what desloratadine actavis is desloratadine actavis contains desloratadine which is an antihistamine. how desloratadine actavis works desloratadine actavis is an antiallergy medicine that does not make you drowsy. it helps control your allergic reaction and its symptoms. when desloratadine actavis should be used desloratadine actavis relieves symptoms associated with allergic rhinitis (inflammation of the nasal passages caused by an allergy, for example, hay fever or allergy to dust mites) in adults and adolescents 12 years of age and older. these symptoms include sneezing, runny or itchy nose, itchy palate, and itchy, red or watery eyes. desloratadine actavis is also used to relieve the symptoms associated with urticaria (a skin condition caused by an allergy). these symptoms include itching and hives. relief of these symptoms lasts a full day and helps you to resume your normal daily activities 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'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4144614040851593}, {'Name': 'DIAGNOSIS', 'Score': 0.6284570693969727}]}, {'Text': 'your allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 231, 'EndOffset': 253}, {'Text': 'its symptoms', 'Type': 'PROBLEM', 'BeginOffset': 258, 'EndOffset': 270}, {'Text': 'desloratadine actavis', 'Type': 'TREATMENT', 'BeginOffset': 277, 'EndOffset': 298}, {'Text': 'desloratadine actavis', 'Type': 'TREATMENT', 'BeginOffset': 314, 'EndOffset': 335}, {'Text': 'symptoms', 'Type': 'PROBLEM', 'BeginOffset': 345, 'EndOffset': 353}, {'Id': 22, 'BeginOffset': 370, 'EndOffset': 387, 'Score': 0.9781147241592407, 'Text': 'allergic rhinitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9645227789878845}]}, {'Text': 'inflammation of the nasal passages', 'Type': 'PROBLEM', 'BeginOffset': 389, 'EndOffset': 423}, {'Text': 'an allergy', 'Type': 'PROBLEM', 'BeginOffset': 434, 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{'Title': '2. what you need to know before you take desloratadine actavis', 'Section_Content': 'do not take desloratadine actavis: if you are allergic to desloratadine, or any of the other ingredients of this medicine (listed in section 6) or to loratadine. warnings and precautions talk to your doctor, pharmacist or nurse before taking desloratadine actavis: if you have poor kidney function. if you have medical or familial history of seizures. use in children and adolescents do not give this medicine to children less than 12 years of age. other medicines and desloratadine actavis there are no known interactions of desloratadine actavis with other medicines. tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. desloratadine actavis with food, drink and alcohol desloratadine actavis may be taken with or without a meal. use caution when taking desloratadine actavis with alcohol. pregnancy, breast-feeding and fertility if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. taking desloratadine actavis is not recommended if you are pregnant or nursing a baby. fertility there is no data available on male/female fertility. driving and using machines at the recommended dose, this medicine is not expected to affect your ability to drive or use machines. although most people do not experience drowsiness, it is recommended not to engage in activities requiring mental alertness, such as driving a car or operating machinery until you have established your own response to the medicinal product.', 'Entity_Recognition': [{'Text': 'desloratadine actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 12, 'EndOffset': 33, 'Score': 0.66888028383255, 'Text': 'desloratadine actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 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{'Title': '3. how to take desloratadine actavis', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. adults and adolescents 12 years of age and over the recommended dose is one tablet once a day with water, with or without food. this medicine is for oral use. swallow the tablet whole. regarding the duration of treatment, your doctor will determine the type of allergic rhinitis you are suffering from and will determine for how long you should take desloratadine actavis. if your allergic rhinitis is intermittent (presence of symptoms for less than 4 days per week or for less than 4 weeks), your doctor will recommend you a treatment schedule that will depend on the evaluation of the history of your disease. if your allergic rhinitis is persistent (presence of symptoms for 4 days or more per week and for more than 4 weeks), your doctor may recommend you a longer term treatment. for urticaria, the duration of treatment may be variable from patient to patient and therefore you should follow the instructions of your doctor. if you take more desloratadine actavis than you should take desloratadine actavis only as it is prescribed for you. no serious problems are expected with accidental overdose. however, if you take more desloratadine actavis than you were told to, tell your doctor, pharmacist or nurse immediately. if you forget to take desloratadine actavis if you forget to take your dose on time, take it as soon as possible and then go back to your regular dosing schedule. do not take a double dose to make up for a forgotten dose. if you stop taking desloratadine actavis if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'desloratadine actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. during the marketing of desloratadine, cases of severe allergic reactions (difficulty in breathing, wheezing, itching, hives and swelling) have been reported very rarely. if you notice any of these serious side effects, stop taking the medicine and seek urgent medical advice straight away. in clinical studies in adults, side effects were about the same as with a dummy tablet. however, fatigue, dry mouth and headache were reported more often than with a dummy tablet. in adolescents, headache was the most commonly reported side effect. in clinical studies with desloratadine, the following side effects were reported as: common: the following may affect up to 1 in 10 people fatigue dry mouth headache adults during the marketing of desloratadine, the following side effects were reported as: very rare: the following may affect up to 1 in 10,000 people severe allergic reactions rash pounding or irregular heartbeat fast heartbeat stomach ache feeling sick (nausea) vomiting upset stomach diarrhoea dizziness drowsiness inability to sleep muscle pain hallucinations seizures restlessness with increased body movement liver inflammation abnormal liver function tests not known: frequency cannot be estimated from the available data unusual weakness yellowing of the skin and/or eyes increased sensitivity of the skin to the sun, even in case of hazy sun, and to uv light, for instance to uv lights of a solarium changes in the way the heart beats abnormal behaviour aggression weight increased increased appetite children not known: frequency cannot be estimated from the available data slow heartbeat abnormal behaviour change in the way the heart beats aggression reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also 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heartbeat fast heartbeat stomach ache feeling sick (nausea)', 'Type': 'PROBLEM', 'BeginOffset': 993, 'EndOffset': 1062}, {'Text': 'vomiting upset', 'Type': 'PROBLEM', 'BeginOffset': 1063, 'EndOffset': 1077}, {'Id': 46, 'BeginOffset': 1078, 'EndOffset': 1095, 'Score': 0.5758917927742004, 'Text': 'stomach diarrhoea', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9858982563018799}]}, {'Id': 47, 'BeginOffset': 1096, 'EndOffset': 1105, 'Score': 0.9966269731521606, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9922711849212646}]}, {'Id': 48, 'BeginOffset': 1106, 'EndOffset': 1116, 'Score': 0.9971911311149597, 'Text': 'drowsiness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9936133027076721}]}, {'Id': 49, 'BeginOffset': 1117, 'EndOffset': 1135, 'Score': 0.9883964657783508, 'Text': 'inability to sleep', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.40055394172668457}]}, {'Id': 50, 'BeginOffset': 1136, 'EndOffset': 1147, 'Score': 0.8080966472625732, 'Text': 'muscle pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9864659905433655}]}, {'Id': 51, 'BeginOffset': 1148, 'EndOffset': 1162, 'Score': 0.9899835586547852, 'Text': 'hallucinations', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.994390070438385}]}, {'Text': 'seizures restlessness', 'Type': 'PROBLEM', 'BeginOffset': 1163, 'EndOffset': 1184}, {'Text': 'increased body movement liver inflammation', 'Type': 'PROBLEM', 'BeginOffset': 1190, 'EndOffset': 1232}, {'Text': 'abnormal liver function tests', 'Type': 'PROBLEM', 'BeginOffset': 1233, 'EndOffset': 1262}, {'Id': 57, 'BeginOffset': 1274, 'EndOffset': 1283, 'Score': 0.47979679703712463, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6147719025611877}]}, {'Text': 'unusual weakness', 'Type': 'PROBLEM', 'BeginOffset': 1328, 'EndOffset': 1344}, {'Id': 59, 'BeginOffset': 1345, 'EndOffset': 1366, 'Score': 0.5526999831199646, 'Text': 'yellowing of the skin', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.819837749004364}]}, {'Id': 9, 'BeginOffset': 1374, 'EndOffset': 1378, 'Score': 0.9782657027244568, 'Text': 'eyes', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 60, 'BeginOffset': 1389, 'EndOffset': 1400, 'Score': 0.8097120523452759, 'Text': 'sensitivity', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.845666229724884}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9782657027244568, 'RelationshipScore': 0.6191238164901733, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 9, 'BeginOffset': 1374, 'EndOffset': 1378, 'Text': 'eyes', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9759719967842102, 'RelationshipScore': 0.9960720539093018, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 10, 'BeginOffset': 1408, 'EndOffset': 1412, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 10, 'BeginOffset': 1408, 'EndOffset': 1412, 'Score': 0.9759719967842102, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a solarium changes', 'Type': 'PROBLEM', 'BeginOffset': 1497, 'EndOffset': 1515}, {'Id': 11, 'BeginOffset': 1531, 'EndOffset': 1536, 'Score': 0.9571741223335266, 'Text': 'heart', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'abnormal behaviour aggression weight increased increased appetite', 'Type': 'PROBLEM', 'BeginOffset': 1543, 'EndOffset': 1608}, {'Id': 65, 'BeginOffset': 1629, 'EndOffset': 1638, 'Score': 0.407930463552475, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4320846199989319}]}, {'Text': 'slow heartbeat abnormal behaviour change', 'Type': 'PROBLEM', 'BeginOffset': 1683, 'EndOffset': 1723}, {'Id': 12, 'BeginOffset': 1739, 'EndOffset': 1744, 'Score': 0.9470056295394897, 'Text': 'heart', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 67, 'BeginOffset': 1775, 'EndOffset': 1787, 'Score': 0.8277244567871094, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8345432281494141}]}, {'Id': 68, 'BeginOffset': 1803, 'EndOffset': 1815, 'Score': 0.8968055844306946, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8196201920509338}]}, {'Id': 69, 'BeginOffset': 1886, 'EndOffset': 1898, 'Score': 0.9478719234466553, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6958472728729248}]}, {'Id': 70, 'BeginOffset': 1947, 'EndOffset': 1959, 'Score': 0.8486847281455994, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7041770815849304}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.5319876670837402, 'RelationshipScore': 0.8773566484451294, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 13, 'BeginOffset': 2013, 'EndOffset': 2021, 'Text': 'appendix', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 13, 'BeginOffset': 2013, 'EndOffset': 2021, 'Score': 0.5319876670837402, 'Text': 'appendix', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 71, 'BeginOffset': 2038, 'EndOffset': 2050, 'Score': 0.7703260183334351, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.744745135307312}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2106, 'EndOffset': 2119}]}

{'Title': '5. how to store desloratadine actavis', 'Section_Content': "keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton, bottle label and blister after 'exp'. the expiry date refers to the last day of that month. blisters: this medicine does not require any special storage conditions. bottles: this medicine does not require any special temperature storage conditions. keep the bottle tightly closed in order to protect from light. tell your pharmacist if you notice any change in the appearance of the tablets. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.", 'Entity_Recognition': [{'Text': 'desloratadine actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Id': 0, 'BeginOffset': 229, 'EndOffset': 237, 'Score': 0.7575451731681824, 'Text': 'blisters', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'the bottle', 'Type': 'TREATMENT', 'BeginOffset': 391, 'EndOffset': 401}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what desloratadine actavis contains - the active substance is desloratadine. each film-coated tablet (tablet) contains 5 mg desloratadine. - the other ingredients are: tablet core: microcrystalline cellulose, starch (pregelatinised), mannitol, talc, magnesium stearate. tablet coating: hypromellose 6cp, titanium dioxide (e171), macrogol 6000, indigo carmine aluminum lake (e132). what desloratadine actavis looks like and contents of the pack blue coloured, round, with diameter of 6 mm, biconvex, film-coated tablets with the marking 'lt' engraved on one side. desloratadine actavis 5 mg film-coated tablets are packed in: blister packs: 7, 10, 14, 20, 21, 30, 50, 90 or 100 tablets. plastic bottles containing a desiccant and closed with a plastic cap: 30 or 100 tablets. do not swallow the desiccant. not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'desloratadine actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'what desloratadine actavis', 'Type': 'PROBLEM', 'BeginOffset': 0, 'EndOffset': 26}, {'Id': 1, 'BeginOffset': 62, 'EndOffset': 75, 'Score': 0.987464427947998, 'Text': 'desloratadine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.7559962868690491, 'RelationshipScore': 0.9975464940071106, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 94, 'EndOffset': 100, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9441123604774475, 'RelationshipScore': 0.9659997820854187, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 102, 'EndOffset': 108, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9862577319145203, 'RelationshipScore': 0.962182343006134, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 119, 'EndOffset': 123, 'Text': '5 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each film-coated tablet (tablet)', 'Type': 'TREATMENT', 'BeginOffset': 77, 'EndOffset': 109}, {'Text': '5 mg desloratadine', 'Type': 'TREATMENT', 'BeginOffset': 119, 'EndOffset': 137}, {'Id': 6, 'BeginOffset': 181, 'EndOffset': 207, 'Score': 0.9959355592727661, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9862577319145203, 'RelationshipScore': 0.9934505224227905, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 119, 'EndOffset': 123, 'Text': '5 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'starch (pregelatinised)', 'Type': 'TREATMENT', 'BeginOffset': 209, 'EndOffset': 232}, {'Id': 8, 'BeginOffset': 234, 'EndOffset': 242, 'Score': 0.7609659433364868, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'talc', 'Type': 'TREATMENT', 'BeginOffset': 244, 'EndOffset': 248}, {'Id': 9, 'BeginOffset': 250, 'EndOffset': 268, 'Score': 0.9872876405715942, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8723644018173218, 'RelationshipScore': 0.9986475110054016, 'RelationshipType': 'FORM', 'Id': 10, 'BeginOffset': 270, 'EndOffset': 276, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 11, 'BeginOffset': 286, 'EndOffset': 298, 'Score': 0.7487548589706421, 'Text': 'hypromellose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.36225008964538574, 'RelationshipScore': 0.9987210631370544, 'RelationshipType': 'DOSAGE', 'Id': 12, 'BeginOffset': 299, 'EndOffset': 302, 'Text': '6cp', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 13, 'BeginOffset': 304, 'EndOffset': 320, 'Score': 0.9972469806671143, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 329, 'EndOffset': 337, 'Score': 0.5521581172943115, 'Text': 'macrogol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '6000', 'Type': 'NUMBER', 'BeginOffset': 338, 'EndOffset': 342}, {'Text': 'indigo carmine aluminum lake', 'Type': 'TREATMENT', 'BeginOffset': 344, 'EndOffset': 372}, {'Text': 'what desloratadine actavis', 'Type': 'PROBLEM', 'BeginOffset': 381, 'EndOffset': 407}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 483, 'EndOffset': 484}, {'Text': 'biconvex, film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 489, 'EndOffset': 518}, {'Id': 18, 'BeginOffset': 563, 'EndOffset': 584, 'Score': 0.9599899053573608, 'Text': 'desloratadine actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.9650241136550903, 'RelationshipScore': 0.9943434000015259, 'RelationshipType': 'STRENGTH', 'Id': 19, 'BeginOffset': 585, 'EndOffset': 589, 'Text': '5 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7002227306365967, 'RelationshipScore': 0.9994513392448425, 'RelationshipType': 'FORM', 'Id': 20, 'BeginOffset': 590, 'EndOffset': 594, 'Text': 'film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.702692985534668, 'RelationshipScore': 0.9996758699417114, 'RelationshipType': 'FORM', 'Id': 21, 'BeginOffset': 595, 'EndOffset': 609, 'Text': 'coated tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 585, 'EndOffset': 586}, {'Text': 'film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 590, 'EndOffset': 609}, {'Text': '7', 'Type': 'NUMBER', 'BeginOffset': 640, 'EndOffset': 641}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 643, 'EndOffset': 645}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 647, 'EndOffset': 649}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 651, 'EndOffset': 653}, {'Text': '21', 'Type': 'NUMBER', 'BeginOffset': 655, 'EndOffset': 657}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 659, 'EndOffset': 661}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 663, 'EndOffset': 665}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 667, 'EndOffset': 669}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 673, 'EndOffset': 676}, {'Text': 'plastic bottles', 'Type': 'TREATMENT', 'BeginOffset': 686, 'EndOffset': 701}, {'Text': 'a plastic cap', 'Type': 'TREATMENT', 'BeginOffset': 741, 'EndOffset': 754}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 756, 'EndOffset': 758}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 762, 'EndOffset': 765}]}

63D135067B8CEA205B852322BF670E5D

https://www.ema.europa.eu/documents/product-information/atectura-breezhaler-epar-product-information_en.pdf

Atectura Breezhaler

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules Each capsule contains 150 mcg of indacaterol (as acetate) and 80 mcg of mometasone furoate. Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 125 mcg of indacaterol (as acetate) and 62.5 mcg of mometasone furoate. Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules Each capsule contains 150 mcg of indacaterol (as acetate) and 160 mcg of mometasone furoate. Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 125 mcg of indacaterol (as acetate) and 127.5 mcg of mometasone furoate. Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules Each capsule contains 150 mcg of indacaterol (as acetate) and 320 mcg of mometasone furoate. Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 125 mcg of indacaterol (as acetate) and 260 mcg of mometasone furoate. Excipient(s) with known effect Each capsule contains approximately 25 mg of lactose monohydrate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Inhalation powder, hard capsule (inhalation powder). Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules Transparent (uncoloured) capsules containing a white powder, with the product code “IM150-80” printed in blue above one blue bar on the body and with the product logo printed in blue and surrounded by two blue bars on the cap. Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules Transparent (uncoloured) capsules containing a white powder, with the product code “IM150-160” printed in grey on the body and with the product logo printed in grey on the cap. Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules Transparent (uncoloured) capsules containing a white powder, with the product code “IM150-320” printed in black above two black bars on the body and with the product logo printed in black and surrounded by two black bars on the cap. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Atectura Breezhaler is indicated as a maintenance treatment of asthma in adults and adolescents 12 years of age and older not adequately controlled with inhaled corticosteroids and inhaled short-acting beta2-agonists. 4.2 Posology and method of administration Posology Adults and adolescents aged 12 years and over The recommended dose is one capsule to be inhaled once daily. Patients should be given the strength containing the appropriate mometasone furoate dosage for the severity of their disease and should be regularly reassessed by a healthcare professional. The maximum recommended dose is 125 mcg/260 mcg once daily. Treatment should be administered at the same time of the day each day. It can be administered irrespective of the time of the day. If a dose is missed, it should be taken as soon as possible. Patients should be instructed not to take more than one dose in a day. Special populations Elderly population No dose adjustment is required in elderly patients (65 years of age or older) (see section 5.2). Renal impairment No dose adjustment is required in patients with renal impairment (see section 5.2). Hepatic impairment No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available for the use of the medicinal product in patients with severe hepatic impairment, therefore it should be used in these patients only if the expected benefit outweighs the potential risk (see section 5.2). Paediatric population The posology in patients 12 years of age and older is the same posology as in adults. The safety and efficacy in paediatric patients below 12 years of age have not been established. No data are available. Method of administration For inhalation use only. The capsules must not be swallowed. The capsules must be administered only using the inhaler provided (see section 6.6) with each new prescription. Patients should be instructed on how to administer the medicinal product correctly. Patients who do not experience improvement in breathing should be asked if they are swallowing the medicinal product rather than inhaling it. 4 The capsules must only be removed from the blister immediately before use. After inhalation, patients should rinse their mouth with water without swallowing (see sections 4.4 and 6.6). For instructions on use of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Deterioration of disease This medicinal product should not be used to treat acute asthma symptoms, including acute episodes of bronchospasm, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician. Patients should not stop treatment without physician supervision since symptoms may recur after discontinuation. It is recommended that treatment with this medicinal product should not be stopped abruptly. If patients find the treatment ineffective, they should continue treatment but must seek medical attention. Increasing use of reliever bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy. Sudden and progressive deterioration in the symptoms of asthma is potentially life-threatening and the patient should undergo urgent medical assessment. Hypersensitivity Immediate hypersensitivity reactions have been observed after administration of this medicinal product. If signs suggesting allergic reactions occur, in particular angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips and face), urticaria or skin rash, treatment should be discontinued immediately and alternative therapy instituted. Paradoxical bronchospasm As with other inhalation therapy, administration of this medicinal product may result in paradoxical bronchospasm, which can be life-threatening. If this occurs, treatment should be discontinued immediately and alternative therapy instituted. Cardiovascular effects of beta agonists Like other medicinal products containing beta2-adrenergic agonists, this medicinal product may produce a clinically significant cardiovascular effect in some patients, as measured by increases in pulse rate, blood pressure and/or symptoms. If such effects occur, treatment may need to be discontinued. This medicinal product should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists. 5 Patients with unstable ischaemic heart disease, a history of myocardial infarction in last 12 months, New York Heart Association (NYHA) class III/IV left ventricular failure, arrhythmia, uncontrolled hypertension, cerebrovascular disease or history of long QT syndrome and patients being treated with medicinal products known to prolong QTc were excluded from studies in the indacaterol/mometasone furoate clinical development programme. Thus safety outcomes in these populations are considered unknown. While beta2-adrenergic agonists have been reported to produce electrocardiographic (ECG) changes, such as flattening of the T wave, prolongation of QT interval and ST segment depression, the clinical significance of these observations is unknown. Long-acting beta2-adrenergic agonists (LABA) or LABA-containing combination products such as Atectura Breezhaler should therefore be used with caution in patients with known or suspected prolongation of the QT interval or who are being treated with medicinal products affecting the QT interval. Hypokalaemia with beta agonists Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe asthma hypokalaemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility to cardiac arrhythmias (see section 4.5). Clinically relevant hypokalaemia has not been observed in clinical studies of indacaterol/mometasone furoate at the recommended therapeutic dose. Hyperglycaemia Inhalation of high doses of beta2-adrenergic agonists and corticosteroids may produce increases in plasma glucose. Upon initiation of treatment, plasma glucose should be monitored more closely in diabetic patients. This medicinal product has not been investigated in patients with Type I diabetes mellitus or uncontrolled Type II diabetes mellitus. Prevention of oropharyngeal infections In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse their mouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribed dose. Systemic effects of corticosteroids Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Possible systemic effects may include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataracts, glaucoma, and, more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is therefore important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained. 6 Visual disturbance may be reported with systemic and topical (including intranasal, inhaled and intraocular) corticosteroid use. Patients presenting with symptoms such as blurred vision or other visual disturbances should be considered for referral to an ophthalmologist for evaluation of possible causes of visual disturbances, which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. This medicinal product should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections. Excipients This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction No specific interaction studies were conducted with indacaterol/mometasone furoate. Information on the potential for interactions is based on the potential for each of the monotherapy components. Medicinal products known to prolong the QTc interval Like other medicinal products containing a beta2-adrenergic agonist, this medicinal product should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants or medicinal products known to prolong the QT interval, as any effect of these on the QT interval may be potentiated. Medicinal products known to prolong the QT interval may increase the risk of ventricular arrhythmia (see sections 4.4 and 5.1). Hypokalaemic treatment Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists (see section 4.4). Beta-adrenergic blockers Beta-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Therefore, this medicinal product should not be given together with beta-adrenergic blockers unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution. Interaction with CYP3A4 and P-glycoprotein inhibitors Inhibition of CYP3A4 and P-glycoprotein (P-gp) has no impact on the safety of therapeutic doses of Atectura Breezhaler. Inhibition of the key contributors of indacaterol clearance (CYP3A4 and P-gp) or mometasone furoate clearance (CYP3A4) raises the systemic exposure of indacaterol or mometasone furoate up to two-fold. Due to the very low plasma concentration achieved after inhaled dosing, clinically significant interactions with mometasone furoate are unlikely. However, there may be a potential for increased systemic exposure to mometasone furoate when strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, nelfinavir, ritonavir, cobicistat) are co-administered. 7 Other long-acting beta2-adrenergic agonists The co-administration of this medicinal product with other medicinal products containing long-acting beta2-adrenergic agonists has not been studied and is not recommended as it may potentiate adverse reactions (see sections 4.8 and 4.9). 4.6 Fertility, pregnancy and lactation Pregnancy There are insufficient data from the use of Atectura Breezhaler or its individual components (indacaterol and mometasone furoate) in pregnant women to determine whether there is a risk. Indacaterol was not teratogenic in rats and rabbits following subcutaneous administration (see section 5.3). In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoate caused increased foetal malformations and decreased foetal survival and growth. Like other medicinal products containing beta2-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle. This medicinal product should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus. Breast-feeding There is no information available on the presence of indacaterol or mometasone furoate in human milk, on the effects on a breast-fed infant, or on the effects on milk production. Other inhaled corticosteroids similar to mometasone furoate are transferred into human milk. Indacaterol (including its metabolites) and mometasone furoate have been detected in the milk of lactating rats. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Reproduction studies and other data in animals did not indicate a concern regarding fertility in either males or females. 4.7 Effects on ability to drive and use machines This medicinal product has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most common adverse reactions over 52 weeks were asthma (exacerbation) (26.9%), nasopharyngitis (12.9%), upper respiratory tract infection (5.9%) and headache (5.8%). 8 Tabulated list of adverse reactions Adverse drug reactions (ADRs) are listed by MedDRA system organ class (Table 1). The frequency of the ADRs is based on the PALLADIUM study. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Table 1 Adverse reactions System organ class Adverse reactions Frequency category Infections and infestations Nasopharyngitis Very common Upper respiratory tract infection Common Candidiasis*1 Uncommon Immune system disorders Hypersensitivity*2 Common Angioedema*3 Uncommon Metabolism and nutrition disorders Hyperglycaemia*4 Uncommon Nervous system disorders Headache*5 Common Eye disorders Vision blurred Uncommon Cataract*6 Uncommon Cardiac disorders Tachycardia*7 Uncommon Respiratory, thoracic and mediastinal disorders Asthma (exacerbation) Very common Oropharyngeal pain*8 Common Dysphonia Common Skin and subcutaneous tissue disorders Rash*9 Uncommon Pruritus*10 Uncommon Musculoskeletal and connective tissue disorders Musculoskeletal pain*11 Common Muscle spasms Uncommon * Indicates grouping of preferred terms (PTs): 1 Oral candidiasis, oropharyngeal candidiasis. 2 Drug eruption, drug hypersensitivity, hypersensitivity, rash, rash erythematous, rash pruritic, urticaria. 3 Allergic oedema, angioedema, periorbital swelling, swelling of eyelid. 4 Blood glucose increased, hyperglycaemia. 5 Headache, tension headache. 6 Cataract, cataract cortical. 7 Heart rate increased, tachycardia, sinus tachycardia, supraventricular tachycardia. 8 Oral pain, oropharyngeal discomfort, oropharyngeal pain, throat irritation, odynophagia. 9 Drug eruption, rash, rash erythematous, rash pruritic. 10 Anal pruritus, eye pruritus, nasal pruritus, pruritus, pruritus genital. 11 Back pain, musculoskeletal pain, myalgia, neck pain, musculoskeletal chest pain. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 4.9 Overdose General supportive measures and symptomatic treatment should be initiated in cases of suspected overdose. An overdose will likely produce signs, symptoms or adverse effects associated with the pharmacological actions of the individual components (e.g. tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia, suppression of hypothalamic pituitary adrenal axis function). Use of cardioselective beta blockers may be considered for treating beta2-adrenergic effects, but only under the supervision of a physician and with extreme caution, since the use of beta2-adrenergic blockers may provoke bronchospasm. In serious cases, patients should be hospitalised. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with corticosteroids or other drugs, excl. anticholinergics, ATC code: R03AK14 Mechanism of action This medicinal product is a combination of indacaterol, a long-acting beta2-adrenergic agonist (LABA), and mometasone furoate, an inhaled synthetic corticosteroid (ICS). Indacaterol The pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in part attributable to increased cyclic-3’, 5’-adenosine monophosphate (cyclic AMP) levels, which cause relaxation of bronchial smooth muscle. When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonist at the human beta2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action. Although beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the human heart, there are also beta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors. Mometasone furoate Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory properties. In vitro, mometasone furoate inhibits the release of leukotrienes from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of leukotriene production and of the production of the Th2 cytokines IL-4 and IL-5 from human CD4+ T-cells. 10 Pharmacodynamic effects The pharmacodynamic response profile of this medicinal product is characterised by rapid onset of action within 5 minutes after dosing and sustained effect over the 24-hour dosing interval, as evidenced by improvements in trough forced expiratory volume in the first second (FEV1) improvements versus comparators 24 hours after dosing. No tachyphylaxis to the lung function benefits of this medicinal product was observed over time. QTc interval The effect of this medicinal product on the QTc interval has not been evaluated in a thorough QT (TQT) study. For mometasone furoate, no QTc-prolonging properties are known. Clinical efficacy and safety Two phase III randomised, double-blind studies (PALLADIUM and QUARTZ) of different durations evaluated the safety and efficacy of Atectura Breezhaler in adult and adolescent patients with persistent asthma. The PALLADIUM study was a 52-week pivotal study evaluating Atectura Breezhaler 125 mcg/127.5 mcg once daily (N=439) and 125 mcg/260 mcg once daily (N=445) compared to mometasone furoate 400 mcg once daily (N=444) and 800 mcg per day (given as 400 mcg twice daily) (N=442), respectively. A third active control arm included subjects treated with salmeterol/fluticasone propionate 50 mcg/500 mcg twice daily (N=446). All subjects were required to have symptomatic asthma (ACQ-7 score ≥1.5) and were on asthma maintenance therapy using an inhaled synthetic corticosteroid (ICS) with or without LABA for at least 3 months prior to study entry. At screening, 31% of patients had history of exacerbation in the previous year. At study entry, the most common asthma medications reported were medium dose of ICS (20%), high dose of ICS (7%) or low dose of ICS in combination with a LABA (69%). The primary objective of the study was to demonstrate superiority of either Atectura Breezhaler 125 mcg/127.5 mcg once daily over mometasone furoate 400 mcg once daily or Atectura Breezhaler 125 mcg/260 mcg once daily over mometasone furoate 400 mcg twice daily in terms of trough FEV1 at week 26. At week 26, Atectura Breezhaler 125 mcg/127.5 mcg and 125 mcg/260 mcg once daily both demonstrated statistically significant improvements in trough FEV1 and Asthma Control Questionnaire (ACQ-7) score compared to mometasone furoate 400 mcg once or twice daily, respectively (see Table 2). Findings at week 52 were consistent with week 26. Atectura Breezhaler 125 mcg/127.5 mcg and 125 mcg/260 mcg once daily both demonstrated a clinically meaningful reduction in the annual rate of moderate or severe exacerbations (secondary endpoint), compared to mometasone furoate 400 mcg once and twice daily (see Table 2). Results for the most clinically relevant endpoints are described in Table 2. 11 Lung function, symptoms and exacerbations Table 2 Results of primary and secondary endpoints in PALLADIUM study at weeks 26 and 52 Endpoint Time point/ Duration Atectura Breezhaler1 vs MF2 Atectura Breezhaler1 vs SAL/FP3 Medium dose vs medium dose High dose vs high dose High dose vs high dose Lung function Trough FEV14 Treatment difference P value (95% CI) Week 26 (primary endpoint) 211 ml <0.001 (167, 255) 132 ml <0.001 (88, 176) 36 ml 0.101 (-7, 80) Week 52 209 ml <0.001 (163, 255) 136 ml <0.001 (90, 183) 48 ml 0.040 (2, 94) Mean morning peak expiratory flow (PEF)* Treatment difference (95% CI) Week 52 30.2 l/min (24.2, 36.3) 28.7 l/min (22.7, 34.8) 13.8 l/min (7.7, 19.8) Mean evening peak expiratory flow (PEF)* Treatment difference (95% CI) Week 52 29.1 l/min (23.3, 34.8) 23.7 l/min (18.0, 29.5) 9.1 l/min (3.3, 14.9) Symptoms ACQ-7 Treatment difference P value (95% CI) Week 26 (key secondary endpoint) -0.248 <0.001 (-0.334, -0.162) -0.171 <0.001 (-0.257, -0.086) -0.054 0.214 (-0.140, 0.031) Week 52 -0.266 (-0.354, -0.177) -0.141 (-0.229, -0.053) 0.010 (-0.078, 0.098) ACQ responders (percentage of patients achieving minimal clinical important difference (MCID) from baseline with ACQ ≥0.5) Percentage Week 26 76% vs 67% 76% vs 72% 76% vs 76% Odds ratio (95% CI) Week 26 1.73 (1.26, 2.37) 1.31 (0.95, 1.81) 1.06 (0.76, 1.46) Percentage Week 52 82% vs 69% 78% vs 74% 78% vs 77% Odds ratio (95% CI) Week 52 2.24 (1.58, 3.17) 1.34 (0.96, 1.87) 1.05 (0.75, 1.49) Percentage of rescue medication free days* Treatment difference (95% CI) Week 52 8.6 (4.7, 12.6) 9.6 (5.7, 13.6) 4.3 (0.3, 8.3) Percentage of days with no symptoms* Treatment difference (95% CI) Week 52 9.1 (4.6, 13.6) 5.8 (1.3, 10.2) 3.4 (-1.1, 7.9) 12 Annualised rate of asthma exacerbations** Moderate or severe exacerbations AR Week 52 0.27 vs 0.56 0.25 vs 0.39 0.25 vs 0.27 RR (95% CI) Week 52 0.47 (0.35, 0.64) 0.65 (0.48, 0.89) 0.93 (0.67, 1.29) Severe exacerbations AR Week 52 0.13 vs 0.29 0.13 vs 0.18 0.13 vs 0.14 RR (95% CI) Week 52 0.46 (0.31, 0.67) 0.71 (0.47, 1.08) 0.89 (0.58, 1.37) * Mean value for the treatment duration ** RR <1.00 favours indacaterol/mometasone furoate. 1 Atectura Breezhaler medium dose: 125 mcg/127.5 mcg od; high dose: 125 mcg/260 mcg od. 2 MF: mometasone furoate medium dose: 400 mcg od; high dose: 400 mcg bid (content doses). Mometasone furoate 127.5 mcg od and 260 mcg od in Atectura Breezhaler are comparable to mometasone furoate 400 mcg od and 800 mcg per day (given as 400 mcg bid). 3 SAL/FP: salmeterol/fluticasone propionate high dose: 50 mcg/500 mcg bid (content dose). 4 Trough FEV1: the mean of the two FEV1 values measured at 23 hours 15 min and 23 hours 45 min after the evening dose. Primary endpoint (trough FEV1 at week 26) and key secondary endpoint (ACQ-7 score at week 26) were part of confirmatory testing strategy and thus controlled for multiplicity. All other endpoints were not part of confirmatory testing strategy. RR = rate ratio, AR = annualised rate od = once daily, bid = twice daily 13 Pre-specified pooled analysis Atectura Breezhaler 125 mcg/260 mcg once daily was also studied as an active comparator in another phase III study (IRIDIUM) in which all subjects had a history of asthma exacerbation requiring systemic corticosteroids in the past year. A pre-specified pooled analysis across the IRIDIUM and PALLADIUM studies was conducted to compare Atectura Breezhaler 125 mcg/260 mcg once daily to salmeterol/fluticasone 50 mcg/500 mcg twice daily for the endpoints of trough FEV1 and ACQ-7 at week 26 and annualised rate of exacerbations. The pooled analysis demonstrated that Atectura Breezhaler improved trough FEV1 by 43 ml (95% CI: 17, 69) and ACQ-7 score by -0.091 (95% CI: -0.153, -0.030) at week 26 and reduced the annualised rate of moderate or severe asthma exacerbations by 22% (RR: 0.78; 95% CI: 0.66, 0.93) and of severe exacerbations by 26% (RR: 0.74; 95% CI: 0.61, 0.91) versus salmeterol/fluticasone. The QUARTZ study was a 12-week study evaluating Atectura Breezhaler 125 mcg/62.5 mcg once daily (N=398) compared to mometasone furoate 200 mcg once daily (N=404). All subjects were required to be symptomatic and on asthma maintenance therapy using a low-dose ICS (with or without LABA) for at least 1 month prior to study entry. At study entry, the most common asthma medications reported were low-dose ICS (43%) and LABA/low-dose ICS (56%). The primary endpoint of the study was to demonstrate superiority of Atectura Breezhaler 125 mcg/62.5 mcg once daily over mometasone furoate 200 mcg once daily in terms of trough FEV1 at week 12. Atectura Breezhaler 125 mcg/62.5 mcg once daily demonstrated a statistically significant improvement in baseline trough FEV1 at week 12 and Asthma Control Questionnaire (ACQ-7) score compared to mometasone furoate 200 mcg once daily. Results for the most clinically relevant endpoints are described in Table 3. 14 Table 3 Results of primary and secondary endpoints in QUARTZ study at week 12 Endpoints Atectura Breezhaler low dose* vs MF low dose** Lung function Trough FEV1 (primary endpoint)*** Treatment difference P value (95% CI) 182 ml <0.001 (148, 217) Mean morning peak expiratory flow (PEF) Treatment difference (95% CI) 27.2 l/min (22.1, 32.4) Evening peak expiratory flow (PEF) Treatment difference (95% CI) 26.1 l/min (21.0, 31.2) Symptoms ACQ-7 (key secondary endpoint) Treatment difference P value (95% CI) -0.218 <0.001 (-0.293, -0.143) Percentage of patients achieving MCID from baseline with ACQ ≥0.5 Percentage Odds ratio (95% CI) 75% vs 65% 1.69 (1.23, 2.33) Percentage of rescue medication free days Treatment difference (95% CI) 8.1 (4.3, 11.8) Percentage of days with no symptoms Treatment difference (95% CI) 2.7 (-1.0, 6.4) * Atectura Breezhaler low dose: 125/62.5 mcg od. ** MF: mometasone furoate low dose: 200 mcg od (content dose). Mometasone furoate 62.5 mcg in Atectura Breezhaler od is comparable to mometasone furoate 200 mcg od (content dose). *** Trough FEV1: the mean of the two FEV1 values measured at 23 hours 15 min and 23 hours 45 min after the evening dose. od = once daily, bid = twice daily 15 Paediatric population In the PALLADIUM study, which included 106 adolescents (12-17 years old), the improvements in trough FEV1 at week 26 were 0.173 litres (95% CI: -0.021, 0.368) for Atectura Breezhaler 125 mcg/260 mcg once daily vs mometasone furoate 800 mcg (i.e. high doses) and 0.397 litres (95% CI: 0.195, 0.599) for Atectura Breezhaler 125 mcg/127.5 mcg once daily vs mometasone furoate 400 mcg once daily (i.e. medium doses). In the QUARTZ study, which included 63 adolescents (12-17 years old), the Least Square means treatment difference for trough FEV1 at day 85 (week 12) was 0.251 litres (95% CI: 0.130, 0.371). For the adolescent subgroups, improvements in lung function, symptoms and exacerbation reductions were consistent with the overall population. The European Medicines Agency has deferred the obligation to submit the results of studies with indacaterol/mometasone furoate in one or more subsets of the paediatric population in asthma (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Following inhalation of Atectura Breezhaler, the median time to reach peak plasma concentrations of indacaterol and mometasone furoate was approximately 15 minutes and 1 hour, respectively. Based on the in vitro performance data, the dose of each of the monotherapy components delivered to the lung is expected to be similar for the indacaterol/mometasone furoate combination and the monotherapy products. Steady-state plasma exposure to indacaterol and mometasone furoate after inhalation of the combination was similar to the systemic exposure after inhalation of indacaterol maleate or mometasone furoate as monotherapy products. Following inhalation of the combination, the absolute bioavailability was estimated to be about 45% for indacaterol and less than 10% for mometasone furoate. Indacaterol Indacaterol concentrations increased with repeated once-daily administration. Steady state was achieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-h dosing interval on day 14 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 60 and 480 mcg (delivered dose). Systemic exposure results from a composite of pulmonary and gastrointestinal absorption; about 75% of systemic exposure was from pulmonary absorption and about 25% from gastrointestinal absorption. Mometasone furoate Mometasone furoate concentrations increased with repeated once-daily administration via the Breezhaler inhaler. Steady state was achieved after 12 days. The mean accumulation ratio of mometasone furoate, i.e. AUC over the 24-h dosing interval on day 14 compared to day 1, was in the range of 1.61 to 1.71 for once-daily inhaled doses between 62.5 and 260 mcg as part of the indacaterol/mometasone furoate combination. Following oral administration of mometasone furoate, the absolute oral systemic bioavailability of mometasone furoate was estimated to be very low (<2%). 16 Distribution Indacaterol After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 to 2,557 litres, indicating an extensive distribution. The in vitro human serum and plasma protein binding were 94.1 to 95.3% and 95.1 to 96.2%, respectively. Mometasone furoate After intravenous bolus administration, the Vd is 332 litres. The in vitro protein binding for mometasone furoate is high, 98% to 99% in concentration range of 5 to 500 ng/ml. Biotransformation Indacaterol After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, an N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified. In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolised indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6 and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low-affinity substrate for the efflux pump P-gp. In vitro the UGT1A1 isoform is a major contributor to the metabolic clearance of indacaterol. However, as shown in a clinical study in populations with different UGT1A1 genotypes, systemic exposure to indacaterol is not significantly affected by the UGT1A1 genotype. Mometasone furoate The portion of an inhaled mometasone furoate dose that is swallowed and absorbed in the gastrointestinal tract undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. In human liver microsomes mometasone furoate is metabolised by CYP3A4. Elimination Indacaterol In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 litres/hour. Compared with the serum clearance of indacaterol of 18.8 to 23.3 litres/hour, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol. In a human ADME study in which indacaterol was given orally, the faecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchanged parent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta. Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing, ranged from 40 to 52 hours which is consistent with the observed time to steady state of approximately 12 to 14 days. 17 Mometasone furoate After intravenous bolus administration, mometasone furoate has a terminal elimination T½ of approximately 4.5 hours. A radiolabelled, orally inhaled dose is excreted mainly in the faeces (74%) and to a lesser extent in the urine (8%). Interactions Concomitant administration of orally inhaled indacaterol and mometasone furoate under steady-state conditions did not affect the pharmacokinetics of either active substance. Linearity/non-linearity Systemic exposure of mometasone furoate increased in a dose proportional manner following single and multiple doses of Atectura Breezhaler 125 mcg/62.5 mcg and 125 mcg/260 mcg in healthy subjects. A less than proportional increase in steady-state systemic exposure was noted in patients with asthma over the dose range of 125 mcg/62.5 mcg to 125 mcg/260 mcg. Dose proportionality assessments were not performed for indacaterol as only one dose was used across all dose strengths. Paediatric population Atectura Breezhaler may be used in adolescent patients (12 years of age and older) at the same posology as in adults. Special populations A population pharmacokinetic analysis in patients with asthma after inhalation of indacaterol/mometasone furoate indicated no significant effect of age, gender, body weight, smoking status, baseline estimated glomerular filtration rate (eGFR) and FEV1 at baseline on the systemic exposure to indacaterol and mometasone furoate. Patients with renal impairment Due to the very low contribution of the urinary pathway to total body elimination of indacaterol and mometasone furoate, the effects of renal impairment on their systemic exposure have not been investigated (see section 4.2). Patients with hepatic impairment The effect of indacaterol/mometasone furoate has not been evaluated in subjects with hepatic impairment. However, studies have been conducted with the monotherapy components (see section 4.2). Indacaterol Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. No data are available for subjects with severe hepatic impairment. Mometasone furoate A study evaluating the administration of a single inhaled dose of 400 mcg mometasone furoate by dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/ml). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels (assay lower limit of quantification was 50 pcg/ml) were few. Other special populations There were no major differences in total systemic exposure (AUC) for both compounds between Japanese and Caucasian subjects. Insufficient pharmacokinetic data are available for other ethnicities or races. 18 5.3 Preclinical safety data The non-clinical assessments of each monotherapy and of the combination product are presented below. Indacaterol and mometasone furoate combination The findings during the 13-week inhalation toxicity studies were predominantly attributable to the mometasone furoate component and were typical pharmacological effects of glucocorticoids. Increased heart rates associated with indacaterol were apparent in dogs after administration of indacaterol/mometasone furoate or indacaterol alone. Indacaterol Effects on the cardiovascular system attributable to the beta2-agonistic properties of indacaterol included tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritation of the nasal cavity and larynx was seen in rodents. Genotoxicity studies did not reveal any mutagenic or clastogenic potential. Carcinogenicity was assessed in a two-year rat study and a six-month transgenic mouse study. Increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in rats were consistent with similar findings reported for other beta2-adrenergic agonists. No evidence of carcinogenicity was seen in mice. All these findings occurred at exposures sufficiently in excess of those anticipated in humans. Following subcutaneous administration in a rabbit study, adverse effects of indacaterol with respect to pregnancy and embryonal/foetal development could only be demonstrated at doses more than 500-fold those achieved following daily inhalation of 150 mcg in humans (based on AUC0-24 h). Although indacaterol did not affect general reproductive performance in a rat fertility study, a decrease in the number of pregnant F1 offspring was observed in the peri- and post-natal developmental rat study at an exposure 14-fold higher than in humans treated with indacaterol. Indacaterol was not embryotoxic or teratogenic in rats or rabbits. Mometasone furoate All observed effects are typical of the glucocorticoid class of compounds and are related to exaggerated pharmacological effects of glucocorticoids. Mometasone furoate showed no genotoxic activity in a standard battery of in vitro and in vivo tests. In carcinogenicity studies in mice and rats, inhaled mometasone furoate demonstrated no statistically significant increase in the incidence of tumours. Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Effects noted were umbilical hernia in rats, cleft palate in mice and gallbladder agenesis, umbilical hernia and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on foetal growth (lower foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice. In studies of reproductive function, subcutaneous mometasone furoate at 15 mcg/kg prolonged gestation and difficult labour occurred, with a reduction in offspring survival and body weight. 19 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule content Lactose monohydrate Capsule shell Gelatin Printing ink 6.2 Incompatibilities Not applicable. 6.3 Shelf life 30 months. 6.4 Special precautions for storage Store in the original package in order to protect from light and moisture. This medicinal product does not require any special temperature storage conditions. 6.5 Nature and contents of container Inhaler body and cap are made from acrylonitrile butadiene styrene, push buttons are made from methyl metacrylate acrylonitrile butadiene styrene. Needles and springs are made from stainless steel. PA/Alu/PVC – Alu perforated unit-dose blister. Each blister contains 10 hard capsules. Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules Single pack containing 10 x 1 or 30 x 1 hard capsules, together with 1 inhaler. Multipacks containing 90 (3 packs of 30 x 1) hard capsules and 3 inhalers. Multipacks containing 150 (15 packs of 10 x 1) hard capsules and 15 inhalers. Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules Single pack containing 10 x 1 or 30 x 1 hard capsules, together with 1 inhaler. Multipacks containing 90 (3 packs of 30 x 1) hard capsules and 3 inhalers. Multipacks containing 150 (15 packs of 10 x 1) hard capsules and 15 inhalers. Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules Single pack containing 10 x 1 or 30 x 1 hard capsules, together with 1 inhaler. Multipacks containing 90 (3 packs of 30 x 1) hard capsules and 3 inhalers. Multipacks containing 150 (15 packs of 10 x 1) hard capsules and 15 inhalers. Not all pack sizes may be marketed. 20 6.6 Special precautions for disposal and other handling The inhaler provided with each new prescription should be used. The inhaler in each pack should be disposed of after all capsules in that pack have been used. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Instructions for handling and use Please read the full Instructions for Use before using the Atectura Breezhaler. Insert Pierce and release Inhale deeply Check capsule is empty Step 1a: Pull off cap Step 2a: Pierce capsule once Hold the inhaler upright. Pierce capsule by firmly pressing both side buttons at the same time. Step 3a: Breathe out fully Do not blow into the inhaler. Check capsule is empty Open the inhaler to see if any powder is left in the capsule. You should hear a noise as the capsule is pierced. Only pierce the capsule once. If there is powder left in the capsule:  Close the inhaler.  Repeat steps 3a to 3d. Step 1b: Open inhaler Step 2b: Release side buttons Step 3b: Inhale medicine deeply Hold the inhaler as shown in the picture. Place the mouthpiece in your mouth and close your lips firmly around it. Do not press the side buttons. Powder Empty remaining 1 2 3 Check 21 Breathe in quickly and as deeply as you can. During inhalation you will hear a whirring noise. You may taste the medicine as you inhale. Step 1c: Remove capsule Separate one of the blisters from the blister card. Peel open the blister and remove the capsule. Do not push the capsule through the foil. Do not swallow the capsule. Step 3c: Hold breath Hold your breath for up to 5 seconds. Step 3d: Rinse mouth Rinse your mouth with water after each dose and spit it out. Remove empty capsule Put the empty capsule in your household waste. Close the inhaler and replace the cap. 22 Step 1d: Insert capsule Never place a capsule directly into the mouthpiece. Important Information  Atectura Breezhaler capsules must always be stored in the blister card and only removed immediately before use.  Do not push the capsule through the foil to remove it from the blister.  Do not swallow the capsule.  Do not use the Atectura Breezhaler capsules with any other inhaler.  Do not use the Atectura Breezhaler inhaler to take any other capsule medicine.  Never place the capsule into your mouth or the mouthpiece of the inhaler.  Do not press the side buttons more than once.  Do not blow into the mouthpiece.  Do not press the side buttons while inhaling through the mouthpiece.  Do not handle capsules with wet hands.  Never wash your inhaler with water. Step 1e: Close inhaler 23 Your Atectura Breezhaler Inhaler pack contains:  One Atectura Breezhaler inhaler  One or more blister cards, each containing 10 Atectura Breezhaler capsules to be used in the inhaler Frequently Asked Questions Why didn’t the inhaler make a noise when I inhaled? The capsule may be stuck in the capsule chamber. If this happens, carefully loosen the capsule by tapping the base of the inhaler. Inhale the medicine again by repeating steps 3a to 3d. What should I do if there is powder left inside the capsule? You have not received enough of your medicine. Close the inhaler and repeat steps 3a to 3d. I coughed after inhaling – does this matter? This may happen. As long as the capsule is empty you have received enough of your medicine. I felt small pieces of the capsule on my tongue – does this matter? This can happen. It is not harmful. The chances of the capsule breaking into small pieces will be increased if the capsule is pierced more than once. Cleaning the inhaler Wipe the mouthpiece inside and outside with a clean, dry, lint-free cloth to remove any powder residue. Keep the inhaler dry. Never wash your inhaler with water. Disposing of the inhaler after use Each inhaler should be disposed of after all capsules have been used. Ask your pharmacist how to dispose of medicines and inhalers that are no longer required. Base Cap Side buttons Blister Screen Capsule chamber Inhaler Inhaler base Blister card Mouthpiece 24 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules EU/1/20/1439/001-004 Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules EU/1/20/1439/005-008 Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules EU/1/20/1439/009-012 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 25 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 26 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany Novartis Farmacéutica, S.A. Ronda de Santa Maria, 158 08210 Barberà del Vallés (Barcelona) Spain The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 27 ANNEX III LABELLING AND PACKAGE LEAFLET 28 A. LABELLING 29 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 62.5 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule 10 x 1 capsules + 1 inhaler 30 x 1 capsules + 1 inhaler 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use ‘QR code to be included’ Scan for more or visit: www.breezhaler-asthma.eu/atectura 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 30 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/001 10 x 1 capsules + 1 inhaler EU/1/20/1439/002 30 x 1 capsules + 1 inhaler 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/62.5 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 31 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 62.5 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule Multipack: 90 (3 packs of 30 x 1) capsules + 3 inhalers. Multipack: 150 (15 packs of 10 x 1) capsules + 15 inhalers. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 32 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/003 90 (3 packs of 30 x 1) capsules + 3 inhalers EU/1/20/1439/004 150 (15 packs of 10 x 1) capsules + 15 inhalers 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/62.5 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 33 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 62.5 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule 10 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 30 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use ‘QR code to be included’ Scan for more or visit: www.breezhaler-asthma.eu/atectura 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 34 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/003 90 (3 packs of 30 x 1) capsules + 3 inhalers EU/1/20/1439/004 150 (15 packs of 10 x 1) capsules + 15 inhalers 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/62.5 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 35 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER LID OF OUTER CARTON OF UNIT PACK AND OF INTERMEDIATE CARTON OF MULTIPACK 1. OTHER 1 Insert 2 Pierce and release 3 Inhale deeply Check Check capsule is empty Read the leaflet before use. 36 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 mcg/62.5 mcg inhalation powder indacaterol/mometasone furoate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Inhalation use only 37 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 127.5 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule 10 x 1 capsules + 1 inhaler 30 x 1 capsules + 1 inhaler 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use ‘QR code to be included’ Scan for more or visit: www.breezhaler-asthma.eu/atectura 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 38 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/005 10 x 1 capsules + 1 inhaler EU/1/20/1439/006 30 x 1 capsules + 1 inhaler 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/127.5 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 39 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 127.5 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule Multipack: 90 (3 packs of 30 x 1) capsules + 3 inhalers. Multipack: 150 (15 packs of 10 x 1) capsules + 15 inhalers. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 40 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/007 90 (3 packs of 30 x 1) capsules + 3 inhalers EU/1/20/1439/008 150 (15 packs of 10 x 1) capsules + 15 inhalers 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/127.5 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 41 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 127.5 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule 10 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 30 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use ‘QR code to be included’ Scan for more or visit: www.breezhaler-asthma.eu/atectura 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 42 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/007 90 (3 packs of 30 x 1) capsules + 3 inhalers EU/1/20/1439/008 150 (15 packs of 10 x 1) capsules + 15 inhalers 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/127.5 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 43 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER LID OF OUTER CARTON OF UNIT PACK AND OF INTERMEDIATE CARTON OF MULTIPACK 1. OTHER 1 Insert 2 Pierce and release 3 Inhale deeply Check Check capsule is empty Read the leaflet before use. 44 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 mcg/127.5 mcg inhalation powder indacaterol/mometasone furoate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Inhalation use only 45 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF UNIT PACK 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 260 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule 10 x 1 capsules + 1 inhaler 30 x 1 capsules + 1 inhaler 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use ‘QR code to be included’ Scan for more or visit: www.breezhaler-asthma.eu/atectura 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 46 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/009 10 x 1 capsules + 1 inhaler EU/1/20/1439/010 30 x 1 capsules + 1 inhaler 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/260 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 47 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 260 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule Multipack: 90 (3 packs of 30 x 1) capsules + 3 inhalers. Multipack: 150 (15 packs of 10 x 1) capsules + 15 inhalers. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 48 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/011 90 (3 packs of 30 x 1) capsules + 3 inhalers EU/1/20/1439/012 150 (15 packs of 10 x 1) capsules + 15 inhalers 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/260 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 49 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 125 micrograms indacaterol (as acetate) and 260 micrograms mometasone furoate. 3. LIST OF EXCIPIENTS Also contains lactose. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Inhalation powder, hard capsule 10 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 30 x 1 capsules + 1 inhaler. Component of a multipack. Not to be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use only with the inhaler provided in the pack. Do not swallow capsules. Inhalation use ‘QR code to be included’ Scan for more or visit: www.breezhaler-asthma.eu/atectura 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 50 8. EXPIRY DATE EXP The inhaler in each pack should be disposed of after all capsules in that pack have been used. 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1439/011 90 (3 packs of 30 x 1) capsules + 3 inhalers EU/1/20/1439/012 150 (15 packs of 10 x 1) capsules + 15 inhalers 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Atectura Breezhaler 125 micrograms/260 micrograms 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 51 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER LID OF OUTER CARTON OF UNIT PACK AND OF INTERMEDIATE CARTON OF MULTIPACK 1. OTHER 1 Insert 2 Pierce and release 3 Inhale deeply Check Check capsule is empty Read the leaflet before use. 52 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Atectura Breezhaler 125 mcg/260 mcg inhalation powder indacaterol/mometasone furoate 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Inhalation use only 53 B. PACKAGE LEAFLET 54 Package leaflet: Information for the user Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder, hard capsules Atectura Breezhaler 125 micrograms/260 micrograms inhalation powder, hard capsules indacaterol/mometasone furoate Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What Atectura Breezhaler is and what it is used for 2. What you need to know before you use Atectura Breezhaler 3. How to use Atectura Breezhaler 4. Possible side effects 5. How to store Atectura Breezhaler 6. Contents of the pack and other information Instructions for use of Atectura Breezhaler inhaler 1. What Atectura Breezhaler is and what it is used for What Atectura Breezhaler is and how it works Atectura Breezhaler contains two active substances called indacaterol and mometasone furoate. Indacaterol belongs to a group of medicines called bronchodilators. It relaxes the muscles of the small airways in the lungs. This helps to open the airways and makes it easier for air to get in and out of the lungs. When it is taken regularly, it helps the small airways to remain open. Mometasone furoate belongs to a group of medicines called corticosteroids (or steroids). Corticosteroids reduce the swelling and irritation (inflammation) in the small airways in the lungs and so gradually ease breathing problems. Corticosteroids also help to prevent attacks of asthma. What Atectura Breezhaler is used for Atectura Breezhaler is used regularly as treatment for asthma in adults and adolescents (12 years of age and older). Asthma is a serious, long-term lung disease where the muscles surrounding the smaller airways become tight (bronchoconstriction) and inflamed. Symptoms come and go and include shortness of breath, wheezing, chest tightness and cough. You should use Atectura Breezhaler every day and not only when you have breathing problems or other symptoms of asthma. This will ensure that it controls your asthma properly. Do not use this medicine to relieve a sudden attack of breathlessness or wheezing. If you have any questions about how Atectura Breezhaler works or why this medicine has been prescribed for you, ask your doctor. 55 2. What you need to know before you use Atectura Breezhaler Follow all the doctor’s instructions carefully. Do not use Atectura Breezhaler - if you are allergic to indacaterol, mometasone furoate or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, ask your doctor for advice. Warnings and precautions Talk to your doctor, pharmacist or nurse before using Atectura Breezhaler if any of the following applies to you: - if you have heart problems, including an irregular or fast heartbeat. - if you have thyroid gland problems. - if you have ever been told you have diabetes or high blood sugar. - if you suffer from seizures or fits. - if you have a low level of potassium in your blood. - if you have severe liver problems. - if you have tuberculosis (TB) of the lung, or any long-standing or untreated infections. During treatment with Atectura Breezhaler Stop using this medicine and get medical help immediately if you have any of the following: - tightness of the chest, coughing, wheezing or breathlessness immediately after using Atectura Breezhaler (signs the medicine is unexpectedly tightening the airways, known as paradoxical bronchospasm). - difficulty breathing or swallowing, swelling of the tongue, lips or face, skin rash, itching and hives (signs of allergic reaction). Children and adolescents Do not give this medicine to children below 12 years of age because it has not been studied in this age group. Other medicines and Atectura Breezhaler Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. In particular, tell your doctor or pharmacist if you are using: - medicines that decrease the level of potassium in your blood. These include diuretics (which increase urine production and can be used to treat high blood pressure, e.g. hydrochlorothiazide), other bronchodilators such as methylxanthines used for breathing problems (e.g. theophylline) or corticosteroids (e.g. prednisolone). - tricyclic antidepressants or monoamine oxidase inhibitors (medicines used in the treatment of depression). - any medicines that may be similar to Atectura Breezhaler (contain similar active substances); using them together may increase the risk of possible side effects. - medicines called beta blockers used to treat high blood pressure or other heart problems (e.g. propranolol) or to treat glaucoma (e.g. timolol). - ketoconazole or itraconazole (medicines used to treat fungal infections) - ritonavir, nelfinavir or cobicistat (medicines used to treat HIV infection). Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will discuss with you whether you can use Atectura Breezhaler. Driving and using machines It is unlikely that this medicine will affect your ability to drive and use machines. 56 Atectura Breezhaler contains lactose This medicine contains about 25 mg of lactose per capsule. If you have been told by your doctor that you have an intolerance to some sugars, speak with your doctor before taking this medicine. 3. How to use Atectura Breezhaler Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. How much Atectura Breezhaler to inhale There are three different strengths of Atectura Breezhaler capsules. Your doctor will decide which is best for you. The usual dose is to inhale the content of one capsule each day. You only need to use the medicine once a day. Do not use more than your doctor tells you to use. You should use Atectura Breezhaler every day, even when your asthma is not troubling you. When to inhale Atectura Breezhaler Inhale Atectura Breezhaler at the same time each day. This will help control your symptoms throughout the day and night. It will also help you to remember to use it. How to inhale Atectura Breezhaler - Atectura Breezhaler is for inhalation use. - In this pack, you will find an inhaler and capsules that contain the medicine. The inhaler enables you to inhale the medicine in the capsule. Only use the capsules with the inhaler provided in this pack. The capsules should remain in the blister until you need to use them. - Peel the backing away from the blister to open it, do not push the capsule through the foil. - When you start a new pack, use the new inhaler supplied in this new pack. - Dispose of the inhaler in each pack after all capsules in that pack have been used. - Do not swallow the capsules. - Please read the instructions for use on the other side of this leaflet for more information on how to use the inhaler. If your symptoms do not improve If your asthma is not getting better or if it gets worse after you have started using Atectura Breezhaler, talk to your doctor. If you use more Atectura Breezhaler than you should If you accidently inhale too much of this medicine, contact your doctor or hospital for advice immediately. You may need medical attention. If you forget to use Atectura Breezhaler If you forget to inhale a dose at the usual time, inhale one as soon as possible on that day. Then inhale the next dose at the usual time on the next day. Do not inhale two doses on the same day. If you stop using Atectura Breezhaler Do not stop using Atectura Breezhaler unless your doctor tells you to. Your asthma symptoms may come back if you stop using it. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 57 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some side effects could be serious Stop using Atectura Breezhaler and get medical help immediately if you have any of the following: Common: may affect up to 1 in every 10 people - difficulty breathing or swallowing, swelling of the tongue, lips, or face, skin rash, itching and hives (signs of allergic reaction). Uncommon: may affect up to 1 in every 100 people - swelling mainly of the tongue, lips, face or throat (possible signs of angioedema). Other side effects Other side effects include the following listed below. If these side effects become severe, please tell your doctor, pharmacist or nurse. Very common: may affect more than 1 in 10 people - sore throat - runny nose - sudden difficulty breathing and feeling of tightness in chest with wheezing or coughing Common: may affect up to 1 in every 10 people - voice alteration (hoarseness) - blocked nose - sneezing, cough - headache - pain in muscles, bones or joints (signs of musculoskeletal pain) Uncommon: may affect up to 1 in every 100 people - fast heart beat - oral thrush (sign of candidiasis) - high level of sugar in the blood - muscle spasm - skin itching - rash - clouding of the lens of your eyes (signs of cataract) - blurred vision Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 58 5. How to store Atectura Breezhaler - Keep this medicine out of the sight and reach of children. - Do not use this medicine after the expiry date which is stated on the carton and blister after “EXP”. The expiry date refers to the last day of that month. - This medicinal product does not require any special temperature storage conditions. - Store the capsules in the original blister in order to protect from light and moisture, and do not remove until immediately before use. - Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Atectura Breezhaler contains - The active substances are indacaterol (as acetate) and mometasone furoate. Atectura Breezhaler 125 micrograms/62.5 micrograms Each capsule contains 173 micrograms of indacaterol acetate (equivalent to 150 micrograms of indacaterol) and 80 micrograms of mometasone furoate. The delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms of indacaterol and 62.5 micrograms of mometasone furoate. Atectura Breezhaler 125 micrograms/127.5 micrograms Each capsule contains 173 micrograms of indacaterol acetate (equivalent to 150 micrograms of indacaterol) and 160 micrograms of mometasone furoate. The delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms of indacaterol and 127.5 micrograms of mometasone furoate. Atectura Breezhaler 125 micrograms/260 micrograms Each capsule contains 173 micrograms of indacaterol acetate (equivalent to 150 micrograms of indacaterol) and 320 micrograms of mometasone furoate. The delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms of indacaterol and 260 micrograms of mometasone furoate. - The other ingredient is lactose monohydrate (see “Atectura Breezhaler contains lactose” in section 2). What Atectura Breezhaler looks like and content of the pack In this pack, you will find an inhaler together with capsules in blisters. The capsules are transparent and contain a white powder. - Atectura Breezhaler 125 micrograms/62.5 micrograms capsules have a blue product code “IM150-80” printed above one blue bar on the body with a logo printed in blue and surrounded by two blue bars on the cap. - Atectura Breezhaler 125 micrograms/127.5 micrograms capsules have a grey product code “IM150-160” printed on the body with a logo printed in grey on the cap. - Atectura Breezhaler 125 micrograms/260 micrograms capsules have a black product code “IM150-320” printed above two black bars on the body with a logo printed in black and surrounded by two black bars on the cap. The following pack sizes are available: Single pack containing 10 x 1 or 30 x 1 hard capsules, together with 1 inhaler. Multipacks comprising 3 cartons, each containing 30 x 1 hard capsules together with 1 inhaler. Multipacks comprising 15 cartons, each containing 10 x 1 hard capsules together with 1 inhaler. Not all pack sizes may be available in your country. 59 Marketing Authorisation Holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany Novartis Farmacéutica, S.A. Ronda de Santa Maria, 158 08210 Barberà del Vallés (Barcelona) Spain For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA Novartis Baltics Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 88 04 52 111 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 60 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA Novartis Baltics Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. 61 Instructions for Use of Atectura Breezhaler Please read full instructions for use of Atectura Breezhaler inhaler before use. These instructions are also available by scanning the QR code or visiting www.breezhaler-asthma.eu/atectura “QR code to be included”. Insert Pierce and release Inhale deeply Check capsule is empty Step 1a: Pull off cap Step 2a: Pierce capsule once Hold the inhaler upright. Pierce capsule by firmly pressing both side buttons at the same time. Step 3a: Breathe out fully Do not blow into the inhaler. Check capsule is empty Open the inhaler to see if any powder is left in the capsule. You should hear a noise as the capsule is pierced. Only pierce the capsule once. If there is powder left in the capsule:  Close the inhaler.  Repeat steps 3a to 3d. Step 1b: Open inhaler Step 2b: Release side buttons Step 3b: Inhale medicine deeply Hold the inhaler as shown in the picture. Place the mouthpiece in your mouth and close your lips firmly around it. Do not press the side buttons. Powder Empty remaining 1 2 3 Check http://www.breezhaler-asthma.eu/atectura 62 Breathe in quickly and as deeply as you can. During inhalation you will hear a whirring noise. You may taste the medicine as you inhale. Step 1c: Remove capsule Separate one of the blisters from the blister card. Peel open the blister and remove the capsule. Do not push the capsule through the foil. Do not swallow the capsule. Step 3c: Hold breath Hold your breath for up to 5 seconds. Step 3d : Rinse mouth Rinse your mouth with water after each dose and spit it out. Remove empty capsule Put the empty capsule in your household waste. Close the inhaler and replace the cap. 63 Step 1d: Insert capsule Never place a capsule directly into the mouthpiece. Important Information  Atectura Breezhaler capsules must always be stored in the blister card and only removed immediately before use.  Do not push the capsule through the foil to remove it from the blister.  Do not swallow the capsule.  Do not use the Atectura Breezhaler capsules with any other inhaler.  Do not use the Atectura Breezhaler inhaler to take any other capsule medicine.  Never place the capsule into your mouth or the mouthpiece of the inhaler.  Do not press the side buttons more than once.  Do not blow into the mouthpiece.  Do not press the side buttons while inhaling through the mouthpiece.  Do not handle capsules with wet hands.  Never wash your inhaler with water. Step 1e: Close inhaler 64 Your Atectura Breezhaler Inhaler pack contains:  One Atectura Breezhaler inhaler  One or more blister cards, each containing 10 Atectura Breezhaler capsules to be used in the inhaler Frequently Asked Questions Why didn’t the inhaler make a noise when I inhaled? The capsule may be stuck in the capsule chamber. If this happens, carefully loosen the capsule by tapping the base of the inhaler. Inhale the medicine again by repeating steps 3a to 3d. What should I do if there is powder left inside the capsule? You have not received enough of your medicine. Close the inhaler and repeat steps 3a to 3d. I coughed after inhaling – does this matter? This may happen. As long as the capsule is empty you have received enough of your medicine. I felt small pieces of the capsule on my tongue – does this matter? This can happen. It is not harmful. The chances of the capsule breaking into small pieces will be increased if the capsule is pierced more than once. Cleaning the inhaler Wipe the mouthpiece inside and outside with a clean, dry, lint-free cloth to remove any powder residue. Keep the inhaler dry. Never wash your inhaler with water. Disposing of the inhaler after use Each inhaler should be disposed of after all capsules have been used. Ask your pharmacist how to dispose of medicines and inhalers that are no longer required. Base Cap Side buttons Blister Screen Capsule chamber Inhaler Inhaler base Blister card Mouthpiece SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you use atectura breezhaler', 'Section_Content': "follow all the doctor's instructions carefully. do not use atectura breezhaler - if you are allergic to indacaterol, mometasone furoate or any of the other ingredients of this medicine (listed in section 6). if you think you may be allergic, ask your doctor for advice. warnings and precautions talk to your doctor, pharmacist or nurse before using atectura breezhaler if any of the following applies to you: - if you have heart problems, including an irregular or fast heartbeat. - if you have thyroid gland problems. - if you have ever been told you have diabetes or high blood sugar. - if you suffer from seizures or fits. - if you have a low level of potassium in your blood. - if you have severe liver problems. - if you have tuberculosis (tb) of the lung, or any long-standing or untreated infections. during treatment with atectura breezhaler stop using this medicine and get medical help immediately if you have any of the following: - tightness of the chest, coughing, wheezing or breathlessness immediately after using atectura breezhaler (signs the medicine is unexpectedly tightening the airways, known as paradoxical bronchospasm). - difficulty breathing or swallowing, swelling of the tongue, lips or face, skin rash, itching and hives (signs of allergic reaction). children and adolescents do not give this medicine to children below 12 years of age because it has not been studied in this age group. other medicines and atectura breezhaler tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. in particular, tell your doctor or pharmacist if you are using: - medicines that decrease the level of potassium in your blood. these include diuretics (which increase urine production and can be used to treat high blood pressure, e.g. hydrochlorothiazide), other bronchodilators such as methylxanthines used for breathing problems (e.g. theophylline) or corticosteroids (e.g. prednisolone). - tricyclic antidepressants or monoamine oxidase inhibitors (medicines used in the treatment of depression). - any medicines that may be similar to atectura breezhaler (contain similar active substances); using them together may increase the risk of possible side effects. - medicines called beta blockers used to treat high blood pressure or other heart problems (e.g. propranolol) or to treat glaucoma (e.g. timolol). - ketoconazole or itraconazole (medicines used to treat fungal infections) - ritonavir, nelfinavir or cobicistat (medicines used to treat hiv infection). pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. your doctor will discuss with you whether you can use atectura breezhaler. driving and using machines it is unlikely that this medicine will affect your ability to drive and use machines. 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{'Title': '3. how to use atectura breezhaler', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. how much atectura breezhaler to inhale there are three different strengths of atectura breezhaler capsules. your doctor will decide which is best for you. the usual dose is to inhale the content of one capsule each day. you only need to use the medicine once a day. do not use more than your doctor tells you to use. you should use atectura breezhaler every day, even when your asthma is not troubling you. when to inhale atectura breezhaler inhale atectura breezhaler at the same time each day. this will help control your symptoms throughout the day and night. it will also help you to remember to use it. how to inhale atectura breezhaler - atectura breezhaler is for inhalation use. - in this pack, you will find an inhaler and capsules that contain the medicine. the inhaler enables you to inhale the medicine in the capsule. only use the capsules with the inhaler provided in this pack. the capsules should remain in the blister until you need to use them. - peel the backing away from the blister to open it, do not push the capsule through the foil. - when you start a new pack, use the new inhaler supplied in this new pack. - dispose of the inhaler in each pack after all capsules in that pack have been used. - do not swallow the capsules. - please read the instructions for use on the other side of this leaflet for more information on how to use the inhaler. if your symptoms do not improve if your asthma is not getting better or if it gets worse after you have started using atectura breezhaler, talk to your doctor. if you use more atectura breezhaler than you should if you accidently inhale too much of this medicine, contact your doctor or hospital for advice immediately. you may need medical attention. if you forget to use atectura breezhaler if you forget to inhale a dose at the usual time, inhale one as soon as possible on that day. then inhale the next dose at the usual time on the next day. do not inhale two doses on the same day. if you stop using atectura breezhaler do not stop using atectura breezhaler unless your doctor tells you to. your asthma symptoms may come back if you stop using it. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'atectura breezhaler', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Text': 'atectura breezhaler capsules', 'Type': 'TREATMENT', 'BeginOffset': 212, 'EndOffset': 240}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 375, 'EndOffset': 387}, {'Id': 4, 'BeginOffset': 466, 'EndOffset': 485, 'Score': 0.3322811722755432, 'Text': 'atectura breezhaler', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FREQUENCY', 'Score': 0.8250521421432495, 'RelationshipScore': 0.9999997615814209, 'RelationshipType': 'FREQUENCY', 'Id': 5, 'BeginOffset': 486, 'EndOffset': 495, 'Text': 'every day', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'your asthma', 'Type': 'PROBLEM', 'BeginOffset': 507, 'EndOffset': 518}, {'Text': 'your symptoms', 'Type': 'PROBLEM', 'BeginOffset': 653, 'EndOffset': 666}, {'Text': 'atectura breezhaler', 'Type': 'TREATMENT', 'BeginOffset': 756, 'EndOffset': 775}, {'Text': 'atectura breezhaler', 'Type': 'TREATMENT', 'BeginOffset': 778, 'EndOffset': 797}, {'Text': 'an inhaler and capsules', 'Type': 'TREATMENT', 'BeginOffset': 851, 'EndOffset': 874}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 888, 'EndOffset': 900}, {'Text': 'the inhaler', 'Type': 'TREATMENT', 'BeginOffset': 902, 'EndOffset': 913}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 936, 'EndOffset': 948}, {'Text': 'the capsules', 'Type': 'TREATMENT', 'BeginOffset': 974, 'EndOffset': 986}, {'Text': 'the inhaler', 'Type': 'TREATMENT', 'BeginOffset': 992, 'EndOffset': 1003}, {'Text': 'this pack', 'Type': 'TREATMENT', 'BeginOffset': 1016, 'EndOffset': 1025}, {'Text': 'the capsules', 'Type': 'TREATMENT', 'BeginOffset': 1027, 'EndOffset': 1039}, {'Text': 'peel', 'Type': 'TREATMENT', 'BeginOffset': 1099, 'EndOffset': 1103}, {'Text': 'the blister', 'Type': 'PROBLEM', 'BeginOffset': 1126, 'EndOffset': 1137}, {'Text': 'a new pack', 'Type': 'TREATMENT', 'BeginOffset': 1209, 'EndOffset': 1219}, {'Text': 'the new inhaler', 'Type': 'TREATMENT', 'BeginOffset': 1225, 'EndOffset': 1240}, {'Text': 'this new pack', 'Type': 'TREATMENT', 'BeginOffset': 1253, 'EndOffset': 1266}, {'Text': 'the inhaler in each pack', 'Type': 'TREATMENT', 'BeginOffset': 1281, 'EndOffset': 1305}, {'Text': 'all capsules in that pack', 'Type': 'TREATMENT', 'BeginOffset': 1312, 'EndOffset': 1337}, {'Text': 'the inhaler', 'Type': 'TREATMENT', 'BeginOffset': 1493, 'EndOffset': 1504}, {'Text': 'your symptoms', 'Type': 'PROBLEM', 'BeginOffset': 1509, 'EndOffset': 1522}, {'Text': 'your asthma', 'Type': 'PROBLEM', 'BeginOffset': 1541, 'EndOffset': 1552}, {'Text': 'medical attention', 'Type': 'TREATMENT', 'BeginOffset': 1839, 'EndOffset': 1856}, {'Text': 'atectura breezhaler', 'Type': 'TREATMENT', 'BeginOffset': 1879, 'EndOffset': 1898}, {'Text': 'atectura breezhaler', 'Type': 'TREATMENT', 'BeginOffset': 2113, 'EndOffset': 2132}, {'Id': 10, 'BeginOffset': 2151, 'EndOffset': 2170, 'Score': 0.3672703802585602, 'Text': 'atectura breezhaler', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5668185949325562}]}, {'Text': 'your asthma symptoms', 'Type': 'PROBLEM', 'BeginOffset': 2204, 'EndOffset': 2224}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2309, 'EndOffset': 2322}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects could be serious stop using atectura breezhaler and get medical help immediately if you have any of the following: common: may affect up to 1 in every 10 people - difficulty breathing or swallowing, swelling of the tongue, lips, or face, skin rash, itching and hives (signs of allergic reaction). uncommon: may affect up to 1 in every 100 people - swelling mainly of the tongue, lips, face or throat (possible signs of angioedema). other side effects other side effects include the following listed below. if these side effects become severe, please tell your doctor, pharmacist or nurse. very common: may affect more than 1 in 10 people - sore throat - runny nose - sudden difficulty breathing and feeling of tightness in chest with wheezing or coughing common: may affect up to 1 in every 10 people - voice alteration (hoarseness) 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{'Title': '5. how to store atectura breezhaler', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information instructions for use of atectura breezhaler inhaler', 'Section_Content': 'what atectura breezhaler contains - the active substances are indacaterol (as acetate) and mometasone furoate. atectura breezhaler 125 micrograms/62.5 micrograms each capsule contains 173 micrograms of indacaterol acetate (equivalent to 150 micrograms of indacaterol) and 80 micrograms of mometasone furoate. the delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms of indacaterol and 62.5 micrograms of mometasone furoate. atectura breezhaler 125 micrograms/127.5 micrograms each capsule contains 173 micrograms of indacaterol acetate (equivalent to 150 micrograms of indacaterol) and 160 micrograms of mometasone furoate. the delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms of indacaterol and 127.5 micrograms of mometasone furoate. atectura breezhaler 125 micrograms/260 micrograms each capsule contains 173 micrograms of indacaterol acetate (equivalent to 150 micrograms of indacaterol) and 320 micrograms of mometasone furoate. the delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms of indacaterol and 260 micrograms of mometasone furoate. - the other ingredient is lactose monohydrate (see "atectura breezhaler contains lactose" in section 2). what atectura breezhaler looks like and content of the pack in this pack, you will find an inhaler together with capsules in blisters. the capsules are transparent and contain a white powder. - atectura breezhaler 125 micrograms/62.5 micrograms capsules have a blue product code "im150-80" printed above one blue bar on the body with a logo printed in blue and surrounded by two blue bars on the cap. - atectura breezhaler 125 micrograms/127.5 micrograms capsules have a grey product code "im150-160" printed on the body with a logo printed in grey on the cap. - atectura breezhaler 125 micrograms/260 micrograms capsules have a black product code "im150-320" printed above two black bars on the body with a logo printed in black and surrounded by two black bars on the cap. the following pack sizes are available: single pack containing 10 x 1 or 30 x 1 hard capsules, together with 1 inhaler. multipacks comprising 3 cartons, each containing 30 x 1 hard capsules together with 1 inhaler. multipacks comprising 15 cartons, each containing 10 x 1 hard capsules together with 1 inhaler. not all pack sizes may be available in your country.', 'Entity_Recognition': [{'Text': 'atectura breezhaler', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'what atectura breezhaler', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 24}, {'Text': 'the active substances', 'Type': 'TREATMENT', 'BeginOffset': 36, 'EndOffset': 57}, {'Text': 'indacaterol (as acetate)', 'Type': 'TREATMENT', 'BeginOffset': 62, 'EndOffset': 86}, {'Id': 2, 'BeginOffset': 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4C6F014617258C188FB3CAA03399D036

https://www.ema.europa.eu/documents/product-information/blincyto-epar-product-information_en.pdf

Blincyto

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One vial of powder contains 38.5 micrograms blinatumomab. Reconstitution with water for injections results in a final blinatumomab concentration of 12.5 micrograms/mL. Blinatumomab is produced in Chinese hamster ovary cells by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for concentrate and solution for solution for infusion. BLINCYTO powder (powder for concentrate): White to off-white powder. Solution (stabiliser): Colourless-to-slightly yellow, clear solution with a pH of 7.0. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL). BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. BLINCYTO is indicated as monotherapy for the treatment of paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation. 4.2 Posology and method of administration Treatment should be initiated under the direction of and supervised by physicians experienced in the treatment of haematological malignancies. For the treatment of Philadelphia chromosome negative relapsed or refractory B-precursor ALL, hospitalisation is recommended for initiation at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle. 3 For the treatment of Philadelphia chromosome negative MRD positive B-precursor ALL, hospitalisation is recommended at a minimum for the first 3 days of the first cycle and the first 2 days of subsequent cycles. In patients with a history or presence of clinically relevant central nervous system (CNS) pathology (see section 4.4), hospitalisation is recommended at a minimum for the first 14 days of the first cycle. In the second cycle, hospitalisation is recommended at a minimum for 2 days, and clinical judgment should be based on tolerance to BLINCYTO in the first cycle. Caution should be exercised as cases of late occurrence of first neurological events have been observed. For all subsequent cycle starts and reinitiation (e.g. if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalisation is recommended. BLINCYTO infusion bags should be prepared to infuse over 24 hours, 48 hours, 72 hours, or 96 hours. See method of administration. Posology Philadelphia chromosome negative relapsed or refractory B-precursor ALL Patients may receive 2 cycles of treatment. A single cycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14 day (2 week) treatment-free interval. Patients who have achieved complete remission (CR/CRh*) after 2 treatment cycles may receive up to 3 additional cycles of BLINCYTO consolidation treatment, based on an individual benefits-risks assessment. Recommended daily dose is by patient weight. Patients greater than or equal to 45 kg receive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA). Patient weight Cycle 1 Subsequent cycles Days 1-7 Days 8-28 Days 29-42 Days 1-28 Days 29-42 Greater than or equal to 45 kg (fixed-dose) 9 mcg/day via continuous infusion 28 mcg/day via continuous infusion 14 day treatment free interval 28 mcg/day via continuous infusion 14 day treatment free interval Less than 45 kg (BSA-based dose) 5 mcg/m2/day via continuous infusion (not to exceed 9 mcg/day) 15 mcg/m2/day via continuous infusion (not to exceed 28 mcg/day) 15 mcg/m2/day via continuous infusion (not to exceed 28 mcg/day) Premedication and additional medication recommendations In adult patients, dexamethasone 20 mg intravenous should be administered 1 hour prior to initiation of each cycle of BLINCYTO therapy. In paediatric patients, dexamethasone 10 mg/m2 (not to exceed 20 mg) should be administered orally or intravenously 6 to 12 hours prior to the start of BLINCYTO (cycle 1, day 1). This should be followed by dexamethasone 5 mg/m2 orally or intravenously within 30 minutes prior to the start of BLINCYTO (cycle 1, day 1). 4 Anti-pyretic use (e.g. paracetamol) is recommended to reduce pyrexia during the first 48 hours of each treatment cycle. Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse. Pre-phase treatment for patients with high tumour burden For patients with ≥ 50% leukaemic blasts in bone marrow or > 15,000/microlitre peripheral blood leukaemic blast counts treat with dexamethasone (not to exceed 24 mg/day). MRD positive B-precursor ALL When considering the use of BLINCYTO as a treatment for Philadelphia chromosome negative MRD positive B-precursor ALL, quantifiable MRD should be confirmed in a validated assay with minimum sensitivity of 10-4 (see section 5.1). Clinical testing of MRD, regardless of the choice of technique, should be performed by a qualified laboratory familiar with the technique, following well established technical guidelines. Patients may receive 1 cycle of induction treatment followed by up to 3 additional cycles of BLINCYTO consolidation treatment. A single cycle of treatment of BLINCYTO induction or consolidation is 28 days (4 weeks) of continuous intravenous infusion followed by a 14 day (2 week) treatment-free interval (total 42 days). The majority of patients who respond to blinatumomab achieve a response after 1 cycle (see section 5.1). Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 1 treatment cycle should be assessed by the treating physician. Recommended dose (for patients at least 45 kg in weight): Treatment cycle(s) Induction Cycle 1 Days 1-28 Days 29-42 28 mcg/day 14-day treatment-free interval Consolidation Cycles 2-4 Days 1-28 Days 29-42 28 mcg/day 14-day treatment-free interval Premedication and additional medication recommendations Prednisone 100 mg intravenously or equivalent (e.g. dexamethasone 16 mg) should be administered 1 hour prior to initiation of each cycle of BLINCYTO therapy. Anti-pyretic use (e.g. paracetamol) is recommended to reduce pyrexia during the first 48 hours of each treatment cycle. Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse. Dose adjustments For patients with Philadelphia chromosome negative relapsed or refractory B-precursor ALL and patients with MRD positive B-precursor ALL receiving BLINCYTO, consideration to discontinue BLINCYTO temporarily or permanently as appropriate should be made in the case of the following severe (grade 3) or life-threatening (grade 4) toxicities (see section 4.4): cytokine release syndrome, 5 tumour lysis syndrome, neurological toxicity, elevated liver enzymes and any other clinically relevant toxicities. If the interruption of treatment after an adverse event is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle. If an interruption due to an adverse event is longer than 7 days, start a new cycle. If the toxicity takes more than 14 days to resolve, discontinue BLINCYTO permanently, except if described differently in the table below. Toxicity Grade* Action for patients greater than or equal to 45 kg Action for patients less than 45 kg Cytokine release syndrome, tumour lysis syndrome Grade 3 Interrupt BLINCYTO until resolved, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. Interrupt BLINCYTO until resolved, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the toxicity does not recur. Grade 4 Discontinue BLINCYTO permanently. Discontinue BLINCYTO permanently. Neurological toxicity Convulsion Discontinue BLINCYTO permanently if more than one convulsion occurs. Discontinue BLINCYTO permanently if more than one convulsion occurs. Grade 3 Interrupt BLINCYTO until no more than grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. For reinitiation, premedicate with a 24 mg dose of dexamethasone. Then reduce dexamethasone step-wise over 4 days. If the toxicity occurred at 9 mcg/day, or if the toxicity takes more than 7 days to resolve, discontinue BLINCYTO permanently. Interrupt BLINCYTO until no more than grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the toxicity does not recur. If the toxicity occurred at 5 mcg/m2/day, or if the toxicity takes more than 7 days to resolve, discontinue BLINCYTO permanently Grade 4 Discontinue BLINCYTO permanently. Discontinue BLINCYTO permanently. Elevated liver enzymes Grade 3 If clinically relevant, interrupt BLINCYTO until no more than grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. If clinically relevant, interrupt BLINCYTO until no more than grade 1 (mild), then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the toxicity does not recur. Grade 4 Consider discontinuing BLINCYTO permanently. Consider discontinuing BLINCYTO permanently. 6 Toxicity Grade* Action for patients greater than or equal to 45 kg Action for patients less than 45 kg Other clinically relevant (as determined by treating physician) adverse reactions Grade 3 Interrupt BLINCYTO until no more than grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. Interrupt BLINCYTO until no more than grade 1 (mild), then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the toxicity does not recur. Grade 4 Consider discontinuing BLINCYTO permanently. Consider discontinuing BLINCYTO permanently. * Based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 is severe, and grade 4 is life-threatening. Special populations Elderly No dose adjustment is necessary in elderly patients (≥ 65 years of age), see section 5.1. There is limited experience with BLINCYTO in patients ≥ 75 years of age. Renal impairment Based on pharmacokinetic analyses, dose adjustment is not necessary in patients with mild to moderate renal dysfunction (see section 5.2). The safety and efficacy of BLINCYTO have not been studied in patients with severe renal impairment. Hepatic impairment Based on pharmacokinetic analyses, no effect of baseline liver function on blinatumomab exposure is expected and adjustment of the initial dose is not necessary (see section 5.2). The safety and efficacy of BLINCYTO have not been studied in patients with severe hepatic impairment. Paediatric population The safety and efficacy of BLINCYTO in children < 1 year of age have not yet been established. There are no data for children < 7 months of age. Currently available data in children are described in section 4.8 and 5.1. Method of administration Important note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, BLINCYTO should be infused through a dedicated lumen. For instructions on the handling and preparation of the medicinal product before administration, see section 6.6. BLINCYTO solution for infusion is administered as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump over a period of up to 96 hours. The BLINCYTO solution for infusion must be administered using intravenous tubing that contains a sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter. 7 The starting volume (270 mL) is more than the volume administered to the patient (240 mL) to account for the priming of the intravenous tubing and to ensure that the patient will receive the full dose of BLINCYTO. Infuse BLINCYTO solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates: • Infusion rate of 10 mL/h for a duration of 24 hours • Infusion rate of 5 mL/h for a duration of 48 hours • Infusion rate of 3.3 mL/h for a duration of 72 hours • Infusion rate of 2.5 mL/h for a duration of 96 hours The choice of the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes. The target therapeutic dose of BLINCYTO delivered does not change. Change of infusion bag The infusion bag must be changed at least every 96 hours by a healthcare professional for sterility reasons. 4.3 Contraindications - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Breast-feeding (see section 4.6). 4.4 Special warnings and precautions for use Neurologic events Neurologic events including events with a fatal outcome have been observed. Grade 3 (CTCAE version 4.0) or higher (severe or life-threatening) neurologic events following initiation of blinatumomab administration included encephalopathy, seizures, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Among patients that experienced a neurologic event, the median time to the first event was within the first two weeks of treatment and the majority of events resolved after treatment interruption and infrequently led to BLINCYTO treatment discontinuation. Elderly patients may be more susceptible to serious neurologic events such as cognitive disorder, encephalopathy, and confusion. Patients with a medical history of neurologic signs and symptoms (such as dizziness, hypoaesthesia, hyporeflexia, tremor, dysaesthesia, paraesthesia, memory impairment) demonstrated a higher rate of neurologic events (such as tremor, dizziness, confusional state, encephalopathy and ataxia). Among these patients, the median time to the first neurologic event was within the first cycle of treatment. There is limited experience in patients with a history or presence of clinically relevant central nervous system (CNS) pathology (e.g. epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, psychosis) as they were excluded from clinical trials. There is a possibility of a higher risk of neurologic events in this population. The potential benefits of treatment should be carefully weighed against the risk of neurologic events and heightened caution should be exercised when administering BLINCYTO to these patients. There is limited experience with blinatumomab in patients with documented active ALL in the CNS or cerebrospinal fluid (CSF). However patients have been treated with blinatumomab in clinical 8 studies after clearance of CSF blasts with CNS directed therapy (such as intrathecal chemotherapy). Therefore once the CSF is cleared, treatment with BLINCYTO may be initiated. It is recommended that a neurological examination be performed in patients prior to starting BLINCYTO therapy and that patients be clinically monitored for signs and symptoms of neurologic events (e.g. writing test). Management of these signs and symptoms to resolution may require either temporary interruption or permanent discontinuation of BLINCYTO (see section 4.2). In the event of a seizure, secondary prophylaxis with appropriate anticonvulsant medicinal products (e.g. levetiracetam) is recommended. Infections In patients receiving blinatumomab, serious infections, including sepsis, pneumonia, bacteraemia, opportunistic infections and catheter site infections have been observed, some of which were life- threatening or fatal. Adult patients with Eastern Cooperative Oncology Group (ECOG) performance status at baseline of 2 experienced a higher incidence of serious infections compared to patients with ECOG performance status of < 2. There is limited experience with BLINCYTO in patients with an active uncontrolled infection. Patients receiving BLINCYTO should be clinically monitored for signs and symptoms of infection and treated appropriately. Management of infections may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2). Cytokine release syndrome and infusion reactions Cytokine release syndrome (CRS) which may be life-threatening or fatal (grade ≥ 4) has been reported in patients receiving BLINCYTO (see section 4.8). Serious adverse events that may be signs and symptoms of CRS included pyrexia, asthenia, headache, hypotension, total bilirubin increased, and nausea; uncommonly, these events led to BLINCYTO discontinuation. The median time to onset of a CRS event was 2 days. Patients should be closely monitored for signs or symptoms of these events. Disseminated intravascular coagulation (DIC) and capillary leak syndrome (CLS, e.g. hypotension, hypoalbuminaemia, oedema and haemoconcentration) have been commonly associated with CRS (see section 4.8). Patients experiencing capillary leak syndrome should be managed promptly. Haemophagocytic histiocytosis/macrophage activation syndrome (MAS) has been uncommonly reported in the setting of CRS. Infusion reactions may be clinically indistinguishable from manifestations of CRS (see section 4.8). The infusion reactions were generally rapid, occurring within 48 hours after initiating infusion. However some patients reported delayed onset of infusion reactions or in later cycles. Patients should be observed closely for infusion reactions, especially during the initiation of the first and second treatment cycles and treated appropriately. Anti-pyretic use (e.g. paracetamol) is recommended to help reduce pyrexia during the first 48 hours of each cycle. To mitigate the risk of CRS, it is important to initiate BLINCYTO (cycle 1, days 1-7) at the recommended starting dose in section 4.2. Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2). Tumour lysis syndrome Tumour lysis syndrome (TLS), which may be life-threatening or fatal (grade ≥ 4) has been observed in patients receiving BLINCYTO. 9 Appropriate prophylactic measures including aggressive hydration and anti-hyperuricaemic therapy (such as allopurinol or rasburicase) should be used for the prevention and treatment of TLS during BLINCYTO treatment, especially in patients with higher leukocytosis or a high tumour burden. Patients should be closely monitored for signs or symptoms of TLS, including renal function and fluid balance in the first 48 hours after the first infusion. In clinical studies, patients with moderate renal impairment showed an increased incidence of TLS compared with patients with mild renal impairment or normal renal function. Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2). Neutropenia and febrile neutropenia Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO. Laboratory parameters (including, but not limited to white blood cell count and absolute neutrophil count) should be monitored routinely during BLINCYTO infusion, especially during the first 9 days of the first cycle, and treated appropriately. Elevated liver enzymes Treatment with BLINCYTO was associated with transient elevations in liver enzymes. The majority of the events were observed within the first week of treatment initiation and did not require interruption or discontinuation of BLINCYTO (see section 4.8). Monitoring of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment especially during the first 48 hours of the first 2 cycles should be performed. Management of these events may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2). Pancreatitis Pancreatitis, life-threatening or fatal, has been reported in patients receiving BLINCYTO in clinical trials and the post-marketing setting. High-dose steroid therapy may have contributed, in some cases, to the pancreatitis. Patients should be closely monitored for signs and symptoms of pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2). Leukoencephalopathy including progressive multifocal leukoencephalopathy Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and anti-leukaemic chemotherapy (including systemic high dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown. Due to the potential for progressive multifocal leukoencephalopathy (PML), patients should be monitored for signs and symptoms. In case of suspicious events consider consultation with a neurologist, brain MRI and examination of cerebral spinal fluid (CSF), see section 4.8. Immunisations The safety of immunisation with live viral vaccines during or following BLINCYTO therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until recovery of B-lymphocytes to normal ranges following last treatment cycle. 10 Due to the potential depletion of B-cells in newborns following exposure to blinatumomab during pregnancy, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell count has recovered (see section 4.6). Contraception Women of childbearing potential have to use effective contraception during and for at least 48 hours, after treatment with BLINCYTO (see section 4.6). Medication errors Medication errors have been observed with BLINCYTO treatment. It is very important that the instructions for preparation (including reconstitution and dilution) and administration are strictly followed to minimise medication errors (including underdose and overdose) (see section 4.2). Excipients with known effect This medicinal product provides less than 1 mmol (23 mg) sodium over a 24 hour infusion i.e. “essentially sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug interaction studies have been performed. Results from an in vitro test in human hepatocytes suggest that blinatumomab did not affect CYP450 enzyme activities. Initiation of BLINCYTO treatment causes transient release of cytokines during the first days of treatment that may suppress CYP450 enzymes. Patients who are receiving medicinal products that are CYP450 and transporter substrates with a narrow therapeutic index should be monitored for adverse effects (e.g. warfarin) or drug concentrations (e.g. cyclosporine) during this time. The dose of the concomitant medicinal product should be adjusted as needed. 4.6 Fertility, pregnancy and lactation Pregnancy Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study conducted in mice, the murine surrogate molecule crossed the placenta and did not induce embryotoxicity, or teratogenicity (see section 5.3). The expected depletions of B and T-cells were observed in the pregnant mice but haematological effects were not assessed in foetuses. There are no data from the use of blinatumomab in pregnant women. Blinatumomab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during and for at least 48 hours after treatment with blinatumomab (see section 4.4). In case of exposure during pregnancy, depletion of B-cells may be expected in newborns due to the pharmacological properties of the product. Consequently, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell count has recovered (see section 4.4). 11 Breast-feeding It is unknown whether blinatumomab or metabolites are excreted in human milk. Based on its pharmacological properties, a risk to the suckling child cannot be excluded. Consequently, as a precautionary measure, breast-feeding is contraindicated during and for at least 48 hours after treatment with blinatumomab. Fertility No studies have been conducted to evaluate the effects of blinatumomab on fertility. No adverse effects on male or female mouse reproductive organs in 13 week toxicity studies with the murine surrogate molecule (see section 5.3). 4.7 Effects on ability to drive and use machines Blinatumomab has major influence on the ability to drive and use machines. Confusion and disorientation, coordination and balance disorders, risk of seizures and disturbances in consciousness can occur (see section 4.4). Due to the potential for neurologic events, patients receiving blinatumomab should refrain from driving, engaging in hazardous occupations or activities such as driving or operating heavy or potentially dangerous machinery while blinatumomab is being administered. Patients must be advised that they may experience neurologic events. 4.8 Undesirable effects Summary of the safety profile The adverse reactions described in this section were identified in clinical studies of patients with B-precursor ALL (N = 843). The most serious adverse reactions that may occur during blinatumomab treatment include: infections (24.8%), neurologic events (13.8%), neutropenia/febrile neutropenia (10.1%), cytokine release syndrome (3.3%), and tumour lysis syndrome (0.7%). The most common adverse reactions were: pyrexia (69.2%), infusion-related reactions (43.4%), infections – pathogen unspecified (42.1%), headache (32.9%), anaemia (22.8%), thrombocytopenia (20.9%), febrile neutropenia (20.2%), oedema (20.0%), neutropenia (19.7%), rash (16.7%), increased liver hepatic enzymes (16.1%), bacterial infectious disorders (15.4%), tremor (15.2%), cough (15.1%), leukopenia (13.4%), back pain (13.3%), chills (13.0%), hypotension (12.8%), viral infectious disorders (12.7%), decreased immunoglobulins (12.5%), cytokine release syndrome (11.6%), tachycardia (11.3%), insomnia (10.7%), fungal infectious disorders (10.6%) and pain in extremity (10.2%). Tabulated list of adverse reactions Adverse reactions are presented below by system organ class and frequency category. Frequency categories were determined from the crude incidence rate reported for each adverse reaction in clinical studies of patients with B-precursor ALL (N = 843). Within each system organ class, adverse reactions are presented in order of decreasing seriousness. 12 MedDRA system organ class Very common (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) Infections and infestations Bacterial infectionsa, b Fungal infectionsa, b Viral infectionsa, b Infections - pathogen unspecifieda, b Sepsis Pneumonia Blood and lymphatic system disorders Febrile neutropenia Anaemia1 Neutropenia2 Thrombocytopenia3 Leukopenia4 Leukocytosis5 Lymphopenia6 Lymphadenopathy Histiocytosis haematophagic Immune system disorders Cytokine release syndromea Hypersensitivity Cytokine storm Metabolism and nutrition disorders Tumour lysis syndrome Psychiatric disordersa Insomnia Confusional state Disorientation Nervous system disordersa Headache Tremor Encephalopathy Aphasia Paraesthesia Seizure Cognitive disorder Memory impairment Dizziness Somnolence Hypoaesthesia Cranial nerve disorderb Ataxia Speech disorder Cardiac disorders Tachycardia7 Vascular disorders Hypotension8 Hypertension9 Flushing Capillary leak syndrome Respiratory, thoracic and mediastinal disorders Cough Dyspnoea Productive cough Respiratory failure Wheezing Dyspnoea exertional Acute respiratory failure Gastrointestinal disorders Nausea Diarrhoea Vomiting Constipation Abdominal pain Pancreatitisa Hepatobiliary disorders Hyperbilirubinaemiaa, 10 Skin and subcutaneous tissue disorders Rash11 Musculoskeletal and connective tissue disorders Back pain Pain in extremity Bone pain General disorders and administration site conditions Pyrexia12 Chills Oedema13 Chest pain14 Pain 13 MedDRA system organ class Very common (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) Investigations Hepatic enzyme increaseda, 15 Decreased immunoglobulins16 Weight increased Blood alkaline phosphatase increased Injury, poisoning and procedural complications Infusion-related reactions17 a Additional information is provided in “Description of selected adverse reactions”. b MedDRA high level group terms (MedDRA version 18.1). Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse reaction in the table above. The terms contributing to the relevant adverse reaction are indicated below: 1 Anaemia includes anaemia and haemoglobin decreased. 2 Neutropenia includes neutropenia and neutrophil count decreased. 3 Thrombocytopenia includes platelet count decreased and thrombocytopenia. 4 Leukopenia includes leukopenia and white blood cell count decreased. 5 Leukocytosis includes leukocytosis and white blood cell count increased. 6 Lymphopenia includes lymphocyte count decreased and lymphopenia. 7 Tachycardia includes sinus tachycardia, supraventricular tachycardia and tachycardia. 8 Hypotension includes blood pressure decreased and hypotension. 9 Hypertension includes blood pressure increased and hypertension. 10 Hyperbilirubinaemia includes blood bilirubin increased and hyperbilirubinaemia. 11 Rash includes erythema, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular and rash pruritic. 12 Pyrexia includes body temperature increased and pyrexia. 13 Oedema includes face oedema, generalised oedema, oedema and oedema peripheral. 14 Chest pain includes chest discomfort, chest pain, musculoskeletal chest pain and non-cardiac chest pain. 15 Hepatic enzyme increased includes alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased and transaminases increased. 16 Decreased immunoglobulins includes blood immunoglobulin G decreased, globulins decreased, hypogammaglobulinaemia, hypoglobulinaemia and immunoglobulins decreased. 17 Infusion-related reactions is a composite term that includes the term infusion-related reaction and the following events occurring with the first 48 hours of infusion and event lasted <=2 days: pyrexia, cytokine release syndrome, hypotension, myalgia, acute kidney injury, hypertension, rash, tachypnea, swelling face, face oedema and rash erythematous. Description of selected adverse reactions Neurologic events In BLINCYTO-treated patients in the randomised phase III clinical study (N = 267) and the single arm phase II clinical study (N = 189), 66.0% of patients experienced one or more neurologic adverse reactions (including psychiatric disorders), primarily involving the central nervous system. Serious and grade ≥ 3 neurologic adverse reactions were observed in 11.6% and 12.1% of patients respectively, of which the most common serious adverse reactions were encephalopathy, tremor, aphasia, and confusional state. The majority of neurologic events (80.5 %) were clinically reversible and resolved following interruption of BLINCYTO. The median time to the first event was within the first two weeks of treatment. One case of fatal encephalopathy has been reported in an earlier phase II clinical single-arm study. Neurologic events were reported for 71.5% of adult patients with MRD positive B-precursor ALL (N = 137) of which 22.6% were considered serious. Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 16.1% and 2.2% of adult patients with MRD positive B-precursor ALL. For clinical management of neurologic events, see section 4.4. 14 Infections Life-threatening or fatal (grade ≥ 4) viral, bacterial and fungal infections have been reported in patients treated with BLINCYTO. In addition, reactivations of virus infection (e.g. Polyoma (BK)) have been observed in the phase II clinical study in adults with Philadelphia chromosome negative relapsed or refractory B-precursor ALL. Patients with Philadelphia chromosome negative relapsed or refractory B-precursor ALL with ECOG performance status at baseline of 2 experienced a higher incidence of serious infections compared to patients with ECOG performance status of < 2. For clinical management of infections, see section 4.4. Cytokine release syndrome (CRS) In BLINCYTO-treated patients in the randomised phase III clinical study (N = 267) and the single arm phase II clinical study (N = 189), serious CRS reactions were reported in 2.4% of patients with a median time to onset of 2 days. Cytokine release syndrome was reported in 2.9% of adult patients with MRD positive B-precursor ALL (N = 137). Grade 3 and serious events were reported for 1.5% each of adult patients with MRD positive B-precursor ALL; no grade ≥ 4 events were reported. Capillary leak syndrome was observed in 1 patient in the phase II clinical study in adult patients with relapsed or refractory B-precursor ALL and in 1 patient in the phase 2 clinical study in adult patients with MRD positive B-precursor ALL. For clinical management of CRS, see section 4.4. Elevated liver enzymes In BLINCYTO-treated patients in the randomised phase III clinical study (N = 267) and the single arm phase II clinical study (N = 189), 22.4% of patients reported elevated liver enzymes and associated signs/symptoms. Serious and grade ≥ 3 adverse reactions (such as ALT increased, AST increased, and blood bilirubin increased) were observed in 1.5% and 13.6% of patients respectively. The median time to onset to the first event was 4 days from the start of BLINCYTO treatment initiation. Elevated liver enzyme events were reported for 12.4% of adult patients with MRD positive B-precursor ALL (N = 137). Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 8.0% and 4.4% of adult patients with MRD positive B-precursor ALL. The duration of hepatic adverse reactions has generally been brief and with rapid resolution, often when continuing uninterrupted treatment with BLINCYTO. For clinical management of elevated liver enzymes, see section 4.4. Pancreatitis Pancreatitis, life-threatening or fatal, has been reported in patients receiving BLINCYTO in the clinical trials and the post-marketing settings. The median time to onset was 7.5 days. For clinical management of pancreatitis, see section 4.4. Leukoencephalopathy including progressive multifocal leukoencephalopathy Leukoencephalopathy has been reported. Patients with brain MRI/CT findings consistent with leukoencephalopathy experienced concurrent serious adverse events including confusional state, tremor, cognitive disorder, encephalopathy, and convulsion. Although there is a potential for the development of progressive multifocal leukoencephalopathy (PML), no confirmed case of PML has been reported in the clinical studies. 15 Paediatric population BLINCYTO has been evaluated in paediatric patients with relapsed or refractory B-precursor ALL in a phase I/II dose escalation/evaluation study, in which 70 paediatric patients, aged 7 months to 17 years, were treated with the recommended dosage regimen. The most frequently reported serious adverse events were pyrexia (11.4%), febrile neutropenia (11.4%), cytokine release syndrome (5.7%), sepsis (4.3%), device-related infection (4.3%), overdose (4.3%), convulsion (2.9%), respiratory failure (2.9%), hypoxia (2.9%), pneumonia (2.9%), and multi-organ failure (2.9%). The adverse reactions in BLINCYTO-treated paediatric patients were similar in type to those seen in adult patients. Adverse reactions that were observed more frequently (≥ 10% difference) in the paediatric population compared to the adult population were anaemia, thrombocytopenia, leukopenia, pyrexia, infusion-related reactions, weight increase, and hypertension. The type and frequency of adverse events were similar across different paediatric sub-groups (gender, age, geographic region). At a dose higher than the recommended dose, a case of fatal cardiac failure occurred in the setting of life-threatening cytokine release syndrome (CRS) and tumour lysis syndrome (TLS), see section 4.4. Other special populations There is limited experience with BLINCYTO in patients ≥ 75 years of age. Generally, safety was similar between elderly patients (≥ 65 years of age) and patients less than 65 years of age treated with BLINCYTO. However, elderly patients may be more susceptible to serious neurologic events such as cognitive disorder, encephalopathy and confusion. Elderly patients with MRD-positive ALL treated with BLINCYTO may have an increased risk of hypogammaglobulinaemia compared to younger patients. It is recommended that immunoglobulin levels are monitored in elderly patients during treatment with BLINCYTO. The safety of BLINCYTO has not been studied in patients with severe renal impairment. Immunogenicity In clinical studies of adult ALL patients treated with BLINCYTO, less than 3% tested positive for anti-blinatumomab antibodies. Six of those patients had anti-blinatumomab antibodies with in vitro neutralising activity. No anti-blinatumomab antibodies were detected in clinical studies of paediatric patients with relapsed or refractory ALL treated with blinatumomab. If formation of anti-blinatumomab antibodies with a clinically significant effect is suspected, contact the Marketing Authorisation Holder to discuss antibody testing. Contact details are provided in section 6 of the package leaflet. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 16 4.9 Overdose Overdoses have been observed including one patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. Overdoses resulted in adverse reactions which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, the infusion should be temporarily interrupted and patients should be monitored. Reinitiation of BLINCYTO at the correct therapeutic dose should be considered when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion (see section 4.2). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, other Antineoplastic agents, ATC code: L01XC19. Mechanism of action Blinatumomab is a bispecific T-cell engager antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B-cells. The anti-tumour activity of blinatumomab immunotherapy is not dependent on T-cells bearing a specific TCR or on peptide antigens presented by cancer cells, but is polyclonal in nature and independent of human leukocyte antigen (HLA) molecules on target cells. Blinatumomab mediates the formation of a cytolytic synapse between the T-cell and the tumour cell, releasing proteolytic enzymes to kill both proliferating and resting target cells. Blinatumomab is associated with transient upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, and results in elimination of CD19+ cells. Pharmacodynamic effects Consistent immune-pharmacodynamic responses were observed in patients studied. During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterised by T-cell activation and initial redistribution, rapid peripheral B-cell depletion, and transient cytokine elevation. Peripheral T-cell redistribution (i.e. T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of blinatumomab infusion or dose escalation. T-cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in the majority of patients. Increase of T-cell counts above baseline (T-cell expansion) was observed in few patients. Peripheral B-cell counts decreased rapidly to an undetectable level during treatment at doses ≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week treatment-free period between treatment cycles. Incomplete depletion of B-cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few non-responders at higher doses. Peripheral lymphocytes were not measured in paediatric subjects. Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α and IFN-γ were measured and, IL-6, IL-10 and IFN-γ were most elevated. Transient elevation of cytokines was observed in the first two days following start of blinatumomab infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation 17 occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle. Clinical efficacy and safety Philadelphia chromosome negative relapsed or refractory B-precursor ALL A total of 456 patients aged ≥ 18 years of age with relapsed or refractory B-precursor ALL were exposed to BLINCYTO during the phase II and phase III clinical studies described below. The safety and efficacy of BLINCYTO compared to standard of care (SOC) chemotherapy were evaluated in a randomised, open-label, multicentre, phase III study. Eligible patients were ≥ 18 years of age and ECOG status ≤ 2 with relapsed or refractory B-cell precursor ALL (had > 5% blasts in the bone marrow and either relapse at any time after allogeneic HSCT, untreated first relapse with first remission duration < 12 months, or refractory to last therapy). Patients were randomised 2:1 to receive BLINCYTO or 1 of 4 prespecified, investigator-selected, SOC backbone chemotherapy regimens. Randomisation was stratified by age (< 35 years versus ≥ 35 years of age), prior salvage therapy (yes versus no), and prior allogeneic HSCT (yes versus no) as assessed at the time of consent. The demographics and baseline characteristics were well-balanced between the two arms (see table 1). Table 1. Demographics and baseline characteristics in phase III study Characteristic BLINCYTO (N = 271) SOC chemotherapy (N = 134) Age Median, years (min, max) 37 (18, 80) 37 (18, 78) Mean, years (SD) 40.8 (17.1) 41.1 (17.3) ≥ 65 Years, n (%) 33 (12.2) 15 (11.2) Prior salvage therapy 164 (60.5) 80 (59.7) 0 114 (42.1) 65 (48.5) 1 91 (33.6) 43 (32.1) ≥ 2 66 (24.3) 26 (19.4) Prior alloHSCT 94 (34.7) 46 (34.3) ECOG status - n (%) 0 96 (35.4) 52 (38.8) 1 134 (49.4) 61 (45.5) 2 41 (15.1) 20 (14.9) Refractory status - n (%) Primary refractory 46 (17.0) 27 (20.1) Refractory to salvage therapy 87 (32.1) 34 (25.4) Maximum of central/local bone marrow blasts - n (%) ≥ 50% 201 (74.2) 104 (77.6) AlloHSCT = allogeneic haematopoietic stem cell transplantation SOC = standard of care BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose adjustment was possible in case of adverse events. Of the 267 patients who received BLINCYTO, the mean number of completed treatment cycles was 2.0; of the 109 patients who received SOC chemotherapy, the mean number of treatment cycles was 1.3. 18 The primary endpoint was overall survival (OS). The median OS was 4.0 months (95% CI: 2.9, 5.3) in the SOC chemotherapy arm compared with 7.7 months (95% CI: 5.6, 9.6) in the BLINCYTO arm. The hazard ratio (95% CI) was 0.71 (0.55, 0.93) between treatment arms favouring BLINCYTO, indicated a 29% reduction in hazard rate in the BLINCYTO arm (p-value = 0.012 (stratified log-rank test)), see figure 1. Consistency in OS results was shown in subgroups by stratification factors. Consistent results were observed after censoring at the time of HSCT; median OS, censored at the time of HSCT, was 6.9 months (95% CI: 5.3, 8.8) in the BLINCYTO group and 3.9 months (95% CI: 2.8, 4.9) in the SOC group (HR, 0.66; 95% CI: 0.50, 0.88; p value = 0.004). The mortality rate following alloHSCT among all responders who did not receive anti-leukemic therapy was 10/38 (26.3%; 95% CI: 13.4, 43.1) in the BLINCYTO group and 3/12 (25%; 95% CI: 5.5, 57.2) in the SOC group; such mortality rate at 100 days post alloHSCT was 4/38 (12.4%; 95% CI: 4.8%, 29.9%) in the BLINCYTO group and 0/12 (0%; 95% CI: not estimable) in the SOC group. Efficacy results from other key endpoints in the study are summarised in table 2. Figure 1. Kaplan-Meier curve of overall survival Table 2. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome negative relapsed or refractory B-cell precursor ALL BLINCYTO (N = 271) SOC chemotherapy (N = 134) Complete remission (CR) CRa/CRh*b/CRic, n (%) [95% CI] 119 (43.9) (37.9, 50.0) 33 (24.6) (17.6, 32.8) Treatment difference [95% CI] 19.3 (9.9, 28.7) p-value < 0.001 CR, n (%) [95% CI] 91 (33.6) (28.0, 39.5) 21 (15.7) (10.0, 23.0) Treatment difference [95% CI] 17.9 (9.6 - 26.2) p-value < 0.001 Event-free survivald 6-month estimate % [95% CI] 30.7 (25.0, 36.5) 12.5 (7.2, 19.2) 18-months estimate % [95% CI] 9.5 (5.1, 15.6) 7.9 (3.7, 14.2) HR [95% CI] 0.55 (0.43, 0.71) Number of subjects at Risk Months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 S ur vi va l P ro ba bi lit y Median OS, mo 7.7 (5.6, 9.6) 4.0 (2.9, 5.3) HR (BLINCYTO/SOC Chemo) (95% CI) 0.71 (0.55, 0.93) p-value (2-sided) 0.012 BLINCYTO 271 176 124 79 45 27 9 4 0 0 SOC Chemo 134 71 41 27 17 7 4 1 0 0 0 3 6 9 12 15 18 21 24 27 BLINCYTO (N=271) SOC Chemo (N=134) BLINCYTO SOC Chemo A censored subject is indicated by a Vertical Bar l. GRH0358 v1 19 BLINCYTO (N = 271) SOC chemotherapy (N = 134) Duration of haematological response- Median time to event [95% CI] CR 8.3 (5.7, 10.7) 7.8 (2.2, 19.0) CR/CRh*/CRi 7.3 (5.8, 9.9) 4.6 (1.8, 19.0) MRDe response for CR/CRh*/CRi MRD evaluable patients (%) [95% CI]f 74/97 (76.3) (66.6, 84.3) 16/33 (48.5) (30.8, 66.5) Duration of MRD response- Median time to event [95% CI] 4.5 months (3.6, 9.0) 3.8 months (1.9, 19.0) Postbaseline alloHSCT - n (%) Overall subjects 65 (24) 32 (23.9) Hematological responders (CR/CRh*/CRi) 50 (42.0) 18 (54.5) Time to alloHSCT among all transplanted patients Median time to event (Interquartile range) 3.7 months (3.0, 5.3) (N = 65) 3.1 months (2.6, 4.3) (N = 32) Time to alloHSCT among CR/CRh*/CRi responders Median time to event [95% CI] (KM estimate) 11.3 months (5.2, NE) (N = 119) 3.6 months (2.3, 7.2) (N = 33) 100 day mortality after alloHSCT n/N (%), [95% CI] 4/38, 12.4% (4.8, 29.9) 0/12, 0.0% (0.0, NE) a. CR was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] > 1,000/microlitre). b. CRh* (complete remission with partial haematologic recovery) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microlitre and ANC > 500/microlitre). c. CRi (complete remission with incomplete haematologic recovery) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and incomplete recovery of peripheral blood counts (platelets > 100,000/microlitre or ANC > 1,000/microlitre). d. EFS time was calculated from the time of randomisation until the date of disease assessment indicating a relapse after achieving a CR/CRh*/CRi or death, whichever is earlier. Subjects who fail to achieve a CR/CRh*/CRi within 12 weeks of treatment initiation are considered treatment failures and assigned an EFS duration of 1 day. e. MRD (minimum residual disease) response was defined as MRD by PCR or flow cytometry < 1 x 10-4. f. Patients who achieved CR/CRh*/CRi and had an evaluable post baseline MRD assessment. Health related quality of life In this open-label study, Health related quality of life (HRQoL) reported by patients were measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30). In a post-hoc sensitivity analysis, compared to SOC, BLINCYTO consistently delayed the time to clinically meaningful deterioration of HRQoL (≥ 10-point worsening from baseline) for global health status [median BLINCYTO versus SOC: 8.1 months versus 1.0 month; HR = 0.60 (95% CI = 0.42, 0.85)], functional scales, symptom scales and individual items. Because the health-related quality of life results are based on a post-hoc sensitivity analysis, the results should be interpreted with caution. BLINCYTO was also evaluated in an open-label, multicentre, single-arm phase II study of 189 patients. Eligible patients were ≥ 18 years of age with Philadelphia chromosome negative relapsed or refractory B-precursor ALL (relapsed with first remission duration of ≤ 12 months in first salvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of allogeneic HSCT, and had ≥ 10% blasts in bone marrow). 20 Premedication, BLINCYTO dose per treatment cycle and route of administration were identical to those in the phase III study. Patients were premedicated with a mandatory cerebrospinal fluid prophylaxis consisting of an intrathecal regimen according to institutional or national guidelines within 1 week prior to start of BLINCYTO treatment. BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose adjustment was possible in the case of adverse events. The treated population included 189 patients who received at least 1 infusion of BLINCYTO; the mean number of cycles per patient was 1.6. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. Among treated patients, the median age was 39 years (range: 18 to 79 years, including 25 patients ≥ 65 years of age), 64 of 189 (33.9%) had undergone HSCT prior to receiving BLINCYTO and 32 of 189 (16.9%) had received more than 2 prior salvage therapies. The primary endpoint was the complete remission/complete remission with partial haematological recovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Eighty-one of 189 (42.9%) patients achieved CR/CRh* within the first 2 treatment cycles with the majority of responses (64 of 81) occurring within 1 cycle of treatment. In the elderly population (≥ 65 years of age) 11 of 25 patients (44.0%) achieved CR/CRh* within the first 2 treatment cycles (see section 4.8 for safety in elderly). Four patients achieved CR during consolidation cycles, resulting in a cumulative CR rate of 35.4% (67/189; 95% CI: 28.6% - 42.7%). Thirty-two of 189 (17%) patients underwent allogeneic HSCT in CR/CRh* induced with BLINCYTO (see table 3). Table 3. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome negative relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL) n (%) n = 189 95% CI Complete remission (CR)1/Complete remission with partial haematological recovery (CRh*)2 81 (42.9%) [35.7% - 50.2%] CR 63 (33.3%) [26.7% - 40.5%] CRh* 18 (9.5%) [5.7% - 14.6%] Blast free hypoplastic or aplastic bone marrow3 17 (9%) [5.3% - 14.0%] Partial remission4 5 (2.6%) [0.9% - 6.1%] Relapse5-free survival (RFS) for CR/CRh* 5.9 months [4.8 to 8.3 months] Overall survival 6.1 months [4.2 to 7.5 months] 1. CR was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] > 1,000/microlitre). 2. CRh* was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microlitre and ANC > 500/microlitre). 3. Blast free hypoplastic or aplastic bone marrow was defined as bone marrow blasts ≤ 5%, no evidence of disease, insufficient recovery of peripheral blood counts: platelets ≤ 50,000/microlitre and/or ANC ≤ 500/microlitre. 4. Partial remission was defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline. 5. Relapse was defined as haematological relapse (blasts in bone marrow greater than 5% following CR) or an extramedullary relapse. In a prespecified exploratory analysis, 60 of 73 MRD evaluable patients with CR/CRh* (82.2%) also had a MRD response (defined as MRD by PCR < 1 x 10-4). Patients with prior allogeneic HSCT had similar response rates to those without prior HSCT, older patients had similar response rates to younger patients, and no substantial difference was observed in remission rates based on the number of lines of prior salvage treatment. In patients with non-CNS/non-testes extramedullary disease (defined as at least 1 lesion ≥ 1.5 cm) at screening (N = 8/189) clinical response rates (25% [95% CI: 3.2-65.1] were lower compared with patients with no evidence of extramedullary disease (N = 181, 43.6% [95% CI: 36.3 - 51.2]) (see figure 2). 21 Patients with the highest tumour burden as measured by the percentage of bone marrow blast cells at baseline (≥ 90%) still had a clinically meaningful response with a CR/CRh* rate of 21.6% (CI 12.9 - 32.7) (see figure 2). Patients with low tumour burden (< 50%) responded best to BLINCYTO treatment with CR/CRh* rate of 72.9% (CI 59.7 - 83.6). Figure 2. Forest plot of CR/CRh* rate during the first two cycles for study MT103-211 (primary analysis set) n = number of patients who achieved CR or CRh* in the first two cycles of treatment in the specified subgroup. N = total number of patients in the specified subgroup. There is limited data in patients with late first relapse of B-precursor ALL defined as a relapse occurring more than 12 months after first remission or more than 12 months after HSCT in the first remission. In clinical phase II studies, 88.9% (8/9) of patients with late first relapse as defined in the individual studies achieved CR/CRh* within the first 2 treatment cycles with 62.5% (6/9) achieving MRD response and 37.5% (3/9) undergoing allogeneic HSCT after treatment with BLINCYTO. The median overall survival (OS) was 17.7 months (CI 3.1 - not estimable). In the randomised, open-label, multicentre, phase III study, 70% (7/10) of post-transplant patients in late first relapse treated with BLINCYTO compared to 20% (1/5) treated with SOC chemotherapy achieved CR/CRh* within the first 2 treatment cycles. Fifty percent (5/10) compared to 0% (0/5) achieved MRD response and 20% (2/10) compared to 40% (2/5) underwent allogeneic HSCT after treatment. The median OS was 15.6 months (CI 5.5 – not estimable) for the BLINCYTO group and 5.3 months (CI 1.1 – not estimable) for the SOC chemotherapy group. MRD positive B-precursor ALL The safety and efficacy of BLINCYTO in adult patients with MRD positive B-precursor ALL were evaluated in an open-label, multicentre, single-arm study. Eligible patients were ≥ 18 years of age with no prior HSCT, had received at least 3 blocks of standard ALL induction therapy, were in complete haematologic remission (defined as < 5% blasts in bone marrow, absolute neutrophil count ≥ 1,000/microlitres, platelets ≥ 50,000/microlitres, and haemoglobin level ≥ 9 g/dL) and had molecular failure or molecular relapse (defined as MRD ≥ 10-3), see table 4. MRD status at screening was determined from bone marrow aspirations using flow cytometry or polymerase chain reaction (PCR) at a minimum sensitivity of 10-4 based on local site evaluations. A central laboratory subsequently confirmed MRD levels by PCR. Final interpretation of MRD results followed EuroMRD Consortium guidelines. 0 20 40 60 80 100 Subgroup Bone Marrow Blast Infiltration (Central Lab) <50% ≥50% to <75% ≥75% to <90% ≥90% Extramedullary Disease at Baseline Yes No Overall Percent Achieving CR/CRh* Rate and 95% Confidence Interval (CI) n/N Rate (95% CI) 43/59 72.9% (59.7%-83.6%) 8/25 32.0% (14.9%-53.5%) 14/31 45.2% (27.3%-64.0%) 16/74 21.6% (12.9%-32.7%) 2/8 25.0% (3.2%-65.1%) 79/181 43.6% (36.3%-51.2%) 81/189 42.9% (35.7%-50.2%) GRH0148v2 22 Table 4. Demographics and baseline characteristics in MRD study Characteristic BLINCYTO (N = 116) Age Median, years (min, max) 45 (18, 76) Mean, years (SD) 44.6 (16.4) ≥ 65 years, n (%) 15 (12.9) Males, n (%) 68 (58.6) Race, n (%) Asian 1 (0.9) Other (mixed) 1 (0.9) White 102 (87.9) Unknown 12 (10.3) Relapse history n (%) Patients in 1st CR 75 (64.7) Patients in 2nd CR 39 (33.6) Patients in 3rd CR 2 (1.7) MRD level at baseline* n (%) ≥ 10-1 and < 1 9 (7.8) ≥ 10-2 and < 10-1 45 (38.8) ≥ 10-3 and < 10-2 52 (44.8) < 10-3 3 (2.6) Below lower limit of quantification 5 (4.3) Unknown 2 (1.7) * Centrally assessed in an assay with minimum sensitivity of 10-4 BLINCYTO was administered as a continuous intravenous infusion. Patients received BLINCYTO at a constant dose of 15 mcg/m2/day (equivalent to the recommended dosage of 28 mcg/day) for all treatment cycles. Patients received up to 4 cycles of treatment. Dose adjustment was possible in case of adverse events. The treated population included 116 patients who received at least one infusion of BLINCYTO; the mean number of completed treatment cycles was 1.8 (range: 1 to 4). The primary endpoint was the proportion of patients who achieved a complete MRD response within one cycle of BLINCYTO treatment. Eighty-eight out of 113 (77.9%) evaluable patients achieved a complete MRD response after one cycle of treatment; see table 5. Two subjects achieved a complete MRD response with 1 additional cycle of BLINCYTO. MRD response rates by age and MRD level at baseline subgroups were consistent with the results in the overall population. RFS in patients with Philadelphia chromosome negative B-precursor ALL at 18 months censored at HSCT or post- BLINCYTO chemotherapy was 54% (33%, 70%). RFS at 18 months not censored at HSCT or post- BLINCYTO chemotherapy was 53% (44%, 62%). Table 5. Efficacy results in patients ≥ 18 years of age with MRD positive B-precursor ALL Complete MRD responsea, n/N (%), [95% CI] 88/113b (77.9) [69.1, 85.1] ≥ 65 years old 12/15 (80.0) [51.9-95.7] Patients in 1st CR 60/73 (82.2) [71.5-90.2] Patients in 2nd CR 27/38 (71.1) [54.1-84.6] Patients in 3rd CR 1/2 (50.0) [1.3-98.7] Duration of complete MRD response [95% CI] 17.3 months [12.6, 23.3] a Complete MRD response was defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity of 10-4 b One hundred thirteen patients (97.4%; 113/116) were included in the primary endpoint full analysis set 23 Paediatric population The safety and efficacy of BLINCYTO were evaluated in an open-label, multicentre, single-arm study in 93 paediatric patients with relapsed or refractory B-precursor ALL (second or later bone marrow relapse, in any marrow relapse after allogeneic HSCT, or refractory to other treatments, and also with > 25% blasts in bone marrow). This was a two-part study, a dose-finding part to determine the appropriate dosing regimen, followed by a single-arm efficacy part using this regimen. BLINCYTO was administered as a continuous intravenous infusion. In the dose-finding part of the study, doses of up to 30 mcg/m2/day were evaluated. The recommended dose for the PK expansion and efficacy parts of the study was determined to be 5 mcg/m2/day on days 1-7 and 15 mcg/m2/day on days 8-28 for cycle 1, and 15 mcg/m2/day on days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. The treated population (in the dose-finding, PK expansion, and efficacy parts) included 70 patients who received at least 1 infusion of BLINCYTO at the recommended dose; the mean number of treatment cycles was 1.5. Among treated patients, the median age was 8 years (range: 7 months to 17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and 39 out of 70 (55.7%) had refractory disease. Most patients had a high tumour burden (≥ 50% leukaemic blasts in bone marrow) at baseline with a median of 75.5% bone marrow blasts. Twenty out of 70 (28.6%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out of 20 (85%) occurring within cycle 1 of treatment. Four patients achieved M1 bone marrow but did not meet the peripheral blood count recovery criteria for CR or CRh*. Eleven of the 20 patients (55%) who achieved CR/CRh* received an allogeneic HSCT. The CR/CRh* for patients less than 2 years of age was 40% (4/10), for patients 2 to 6 years was 30.0% (6/20); and for patients aged 7 to 17 years was 25% (10/40). 3 patients < 1 year of age refractory to prior treatment and without prior alloHSCT received one cycle of Blincyto at a dose of 5-15 µg/m2/day. None of the 3 subjects < 1 year old achieved a CR/CRh*, 1 patient had progressive disease (OS 2.3 months) and 2 were non-responders (OS 1.1 months and 8.7 months, respectively). The type of adverse events observed in infants were similar to those observed in the overall paediatric population. See table 6 for the efficacy results. Table 6. Efficacy results in patients < 18 years of age with relapsed or refractory B-cell precursor ALL N = 70 CRa/CRh*b, n (%) [95% CI] 20 (28.6%) [18.4% – 40.6%] CR, n (%) [95% CI] 11 (15.7%) [8.1% – 26.4%] CRh*, n (%) [95% CI] 9 (12.9%) [6.1% – 23.0%] Complete MRD response for CR /CRh*c, n1/n2d (%) [95% CI] 11/20 (55.0%) [31.5 – 76.9] CR, n1/n2d (%) [95% CI] 6/11 (54.5%) [23.4 – 83.3] CRh*, n1/n2d (%) [95% CI] 5/9 (55.6%) [21.2 – 86.3] Median relapsee-free survival (RFS)e for CR /CRh* [95% CI] 6.8 months [2.2 to 12.0 months] Median overall survival [95% CI] 7.5 months [4.0 to 11.8 months] 100-day mortality after alloHSCTf n/N (%), [95% CI] 1/6 (16.7%) [2.5% – 72.7%] a. CR was defined as M1 marrow (≤ 5% of blasts in the bone marrow), no evidence of circulating blasts or extramedullary disease, and full recovery of peripheral blood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] > 1,000/microlitre) and no relapse within 28 days. b. CRh*was defined as M1 marrow (≤ 5% of blasts in the bone marrow), no evidence of circulating blasts or extramedullary disease, and partial recovery of peripheral blood counts (platelets > 50,000/microlitre and ANC > 500/microlitre) and no relapse within 28 days. c. Complete MRD response No detectable signal for leukemic cells either by PCR or flow cytometry. 24 d. n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. One CR /CRh*responder with missing MRD data was considered as a MRD- nonresponder. e. Relapse was defined as haematological relapse (blasts in bone marrow greater than 25% following CR) or an extramedullary relapse. f. Only patients with HSCT in CR/CRh* remission (with no anti-leukemia agents used prior to HSCT) are included. 5.2 Pharmacokinetic properties The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day (approximately equivalent to 9-162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed/refractory ALL, the mean (SD) Css was 230 (359) pg/mL and 612 (532) pg/mL, respectively. The pharmacokinetics of blinatumomab in patients with MRD positive B-precursor ALL was similar to patients with relapsed or refractory ALL. Distribution The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) L with the continuous intravenous infusion of blinatumomab. Biotransformation The metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways. Elimination The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 2.92 (2.83) L/hour. The mean (SD) half-life was 2.11 (1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses. Body surface area, gender and age A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics on blinatumomab pharmacokinetics. Results suggest that age (7 months to 80 years) and gender do not influence the pharmacokinetics of blinatumomab. Body surface area (0.37 to 2.70 m2) influences the pharmacokinetics of blinatumomab. However the influence is negligible in adults and body surface area based dosing is recommended in the paediatric population. Renal impairment No formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal impairment. Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab clearance values between patients with moderate renal dysfunction and normal renal function. However high inter-patient variability was discerned (CV% up to 95.6%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function, no clinically meaningful impact of renal function on clinical outcomes is expected. 25 Hepatic impairment No formal pharmacokinetic studies of blinatumomab have been conducted in patients with hepatic impairment. Baseline ALT and AST levels were used to assess the effect of hepatic impairment on the clearance of blinatumomab. Population pharmacokinetic analysis suggested that there was no association between ALT or AST levels and the clearance of blinatumomab. Paediatric population The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m2/day in paediatric patients. At the recommended doses, the mean (SD) steady state concentration (Css) values were 162 (179) and 533 (392) pg/mL at 5 and 15 mcg/m2/day doses, respectively. The estimated mean (SD) volume of distribution (Vz), clearance (CL) and terminal half-life (t1/2,z) were 3.91 (3.36) L/m2, 1.88 (1.90) L/hr/m2 and 2.19 (1.53) hours, respectively. 5.3 Preclinical safety data Repeat-dose toxicity studies conducted with blinatumomab and the murine surrogate revealed the expected pharmacologic effects (including release of cytokines, decreases in leukocyte counts, depletion of B-cells, decreases in T-cells, decreased cellularity in lymphoid tissues). These changes reversed after cessation of treatment. Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity or teratogenicity. The expected depletions of B- and T-cells were observed in the pregnant mice but haematological effects were not assessed in foetuses. No studies have been conducted to evaluate treatment-related effects on fertility. There were no effects on male or female reproductive organs in toxicity studies with the murine surrogate. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder Citric acid monohydrate (E330) Trehalose dihydrate Lysine hydrochloride Polysorbate 80 Sodium hydroxide (for pH-adjustment) Solution (stabiliser) Citric acid monohydrate (E330) Lysine hydrochloride Polysorbate 80 Sodium hydroxide (for pH-adjustment) Water for injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 26 6.3 Shelf life Unopened vials 5 years Reconstituted solution Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C or 4 hours at or below 27°C. From a microbiological point of view, unless the method of reconstituting precludes the risks of microbial contamination, the reconstituted solution should be diluted immediately. If not diluted immediately, in-use storage times and conditions are the responsibility of the user. Diluted solution (prepared infusion bag) Chemical and physical in-use stability has been demonstrated for 10 days at 2°C - 8°C or 96 hours at or below 27°C. From a microbiological point of view, the prepared infusion bags should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in controlled and validated aseptic conditions. 6.4 Special precautions for storage Store and transport refrigerated (2°C - 8°C). Do not freeze. Store the vials in the original package in order to protect from light. For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Each BLINCYTO pack contains 1 vial of powder for concentrate for solution for infusion and 1 vial of solution (stabiliser): • 38.5 micrograms blinatumomab powder in a vial (type I glass) with a stopper (elastomeric rubber), seal (aluminium) and a flip off cap and • 10 mL solution in a vial (type I glass) with a stopper (elastomeric rubber), seal (aluminium) and a flip off cap. 6.6 Special precautions for disposal and other handling Aseptic preparation Aseptic handling must be ensured when preparing the infusion. Preparation of BLINCYTO should be: - performed under aseptic conditions by trained personnel in accordance with good practice rules especially with respect to the aseptic preparation of parenteral products. - prepared in a laminar flow hood or biological safety cabinet using standard precautions for the safe handling of intravenous agents. It is very important that the instructions for preparation and administration provided in this section are strictly followed to minimise medication errors (including underdose and overdose). 27 Special instructions to support accurate preparation • A solution (stabiliser) is provided inside the BLINCYTO package and is used to coat the pre- filled infusion bag prior to addition of reconstituted BLINCYTO. Do not use this solution (stabiliser) for reconstitution of BLINCYTO powder for concentrate. • The entire volume of the reconstituted and diluted BLINCYTO will be more than the volume to be administered to the patient (240 mL). This is to account for intravenous infusion line loss and to assure that the patient will receive the full dose of BLINCYTO. • When preparing an infusion bag, remove all air from infusion bag. This is particularly important when using an ambulatory infusion pump. • Use the specific volumes described in the reconstitution and dilution instructions below to minimise errors in calculation. Other instructions • BLINCYTO is compatible with polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes. • Pump specifications: The infusion pump to administer BLINCYTO solution for infusion should be programmable, lockable and have an alarm. Elastomeric pumps should not be used. • Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Preparation of the solution for infusion Specific reconstitution and dilution instructions are provided for each dose and infusion time. Verify the prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation section listed below. Table 7 provides instructions for patients weighing greater than or equal to 45 kg, whereas table 8 and table 9 provide instructions for patients weighing less than 45 kg. Follow the steps for reconstituting BLINCYTO and preparing the infusion bag detailed below table 9. Table 7. For patients weighing greater than or equal to 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag Sodium chloride 9 mg/mL (0.9%) solution for injection (starting volume) 250 mL (usual overfill volume of 265 to 275 mL) Solution (stabiliser) 5.5 mL Dose Infusion duration Infusion rate Reconstituted BLINCYTO (number of packages) 9 mcg/day 24 hours 10 mL/hour 0.83 mL (1) 48 hours 5 mL/hour 1.7 mL (1) 72 hours 3.3 mL/hour 2.5 mL (1) 96 hours 2.5 mL/hour 3.3 mL (2) 28 mcg/day 24 hours 10 mL/hour 2.6 mL (1) 48 hours 5 mL/hour 5.2 mL (2) 72 hours 3.3 mL/hour 8 mL (3) 96 hours 2.5 mL/hour 10.7 mL (4) 28 Table 8. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag for 5 mcg/m2/day dose Sodium chloride 9 mg/mL (0.9%) solution for injection (starting volume) 250 mL (usual overfill volume of 265 to 275 mL) Solution (stabiliser) 5.5 mL Dose Infusion duration Infusion rate BSA (m2) Reconstituted BLINCYTO (number of packages) 5 mcg/m2/day 24 hours 10 mL/hour 1.50 – 1.59 0.70 mL (1) 1.40 – 1.49 0.66 mL (1) 1.30 – 1.39 0.61 mL (1) 1.20 – 1.29 0.56 mL (1) 1.10 – 1.19 0.52 mL (1) 1.00 – 1.09 0.47 mL (1) 0.90 – 0.99 0.43 mL (1) 0.80 – 0.89 0.38 mL (1) 0.70 – 0.79 0.33 mL (1) 0.60 – 0.69 0.29 mL (1) 0.50 – 0.59 0.24 mL (1) 0.40 – 0.49 0.20 mL (1) 48 hours 5 mL/hour 1.50 – 1.59 1.4 mL (1) 1.40 – 1.49 1.3 mL (1) 1.30 – 1.39 1.2 mL (1) 1.20 – 1.29 1.1 mL (1) 1.10 – 1.19 1.0 mL (1) 1.00 – 1.09 0.94 mL (1) 0.90 – 0.99 0.85 mL (1) 0.80 – 0.89 0.76 mL (1) 0.70 – 0.79 0.67 mL (1) 0.60 – 0.69 0.57 mL (1) 0.50 – 0.59 0.48 mL (1) 0.40 – 0.49 0.39 mL (1) 72 hours 3.3 mL/hour 1.50 – 1.59 2.1 mL (1) 1.40 – 1.49 2.0 mL (1) 1.30 – 1.39 1.8 mL (1) 1.20 – 1.29 1.7 mL (1) 1.10 – 1.19 1.6 mL (1) 1.00 – 1.09 1.4 mL (1) 0.90 – 0.99 1.3 mL (1) 0.80 – 0.89 1.1 mL (1) 0.70 – 0.79 1 mL (1) 0.60 – 0.69 0.86 mL (1) 0.50 – 0.59 0.72 mL (1) 0.40 – 0.49 0.59 mL (1) 96 hours 2.5 mL/hour 1.50 – 1.59 2.8 mL (1) 1.40 – 1.49 2.6 mL (1) 1.30 – 1.39 2.4 mL (1) 1.20 – 1.29 2.3 mL (1) 1.10 – 1.19 2.1 mL (1) 1.00 – 1.09 1.9 mL (1) 0.90 – 0.99 1.7 mL (1) 0.80 – 0.89 1.5 mL (1) 0.70 – 0.79 1.3 mL (1) 0.60 – 0.69 1.2 mL (1) 0.50 – 0.59 0.97 mL (1) 0.40 – 0.49 0.78 mL (1) 29 Table 9. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag for 15 mcg/m2/day dose Sodium chloride 9 mg/mL (0.9%) (starting volume) 250 mL (usual overfill volume of 265 to 275 mL) Solution (stabiliser) 5.5 mL Dose Infusion duration Infusion rate BSA (m2) Reconstituted BLINCYTO (number of packages) 15 mcg/m2/day 24 hours 10 mL/hour 1.50 – 1.59 2.1 mL (1) 1.40 – 1.49 2.0 mL (1) 1.30 – 1.39 1.8 mL (1) 1.20 – 1.29 1.7 mL (1) 1.10 – 1.19 1.6 mL (1) 1.00 – 1.09 1.4 mL (1) 0.90 – 0.99 1.3 mL (1) 0.80 – 0.89 1.1 mL (1) 0.70 – 0.79 1.00 mL (1) 0.60 – 0.69 0.86 mL (1) 0.50 – 0.59 0.72 mL (1) 0.40 – 0.49 0.59 mL (1) 48 hours 5 mL/hour 1.50 – 1.59 4.2 mL (2) 1.40 – 1.49 3.9 mL (2) 1.30 – 1.39 3.7 mL (2) 1.20 – 1.29 3.4 mL (2) 1.10 – 1.19 3.1 mL (2) 1.00 – 1.09 2.8 mL (1) 0.90 – 0.99 2.6 mL (1) 0.80 – 0.89 2.3 mL (1) 0.70 – 0.79 2.0 mL (1) 0.60 – 0.69 1.7 mL (1) 0.50 – 0.59 1.4 mL (1) 0.40 – 0.49 1.2 mL (1) 72 hours 3.3 mL/hour 1.50 – 1.59 6.3 mL (3) 1.40 – 1.49 5.9 mL (3) 1.30 – 1.39 5.5 mL (2) 1.20 – 1.29 5.1 mL (2) 1.10 – 1.19 4.7 mL (2) 1.00 – 1.09 4.2 mL (2) 0.90 – 0.99 3.8 mL (2) 0.80 – 0.89 3.4 mL (2) 0.70 – 0.79 3.0 mL (2) 0.60 – 0.69 2.6 mL (1) 0.50 – 0.59 2.2 mL (1) 0.40 – 0.49 1.8 mL (1) 96 hours 2.5 mL/hour 1.50 – 1.59 8.4 mL (3) 1.40 – 1.49 7.9 mL (3) 1.30 – 1.39 7.3 mL (3) 1.20 – 1.29 6.8 mL (3) 1.10 – 1.19 6.2 mL (3) 1.00 – 1.09 5.7 mL (3) 0.90 – 0.99 5.1 mL (2) 0.80 – 0.89 4.6 mL (2) 0.70 – 0.79 4.0 mL (2) 0.60 – 0.69 3.4 mL (2) 0.50 – 0.59 2.9 mL (2) 0.40 – 0.49 2.3 mL (1) 30 BSA = body surface area These supplies are also required, but not included in the package • Sterile single-use disposable syringes • 21-23 gauge needle(s) (recommended) • Water for injections • Infusion bag with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection; o To minimise the number of aseptic transfers, use a 250 mL pre-filled infusion bag. BLINCYTO dose calculations are based on a usual overfill volume of 265 to 275 mL sodium chloride 9 mg/mL (0.9%) solution for injection. o Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes. • Polyolefin, PVC non-DEHP, or EVA intravenous tubing with a sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter. o Ensure that the tubing is compatible with the infusion pump. Reconstitution and preparation of BLINCYTO solution for infusion using an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection 1. Use an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection that usually contains a total volume of 265 to 275 mL. 2. To coat the infusion bag, using a syringe, aseptically transfer 5.5 mL of the solution (stabiliser) to the infusion bag. Gently mix the contents of the bag to avoid foaming. Discard the remaining solution (stabiliser) vial. 3. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate using 3 mL of water for injections. Direct the water for injections toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. • Do not reconstitute BLINCYTO powder for concentrate with the solution (stabiliser). • The addition of water for injections to the powder for concentrate results in a total volume of 3.08 mL for a final BLINCYTO concentration of 12.5 mcg/mL. 4. Visually inspect the reconstituted solution for particulate matter and discolouration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colourless-to-slightly yellow. Do not use if the solution is cloudy or has precipitated. 5. Using a syringe, aseptically transfer reconstituted BLINCYTO into the infusion bag (refer to table 7 to table 9 for the specific volume of reconstituted BLINCYTO). Gently mix the contents of the bag to avoid foaming. Discard any remaining BLINCYTO reconstituted solution. 6. Under aseptic conditions, attach the intravenous tubing to the infusion bag with the sterile 0.2 micron in-line filter. 7. Remove air from the infusion bag and prime the intravenous infusion line only with the prepared solution for infusion. Do not prime with sodium chloride 9 mg/mL (0.9%) solution for injection. 8. Store at 2°C - 8°C if not used immediately. 7. MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands 31 8. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1047/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 23 November 2015 Date of last renewal: 19 April 2018 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ http://www.ema.europa.eu/ 32 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 33 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Lonza Biologics plc 228 Bath Road Slough Berkshire, SL1 4DX UK Name and address of the manufacturers responsible for batch release Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands Amgen NV Telecomlaan 5-7 1831 Diegem Belgium B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. 34 An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures Prior to launch of BLINCYTO in each Member State, the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority. The MAH shall ensure that in each Member State where BLINCYTO is marketed, all healthcare professionals (HCP) and patients / caregivers who are expected to prescribe, dispense and use BLINCYTO are provided with the following educational packages: • Physician educational material • Pharmacist educational material • Nurse educational material • Patient / caregivers educational material • Patient alert card The physician educational material should contain: 1. A link to the Summary of Product Characteristics (SmPC) 2. The guide for physicians shall contain the following key elements: • Remarks on the importance of reporting ADRs • Information on treatment with BLINCYTO, administration and posology, duration of hospitalisation, interruption and / or permanent discontinuation of the treatment Medication errors (ME) • Data from clinical trials, causes of ME, frequency, severity and outcomes. • Reminder to counsel the patients on how to reduce the risk of ME while using the infusion pump. Neurologic events • Data from clinical trials, frequency and severity (grade 3 and 4 neurological toxicities were observed) • Recommendation to monitor patients for signs and symptoms of neurotoxicity • Management of neurotoxicity (including dose adjustment and dose interruption) • Recommendation for patients not to drive while receiving BLINCYTO and to contact immediately the treating physician if they experience neurological symptoms The pharmacist educational material should contain: 1. A link to the Summary of Product Characteristics (SmPC) 2. The guide for pharmacists, containing the following key elements: • Remarks on the importance of reporting ADRs • Detailed description of the reconstitution and preparation procedures of BLINCYTO infusion solution for intravenous administration under aseptic conditions, using aseptic techniques. The nurse educational material should contain: 1. A link to the Summary of Product Characteristics (SmPC) 2. The nurse educational guide, including the following key elements: • Remarks on the importance of reporting ADRs • Description of the administration procedures of BLINCYTO 35 • Description on patient’s monitoring and management of early signs and symptoms of neurological events • Recommendation for patients not to drive while receiving BLINCYTO and to contact immediately the treating physician/nurse if they experience neurological symptoms The patient (including caregivers) educational material should contain: 1. The patient information guide, including the following key elements: • Remarks on the importance of reporting ADRs • Description of the administration procedures of BLINCYTO and how to reduce the risk of ME while using the infusion pump. • Description of the main signs and / or symptoms of neurologic events and the importance of notifying the treating physician or nurse immediately if symptoms occur • Recommendation for patients not to drive while receiving BLINCYTO 2. A link to the package leaflet The patient alert card should contain: • A warning message for HCPs treating the patient at any time, including emergency conditions, that the patient is using BLINCYTO • Contact details of the BLINCYTO prescriber • BLINCYTO treatment start date • Remarks on the importance of reporting ADRs • Obligation to complete post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date Non-interventional post-authorisation safety study (PASS): Study 20150136: an observational study of blinatumomab safety and effectiveness, utilisation, and treatment practices* Q42021 * The study protocol needs to be developed and presented for PRAC review within 2 months after the EU Commission Decision. Description Due date Non-interventional post-authorisation safety study (PASS): The applicant should submit the final results of a follow-up observational study to further characterise the long-term safety of BLINCYTO including developmental aspects, HSCT and secondary malignancy in high-risk paediatric patients enrolled in Study 20120215*. Q42036 * The study protocol needs to be developed and presented for PRAC review within 3 months after the EU Commission Decision. 36 ANNEX III LABELLING AND PACKAGE LEAFLET 37 A. LABELLING 38 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion blinatumomab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of powder contains 38.5 micrograms of blinatumomab. After reconstitution with water for injections each vial contains 12.5 micrograms/mL of blinatumomab. 3. LIST OF EXCIPIENTS Powder: citric acid monohydrate (E330), trehalose dihydrate, lysine hydrochloride, polysorbate 80 and sodium hydroxide. Solution (stabiliser): citric acid monohydrate (E330), lysine hydrochloride, polysorbate 80, sodium hydroxide and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for concentrate and solution for solution for infusion 1 vial of powder. 1 vial of solution (stabiliser). Add to the sodium chloride bag only. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravenous use after reconstitution and dilution. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake the reconstituted solution. 8. EXPIRY DATE EXP 39 9. SPECIAL STORAGE CONDITIONS Store and transport refrigerated. Do not freeze. Store in the original carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1047/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 40 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS POWDER VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION BLINCYTO 38.5 mcg powder for concentrate blinatumomab IV after reconstitution and dilution 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER 41 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SOLUTION (STABILISER) VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Solution (stabiliser). BLINCYTO 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10 ml 6. OTHER Add to the sodium chloride bag only. 42 B. PACKAGE LEAFLET 43 Package leaflet: Information for the patient BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion blinatumomab This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What BLINCYTO is and what it is used for 2. What you need to know before you use BLINCYTO 3. How to use BLINCYTO 4. Possible side effects 5. How to store BLINCYTO 6. Contents of the pack and other information 1. What BLINCYTO is and what it is used for The active ingredient in BLINCYTO is blinatumomab. This belongs to a group of medicines called antineoplastic agents which target cancer cells. BLINCYTO is used to treat adults with acute lymphoblastic leukaemia. Acute lymphoblastic leukaemia is a cancer of the blood in which a particular kind of white blood cell called “B-lymphocyte” is growing out of control. This medicine works by enabling your immune system to attack and destroy these abnormal white blood cancer cells. BLINCYTO is used when acute lymphoblastic leukaemia has come back or has not responded to previous treatment (referred to as relapsed/refractory acute lymphoblastic leukaemia). It is also used in patients with acute lymphoblastic leukaemia who still have a small number of cancer cells remaining after previous treatment (referred to as minimal residual disease). BLINCYTO is used to treat children (≥ 1 year old), teenagers and young adults with acute lymphoblastic leukaemia (ALL) when previous treatments have not worked or have stopped working. 2. What you need to know before you use BLINCYTO Do not use BLINCYTO: - if you are allergic to blinatumomab or any of the other ingredients of this medicine (listed in section 6). - if you are breast-feeding. 44 Warnings and precautions Talk to your doctor, pharmacist or nurse before using BLINCYTO if any of these apply to you. BLINCYTO may not be suitable for you: • if you have ever had neurological problems, for example, shaking (or tremor), abnormal sensations, seizures, memory loss, confusion, disorientation, loss of balance, or difficulty in speaking. If you are still suffering from active neurological problems or conditions, tell your doctor. If your leukaemia has spread to your brain and/or spinal cord, your doctor may have to treat this first before you can start treatment with BLINCYTO. Your doctor will assess your nervous system and conduct tests before deciding if you should receive BLINCYTO. Your doctor may need to take special care of you during your treatment with BLINCYTO. • if you have an active infection. • if you have ever had an infusion reaction after previously using BLINCYTO. Symptoms may include wheezing, flushing, face swelling, difficulty breathing, low or high blood pressure. • if you think you may need any vaccinations in the near future, including those needed to travel to other countries. Some vaccines must not be given within two weeks before, at the same time as or in the months after you receive treatment with BLINCYTO. Your doctor will check if you should have the vaccination. Tell your doctor, pharmacist or nurse immediately if you experience any of the following reactions whilst receiving BLINCYTO as these may need to be treated and your dose adjusted: • if you experience seizures, difficulty in speaking or slurred speech, confusion and disorientation, or loss of balance. • if you develop chills or shivering, or feel warm; you should take your temperature as you may have a fever - these may be symptoms of an infection. • if you develop a reaction at any time during your infusion, which may include dizziness, feeling faint, nauseated, face swelling, difficulty breathing, wheezing, or rash. • if you have severe and persistent stomach pain, with or without nausea and vomiting, as these may be symptoms of a serious and potentially fatal condition known as pancreatitis (inflammation of the pancreas). Your doctor or nurse will monitor you for signs and symptoms of these reactions. Tell your doctor, pharmacist or nurse immediately if you became pregnant whilst receiving BLINCYTO. Your doctor will talk to you about precautions in using vaccinations for your baby. Before each infusion cycle of BLINCYTO, you will be given medicines which help reduce a potentially life-threatening complication known as tumour lysis syndrome, which is caused by chemical disturbances in the blood due to the breakdown of dying cancer cells. You may also be given medicines to reduce fever. During treatment, especially in the first few days after treatment start, you may experience a severe low white blood cell count (neutropenia), severe low white blood cell count with a fever (febrile neutropenia), elevated liver enzymes, or elevated uric acid. Your doctor will take regular blood tests to monitor your blood counts during treatment with BLINCYTO. Children and adolescents BLINCYTO should not be used in children below 1 year of age. Other medicines and BLINCYTO Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. 45 Pregnancy and breast-feeding If you are pregnant, are breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or nurse for advice before taking this medicine. Contraception Women who are able to become pregnant have to use effective contraception during treatment and for at least 48 hours after your last treatment. Talk to your doctor or nurse about suitable methods of contraception. Pregnancy The effects of BLINCYTO in pregnant women are not known but based on its mechanism of action, BLINCYTO may harm your unborn baby. You should not use BLINCYTO during pregnancy, unless your doctor thinks that it is the best medicine for you. If you become pregnant during BLINCYTO treatment, please inform your doctor or nurse. Your doctor will talk to you about precautions in using vaccinations for your baby. Breast-feeding You must not breast-feed during and for at least 48 hours after your last treatment. It is not known whether BLINCYTO is excreted in breast milk but a risk for suckling baby cannot be excluded. Driving and using machines Do not drive, use heavy machines, or engage in hazardous activities while you are being given BLINCYTO. BLINCYTO can cause neurological problems such as dizziness, seizures, confusion, coordination and balance disorders. BLINCYTO contains sodium This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’. 3. How to use BLINCYTO Always use this medicine exactly as your doctor, pharmacist or nurse have told you. Check with your doctor, pharmacist or nurse if you are not sure. How BLINCYTO is given BLINCYTO will be given to you through a vein (intravenous) continuously for 4 weeks using an infusion pump (this is 1 treatment cycle). You will then have a 2-week break where you will not be given the infusion. Your infusion catheter will be attached to you at all times during each cycle of your treatment. BLINCYTO is usually given for 2 treatment cycles if you have relapsed/refractory acute lymphoblastic leukaemia, or for 1 treatment cycle if you have minimal residual disease acute lymphoblastic leukaemia. If you respond to this treatment, your doctor may decide to give you up to 3 additional cycles of treatment. The number of treatment cycles and the dose which you will be given will depend on how you tolerate and respond to BLINCYTO. Your doctor will discuss with you how long your treatment will last. Your treatment may also be interrupted depending on how you tolerate BLINCYTO. 46 If you have relapsed/refractory acute lymphoblastic leukaemia it is recommended that the first 9 days of treatment and the first two days of the second cycle will be given to you in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. If you have minimal residual disease acute lymphoblastic leukaemia, it is recommended that the first 3 days of treatment and the first 2 days of subsequent cycles will be given to you in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. If you have or had neurological problems, it is recommended that the first 14 days of treatment will be given to you in a hospital or clinic. Your doctor will discuss with you if you can continue treatment at home after your initial hospital stay. Treatment may include a bag change by a nurse. Your doctor will determine when your BLINCYTO infusion bag will be changed, which may range from every day to every 4 days. The infusion rate may be faster or slower depending on how often the bag is changed. Your first cycle If you have relapsed/refractory acute lymphoblastic leukaemia and your body weight is greater than or equal to 45 kilograms the recommended initial dose in your first cycle is 9 micrograms per day for 1 week. Your doctor may decide to then increase your dose to 28 micrograms per day for weeks 2, 3, and 4 of your treatment. If your body weight is less than 45 kilograms, the recommended initial dose in your first cycle will be based on your weight and height. Your doctor may decide to then increase your dose for weeks 2, 3, and 4 of your treatment. If you have minimal residual disease acute lymphoblastic leukaemia, your dose of BLINCYTO will be 28 micrograms per day throughout the first cycle. Your next cycles If your doctor determines that you should be given more cycles of BLINCYTO and if your body weight is greater than or equal to 45 kilograms, your pump will be set to infuse a dose of 28 micrograms per day. If your doctor determines that you should be given more cycles of BLINCYTO and if your body weight is less than 45 kilograms, your pump will be set to infuse a dose based on your weight and height. Medicines given before each cycle of BLINCYTO Before your treatment with BLINCYTO, you will be given other medicines (pre-medication) to help reduce infusion reactions and other possible side effects. These may include corticosteroids (e.g. dexamethasone). Infusion catheter If you have a catheter for infusion, it is very important to keep the area around the catheter clean; otherwise you could get an infection. Your doctor or nurse will show you how to care for your catheter site. Infusion pump and intravenous tubing Do not adjust the settings on the pump, even if there is a problem or the pump alarm sounds. Any changes to the pump settings may result in a dose that is too high or too low. 47 Contact your doctor or nurse immediately if: • there is a problem with the pump or the pump alarm sounds • the infusion bag empties before the scheduled bag change • if the infusion pump stops unexpectedly. Do not try to restart your pump. Your doctor or nurse will advise you on how to manage your daily activities around your infusion pump. Contact your doctor or nurse if you have questions. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these side effects may be serious. Tell your doctor immediately if you get any of the following or combination of the following side effects: • chills, shivering, fever, rapid heart rate, decreased blood pressure, aching muscles, feeling tired, coughing, difficulty breathing, confusion, redness, swelling or discharge in the affected area or at the site of the infusion line - these may be signs of an infection. • neurologic events: shaking (or tremor), confusion, disturbances of brain function (encephalopathy), difficulty in communicating (aphasia), seizure (convulsion). • fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may become severe - these may be signs of a so-called cytokine release syndrome. • if you have severe and persistent stomach pain, with or without nausea and vomiting, as these may be symptoms of a serious and potentially fatal condition known as pancreatitis (inflammation of the pancreas). Treatment with BLINCYTO can cause a decrease in the levels of certain white blood cells with or without fever (febrile neutropenia or neutropenia) or can lead to increased blood levels of potassium, uric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome). Your doctor will take regular blood tests during treatment with BLINCYTO. Other side effects include: Very common side effects (may affect more than 1 in 10 people): • infections in the blood including bacteria, fungi, viruses, or other types of infection • decreased levels of certain white blood cells with or without fever ((febrile) neutropenia, leukopenia), decreased levels of red blood cells, decreased levels of platelets • fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may become severe (cytokine release syndrome) • not being able to sleep • headache, shaking (or tremor) • rapid heart rate (tachycardia) • low blood pressure • cough • nausea, diarrhoea, vomiting, constipation, abdominal pain • rash • back pain, pain in extremity • fever (pyrexia), swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (oedema), chills • low levels of antibodies called “immunoglobulins” which help the immune system fight infection (decreased immunoglobulins) • increased levels of liver enzymes (ALT, AST, GGT) • reactions related to infusion may include, wheezing, flushing, face swelling, difficulty breathing, low blood pressure, high blood pressure. 48 Common side effects (may affect up to 1 in 10 people): • serious infection which can result in organ failure, shock or can be fatal (sepsis) • lung infection (pneumonia) • increased levels of white blood cell count (leucocytosis), decreased levels of certain white blood cells (lymphopenia) • allergic reaction • complications occurring after cancer treatment leading to increased blood levels of potassium, uric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome) • confusion, disorientation • disturbances of brain function (encephalopathy) such as difficulty in communicating (aphasia), tingling of skin (paraesthesia), seizure, difficulty thinking or processing thoughts, difficulty remembering, difficulty in controlling movement (ataxia) • feeling sleepy (somnolence), numbness, dizziness • nerve problems affecting the head and neck such as visual disturbances, drooping eyelid and/or sagging muscles on one side of the face, difficulty hearing or trouble swallowing (cranial nerve disorders) • wheezing or difficulty in breathing (dyspnoea), breathlessness (respiratory failure) • high blood pressure (hypertension) • flushing • coughing with phlegm • increased bilirubin in the blood • bone pain • chest pain or other pain • high levels of some enzymes including blood enzymes • increase in your weight Uncommon side effects (may affect up to 1 in 100 people): • excessive activation of white blood cells associated with inflammation (hemophagocytic histiocytosis) • swollen lymph nodes (lymphadenopathy) • fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may be severe and can be fatal (cytokine storm) • a condition which causes fluid to leak from the small blood vessels into your body (capillary leak syndrome) • difficulty in speaking Additionally, the side effects that happened more often in adolescents and children include: • decreased levels of red blood cells (anaemia), decreased levels of platelets (thrombocytopenia), decreased levels of certain white blood cells (leukopenia) • fever (pyrexia) • reactions related to infusion may include face swelling, low blood pressure, high blood pressure (infusion-related reaction) • increase in your weight • high blood pressure (hypertension) Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 49 5. How to store BLINCYTO Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month. Unopened vials: - Store and transport refrigerated (2°C - 8°C). - Do not freeze. - Store in the original carton in order to protect from light. Reconstituted solution (BLINCYTO solution): - When refrigerated, the reconstituted solution must be used within 24 hours. Alternatively the vials can be stored at room temperature (up to 27°C) for up to 4 hours. Diluted solution (prepared infusion bag): If your infusion bag is changed at home: - Infusion bags containing BLINCYTO solution for infusion will arrive in special packaging containing cooling packs. • Do not open the package. • Store the package at room temperature (up to 27°C). • Do not refrigerate or freeze the package. - The package will be opened by your nurse and the infusion bags will be stored in a refrigerator until infusion. - When refrigerated, the infusion bags must be used within 10 days of preparation. - Once at room temperature (up to 27°C) the solution will be infused within 96 hours. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What BLINCYTO contains - The active substance is blinatumomab. Each vial of powder contains 38.5 micrograms of blinatumomab. Reconstitution with water for injections results in a final blinatumomab concentration of 12.5 micrograms/mL. - The other ingredients in the powder are citric acid monohydrate (E330), trehalose dihydrate, lysine hydrochloride, polysorbate 80, and sodium hydroxide. - The solution (stabiliser) contains citric acid monohydrate (E330), lysine hydrochloride, polysorbate 80, sodium hydroxide and water for injections. What BLINCYTO looks like and contents of the pack BLINCYTO is a powder for concentrate and solution for solution for infusion. Each pack of BLINCYTO contains: • 1 glass vial containing a white to off-white powder. • 1 glass vial containing a colourless-to-slightly yellow, clear solution. Marketing Authorisation Holder and Manufacturer Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands 50 Marketing Authorisation Holder Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands Manufacturer Amgen NV Telecomlaan 5-7 1831 Diegem Belgium For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien s.a. Amgen n.v. Tel/Tél: +32 (0)2 7752711 Lietuva Amgen Switzerland AG Vilniaus filialas Tel: +370 5 219 7474 България Амджен България ЕООД Тел.: +359 (0)2 424 7440 Luxembourg/Luxemburg s.a. Amgen Belgique/Belgien Tel/Tél: +32 (0)2 7752711 Česká republika Amgen s.r.o. Tel: +420 221 773 500 Magyarország Amgen Kft. Tel.: +36 1 35 44 700 Danmark Amgen, filial af Amgen AB, Sverige Tlf: +45 39617500 Malta Amgen B.V. The Netherlands Tel: +31 (0)76 5732500 Deutschland AMGEN GmbH Tel.: +49 89 1490960 Nederland Amgen B.V. Tel: +31 (0)76 5732500 Eesti Amgen Switzerland AG Vilniaus filialas Tel: +372 586 09553 Norge Amgen AB Tel: +47 23308000 Ελλάδα Amgen Ελλάς Φαρμακευτικά Ε.Π.Ε. Τηλ.: +30 210 3447000 Österreich Amgen GmbH Tel: +43 (0)1 50 217 España Amgen S.A. Tel: +34 93 600 18 60 Polska Amgen Biotechnologia Sp. z o.o. Tel.: +48 22 581 3000 France Amgen S.A.S. Tél: +33 (0)9 69 363 363 Portugal Amgen Biofarmacêutica, Lda. Tel: +351 21 422 0606 Hrvatska Amgen d.o.o. Tel: +385 (0)1 562 57 20 România Amgen România SRL Tel: +4021 527 3000 51 Ireland Amgen Ireland Limited Tel: +353 1 8527400 Slovenija AMGEN zdravila d.o.o. Tel: +386 (0)1 585 1767 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Amgen Slovakia s.r.o. Tel: +421 2 321 114 49 Italia Amgen S.r.l. Tel: +39 02 6241121 Suomi/Finland Amgen AB, sivuliike Suomessa/Amgen AB, filial i Finland Puh/Tel: +358 (0)9 54900500 Kύπρος C.A. Papaellinas Ltd Τηλ.: +357 22741 741 Sverige Amgen AB Tel: +46 (0)8 6951100 Latvija Amgen Switzerland AG Rīgas filiāle Tel: +371 257 25888 United Kingdom Amgen Limited Tel: +44 (0)1223 420305 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. The following information is intended for healthcare professionals only: BLINCYTO solution for infusion is administered as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump, over a period of up to 96 hours. Philadelphia chromosome negative relapsed or refractory B-precursor ALL Recommended daily dose by patient weight. Patients greater than or equal to 45 kg receive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA). http://www.ema.europa.eu/ http://www.ema.europa.eu/ 52 Patient weight Cycle 1 Subsequent cycles Days 1-7 Days 8-28 Days 29-42 Days 1-28 Days 29-42 Greater than or equal to 45 kg (fixed-dose) 9 mcg/day via continuous infusion 28 mcg/day via continuous infusion 14 day treatment free interval 28 mcg/day via continuous infusion 14 day treatment free interval Less than 45 kg (BSA-based dose) 5 mcg/m2/day via continuous infusion (not to exceed 9 mcg/day) 15 mcg/m2/day via continuous infusion (not to exceed 28 mcg/day) 15 mcg/m2/da y via continuous infusion (not to exceed 28 mcg/day) MRD positive B-precursor ALL The recommended dose of BLINCYTO throughout each 4-week treatment cycle is 28 mcg/day. The starting volume (270 mL) is more than the volume administered to the patient (240 mL) to account for the priming of the intravenous tubing and to ensure that the patient will receive the full dose of BLINCYTO. Infuse BLINCYTO solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates: • Infusion rate of 10 mL/h for a duration of 24 hours • Infusion rate of 5 mL/h for a duration of 48 hours • Infusion rate of 3.3 mL/h for a duration of 72 hours • Infusion rate of 2.5 mL/h for a duration of 96 hours The choice of the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes. The target therapeutic dose of BLINCYTO delivered does not change. Aseptic preparation Aseptic handling must be ensured when preparing the infusion. Preparation of BLINCYTO should be: - performed under aseptic conditions by trained personnel in accordance with good practice rules especially with respect to the aseptic preparation of parenteral products. - prepared in a laminar flow hood or biological safety cabinet using standard precautions for the safe handling of intravenous agents. It is very important that the instructions for preparation and administration provided in this section are strictly followed to minimise medication errors (including underdose and overdose). Special instructions to support accurate preparation • A solution (stabiliser) is provided inside the BLINCYTO package and is used to coat the pre-filled infusion bag prior to addition of reconstituted BLINCYTO. Do not use this solution (stabiliser) for reconstitution of BLINCYTO powder for concentrate. • The entire volume of the reconstituted and diluted BLINCYTO will be more than the volume to be administered to the patient (240 mL). This is to account for intravenous infusion line loss and to assure that the patient will receive the full dose of BLINCYTO. 53 • When preparing an infusion bag, remove all air from infusion bag. This is particularly important when using an ambulatory infusion pump. • Use the specific volumes described in the reconstitution and dilution instructions below to minimise errors in calculation. Other instructions • BLINCYTO is compatible with polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes. • Pump specifications: The infusion pump to administer BLINCYTO solution for infusion should be programmable, lockable and have an alarm. Elastomeric pumps should not be used. • Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Preparation of the solution for infusion Specific reconstitution and dilution instructions are provided for each dose and infusion time. Verify the prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation in the relevant table below. Table 1 provides instructions for patients weighing greater than or equal to 45 kg whereas table 2 and table 3 provide instructions for patients weighing less than 45 kg. Follow the steps for reconstituting BLINCYTO and preparing the infusion bag detailed below table 3. Table 1. For patients weighing greater than or equal to 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag Pre-filled bag containing sodium chloride 9 mg/mL (0.9%) solution for injection 250 mL (usual overfill volume of 265 to 275 mL) Solution (stabiliser) 5.5 mL Dose Infusion duration (hours) Infusion rate (mL/hour) Reconstituted BLINCYTO (number of packages) 9 mcg/day 24 10 0.83 mL (1) 48 5 1.7 mL (1) 72 3.3 2.5 mL (1) 96 2.5 3.3 mL (2) 28 mcg/day 24 10 2.6 mL (1) 48 5 5.2 mL (2) 72 3.3 8 mL (3) 96 2.5 10.7 mL (4) 54 Table 2. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag for 5 mcg/m2/day dose Sodium chloride 9 mg/mL (0.9%) solution for injection (starting volume) 250 mL (usual overfill volume of 265 to 275 mL) Solution (stabiliser) 5.5 mL Dose Infusion duration Infusion rate BSA (m2) Reconstituted BLINCYTO (number of packages) 5 mcg/m2/day 24 hours 10 mL/hour 1.50 – 1.59 0.70 mL (1) 1.40 – 1.49 0.66 mL (1) 1.30 – 1.39 0.61 mL (1) 1.20 – 1.29 0.56 mL (1) 1.10 – 1.19 0.52 mL (1) 1.00 – 1.09 0.47 mL (1) 0.90 – 0.99 0.43 mL (1) 0.80 – 0.89 0.38 mL (1) 0.70 – 0.79 0.33 mL (1) 0.60 – 0.69 0.29 mL (1) 0.50 – 0.59 0.24 mL (1) 0.40 – 0.49 0.20 mL (1) 48 hours 5 mL/hour 1.50 – 1.59 1.4 mL (1) 1.40 – 1.49 1.3 mL (1) 1.30 – 1.39 1.2 mL (1) 1.20 – 1.29 1.1 mL (1) 1.10 – 1.19 1.0 mL (1) 1.00 – 1.09 0.94 mL (1) 0.90 – 0.99 0.85 mL (1) 0.80 – 0.89 0.76 mL (1) 0.70 – 0.79 0.67 mL (1) 0.60 – 0.69 0.57 mL (1) 0.50 – 0.59 0.48 mL (1) 0.40 – 0.49 0.39 mL (1) 72 hours 3.3 mL/hour 1.50 – 1.59 2.1 mL (1) 1.40 – 1.49 2.0 mL (1) 1.30 – 1.39 1.8 mL (1) 1.20 – 1.29 1.7 mL (1) 1.10 – 1.19 1.6 mL (1) 1.00 – 1.09 1.4 mL (1) 0.90 – 0.99 1.3 mL (1) 0.80 – 0.89 1.1 mL (1) 0.70 – 0.79 1 mL (1) 0.60 – 0.69 0.86 mL (1) 0.50 – 0.59 0.72 mL (1) 0.40 – 0.49 0.59 mL (1) 96 hours 2.5 mL/hour 1.50 – 1.59 2.8 mL (1) 1.40 – 1.49 2.6 mL (1) 1.30 – 1.39 2.4 mL (1) 1.20 – 1.29 2.3 mL (1) 1.10 – 1.19 2.1 mL (1) 1.00 – 1.09 1.9 mL (1) 0.90 – 0.99 1.7 mL (1) 0.80 – 0.89 1.5 mL (1) 0.70 – 0.79 1.3 mL (1) 0.60 – 0.69 1.2 mL (1) 0.50 – 0.59 0.97 mL (1) 0.40 – 0.49 0.78 mL (1) 55 Table 3. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag for 15 mcg/m2/day dose Sodium chloride 9 mg/mL (0.9%) solution for injection (starting volume) 250 mL (usual overfill volume of 265 to 275 mL) Solution (stabiliser) 5.5 mL Dose Infusion duration Infusion rate BSA (m2) Reconstituted BLINCYTO (number of packages) 15 mcg/m2/day 24 hours 10 mL/hour 1.50 – 1.59 2.1 mL (1) 1.40 – 1.49 2.0 mL (1) 1.30 – 1.39 1.8 mL (1) 1.20 – 1.29 1.7 mL (1) 1.10 – 1.19 1.6 mL (1) 1.00 – 1.09 1.4 mL (1) 0.90 – 0.99 1.3 mL (1) 0.80 – 0.89 1.1 mL (1) 0.70 – 0.79 1.00 mL (1) 0.60 – 0.69 0.86 mL (1) 0.50 – 0.59 0.72 mL (1) 0.40 – 0.49 0.59 mL (1) 48 hours 5 mL/hour 1.50 – 1.59 4.2 mL (2) 1.40 – 1.49 3.9 mL (2) 1.30 – 1.39 3.7 mL (2) 1.20 – 1.29 3.4 mL (2) 1.10 – 1.19 3.1 mL (2) 1.00 – 1.09 2.8 mL (1) 0.90 – 0.99 2.6 mL (1) 0.80 – 0.89 2.3 mL (1) 0.70 – 0.79 2.0 mL (1) 0.60 – 0.69 1.7 mL (1) 0.50 – 0.59 1.4 mL (1) 0.40 – 0.49 1.2 mL (1) 72 hours 3.3 mL/hour 1.50 – 1.59 6.3 mL (3) 1.40 – 1.49 5.9 mL (3) 1.30 – 1.39 5.5 mL (2) 1.20 – 1.29 5.1 mL (2) 1.10 – 1.19 4.7 mL (2) 1.00 – 1.09 4.2 mL (2) 0.90 – 0.99 3.8 mL (2) 0.80 – 0.89 3.4 mL (2) 0.70 – 0.79 3.0 mL (2) 0.60 – 0.69 2.6 mL (1) 0.50 – 0.59 2.2 mL (1) 0.40 – 0.49 1.8 mL (1) 96 hours 2.5 mL/hour 1.50 – 1.59 8.4 mL (3) 1.40 – 1.49 7.9 mL (3) 1.30 – 1.39 7.3 mL (3) 1.20 – 1.29 6.8 mL (3) 1.10 – 1.19 6.2 mL (3) 1.00 – 1.09 5.7 mL (3) 0.90 – 0.99 5.1 mL (2) 0.80 – 0.89 4.6 mL (2) 0.70 – 0.79 4.0 mL (2) 0.60 – 0.69 3.4 mL (2) 0.50 – 0.59 2.9 mL (2) 0.40 – 0.49 2.3 mL (1) 56 These supplies are also required, but not included in the package • Sterile single-use disposable syringes • 21-23 gauge needle(s) (recommended) • Water for injections • Infusion bag with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection; o To minimise the number of aseptic transfers, use a 250 mL pre-filled infusion bag. BLINCYTO dose calculations are based on a usual overfill volume of 265 to 275 mL sodium chloride 9 mg/mL (0.9%) solution for injection. o Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes. • Polyolefin, PVC non-DEHP, or EVA intravenous tubing with a sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter. o Ensure that the tubing is compatible with the infusion pump. Reconstitution and preparation of BLINCYTO solution for infusion using an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection 1. Use an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection that usually contains a total volume of 265 to 275 mL. 2. To coat the infusion bag, using a syringe, aseptically transfer 5.5 mL of the solution (stabiliser) to the infusion bag. Gently mix the contents of the bag to avoid foaming. Discard the remaining solution (stabiliser) vial. 3. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate using 3 mL of water for injections. Direct the water for injections toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. • Do not reconstitute BLINCYTO powder for concentrate with the solution (stabiliser). • The addition of water for injections to the powder for concentrate results in a total volume of 3.08 mL for a final BLINCYTO concentration of 12.5 mcg/mL. 4. Visually inspect the reconstituted solution for particulate matter and discolouration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colourless-to-slightly yellow. Do not use if the solution is cloudy or has precipitated. 5. Using a syringe, aseptically transfer reconstituted BLINCYTO into the infusion bag (refer to table 1 to table 3 for the specific volume of reconstituted BLINCYTO). Gently mix the contents of the bag to avoid foaming. Discard any remaining BLINCYTO reconstituted solution. 6. Under aseptic conditions, attach the intravenous tubing to the infusion bag with the sterile 0.2 micron in-line filter. 7. Remove air from the infusion bag and prime the intravenous infusion line only with the prepared solution for infusion. Do not prime with sodium chloride 9 mg/mL (0.9%) solution for injection. 8. Store at 2°C – 8°C if not used immediately. For instructions on administration, see Summary of Product Characteristics section 4.2. Method of administration Important Note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via multi-lumen venous catheter, BLINCYTO should be infused through a dedicated lumen. BLINCYTO solution for infusion is administered as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump over a period of up to 96 hours. 57 The BLINCYTO solution for infusion must be administered using intravenous tubing that contains a sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter. The infusion bag must be changed at least every 96 hours by a healthcare professional for sterility reasons. Storage conditions and shelf life Unopened vials: 5 years (2°C - 8°C) Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C or 4 hours at or below 27°C. From a microbiological point of view, unless the method of reconstituting precludes the risks of microbial contamination, the reconstituted solution should be diluted immediately. If not diluted immediately, in-use storage times and conditions are the responsibility of the user. Diluted solution (prepared infusion bag) Chemical and physical in-use stability has been demonstrated for 10 days at 2°C - 8°C or 96 hours at or below 27°C. From a microbiological point of view, the prepared infusion bags should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in controlled and validated aseptic conditions. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what blincyto is and what it is used for', 'Section_Content': 'the active ingredient in blincyto is blinatumomab. this belongs to a group of medicines called antineoplastic agents which target cancer cells. blincyto is used to treat adults with acute lymphoblastic leukaemia. acute lymphoblastic leukaemia is a cancer of the blood in which a particular kind of white blood cell called "b-lymphocyte" is growing out of control. this medicine works by enabling your immune system to attack and destroy these abnormal white blood cancer cells. blincyto is used when acute lymphoblastic leukaemia has come back or has not responded to previous treatment (referred to as relapsed/refractory acute lymphoblastic leukaemia). it is also used in patients with acute lymphoblastic leukaemia who still have a small number of cancer cells remaining after previous treatment (referred to as minimal residual disease). blincyto is used to treat children (≥ 1 year old), teenagers and young adults with acute lymphoblastic leukaemia (all) when previous treatments have not worked or have stopped working.', 'Entity_Recognition': [{'Text': 'blincyto', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 25, 'EndOffset': 33, 'Score': 0.39556774497032166, 'Text': 'blincyto', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 37, 'EndOffset': 49, 'Score': 0.9883153438568115, 'Text': 'blinatumomab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a group of medicines', 'Type': 'TREATMENT', 'BeginOffset': 67, 'EndOffset': 87}, {'Id': 17, 'BeginOffset': 95, 'EndOffset': 116, 'Score': 0.5930503010749817, 'Text': 'antineoplastic agents', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'target cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 123, 'EndOffset': 142}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 182, 'EndOffset': 211}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 213, 'EndOffset': 242}, {'Text': 'a cancer', 'Type': 'PROBLEM', 'BeginOffset': 246, 'EndOffset': 254}, {'Text': 'the blood', 'Type': 'PROBLEM', 'BeginOffset': 258, 'EndOffset': 267}, {'Text': 'white blood cell', 'Type': 'TEST', 'BeginOffset': 298, 'EndOffset': 314}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 364, 'EndOffset': 377}, {'Text': 'these abnormal white blood cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 437, 'EndOffset': 476}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 500, 'EndOffset': 529}, {'Text': 'previous treatment', 'Type': 'TREATMENT', 'BeginOffset': 568, 'EndOffset': 586}, {'Id': 10, 'BeginOffset': 603, 'EndOffset': 652, 'Score': 0.4433751404285431, 'Text': 'relapsed/refractory acute lymphoblastic leukaemia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9565421938896179}]}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 688, 'EndOffset': 717}, {'Text': 'cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 751, 'EndOffset': 763}, {'Text': 'previous treatment', 'Type': 'TREATMENT', 'BeginOffset': 780, 'EndOffset': 798}, {'Text': 'minimal residual disease)', 'Type': 'PROBLEM', 'BeginOffset': 815, 'EndOffset': 840}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 880, 'EndOffset': 881}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 925, 'EndOffset': 954}, {'Text': 'previous treatments', 'Type': 'TREATMENT', 'BeginOffset': 966, 'EndOffset': 985}]}

{'Title': '2. what you need to know before you use blincyto', 'Section_Content': "do not use blincyto: - if you are allergic to blinatumomab or any of the other ingredients of this medicine (listed in section 6). - if you are breast-feeding. warnings and precautions talk to your doctor, pharmacist or nurse before using blincyto if any of these apply to you. blincyto may not be suitable for you: if you have ever had neurological problems, for example, shaking (or tremor), abnormal sensations, seizures, memory loss, confusion, disorientation, loss of balance, or difficulty in speaking. if you are still suffering from active neurological problems or conditions, tell your doctor. if your leukaemia has spread to your brain and/or spinal cord, your doctor may have to treat this first before you can start treatment with blincyto. your doctor will assess your nervous system and conduct tests before deciding if you should receive blincyto. your doctor may need to take special care of you during your treatment with blincyto. if you have an active infection. if you have ever had an infusion reaction after previously using blincyto. symptoms may include wheezing, flushing, face swelling, difficulty breathing, low or high blood pressure. if you think you may need any vaccinations in the near future, including those needed to travel to other countries. some vaccines must not be given within two weeks before, at the same time as or in the months after you receive treatment with blincyto. your doctor will check if you should have the vaccination. tell your doctor, pharmacist or nurse immediately if you experience any of the following reactions whilst receiving blincyto as these may need to be treated and your dose adjusted: if you experience seizures, difficulty in speaking or slurred speech, confusion and disorientation, or loss of balance. if you develop chills or shivering, or feel warm; you should take your temperature as you may have a fever - these may be symptoms of an infection. if you develop a reaction at any time during your infusion, which may include dizziness, feeling faint, nauseated, face swelling, difficulty breathing, wheezing, or rash. if you have severe and persistent stomach pain, with or without nausea and vomiting, as these may be symptoms of a serious and potentially fatal condition known as pancreatitis (inflammation of the pancreas). your doctor or nurse will monitor you for signs and symptoms of these reactions. tell your doctor, pharmacist or nurse immediately if you became pregnant whilst receiving blincyto. your doctor will talk to you about precautions in using vaccinations for your baby. before each infusion cycle of blincyto, you will be given medicines which help reduce a potentially life-threatening complication known as tumour lysis syndrome, which is caused by chemical disturbances in the blood due to the breakdown of dying cancer cells. you may also be given medicines to reduce fever. during treatment, especially in the first few days after treatment start, you may experience a severe low white blood cell count (neutropenia), severe low white blood cell count with a fever (febrile neutropenia), elevated liver enzymes, or elevated uric acid. your doctor will take regular blood tests to monitor your blood counts during treatment with blincyto. children and adolescents blincyto should not be used in children below 1 year of age. other medicines and blincyto tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding if you are pregnant, are breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or nurse for advice before taking this medicine. contraception women who are able to become pregnant have to use effective contraception during treatment and for at least 48 hours after your last treatment. talk to your doctor or nurse about suitable methods of contraception. pregnancy the effects of blincyto in pregnant women are not known but based on its mechanism of action, blincyto may harm your unborn baby. you should not use blincyto during pregnancy, unless your doctor thinks that it is the best medicine for you. if you become pregnant during blincyto treatment, please inform your doctor or nurse. your doctor will talk to you about precautions in using vaccinations for your baby. breast-feeding you must not breast-feed during and for at least 48 hours after your last treatment. it is not known whether blincyto is excreted in breast milk but a risk for suckling baby cannot be excluded. driving and using machines do not drive, use heavy machines, or engage in hazardous activities while you are being given blincyto. blincyto can cause neurological problems such as dizziness, seizures, confusion, coordination and balance disorders. blincyto contains sodium this medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 'sodium-free'.", 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{'Title': '3. how to use blincyto', 'Section_Content': 'always use this medicine exactly as your doctor, pharmacist or nurse have told you. check with your doctor, pharmacist or nurse if you are not sure. how blincyto is given blincyto will be given to you through a vein (intravenous) continuously for 4 weeks using an infusion pump (this is 1 treatment cycle). you will then have a 2-week break where you will not be given the infusion. your infusion catheter will be attached to you at all times during each cycle of your treatment. blincyto is usually given for 2 treatment cycles if you have relapsed/refractory acute lymphoblastic leukaemia, or for 1 treatment cycle if you have minimal residual disease acute lymphoblastic leukaemia. if you respond to this treatment, your doctor may decide to give you up to 3 additional cycles of treatment. the number of treatment cycles and the dose which you will be given will depend on how you tolerate and respond to blincyto. your doctor will discuss with you how long your treatment will last. your treatment may also be interrupted depending on how you tolerate blincyto. if you have relapsed/refractory acute lymphoblastic leukaemia it is recommended that the first 9 days of treatment and the first two days of the second cycle will be given to you in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. if you have minimal residual disease acute lymphoblastic leukaemia, it is recommended that the first 3 days of treatment and the first 2 days of subsequent cycles will be given to you in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. if you have or had neurological problems, it is recommended that the first 14 days of treatment will be given to you in a hospital or clinic. your doctor will discuss with you if you can continue treatment at home after your initial hospital stay. treatment may include a bag change by a nurse. your doctor will determine when your blincyto infusion bag will be changed, which may range from every day to every 4 days. the infusion rate may be faster or slower depending on how often the bag is changed. your first cycle if you have relapsed/refractory acute lymphoblastic leukaemia and your body weight is greater than or equal to 45 kilograms the recommended initial dose in your first cycle is 9 micrograms per day for 1 week. your doctor may decide to then increase your dose to 28 micrograms per day for weeks 2, 3, and 4 of your treatment. if your body weight is less than 45 kilograms, the recommended initial dose in your first cycle will be based on your weight and height. your doctor may decide to then increase your dose for weeks 2, 3, and 4 of your treatment. if you have minimal residual disease acute lymphoblastic leukaemia, your dose of blincyto will be 28 micrograms per day throughout the first cycle. your next cycles if your doctor determines that you should be given more cycles of blincyto and if your body weight is greater than or equal to 45 kilograms, your pump will be set to infuse a dose of 28 micrograms per day. if your doctor determines that you should be given more cycles of blincyto and if your body weight is less than 45 kilograms, your pump will be set to infuse a dose based on your weight and height. medicines given before each cycle of blincyto before your treatment with blincyto, you will be given other medicines (pre-medication) to help reduce infusion reactions and other possible side effects. these may include corticosteroids (e.g. dexamethasone). infusion catheter if you have a catheter for infusion, it is very important to keep the area around the catheter clean; otherwise you could get an infection. your doctor or nurse will show you how to care for your catheter site. infusion pump and intravenous tubing do not adjust the settings on the pump, even if there is a problem or the pump alarm sounds. any changes to the pump 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some of these side effects may be serious. tell your doctor immediately if you get any of the following or combination of the following side effects: chills, shivering, fever, rapid heart rate, decreased blood pressure, aching muscles, feeling tired, coughing, difficulty breathing, confusion, redness, swelling or discharge in the affected area or at the site of the infusion line - these may be signs of an infection. neurologic events: shaking (or tremor), confusion, disturbances of brain function (encephalopathy), difficulty in communicating (aphasia), seizure (convulsion). fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may become severe - these may be signs of a so-called cytokine release syndrome. if you have severe and persistent stomach pain, with or without nausea and vomiting, as these may be symptoms of a serious and potentially fatal condition known as pancreatitis (inflammation of the pancreas). treatment with blincyto can cause a decrease in the levels of certain white blood cells with or without fever (febrile neutropenia or neutropenia) or can lead to increased blood levels of potassium, uric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome). your doctor will take regular blood tests during treatment with blincyto. other side effects include: very common side effects (may affect more than 1 in 10 people): infections in the blood including bacteria, fungi, viruses, or other types of infection decreased levels of certain white blood cells with or without fever ((febrile) neutropenia, leukopenia), decreased levels of red blood cells, decreased levels of platelets fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may become severe (cytokine release syndrome) not being able to sleep headache, shaking (or tremor) rapid heart rate (tachycardia) low blood pressure cough nausea, diarrhoea, vomiting, constipation, abdominal pain rash back pain, pain in extremity fever (pyrexia), swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (oedema), chills low levels of antibodies called "immunoglobulins" which help the immune system fight infection (decreased immunoglobulins) increased levels of liver enzymes (alt, ast, ggt) reactions related to infusion may include, wheezing, flushing, face swelling, difficulty breathing, low blood pressure, high blood pressure. common side effects (may affect up to 1 in 10 people): serious infection which can result in organ failure, shock or can be fatal (sepsis) lung infection (pneumonia) increased levels of white blood cell count (leucocytosis), decreased levels of certain white blood cells (lymphopenia) allergic reaction complications occurring after cancer treatment leading to increased blood levels of potassium, uric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome) confusion, disorientation disturbances of brain function (encephalopathy) such as difficulty in communicating (aphasia), tingling of skin (paraesthesia), seizure, difficulty thinking or processing thoughts, difficulty remembering, difficulty in controlling movement (ataxia) feeling sleepy (somnolence), numbness, dizziness nerve problems affecting the head and neck such as visual disturbances, drooping eyelid and/or sagging muscles on one side of the face, difficulty hearing or trouble swallowing (cranial nerve disorders) wheezing or difficulty in breathing (dyspnoea), breathlessness (respiratory failure) high blood pressure (hypertension) flushing coughing with phlegm increased bilirubin in the blood bone pain chest pain or other pain high levels of some enzymes including blood enzymes increase in your weight uncommon side effects (may affect up to 1 in 100 people): excessive activation of white blood cells associated with inflammation (hemophagocytic histiocytosis) swollen lymph nodes (lymphadenopathy) fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may be severe and can be fatal (cytokine storm) a condition which causes fluid to leak from the small blood vessels into your body (capillary leak syndrome) difficulty in speaking additionally, the side effects that happened more often in adolescents and children include: decreased levels of red blood cells (anaemia), decreased levels of platelets (thrombocytopenia), decreased levels of certain white blood cells (leukopenia) fever (pyrexia) reactions related to infusion may include face swelling, low blood pressure, high blood pressure (infusion-related reaction) increase in your weight high blood pressure (hypertension) reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed 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0.6263872385025024}]}, {'Id': 222, 'BeginOffset': 4193, 'EndOffset': 4207, 'Score': 0.8522250652313232, 'Text': 'cytokine storm', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6141871213912964}]}, {'Text': 'a condition', 'Type': 'PROBLEM', 'BeginOffset': 4209, 'EndOffset': 4220}, {'Id': 223, 'BeginOffset': 4234, 'EndOffset': 4247, 'Score': 0.8651446104049683, 'Text': 'fluid to leak', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5985412001609802}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.5864426493644714, 'RelationshipScore': 0.9280692338943481, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 217, 'BeginOffset': 4257, 'EndOffset': 4276, 'Text': 'small blood vessels', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9483739137649536, 'RelationshipScore': 0.8991792798042297, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 218, 'BeginOffset': 4287, 'EndOffset': 4291, 'Text': 'body', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the small blood vessels', 'Type': 'PROBLEM', 'BeginOffset': 4253, 'EndOffset': 4276}, {'Id': 218, 'BeginOffset': 4287, 'EndOffset': 4291, 'Score': 0.9483739137649536, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 224, 'BeginOffset': 4293, 'EndOffset': 4316, 'Score': 0.6186546683311462, 'Text': 'capillary leak syndrome', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9264922142028809}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.5864426493644714, 'RelationshipScore': 0.9907773733139038, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 217, 'BeginOffset': 4257, 'EndOffset': 4276, 'Text': 'small blood vessels', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 225, 'BeginOffset': 4318, 'EndOffset': 4340, 'Score': 0.8702888488769531, 'Text': 'difficulty in speaking', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 226, 'BeginOffset': 4359, 'EndOffset': 4371, 'Score': 0.8606482148170471, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5047698616981506}, {'Name': 'DIAGNOSIS', 'Score': 0.5606966018676758}]}, {'Id': 227, 'BeginOffset': 4434, 'EndOffset': 4469, 'Score': 0.7981637716293335, 'Text': 'decreased levels of red blood cells', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8151267766952515}]}, {'Text': 'anaemia)', 'Type': 'PROBLEM', 'BeginOffset': 4471, 'EndOffset': 4479}, {'Id': 229, 'BeginOffset': 4481, 'EndOffset': 4510, 'Score': 0.7394529581069946, 'Text': 'decreased levels of platelets', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.4153076112270355}]}, {'Id': 230, 'BeginOffset': 4512, 'EndOffset': 4528, 'Score': 0.9924219250679016, 'Text': 'thrombocytopenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8927962183952332}]}, {'Text': 'decreased levels of certain white blood cells', 'Type': 'PROBLEM', 'BeginOffset': 4531, 'EndOffset': 4576}, {'Id': 233, 'BeginOffset': 4578, 'EndOffset': 4588, 'Score': 0.9942110776901245, 'Text': 'leukopenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9021443128585815}]}, {'Text': 'fever (pyrexia) reactions', 'Type': 'PROBLEM', 'BeginOffset': 4590, 'EndOffset': 4615}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 4627, 'EndOffset': 4635}, {'Id': 237, 'BeginOffset': 4648, 'EndOffset': 4661, 'Score': 0.6366598010063171, 'Text': 'face swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.566415011882782}, {'Name': 'DIAGNOSIS', 'Score': 0.5767362713813782}]}, {'Id': 238, 'BeginOffset': 4663, 'EndOffset': 4681, 'Score': 0.8420239686965942, 'Text': 'low blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5895093083381653}]}, {'Id': 239, 'BeginOffset': 4683, 'EndOffset': 4702, 'Score': 0.9506616592407227, 'Text': 'high blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6351041197776794}]}, {'Id': 240, 'BeginOffset': 4704, 'EndOffset': 4729, 'Score': 0.5450220108032227, 'Text': 'infusion-related reaction', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5830278396606445}]}, {'Text': 'your weight high blood pressure (hypertension)', 'Type': 'PROBLEM', 'BeginOffset': 4743, 'EndOffset': 4789}, {'Id': 243, 'BeginOffset': 4803, 'EndOffset': 4815, 'Score': 0.9147496223449707, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6117187142372131}, {'Name': 'DIAGNOSIS', 'Score': 0.43839001655578613}]}, {'Id': 244, 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5066, 'EndOffset': 5078, 'Score': 0.85993891954422, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.706728458404541}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 5134, 'EndOffset': 5147}]}

{'Title': '5. how to store blincyto', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. the expiry date refers to the last day of that month. unopened vials: - store and transport refrigerated (2 - 8). - do not freeze. - store in the original carton in order to protect from light. reconstituted solution (blincyto solution): - when refrigerated, the reconstituted solution must be used within 24 hours. alternatively the vials can be stored at room temperature (up to 27) for up to 4 hours. diluted solution (prepared infusion bag): if your infusion bag is changed at home: - infusion bags containing blincyto solution for infusion will arrive in special packaging containing cooling packs. do not open the package. store the package at room temperature (up to 27). do not refrigerate or freeze the package. - the package will be opened by your nurse and the infusion bags will be stored in a refrigerator until infusion. - when refrigerated, the infusion bags must be used within 10 days of preparation. - once at room temperature (up to 27) the solution will be infused within 96 hours. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'blincyto', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'reconstituted solution (blincyto solution', 'Type': 'TREATMENT', 'BeginOffset': 351, 'EndOffset': 392}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 416, 'EndOffset': 442}, {'Id': 4, 'BeginOffset': 456, 'EndOffset': 471, 'Score': 0.9109519720077515, 'Text': 'within 24 hours', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_MEDICATION_NAME', 'Traits': [], 'Attributes': [{'Type': 'GENERIC_NAME', 'Score': 0.31020620465278625, 'RelationshipScore': 0.6317497491836548, 'RelationshipType': 'OVERLAP', 'Id': 0, 'BeginOffset': 375, 'EndOffset': 392, 'Text': 'blincyto solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 463, 'EndOffset': 465}, {'Text': '27', 'Type': 'NUMBER', 'BeginOffset': 538, 'EndOffset': 540}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 552, 'EndOffset': 553}, {'Text': 'diluted solution (prepared infusion bag', 'Type': 'TREATMENT', 'BeginOffset': 561, 'EndOffset': 600}, {'Text': 'your infusion bag', 'Type': 'TREATMENT', 'BeginOffset': 606, 'EndOffset': 623}, {'Text': 'infusion bags', 'Type': 'TREATMENT', 'BeginOffset': 646, 'EndOffset': 659}, {'Text': 'blincyto solution', 'Type': 'TREATMENT', 'BeginOffset': 671, 'EndOffset': 688}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 693, 'EndOffset': 701}, {'Text': 'cooling packs', 'Type': 'TREATMENT', 'BeginOffset': 746, 'EndOffset': 759}, {'Text': '27', 'Type': 'NUMBER', 'BeginOffset': 831, 'EndOffset': 833}, {'Text': 'the package', 'Type': 'TREATMENT', 'BeginOffset': 880, 'EndOffset': 891}, {'Text': 'the infusion bags', 'Type': 'TREATMENT', 'BeginOffset': 925, 'EndOffset': 942}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 982, 'EndOffset': 990}, {'Text': 'the infusion bags', 'Type': 'TREATMENT', 'BeginOffset': 1013, 'EndOffset': 1030}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 1051, 'EndOffset': 1053}, {'Text': '27', 'Type': 'NUMBER', 'BeginOffset': 1109, 'EndOffset': 1111}, {'Text': '96', 'Type': 'NUMBER', 'BeginOffset': 1149, 'EndOffset': 1151}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what blincyto contains - the active substance is blinatumomab. each vial of powder contains 38.5 micrograms of blinatumomab. reconstitution with water for injections results in a final blinatumomab concentration of 12.5 micrograms/ml. - the other ingredients in the powder are citric acid monohydrate (e330), trehalose dihydrate, lysine hydrochloride, polysorbate 80, and sodium hydroxide. - the solution (stabiliser) contains citric acid monohydrate (e330), lysine hydrochloride, polysorbate 80, sodium hydroxide and water for injections. what blincyto looks like and contents of the pack blincyto is a powder for concentrate and solution for solution for infusion. each pack of blincyto contains: 1 glass vial containing a white to off-white powder. 1 glass vial containing a colourless-to-slightly yellow, clear solution.', 'Entity_Recognition': [{'Text': 'blincyto', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 49, 'EndOffset': 61, 'Score': 0.9882578253746033, 'Text': 'blinatumomab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8730118274688721, 'RelationshipScore': 0.999515175819397, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 76, 'EndOffset': 82, 'Text': 'powder', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'powder', 'Type': 'TREATMENT', 'BeginOffset': 76, 'EndOffset': 82}, {'Text': '38.5', 'Type': 'NUMBER', 'BeginOffset': 92, 'EndOffset': 96}, {'Id': 3, 'BeginOffset': 111, 'EndOffset': 123, 'Score': 0.9948712587356567, 'Text': 'blinatumomab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8730118274688721, 'RelationshipScore': 0.6046220660209656, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 76, 'EndOffset': 82, 'Text': 'powder', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9886077642440796, 'RelationshipScore': 0.9999771118164062, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 92, 'EndOffset': 107, 'Text': '38.5 micrograms', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 155, 'EndOffset': 165}, {'Text': 'a final blinatumomab concentration', 'Type': 'TREATMENT', 'BeginOffset': 177, 'EndOffset': 211}, {'Text': '12.5', 'Type': 'NUMBER', 'BeginOffset': 215, 'EndOffset': 219}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 262, 'EndOffset': 272}, {'Id': 6, 'BeginOffset': 277, 'EndOffset': 300, 'Score': 0.9809483289718628, 'Text': 'citric acid monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 309, 'EndOffset': 328, 'Score': 0.9736096262931824, 'Text': 'trehalose dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 330, 'EndOffset': 350, 'Score': 0.9961367249488831, 'Text': 'lysine hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 352, 'EndOffset': 366, 'Score': 0.6516057252883911, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 372, 'EndOffset': 388, 'Score': 0.9997555613517761, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.4079577624797821, 'RelationshipScore': 0.9998207688331604, 'RelationshipType': 'FORM', 'Id': 11, 'BeginOffset': 396, 'EndOffset': 404, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the solution (stabiliser)', 'Type': 'TREATMENT', 'BeginOffset': 392, 'EndOffset': 417}, {'Id': 13, 'BeginOffset': 427, 'EndOffset': 450, 'Score': 0.9977720379829407, 'Text': 'citric acid monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 459, 'EndOffset': 479, 'Score': 0.9973077774047852, 'Text': 'lysine hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5094868540763855, 'RelationshipScore': 0.6837558150291443, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 17, 'BeginOffset': 528, 'EndOffset': 538, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 15, 'BeginOffset': 481, 'EndOffset': 495, 'Score': 0.7380578517913818, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 497, 'EndOffset': 513, 'Score': 0.9994565844535828, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5094868540763855, 'RelationshipScore': 0.99994957447052, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 17, 'BeginOffset': 528, 'EndOffset': 538, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 528, 'EndOffset': 538}, {'Text': 'the pack blincyto', 'Type': 'TREATMENT', 'BeginOffset': 581, 'EndOffset': 598}, {'Text': 'a powder', 'Type': 'TREATMENT', 'BeginOffset': 602, 'EndOffset': 610}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 657, 'EndOffset': 665}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 699, 'EndOffset': 700}, {'Text': 'white powder', 'Type': 'TREATMENT', 'BeginOffset': 738, 'EndOffset': 750}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 752, 'EndOffset': 753}]}

FCFCCD0CE6929608B66C7313BC4E0B2A

https://www.ema.europa.eu/documents/product-information/imatinib-actavis-epar-product-information_en.pdf

Imatinib Actavis

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 50 mg hard capsules Imatinib Actavis 100 mg hard capsules Imatinib Actavis 400 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Imatinib Actavis 50 mg hard capsules Each hard capsule contains 50 mg imatinib (as mesilate). Imatinib Actavis 100 mg hard capsules Each hard capsule contains 100 mg imatinib (as mesilate). Imatinib Actavis 400 mg hard capsules Each hard capsule contains 400 mg imatinib (as mesilate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule (capsule). Imatinib Actavis 50 mg hard capsules Hard capsule of size 3 with light yellow cap and light yellow body imprinted with “50 mg” in black ink. Imatinib Actavis 100 mg hard capsules Hard capsule of size 1 with light orange cap and light orange body imprinted with “100 mg” in black ink. Imatinib Actavis 400 mg hard capsules Hard capsule of size 00 with orange opaque colour cap and body imprinted with “400 mg” in black ink. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Imatinib Actavis is indicated for the treatment of - paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment. - paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis. - adult patients with Ph+ CML in blast crisis. - adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy. - adult patients with relapsed or refractory Ph+ ALL as monotherapy. - adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. - adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement. 2 The effect of imatinib on the outcome of bone marrow transplantation has not been determined. Imatinib Actavis is indicated for - the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. In adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic DFSP. The experience with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited (see section 5.1). There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases. 4.2 Posology and method of administration Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate. Posology Posology for CML in adult patients The recommended dose of imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts ≥ 30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated. Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with blast crisis may be considered in the absence of severe adverse drug reaction and severe non- leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages. Posology for CML in paediatric patients Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase CML and advanced phase CML (not to exceed the total dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening. The dose recommendation is currently based on a small number of paediatric patients (see sections 5.1 and 5.2). There is no experience with the treatment of children below 2 years of age. Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia- related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages. Posology for Ph+ ALL in adult patients 3 The recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological experts in the management of this disease should supervise the therapy throughout all phases of care. Treatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe when administered at 600 mg/day in combination with chemotherapy in the induction phase, the consolidation and maintenance phases of chemotherapy (see section 5.1) for adult patients with newly diagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment programme selected, but generally longer exposures to imatinib have yielded better results. For adult patients with relapsed or refractory Ph+ALL imatinib monotherapy at 600 mg/day is safe, effective and can be given until disease progression occurs. Posology for Ph+ ALL in paediatric patients Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg). Posology for MDS/MPD The recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD. Treatment duration: In the only clinical trial performed up to now, treatment with imatinib was continued until disease progression (see section 5.1). At the time of analysis, the treatment duration was a median of 47 months (24 days - 60 months). Posology for HES/CEL The recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL. Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. Treatment should be continued as long as the patient continues to benefit. Posology for DFSP The recommended dose of imatinib is 800 mg/day for adult patients with DFSP. Dose adjustment for adverse reactions Non-haematological adverse reactions If a severe non-haematological adverse reaction develops with imatinib use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m2/day. Haematological adverse reactions Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below. Dose adjustments for neutropenia and thrombocytopenia: HES/CEL (starting dose 100 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 4 MDS/MPD (starting dose 400 mg) HES/CEL (at dose 400 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume imatinib at reduced dose of 300 mg. Paediatric chronic phase CML (at dose 340 mg/m2) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume imatinib at reduced dose of 260 mg/m2. CML in blast crisis and Ph+ ALL (starting dose 600 mg) aANC < 0.5 x 109/L and/or platelets < 10 x 109/L 1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 400 mg. 3. If cytopenia persists for 2 weeks, reduce further to 300 mg. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L, then resume treatment at 300 mg. Paediatric accelerated phase CML and blast crisis (starting dose 340 mg/m2) aANC < 0.5 x 109/L and/or platelets < 10 x 109/L 1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 260 mg/m2. 3. If cytopenia persists for 2 weeks, reduce further to 200 mg/m2. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L, then resume treatment at 200 mg/m2. DFSP (at dose 800 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. 2. Resume treatment with imatinib at 600 mg. 3. In the event of recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume imatinib at reduced dose of 400 mg. ANC = absolute neutrophil count a occurring after at least 1 month of treatment Special populations 5 Paediatric use: There is no experience in children with CML below 2 years of age and with Ph+ALL below 1 year of age (see section 5.1).There is very limited experience in children with MDS/MPD, DFSP, and HES/CEL. The safety and efficacy of imatinib in children with MDS/MPD, DFSP and HES/CEL aged less than 18 years of age have not been established in clinical trials. Currently available published data are summarised in section 5.1 but no recommendation on a posology can be made. Hepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). Liver dysfunction classification: Liver dysfunction Liver function tests Mild Total bilirubin: = 1.5 ULN AST: >ULN (can be normal or <ULN if total bilirubin is >ULN) Moderate Total bilirubin: >1.5-3.0 ULN AST: any Severe Total bilirubin: >3-10 ULN AST: any ULN = upper limit of normal for the institution AST = aspartate aminotransferase Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum recommended dose of 400 mg daily as starting dose. However, in these patients caution is recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack of efficacy (see sections 4.4 and 5.2). Elderly patients: Imatinib pharmacokinetics have not been specifically studied in older people. No significant age-related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65 and older. No specific dose recommendation is necessary in older people. Method of administration The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening. For patients (children) unable to swallow the capsules, their content may be diluted in a glass of either still water or apple juice. Since studies in animals have shown reproductive toxicity, and the potential risk for the human foetus is unknown, women of child-bearing potential who open capsules should be advised to handle the contents with caution and avoid skin-eye contact or inhalation (see section 4.6). Hands should be washed immediately after handling open capsules. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use When imatinib is co-administered with other medicinal products, there is a potential for drug interactions. Caution should be used when taking imatinib with protease inhibitors, azole antifungals, certain macrolides (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, 6 terfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (see section 4.5). Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided (see section 4.5). Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib (see section 4.5). Thyroid stimulating hormone (TSH) levels should be closely monitored in such patients. Hepatotoxicity Metabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see sections 4.2, 4.8 and 5.2). It should be noted that GIST patients may have hepatic metastases which could lead to hepatic impairment. Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic reactions has been detected. Hepatic function should be carefully monitored in circumstances where imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see sections 4.5 and 4.8). Fluid retention Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients taking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in elderly patients and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction. Patients with cardiac disease Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated. In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL population before treatment initiation. Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of therapy. Gastrointestinal haemorrhage 7 In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra-tumoural haemorrhages were reported (see section 4.8). Based on the available data, no predisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified that place patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard practices and procedures for the monitoring and management of haemorrhage in all patients should be applied. In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has been reported in post-marketing experience in patients with CML, ALL and other diseases (see section 4.8). When needed, discontinuation of imatinib treatment may be considered. Tumour lysis syndrome Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (see section 4.8). Hepatitis B reactivation Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with Imatinib Actavis. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Imatinib Actavis should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8). Phototoxicity Exposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associated with imatinib treatment. Patients should be instructed to use measures such as protective clothing and sunscreen with high sun protection factor (SPF). Thrombotic microangiopathy BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy (TMA), including individual case reports for Imatinib Actavis (see section 4.8). If laboratory or clinical findings associated with TMA occur in a patient receiving Imatinib Actavis, treatment should be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti- ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated in conjunction with low ADAMTS13 activity, treatment with Imatinib Actavis should not be resumed. Laboratory tests Complete blood counts must be performed regularly during therapy with imatinib. Treatment of CML patients with imatinib has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely to be related to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, as recommended in section 4.2. Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving imatinib. In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment should be given the minimum starting dose. Patients with severe renal impairment should be treated with caution. The dose can be reduced if not tolerated (see sections 4.2 and 5.2). 8 Long-term treatment with imatinib may be associated with a clinically significant decline in renal function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and closely monitored during therapy, with particular attention to those patients exhibiting risk factors for renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be prescribed in accordance with standard treatment guidelines. Paediatric population There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib. In an observational study in the CML paediatric population, a statistically significant decrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and 24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. Close monitoring of growth in children under imatinib treatment is recommended (see section 4.8). Excipients(s) Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially ‘sodium-free’. 4.5 Interaction with other medicinal products and other forms of interaction Active substances that may increase imatinib plasma concentrations: Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib with inhibitors of the CYP3A4 family. Active substances that may decrease imatinib plasma concentrations: Substances that are inducers of CYP3A4 activity e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-∞) by at least 54% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic medicinal products (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. Concomitant use of rifampicin or other strong CYP3A4 inducers and imatinib should be avoided. Active substances that may have their plasma concentration altered by imatinib Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.). Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. haemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard heparin instead of coumarin derivatives such as warfarin. 9 In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23% (90%CI [1.16-1.30]). Dose adjustments do not seem to be necessary when imatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol. In patients treated with metoprolol clinical monitoring should be considered. In vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/L. This inhibition has not been observed in vivo after the administration of imatinib 400 mg and paracetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied. Caution should therefore be exercised when using high doses of imatinib and paracetamol concomitantly. In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown. In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see section 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not well characterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase and it has been reported that concomitant use with L-asparaginase could be associated with increased hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires special precaution. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential must be advised to use effective contraception during treatment. Pregnancy There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib. Studies in animals have however shown reproductive toxicity (see section 5.3) and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus. Breast-feeding There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not breast-feed. Fertility In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies on patients receiving imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on imatinib treatment should consult with their physician. 4.7 Effects on ability to drive and use machines 10 Patients should be advised that they may experience undesirable effects such as dizziness,blurred vision or somnolence during treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery. 4.8 Undesirable effects Summary of safety profile Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and the co-administration of numerous medicinal products. In clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse reactions in 4% of patients. The adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression seen in CML patients than in GIST, which is probably due to the underlying disease. In the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour sites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be serious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in both settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial oedemas were a common finding in all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of imatinib. When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering the limited safety database, the adverse events thus far reported in children are consistent with the known safety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ALL is very limited though no new safety concerns have been identified. Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight gain with or without superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding imatinib temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may be serious or life- threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials. Adverse reactions Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first. Adverse reactions and their frequencies are reported in Table 1. Table 1 Tabulated summary of adverse reactions Infections and infestations Uncommon Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, 11 cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis Rare Fungal infection Not known Hepatitis B reactivation* Neoplasm benign, malignant and unspecified (including cysts and polyps) Rare Tumour lysis syndrome Not known Tumour haemorrhage/tumour necrosis* Immune system disorders Not known Anaphylactic shock* Blood and lymphatic system disorders Very common Neutropenia, thrombocytopenia, anaemia Common Pancytopenia, febrile neutropenia Uncommon Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Rare Haemolytic anaemia, thrombotic microangiopathy Metabolism and nutrition disorders Common Anorexia Uncommon Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia Rare Hyperkalaemia, hypomagnesaemia Psychiatric disorders Common Insomnia Uncommon Depression, libido decreased, anxiety Rare Confusional state Nervous system disorders Very common Headache2 Common Dizziness, paraesthesia, taste disturbance, hypoaesthesia Uncommon Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage Rare Increased intracranial pressure, convulsions, optic neuritis Not known Cerebral oedema* Eye disorders Common Eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision Uncommon Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema Rare Cataract, glaucoma, papilloedema Not known Vitreous haemorrhage* Ear and labyrinth disorders Uncommon Vertigo, tinnitus, hearing loss Cardiac disorders Uncommon Palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema Rare Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Not known Pericarditis*, cardiac tamponade* Vascular disorders4 Common Flushing, haemorrhage Uncommon Hypertension, haematoma, subdural haematoma, peripheral coldness, hypotension, Raynaud’s phenomenon Not known Thrombosis/embolism* Respiratory, thoracic and mediastinal disorders Common Dyspnoea, epistaxis, cough Uncommon Pleural effusion5, pharyngolaryngeal pain, pharyngitis Rare Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary 12 haemorrhage Not known Acute respiratory failure11*, interstitial lung disease* Gastrointestinal disorders Very common Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain6 Common Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis Uncommon Stomatitis, mouth ulceration, gastrointestinal haemorrhage7, eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis Rare Colitis, ileus, inflammatory bowel disease Not known Ileus/intestinal obstruction*, gastrointestinal perforation*, diverticulitis*, gastric antral vascular ectasia (GAVE)* Hepatobiliary disorders Common Increased hepatic enzymes Uncommon Hyperbilirubinaemia, hepatitis, jaundice Rare Hepatic failure8, hepatic necrosis Skin and subcutaneous tissue disorders Very common Periorbital oedema, dermatitis/eczema/rash Common Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction Uncommon Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptions Rare Acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discolouration, angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis (AGEP) Not known Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)*, pseudoporphyria* Musculoskeletal and connective tissue disorders Very common Muscle spasm and cramps, musculoskeletal pain including myalgia9, arthralgia, bone pain10 Common Joint swelling Uncommon Joint and muscle stiffness Rare Muscular weakness, arthritis, rhabdomyolysis/myopathy Not known Avascular necrosis/hip necrosis*, growth retardation in children* Renal and urinary disorders Uncommon Renal pain, haematuria, renal failure acute, urinary frequency increased Not known Renal failure chronic Reproductive system and breast disorders Uncommon Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema Rare Haemorrhagic corpus luteum/haemorrhagic ovarian cyst General disorders and administration site conditions Very common Fluid retention and oedema, fatigue Common Weakness, pyrexia, anasarca, chills, rigors Uncommon Chest pain, malaise Investigations Very common Weight increased Common Weight decreased Uncommon Blood creatinine increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased Rare Blood amylase increased 13 * These types of reactions have been reported mainly from post-marketing experience with imatinib. This includes spontaneous case reports as well as serious adverse events from ongoing studies, the expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved indications. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure. 1 Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST. 2 Headache was the most common in GIST patients. 3 On a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML. 4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC). 5 Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML. 6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients. 8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported. 9 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed in post-marketing. 10 Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients. 11 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions. Laboratory test abnormalities Haematology In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/L) and thrombocytopenias (platelet count < 50 x 109/L) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64% and 44–63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic phase CML grade 4 neutropenia (ANC < 0.5 x 109/L) and thrombocytopenia (platelet count < 10 x 109/L) were observed in 3.6% and < 1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the first several months of therapy. In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra- tumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter. Biochemistry Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 14 ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) elevations were observed. Bilirubin elevation was below 3%. There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal, including one patient on high dose paracetamol. Description of selected adverse reactions Hepatitis B reactivation Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of imatinib overdose have been reported spontaneously and in the literature. In the event of overdose the patient should be observed and appropriate symptomatic treatment given. Generally the reported outcome in these cases was “improved” or “recovered”. Events that have been reported at different dose ranges are as follows: Adult population 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain. 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. Paediatric population One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor, ATC code: L01XE01 Mechanism of action Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and 15 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases. Pharmacodynamic effects Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients. In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl positive tumour cells. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), PDGF-R, and inhibits PDGF-mediated cellular events. Constitutive activation of the PDGF receptor or the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. Imatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase activity. Clinical studies in chronic myeloid leukaemia The effectiveness of imatinib is based on overall haematological and cytogenetic response rates and progression-free survival. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. A large, international, open-label, non-controlled phase II study was conducted in patients with Philadelphia chromosome positive (Ph+) CML in the blast crisis phase of the disease. In addition, children and adolescents have been treated in two phase I studies (in patients with CML or Ph+ acute leukaemia) and one phase II study. In the clinical study 38% of patients were ≥ 60 years of age and 12% of patients were ≥ 70 years of age. Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 223 patients were started at 600 mg. The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. In this study, 31% of patients achieved a haematological response (36% in previously untreated patients and 22% in previously treated patients) (Table 2). The rate of response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, p=0.0220). The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively. Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate of haematological response was 70% with a duration of 2–3 months. 16 Table 2 Response in adult CML study Study 0102 38-month data Myeloid blast crisis (n=260) % of patients (CI95%) Haematological response1 Complete haematological response (CHR) No evidence of leukaemia (NEL) Return to chronic phase (RTC) 31% (25.2–36.8) 8% 5% 18% Major cytogenetic response2 Complete (Confirmed3) [95% CI] Partial 15% (11.2–20.4) 7% (2%) [0.6–4.4] 8% 1 Haematological response criteria (all responses to be confirmed after ≥ 4 weeks): CHR: In study 0102 [ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, no blood blasts, BM blasts < 5% and no extramedullary disease] NEL Same criteria as for CHR but ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB, no extramedullary disease other than spleen and liver. BM = bone marrow, PB = peripheral blood 2 Cytogenetic response criteria: A major response combines both complete and partial responses: complete (0% Ph+ metaphases), partial (1–35%) 3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least one month after the initial bone marrow study. Paediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML (n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase I trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a prior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5), 340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronic phase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial cytogenetic response, respectively, for a rate of MCyR of 77%. A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been enrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib 340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete cytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16% for a MCyR of 81%. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months. The European Medicines Agency has waived the obligation to submit the results of studies with imatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)- positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use). Clinical studies in Ph+ ALL Newly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction in 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a significantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; 17 p=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or who responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a complete haematological response. This clinical effect was associated with a higher reduction in bcr- abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy (p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 3) after induction and the levels of bcr-abl transcripts were identical in the two arms at 8 weeks. As expected on the basis of the study design, no difference was observed in remission duration, disease-free survival or overall survival, although patients with complete molecular response and remaining in minimal residual disease had a better outcome in terms of both remission duration (p=0.01) and disease-free survival (p=0.02). The results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled clinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. Imatinib in combination with chemotherapy induction (see Table 3) resulted in a complete haematological response rate of 93% (147 out of 158 evaluable patients) and in a major cytogenetic response rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was 48% (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in two studies (AJP01 and AUS01). Table 3 Chemotherapy regimen used in combination with imatinib Study ADE10 Prephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3, 4, 5; MTX 12 mg intrathecal, day 1 Remission induction DEX 10 mg/m2 oral, days 6-7, 13-16; VCR 1 mg i.v., days 7, 14; IDA 8 mg/m2 i.v. (0.5 h), days 7, 8, 14, 15; CP 500 mg/m2 i.v.(1 h) day 1; Ara- C 60 mg/m2 i.v., days 22-25, 29-32 Consolidation therapy I, III, V MTX 500 mg/m2 i.v. (24 h), days 1, 15; 6-MP 25 mg/m2 oral, days 1-20 Consolidation therapy II, IV Ara-C 75 mg/m2 i.v. (1 h), days 1-5; VM26 60 mg/m2 i.v. (1 h), days 1-5 Study AAU02 Induction therapy (de novo Ph+ ALL) Daunorubicin 30 mg/m2 i.v., days 1-3, 15-16; VCR 2 mg total dose i.v., days 1, 8, 15, 22; CP 750 mg/m2 i.v., days 1, 8; prednisone 60 mg/m2 oral, days 1-7, 15-21; IDA 9 mg/m2 oral, days 1-28; MTX 15 mg intrathecal, days 1, 8, 15, 22; Ara-C 40 mg intrathecal, days 1, 8, 15, 22; methylprednisolone 40 mg intrathecal, days 1, 8, 15, 22 Consolidation (de novo Ph+ ALL) Ara-C 1,000 mg/m2 /12 h i.v.(3 h), days 1-4; mitoxantrone 10 mg/m2 i.v. days 3-5; MTX 15 mg intrathecal, day 1; methylprednisolone 40 mg intrathecal, day 1 Study ADE04 Prephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3-5; MTX 15 mg intrathecal, day 1 Induction therapy I DEX 10 mg/m2 oral, days 1-5; VCR 2 mg i.v., days 6, 13, 20; daunorubicin 45 mg/m2 i.v., days 6-7, 13-14 Induction therapy II CP 1 g/m2 i.v. (1 h), days 26, 46; Ara-C 75 mg/m2 i.v. (1 h), days 28-31, 35-38, 42-45; 6-MP 60 mg/m2 oral, days 26-46 18 Consolidation therapy DEX 10 mg/m2 oral, days 1-5; vindesine 3 mg/m2 i.v., day 1; MTX 1.5 g/m2 i.v. (24 h), day 1; etoposide 250 mg/m2 i.v. (1 h) days 4-5; Ara- C 2x 2 g/m2 i.v. (3 h, q 12 h), day 5 Study AJP01 Induction therapy CP 1.2 g/m2 i.v. (3 h), day 1; daunorubicin 60 mg/m2 i.v. (1 h), days 1-3; vincristine 1.3 mg/m2 i.v., days 1, 8, 15, 21; prednisolone 60 mg/m2/day oral Consolidation therapy Alternating chemotherapy course: high dose chemotherapy with MTX 1 g/m2 i.v. (24 h), day 1, and Ara-C 2 g/m2 i.v. (q 12 h), days 2-3, for 4 cycles Maintenance VCR 1.3 g/m2 i.v., day 1; prednisolone 60 mg/m2 oral, days 1-5 Study AUS01 Induction- consolidation therapy Hyper-CVAD regimen: CP 300 mg/m2 i.v. (3 h, q 12 h), days 1-3; vincristine 2 mg i.v., days 4, 11; doxorubicine 50 mg/m2 i.v. (24 h), day 4; DEX 40 mg/day on days 1-4 and 11-14, alternated with MTX 1 g/m2 i.v. (24 h), day 1, Ara-C 1 g/m2 i.v. (2 h, q 12 h), days 2-3 (total of 8 courses) Maintenance VCR 2 mg i.v. monthly for 13 months; prednisolone 200 mg oral, 5 days per month for 13 months All treatment regimens include administration of steroids for CNS prophylaxis. Ara-C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; 6-MP: 6-mercaptopurine; VM26: Teniposide; VCR: vincristine; IDA: idarubicine; i.v.: intravenous Paediatric patients: In study I2301, a total of 93 paediatric, adolescent and young adult patients (from 1 to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort, non-randomised phase III trial, and were treated with imatinib (340 mg/m2/day) in combination with intensive chemotherapy after induction therapy. Imatinib was administered intermittently in cohorts 1-5, with increasing duration and earlier start of imatinib from cohort to cohort; cohort 1 receiving the lowest intensitiy and cohort 5 receiving the highest intensity of imatinib (longest duration in days with continuous daily imatinib dosing during the first chemotherapy treatment courses). Continuous daily exposure to imatinib early in the course of treatment in combination with chemotherapy in cohort 5-patients (n=50) improved the 4-year event-free survival (EFS) compared to historical controls (n=120), who received standard chemotherapy without imatinib (69.6% vs. 31.6%, respectively). The estimated 4-year OS in cohort 5-patients was 83.6% compared to 44.8% in the historical controls. 20 out of the 50 (40%) patients in cohort 5 received haematopoietic stem cell transplant. Table 4 Chemotherapy regimen used in combination with imatinib in study I2301 Consolidation block 1 (3 weeks) VP-16 (100 mg/m2/day, IV): days 1-5 Ifosfamide (1.8 g/m2/day, IV): days 1-5 MESNA (360 mg/m2/dose q3h, x 8 doses/day, IV): days 1-5 G-CSF (5 μg/kg, SC): days 6-15 or until ANC > 1500 post nadir IT Methotrexate (age-adjusted): day 1 ONLY Triple IT therapy (age-adjusted): day 8, 15 Consolidation block 2 (3 weeks) Methotrexate (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: Days 2 and 3 Triple IT therapy (age-adjusted): day 1 ARA-C (3 g/m2/dose q 12 h x 4, IV): days 2 and 3 G-CSF (5 μg/kg, SC): days 4-13 or until ANC > 1500 post nadir 19 Reinduction block 1 (3 weeks) VCR (1.5 mg/m2/day, IV): days 1, 8, and 15 DAUN (45 mg/m2/day bolus, IV): days 1 and 2 CPM (250 mg/m2/dose q12h x 4 doses, IV): days 3 and 4 PEG-ASP (2500 IUnits/m2, IM): day 4 G-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir Triple IT therapy (age-adjusted): days 1 and 15 DEX (6 mg/m2/day, PO): days 1-7 and 15-21 Intensification block 1 (9 weeks) Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: Days 2, 3, 16, and 17 Triple IT therapy (age-adjusted): days 1 and 22 VP-16 (100 mg/m2/day, IV): days 22-26 CPM (300 mg/m2/day, IV): days 22-26 MESNA (150 mg/m2/day, IV): days 22-26 G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir ARA-C (3 g/m2, q12h, IV): days 43, 44 L-ASP (6000 IUnits/m2, IM): day 44 Reinduction block 2 (3 weeks) VCR (1.5 mg/m2/day, IV): days 1, 8 and 15 DAUN (45 mg/m2/day bolus, IV): days 1 and 2 CPM (250 mg/m2/dose q12h x 4 doses, iv): Days 3 and 4 PEG-ASP (2500 IUnits/m2, IM): day 4 G-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir Triple IT therapy (age-adjusted): days 1 and 15 DEX (6 mg/m2/day, PO): days 1-7 and 15-21 Intensification block 2 (9 weeks) Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2, 3, 16, and 17 Triple IT therapy (age-adjusted): days 1 and 22 VP-16 (100 mg/m2/day, IV): days 22-26 CPM (300 mg/m2/day, IV): days 22-26 MESNA (150 mg/m2/day, IV): days 22-26 G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir ARA-C (3 g/m2, q12h, IV): days 43, 44 L-ASP (6000 IUnits/m2, IM): day 44 Maintenance (8-week cycles) Cycles 1–4 MTX (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2 and 3 Triple IT therapy (age-adjusted): days 1, 29 VCR (1.5 mg/m2, IV): days 1, 29 DEX (6 mg/m2/day PO): days 1-5; 29-33 6-MP (75 mg/m2/day, PO): days 8-28 Methotrexate (20 mg/m2/week, PO): days 8, 15, 22 VP-16 (100 mg/m2, IV): days 29-33 CPM (300 mg/m2, IV): days 29-33 MESNA IV days 29-33 G-CSF (5 μg/kg, SC): days 34-43 Maintenance (8-week cycles) Cycle 5 Cranial irradiation (Block 5 only) 12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis 18 Gy in 10 fractions for patients that are CNS3 at diagnosis VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1-5; 29-33 6-MP (75 mg/m2/day, PO): days 11-56 (Withhold 6-MP during the 6-10 days of cranial irradiation beginning on day 1 of Cycle 5. Start 6-MP the 1st day after cranial irradiation completion.) Methotrexate (20 mg/m2/week, PO): days 8, 15, 22, 29, 36, 43, 50 20 Maintenance (8-week cycles) Cycles 6-12 VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1-5; 29-33 6-MP (75 mg/m2/day, PO): days 1-56 Methotrexate (20 mg/m2/week, PO): days 1, 8, 15, 22, 29, 36, 43, 50 G-CSF = granulocyte colony stimulating factor, VP-16 = etoposide, MTX = methotrexate, IV = intravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = cytarabine, CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = daunorubicin, 6-MP = 6-mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = PEG asparaginase, MESNA= 2-mercaptoethane sulfonate sodium, iii= or until MTX level is < 0.1 µM, q6h = every 6 hours, Gy= Gray Study AIT07 was a multicentre, open-label, randomised, phase II/III study that included 128 patients (1 to < 18 years) treated with imatinib in combination with chemotherapy. Safety data from this study seem to be in line with the safety profile of imatinib in Ph+ ALL patients. Relapsed/refractory Ph+ ALL: When imatinib was used as single agent in patients with relapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a haematological response rate of 30% (9% complete) and a major cytogenetic response rate of 23%. (Of note, out of the 411 patients, 353 were treated in an expanded access program without primary response data collected.) The median time to progression in the overall population of 411 patients with relapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the 401 evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to include only those patients age 55 or older. Clinical studies in MDS/MPD Experience with imatinib in this indication is very limited and is based on haematological and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit or increased survival. One open label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD who were treated with imatinib 400 mg daily. Three patients presented a complete haematological response (CHR) and one patient experienced a partial haematological response (PHR). At the time of the original analysis, three of the four patients with detected PDGFR gene rearrangements developed haematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years. An observational registry (study L2401) was conducted to collect long-term safety and efficacy data in patients suffering from myeloproliferative neoplasms with PDGFR- β rearrangement and who were treated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily dose of 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due to the observational nature of this registry, haematologic, cytogenetic and molecular assessment data were available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assuming conservatively that patients with missing data were non-responders, CHR was observed in 20/23 (87%) patients, CCyR in 9/23 (39.1%) patients, and MR in 11/23 (47.8%) patients, respectively. When the response rate is calculated from patients with at least one valid assessment, the response rate for CHR, CCyR and MR was 20/22 (90.9%), 9/9 (100%) and 11/17 (64.7%), respectively. In addition a further 24 patients with MDS/MPD were reported in 13 publications. 21 patients were treated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients PDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR. The age of these patients ranged from 2 to 79 years. In a recent publication updated information from 6 of these 11 patients revealed that all these patients remained in cytogenetic remission (range 32-38 months). The same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR gene rearrangements (5 patients from study B2225). These patients received imatinib for a median of 47 months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease or disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic responses have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59), 21 respectively. The overall survival is 65 months since diagnosis (range 25-234). Imatinib administration to patients without the genetic translocation generally results in no improvement. There are no controlled trials in paediatric patients with MDS/MPD. Five (5) patients with MDS/MPD associated with PDGFR gene re-arrangements were reported in 4 publications. The age of these patients ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses ranging from 92.5 to 340 mg/m2 daily. All patients achieved complete haematological response, cytogenetic response and/or clinical response. Clinical studies in HES/CEL One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL were treated with 100 mg to 1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published case reports and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogenetic abnormalities were evaluated in 117 of the total population of 176 patients. In 61 of these 117 patients FIP1L1-PDGFRα fusion kinase was identified. An additional four HES patients were found to be FIP1L1-PDGFRα-positive in other 3 published reports. All 65 FIP1L1-PDGFRα fusion kinase positive patients achieved a CHR sustained for months (range from 1+ to 44+ months censored at the time of the reporting). As reported in a recent publication 21 of these 65 patients also achieved complete molecular remission with a median follow-up of 28 months (range 13-67 months). The age of these patients ranged from 25 to 72 years. Additionally, improvements in symptomatology and other organ dysfunction abnormalities were reported by the investigators in the case reports. Improvements were reported in cardiac, nervous, skin/subcutaneous tissue, respiratory/thoracic/mediastinal, musculoskeletal/connective tissue/vascular, and gastrointestinal organ systems. There are no controlled trials in paediatric patients with HES/CEL. Three (3) patients with HES and CEL associated with PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from 2 to 16 years and imatinib was given at dose 300 mg/m2 daily or doses ranging from 200 to 400 mg daily. All patients achieved complete haematological response, complete cytogenetic response and/or complete molecular response. Clinical studies in DFSP One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients with DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to 75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered amenable to further resective surgery at the time of study entry. The primary evidence of efficacy was based on objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and 8 partially. Three of the partial responders were subsequently rendered disease free by surgery. The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. A further 6 DFSP patients treated with imatinib were reported in 5 published case reports, their ages ranging from 18 months to 49 years. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. 5 patients responded, 3 completely and 2 partially. The median duration of therapy in the published literature ranged between 4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, was present in nearly all responders to imatinib treatment. There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from newborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to 520 mg/m2 daily. All patients achieved partial and/or complete response. 5.2 Pharmacokinetic properties Pharmacokinetics of imatinib 22 The pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg. Plasma pharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma concentrations had reached steady state. Absorption Mean absolute bioavailability for imatinib is 98%. There was high between-patient variability in plasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior gastrointestinal surgery on drug absorption has not been investigated. Distribution At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein. Biotransformation The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound. Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating radioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor metabolites. The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V) only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of imatinib metabolism which could have clinical relevance. Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/L, respectively. Maximal plasma concentrations of imatinib in patients are 2–4 μmol/L, consequently an inhibition of CYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did not interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a result of competitive inhibition of CYP2C8 (Ki - 34.7 µM). This Ki value is far higher than the expected plasma levels of imatinib in patients, consequently no interaction is expected upon co- administration of either 5-fluorouracil or paclitaxel and imatinib. Elimination Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites. Plasma pharmacokinetics Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when dosed once daily. Population pharmacokinetics Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on the volume of distribution (12% increase in patients > 65 years old). This change is not thought to be clinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient 23 weighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the clearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment based on kg bodyweight. There is no effect of gender on the kinetics of imatinib. Pharmacokinetics in paediatric population As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same exposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after repeated once-daily dosing. Based on pooled population pharmacokinetic analysis in paediatric patients with haematological disorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily. Organ function impairment Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4). Although the results of pharmacokinetic analysis showed that there is considerable inter-subject variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8). 5.3 Preclinical safety data The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits. Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and monkeys, accompanied by bone marrow changes in rats and dogs. The liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. No histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal papilla and in the urinary bladder was observed at doses ≥ 6 mg/kg in the 13-week study, without changes in serum or urinary parameters. An increased rate of opportunistic infections was observed with chronic imatinib treatment. In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the lowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on body surface. Treatment resulted in worsening of normally suppressed malarial infections in these animals. 24 Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post- implantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg. In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn pups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not affected, while an increased number of resorptions and a decreased number of viable foetuses was noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. These effects were not seen at doses ≤ 30 mg/kg. No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 postpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, effects upon growth, delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at approximately 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥ 30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non- glandular stomach. Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 30 mg/kg/day. 25 The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet clarified. Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. The active substance imatinib demonstrates an environmental risk for sediment organisms. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Imatinib Actavis 50 mg hard capsules Capsule content Cellulose microcrystalline Copovidone Crospovidone Sodium stearyl fumarate Silica, hydrophobic colloidal Silica, colloidal anhydrous Capsule shell Hypromellose Titanium dioxide (E171) Iron oxide yellow (E172) Printing ink Shellac Black iron oxide (E172) Propylene glycol Ammonia solution Potassium hydroxide Imatinib Actavis 100 mg hard capsules Capsule content Cellulose microcrystalline Copovidone Crospovidone Sodium stearyl fumarate Silica, hydrophobic colloidal Silica, colloidal anhydrous Capsule shell Hypromellose Titanium dioxide (E171) Iron oxide yellow (E172) Iron oxide red (E172) Printing ink Shellac Black iron oxide (E172) Propylene glycol Ammonia solution Potassium hydroxide 26 Imatinib Actavis 400 mg hard capsules Capsule content Cellulose microcrystalline Copovidone Crospovidone Sodium stearyl fumarate Silica, hydrophobic colloidal Silica, colloidal anhydrous Capsule shell Hypromellose Titanium dioxide (E171) Iron oxide yellow (E172) Iron oxide red (E172) Iron oxide black (E172) Printing ink Shellac Glaze-45% Black iron oxide (E172) Propylene glycol Ammonium Hydroxide 28% 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Do not store above 25°C. Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Imatinib Actavis 50 mg hard capsules Al/PVC/Aclar blister. One blister contains 10 capsules. Pack containing either 30 or 90 capsules. Imatinib Actavis 100 mg hard capsules Al/PVC/Aclar blister. One blister contains either 8 or 10 capsules. Pack containing either 24, 48, 60, 96, 120 or 180 capsules Imatinib Actavis 400 mg hard capsules Al/PVC-PVDC blister. One blister contains 10 capsules. Pack containing either 10, 30, 60, or 90 capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Handling of opened capsules by women of child-bearing potential Since studies in animals have shown reproductive toxicity, and the potential risk for the human foetus is unknown, women of child-bearing potential who open capsules should be advised to handle the 27 contents with caution and avoid skin-eye contact or inhalation (see section 4.6). Hands should be washed immediately after handling open capsules. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. Reykjavíkurvegur 76-78 IS-220 Hafnarfjörður Iceland 8. MARKETING AUTHORISATION NUMBER(S) Imatinib Actavis 50 mg hard capsules EU/1/13/825/001 EU/1/13/825/002 Imatinib Actavis 100 mg hard capsules EU/1/13/825/003 EU/1/13/825/004 EU/1/13/825/005 EU/1/13/825/006 EU/1/13/825/007 EU/1/13/825/019 Imatinib Actavis 400 mg hard capsules EU/1/13/825/020 EU/1/13/825/021 EU/1/13/825/022 EU/1/13/825/023 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 17 April 2013 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 28 http://www.ema.europa.eu/ 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 100 mg film-coated tablets Imatinib Actavis 400 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Imatinib Actavis 100 mg film-coated tablets Each film-coated tablet contains 100 mg imatinib (as mesilate). Excipients with known effect: Each film-coated tablet contains 0.19 mg lecithin (soya) (E322) Imatinib Actavis 400 mg film-coated tablets Each film-coated tablet contains 400 mg imatinib (as mesilate). Excipients with known effect: Each film-coated tablet contains 0.75 mg lecithin (soya) (E322) For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Imatinib Actavis 100 mg film-coated tablets Round, 9.2 mm in diameter, biconvex dark yellow to brownish film-coated tablet, embossed with company logo on one side and “36” with score line on the other side. The tablet can be divided into equal doses. Imatinib Actavis 400 mg film-coated tablets Oval-shape, 18.6x6.6 mm, biconvex dark yellow to brownish film-coated tablet, embossed with company logo on one side and “37” with score line on the other side. The score line is not intended for breaking the tablet. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Imatinib Actavis is indicated for the treatment of - paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment. - paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis. - adult patients with Ph+ CML in blast crisis. - adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy. - adult patients with relapsed or refractory Ph+ ALL as monotherapy. - adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. - adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement. 29 The effect of imatinib on the outcome of bone marrow transplantation has not been determined. Imatinib Actavis is indicated for - the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. In adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic DFSP. The experience with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited (see section 5.1). There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases. 4.2 Posology and method of administration Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate. Posology Posology for CML in adult patients The recommended dose of imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts ≥ 30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated. Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with blast crisis may be considered in the absence of severe adverse drug reaction and severe non- leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages. Posology for CML in paediatric patients Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase CML and advanced phase CML (not to exceed the total dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening. The dose recommendation is currently based on a small number of paediatric patients (see sections 5.1 and 5.2). There is no experience with the treatment of children below 2 years of age. Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia- related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages. Posology for Ph+ ALL in adult patients 30 The recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological experts in the management of this disease should supervise the therapy throughout all phases of care. Treatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe when administered at 600 mg/day in combination with chemotherapy in the induction phase, the consolidation and maintenance phases of chemotherapy (see section 5.1) for adult patients with newly diagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment programme selected, but generally longer exposures to imatinib have yielded better results. For adult patients with relapsed or refractory Ph+ALL imatinib monotherapy at 600 mg/day is safe, effective and can be given until disease progression occurs. Posology for Ph+ ALL in paediatric patients Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg). Posology for MDS/MPD The recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD. Treatment duration: In the only clinical trial performed up to now, treatment with imatinib was continued until disease progression (see section 5.1). At the time of analysis, the treatment duration was a median of 47 months (24 days - 60 months). Posology for HES/CEL The recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL. Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. Treatment should be continued as long as the patient continues to benefit. Posology for DFSP The recommended dose of imatinib is 800 mg/day for adult patients with DFSP. Dose adjustment for adverse reactions Non-haematological adverse reactions If a severe non-haematological adverse reaction develops with imatinib use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m2/day. Haematological adverse reactions Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below. Dose adjustments for neutropenia and thrombocytopenia: HES/CEL (starting dose 100 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 31 MDS/MPD (starting dose 400 mg) HES/CEL (at dose 400 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume imatinib at reduced dose of 300 mg. Paediatric chronic phase CML (at dose 340 mg/m2) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume imatinib at reduced dose of 260 mg/m2. CML in blast crisis and Ph+ ALL (starting dose 600 mg) aANC < 0.5 x 109/L and/or platelets < 10 x 109/L 1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 400 mg. 3. If cytopenia persists for 2 weeks, reduce further to 300 mg. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L, then resume treatment at 300 mg. Paediatric accelerated phase CML and blast crisis (starting dose 340 mg/m2) aANC < 0.5 x 109/L and/or platelets < 10 x 109/L 1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 260 mg/m2. 3. If cytopenia persists for 2 weeks, reduce further to 200 mg/m2. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L, then resume treatment at 200 mg/m2. DFSP (at dose 800 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. 2. Resume treatment with imatinib at 600 mg. 3. In the event of recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume imatinib at reduced dose of 400 mg. ANC = absolute neutrophil count a occurring after at least 1 month of treatment Special populations 32 Paediatric use: There is no experience in children with CML below 2 years of age and with Ph+ALL below 1 year of age (see section 5.1). There is very limited experience in children with MDS/MPD, DFSP, and HES/CEL. The safety and efficacy of imatinib in children with MDS/MPD, DFSP and HES/CEL aged less than 18 years of age have not been established in clinical trials. Currently available published data are summarised in section 5.1 but no recommendation on a posology can be made. Hepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). Liver dysfunction classification: Liver dysfunction Liver function tests Mild Total bilirubin: = 1.5 ULN AST: >ULN (can be normal or <ULN if total bilirubin is >ULN) Moderate Total bilirubin: >1.5-3.0 ULN AST: any Severe Total bilirubin: >3-10 ULN AST: any ULN = upper limit of normal for the institution AST = aspartate aminotransferase Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum recommended dose of 400 mg daily as starting dose. However, in these patients caution is recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack of efficacy (see sections 4.4 and 5.2). Elderly patients: Imatinib pharmacokinetics have not been specifically studied in older people. No significant age-related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65 and older. No specific dose recommendation is necessary in older people. Method of administration For doses of 400 mg and above (see dosage recommendation above) a 400 mg tablet (not divisible) is available. For doses other than 400 mg and 800 mg (see dosage recommendation above) a 100 mg divisible tablet is available. The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 33 Hypersensitivity to soya or peanut. 4.4 Special warnings and precautions for use When imatinib is co-administered with other medicinal products, there is a potential for drug interactions. Caution should be used when taking imatinib with protease inhibitors, azole antifungals, certain macrolides (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (see section 4.5). Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided (see section 4.5). Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib (see section 4.5). Thyroid stimulating hormone (TSH) levels should be closely monitored in such patients. Hepatotoxicity Metabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see sections 4.2, 4.8 and 5.2). It should be noted that GIST patients may have hepatic metastases which could lead to hepatic impairment. Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic reactions has been detected. Hepatic function should be carefully monitored in circumstances where imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see sections 4.5 and 4.8). Fluid retention Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients taking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in elderly patients and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction. Patients with cardiac disease Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated. In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL population before treatment initiation. 34 Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of therapy. Gastrointestinal haemorrhage In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra-tumoural haemorrhages were reported (see section 4.8). Based on the available data, no predisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified that place patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard practices and procedures for the monitoring and management of haemorrhage in all patients should be applied. In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has been reported in post-marketing experience in patients with CML, ALL and other diseases (see section 4.8). When needed, discontinuation of imatinib treatment may be considered. Tumour lysis syndrome Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (see section 4.8). Hepatitis B reactivation Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with Imatinib Actavis. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Imatinib Actavis should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8). Phototoxicity Exposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associated with imatinib treatment. Patients should be instructed to use measures such as protective clothing and sunscreen with high sun protection factor (SPF). Thrombotic microangiopathy BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy (TMA), including individual case reports for Imatinib Actavis (see section 4.8). If laboratory or clinical findings associated with TMA occur in a patient receiving Imatinib Actavis, treatment should be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti- ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated in conjunction with low ADAMTS13 activity, treatment with Imatinib Actavis should not be resumed. Laboratory tests Complete blood counts must be performed regularly during therapy with imatinib. Treatment of CML patients with imatinib has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely to be related to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, as recommended in section 4.2. 35 Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving imatinib. In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment should be given the minimum starting dose. Patients with severe renal impairment should be treated with caution. The dose can be reduced if not tolerated (see sections 4.2 and 5.2). Long-term treatment with imatinib may be associated with a clinically significant decline in renal function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and closely monitored during therapy, with particular attention to those patients exhibiting risk factors for renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be prescribed in accordance with standard treatment guidelines. Paediatric population There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib. In an observational study in the CML paediatric population, a statistically significant decrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and 24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. Close monitoring of growth in children under imatinib treatment is recommended (see section 4.8). Excipients Lecithin (soya) This medicinal product contains lecithin (soya). Patients, who are allergic to peanut or soya, may not use this medicinal product. Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’. 4.5 Interaction with other medicinal products and other forms of interaction Active substances that may increase imatinib plasma concentrations: Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib with inhibitors of the CYP3A4 family. Active substances that may decrease imatinib plasma concentrations: Substances that are inducers of CYP3A4 activity e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-∞) by at least 54% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic medicinal products (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. Concomitant use of rifampicin or other strong CYP3A4 inducers and imatinib should be avoided. Active substances that may have their plasma concentration altered by imatinib: 36 Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.). Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. haemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard heparin instead of coumarin derivatives such as warfarin. In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23% (90%CI [1.16-1.30]). Dose adjustments do not seem to be necessary when imatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol. In patients treated with metoprolol clinical monitoring should be considered. In vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/L. This inhibition has not been observed in vivo after the administration of imatinib 400 mg and paracetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied. Caution should therefore be exercised when using high doses of imatinib and paracetamol concomitantly. In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown. In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see section 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not well characterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase and it has been reported that concomitant use with L-asparaginase could be associated with increased hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires special precaution. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential must be advised to use effective contraception during treatment. Pregnancy There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib. Studies in animals have however shown reproductive toxicity (see section 5.3) and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus. Breast-feeding There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total 37 exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not breast-feed. Fertility In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies on patients receiving imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on imatinib treatment should consult with their physician. 4.7 Effects on ability to drive and use machines Patients should be advised that they may experience undesirable effects such as dizziness,blurred vision or somnolence during treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery. 4.8 Undesirable effects Summary of safety profile Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and the co-administration of numerous medicinal products. In clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse reactions in 4% of patients. The adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression seen in CML patients than in GIST, which is probably due to the underlying disease. In the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour sites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be serious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in both settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial oedemas were a common finding in all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of imatinib. When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering the limited safety database, the adverse events thus far reported in children are consistent with the known safety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ALL is very limited though no new safety concerns have been identified. Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight gain with or without superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding imatinib temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may be serious or life- threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials. Adverse reactions Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: very common 38 (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first. Adverse reactions and their frequencies are reported in Table 1. Table 1 Tabulated summary of adverse reactions Infections and infestations Uncommon Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis Rare Fungal infection Not known Hepatitis B reactivation* Neoplasm benign, malignant and unspecified (including cysts and polyps) Rare Tumour lysis syndrome Not known Tumour haemorrhage/tumour necrosis* Immune system disorders Not known Anaphylactic shock* Blood and lymphatic system disorders Very common Neutropenia, thrombocytopenia, anaemia Common Pancytopenia, febrile neutropenia Uncommon Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Rare Haemolytic anaemia, thrombotic microangiopathy Metabolism and nutrition disorders Common Anorexia Uncommon Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia Rare Hyperkalaemia, hypomagnesaemia Psychiatric disorders Common Insomnia Uncommon Depression, libido decreased, anxiety Rare Confusional state Nervous system disorders Very common Headache2 Common Dizziness, paraesthesia, taste disturbance, hypoaesthesia Uncommon Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage Rare Increased intracranial pressure, convulsions, optic neuritis Not known Cerebral oedema* Eye disorders Common Eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision Uncommon Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema Rare Cataract, glaucoma, papilloedema Not known Vitreous haemorrhage* Ear and labyrinth disorders Uncommon Vertigo, tinnitus, hearing loss Cardiac disorders Uncommon Palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema Rare Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina 39 pectoris, pericardial effusion Not known Pericarditis*, cardiac tamponade* Vascular disorders4 Common Flushing, haemorrhage Uncommon Hypertension, haematoma, subdural haematoma, peripheral coldness, hypotension, Raynaud’s phenomenon Not known Thrombosis/embolism* Respiratory, thoracic and mediastinal disorders Common Dyspnoea, epistaxis, cough Uncommon Pleural effusion5, pharyngolaryngeal pain, pharyngitis Rare Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage Not known Acute respiratory failure11*, interstitial lung disease* Gastrointestinal disorders Very common Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain6 Common Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis Uncommon Stomatitis, mouth ulceration, gastrointestinal haemorrhage7, eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis Rare Colitis, ileus, inflammatory bowel disease Not known Ileus/intestinal obstruction*, gastrointestinal perforation*, diverticulitis*, gastric antral vascular ectasia (GAVE)* Hepatobiliary disorders Common Increased hepatic enzymes Uncommon Hyperbilirubinaemia, hepatitis, jaundice Rare Hepatic failure8, hepatic necrosis Skin and subcutaneous tissue disorders Very common Periorbital oedema, dermatitis/eczema/rash Common Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction Uncommon Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptions Rare Acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discolouration, angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis (AGEP) Not known Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)*, pseudoporphyria* Musculoskeletal and connective tissue disorders Very common Muscle spasm and cramps, musculoskeletal pain including myalgia9, arthralgia, bone pain10 Common Joint swelling Uncommon Joint and muscle stiffness Rare Muscular weakness, arthritis, rhabdomyolysis/myopathy Not known Avascular necrosis/hip necrosis*, growth retardation in children* Renal and urinary disorders Uncommon Renal pain, haematuria, renal failure acute, urinary frequency increased Not known Renal failure chronic Reproductive system and breast disorders Uncommon Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema Rare Haemorrhagic corpus luteum/haemorrhagic ovarian cyst 40 General disorders and administration site conditions Very common Fluid retention and oedema, fatigue Common Weakness, pyrexia, anasarca, chills, rigors Uncommon Chest pain, malaise Investigations Very common Weight increased Common Weight decreased Uncommon Blood creatinine increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased Rare Blood amylase increased * These types of reactions have been reported mainly from post-marketing experience with imatinib. This includes spontaneous case reports as well as serious adverse events from ongoing studies, the expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved indications. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure. 1 Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST. 2 Headache was the most common in GIST patients. 3 On a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML. 4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC). 5 Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML. 6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients. 8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported. 9 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed in post-marketing. 10 Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients. 11 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions. Laboratory test abnormalities Haematology In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/L) and thrombocytopenias (platelet count < 50 x 109/L) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64% and 44–63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic phase CML grade 4 neutropenia (ANC < 0.5 x 109/L) and thrombocytopenia (platelet count < 10 x 109/L) were observed in 3.6% and < 1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the first several months of therapy. In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra- tumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 41 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter. Biochemistry Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) elevations were observed. Bilirubin elevation was below 3%. There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal, including one patient on high dose paracetamol. Description of selected adverse reactions Hepatitis B reactivation Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of imatinib overdose have been reported spontaneously and in the literature. In the event of overdose the patient should be observed and appropriate symptomatic treatment given. Generally the reported outcome in these cases was “improved” or “recovered”. Events that have been reported at different dose ranges are as follows: Adult population 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain. 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. Paediatric population One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given. 5. PHARMACOLOGICAL PROPERTIES 42 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor, ATC code: L01XE01 Mechanism of action Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases. Pharmacodynamic effects Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients. In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl positive tumour cells. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), PDGF-R, and inhibits PDGF-mediated cellular events. Constitutive activation of the PDGF receptor or the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. Imatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase activity. Clinical studies in chronic myeloid leukaemia The effectiveness of imatinib is based on overall haematological and cytogenetic response rates and progression-free survival. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. A large, international, open-label, non-controlled phase II study was conducted in patients with Philadelphia chromosome positive (Ph+) CML -in the blast crisis phase of the disease. In addition, children and adolescents have been treated in two phase I studies (in patients with CML or Ph+ acute leukaemia) and one phase II study. In the clinical study 38% of patients were ≥ 60 years of age and 12% of patients were ≥ 70 years of age. Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 223 patients were started at 600 mg. The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. In this study, 31% of patients achieved a haematological response (36% in previously untreated patients and 22% in previously treated patients) (Table 2). The rate of response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, p=0.0220). The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively. 43 Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate of haematological response was 70% with a duration of 2–3 months. Table 2 Response in adult CML study Study 0102 38-month data Myeloid blast crisis (n=260) % of patients (CI95%) Haematological response1 Complete haematological response (CHR) No evidence of leukaemia (NEL) Return to chronic phase (RTC) 31% (25.2–36.8) 8% 5% 18% Major cytogenetic response2 Complete (Confirmed3) [95% CI] Partial 15% (11.2–20.4) 7% (2%) [0.6–4.4] 8% 1 Haematological response criteria (all responses to be confirmed after ≥ 4 weeks): CHR: In study 0102 [ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, no blood blasts, BM blasts < 5% and no extramedullary disease] NEL Same criteria as for CHR but ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB, no extramedullary disease other than spleen and liver. BM = bone marrow, PB = peripheral blood 2 Cytogenetic response criteria: A major response combines both complete and partial responses: complete (0% Ph+ metaphases), partial (1–35%) 3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least one month after the initial bone marrow study. Paediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML (n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase I trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a prior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5), 340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronic phase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial cytogenetic response, respectively, for a rate of MCyR of 77%. A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been enrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib 340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete cytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16% for a MCyR of 81%. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months. The European Medicines Agency has waived the obligation to submit the results of studies with imatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)- positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use). Clinical studies in Ph+ ALL 44 Newly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction in 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a significantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; p=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or who responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a complete haematological response. This clinical effect was associated with a higher reduction in bcr- abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy (p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 3) after induction and the levels of bcr-abl transcripts were identical in the two arms at 8 weeks. As expected on the basis of the study design, no difference was observed in remission duration, disease-free survival or overall survival, although patients with complete molecular response and remaining in minimal residual disease had a better outcome in terms of both remission duration (p=0.01) and disease-free survival (p=0.02). The results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled clinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. Imatinib in combination with chemotherapy induction (see Table 3) resulted in a complete haematological response rate of 93% (147 out of 158 evaluable patients) and in a major cytogenetic response rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was 48% (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in two studies (AJP01 and AUS01). Table 3 Chemotherapy regimen used in combination with imatinib Study ADE10 Prephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3, 4, 5; MTX 12 mg intrathecal, day 1 Remission induction DEX 10 mg/m2 oral, days 6-7, 13-16; VCR 1 mg i.v., days 7, 14; IDA 8 mg/m2 i.v. (0.5 h), days 7, 8, 14, 15; CP 500 mg/m2 i.v.(1 h) day 1; Ara- C 60 mg/m2 i.v., days 22-25, 29-32 Consolidation therapy I, III, V MTX 500 mg/m2 i.v. (24 h), days 1, 15; 6-MP 25 mg/m2 oral, days 1-20 Consolidation therapy II, IV Ara-C 75 mg/m2 i.v. (1 h), days 1-5; VM26 60 mg/m2 i.v. (1 h), days 1-5 Study AAU02 Induction therapy (de novo Ph+ ALL) Daunorubicin 30 mg/m2 i.v., days 1-3, 15-16; VCR 2 mg total dose i.v., days 1, 8, 15, 22; CP 750 mg/m2 i.v., days 1, 8; prednisone 60 mg/m2 oral, days 1-7, 15-21; IDA 9 mg/m2 oral, days 1-28; MTX 15 mg intrathecal, days 1, 8, 15, 22; Ara-C 40 mg intrathecal, days 1, 8, 15, 22; methylprednisolone 40 mg intrathecal, days 1, 8, 15, 22 Consolidation (de novo Ph+ ALL) Ara-C 1,000 mg/m2 /12 h i.v.(3 h), days 1-4; mitoxantrone 10 mg/m2 i.v. days 3-5; MTX 15 mg intrathecal, day 1; methylprednisolone 40 mg intrathecal, day 1 Study ADE04 Prephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3-5; MTX 15 mg intrathecal, day 1 Induction therapy I DEX 10 mg/m2 oral, days 1-5; VCR 2 mg i.v., days 6, 13, 20; daunorubicin 45 mg/m2 i.v., days 6-7, 13-14 Induction therapy II CP 1 g/m2 i.v. (1 h), days 26, 46; Ara-C 75 mg/m2 i.v. (1 h), days 28-31, 35-38, 42-45; 6-MP 60 mg/m2 oral, days 26-46 45 Consolidation therapy DEX 10 mg/m2 oral, days 1-5; vindesine 3 mg/m2 i.v., day 1; MTX 1.5 g/m2 i.v. (24 h), day 1; etoposide 250 mg/m2 i.v. (1 h) days 4-5; Ara- C 2x 2 g/m2 i.v. (3 h, q 12 h), day 5 Study AJP01 Induction therapy CP 1.2 g/m2 i.v. (3 h), day 1; daunorubicin 60 mg/m2 i.v. (1 h), days 1-3; vincristine 1.3 mg/m2 i.v., days 1, 8, 15, 21; prednisolone 60 mg/m2/day oral Consolidation therapy Alternating chemotherapy course: high dose chemotherapy with MTX 1 g/m2 i.v. (24 h), day 1, and Ara-C 2 g/m2 i.v. (q 12 h), days 2-3, for 4 cycles Maintenance VCR 1.3 g/m2 i.v., day 1; prednisolone 60 mg/m2 oral, days 1-5 Study AUS01 Induction- consolidation therapy Hyper-CVAD regimen: CP 300 mg/m2 i.v. (3 h, q 12 h), days 1-3; vincristine 2 mg i.v., days 4, 11; doxorubicine 50 mg/m2 i.v. (24 h), day 4; DEX 40 mg/day on days 1-4 and 11-14, alternated with MTX 1 g/m2 i.v. (24 h), day 1, Ara-C 1 g/m2 i.v. (2 h, q 12 h), days 2-3 (total of 8 courses) Maintenance VCR 2 mg i.v. monthly for 13 months; prednisolone 200 mg oral, 5 days per month for 13 months All treatment regimens include administration of steroids for CNS prophylaxis. Ara-C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; 6-MP: 6-mercaptopurine; VM26: Teniposide; VCR: vincristine; IDA: idarubicine; i.v.: intravenous Paediatric patients: In study I2301, a total of 93 paediatric, adolescent and young adult patients (from 1 to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort, non-randomised phase III trial, and were treated with imatinib (340 mg/m2/day) in combination with intensive chemotherapy after induction therapy. Imatinib was administered intermittently in cohorts 1-5, with increasing duration and earlier start of imatinib from cohort to cohort; cohort 1 receiving the lowest intensitiy and cohort 5 receiving the highest intensity of imatinib (longest duration in days with continuous daily imatinib dosing during the first chemotherapy treatment courses). Continuous daily exposure to imatinib early in the course of treatment in combination with chemotherapy in cohort 5-patients (n=50) improved the 4-year event-free survival (EFS) compared to historical controls (n=120), who received standard chemotherapy without imatinib (69.6% vs. 31.6%, respectively). The estimated 4-year OS in cohort 5-patients was 83.6% compared to 44.8% in the historical controls. 20 out of the 50 (40%) patients in cohort 5 received haematopoietic stem cell transplant. Table 4 Chemotherapy regimen used in combination with imatinib in study I2301 Consolidation block 1 (3 weeks) VP-16 (100 mg/m2/day, IV): days 1-5 Ifosfamide (1.8 g/m2/day, IV): days 1-5 MESNA (360 mg/m2/dose q3h, x 8 doses/day, IV): days 1-5 G-CSF (5 μg/kg, SC): days 6-15 or until ANC > 1500 post nadir IT Methotrexate (age-adjusted): day 1 ONLY Triple IT therapy (age-adjusted): day 8, 15 Consolidation block 2 (3 weeks) Methotrexate (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: Days 2 and 3 Triple IT therapy (age-adjusted): day 1 ARA-C (3 g/m2/dose q 12 h x 4, IV): days 2 and 3 G-CSF (5 μg/kg, SC): days 4-13 or until ANC > 1500 post nadir 46 Reinduction block 1 (3 weeks) VCR (1.5 mg/m2/day, IV): days 1, 8, and 15 DAUN (45 mg/m2/day bolus, IV): days 1 and 2 CPM (250 mg/m2/dose q12h x 4 doses, IV): days 3 and 4 PEG-ASP (2500 IUnits/m2, IM): day 4 G-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir Triple IT therapy (age-adjusted): days 1 and 15 DEX (6 mg/m2/day, PO): days 1-7 and 15-21 Intensification block 1 (9 weeks) Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: Days 2, 3, 16, and 17 Triple IT therapy (age-adjusted): days 1 and 22 VP-16 (100 mg/m2/day, IV): days 22-26 CPM (300 mg/m2/day, IV): days 22-26 MESNA (150 mg/m2/day, IV): days 22-26 G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir ARA-C (3 g/m2, q12h, IV): days 43, 44 L-ASP (6000 IUnits/m2, IM): day 44 Reinduction block 2 (3 weeks) VCR (1.5 mg/m2/day, IV): days 1, 8 and 15 DAUN (45 mg/m2/day bolus, IV): days 1 and 2 CPM (250 mg/m2/dose q12h x 4 doses, iv): Days 3 and 4 PEG-ASP (2500 IUnits/m2, IM): day 4 G-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir Triple IT therapy (age-adjusted): days 1 and 15 DEX (6 mg/m2/day, PO): days 1-7 and 15-21 Intensification block 2 (9 weeks) Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2, 3, 16, and 17 Triple IT therapy (age-adjusted): days 1 and 22 VP-16 (100 mg/m2/day, IV): days 22-26 CPM (300 mg/m2/day, IV): days 22-26 MESNA (150 mg/m2/day, IV): days 22-26 G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir ARA-C (3 g/m2, q12h, IV): days 43, 44 L-ASP (6000 IUnits/m2, IM): day 44 Maintenance (8-week cycles) Cycles 1–4 MTX (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2 and 3 Triple IT therapy (age-adjusted): days 1, 29 VCR (1.5 mg/m2, IV): days 1, 29 DEX (6 mg/m2/day PO): days 1-5; 29-33 6-MP (75 mg/m2/day, PO): days 8-28 Methotrexate (20 mg/m2/week, PO): days 8, 15, 22 VP-16 (100 mg/m2, IV): days 29-33 CPM (300 mg/m2, IV): days 29-33 MESNA IV days 29-33 G-CSF (5 μg/kg, SC): days 34-43 Maintenance (8-week cycles) Cycle 5 Cranial irradiation (Block 5 only) 12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis 18 Gy in 10 fractions for patients that are CNS3 at diagnosis VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1-5; 29-33 6-MP (75 mg/m2/day, PO): days 11-56 (Withhold 6-MP during the 6-10 days of cranial irradiation beginning on day 1 of Cycle 5. Start 6-MP the 1st day after cranial irradiation completion.) Methotrexate (20 mg/m2/week, PO): days 8, 15, 22, 29, 36, 43, 50 47 Maintenance (8-week cycles) Cycles 6-12 VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1-5; 29-33 6-MP (75 mg/m2/day, PO): days 1-56 Methotrexate (20 mg/m2/week, PO): days 1, 8, 15, 22, 29, 36, 43, 50 G-CSF = granulocyte colony stimulating factor, VP-16 = etoposide, MTX = methotrexate, IV = intravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = cytarabine, CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = daunorubicin, 6-MP = 6-mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = PEG asparaginase, MESNA= 2-mercaptoethane sulfonate sodium, iii= or until MTX level is < 0.1 µM, q6h = every 6 hours, Gy= Gray Study AIT07 was a multicentre, open-label, randomised, phase II/III study that included 128 patients (1 to < 18 years) treated with imatinib in combination with chemotherapy. Safety data from this study seem to be in line with the safety profile of imatinib in Ph+ ALL patients. Relapsed/refractory Ph+ ALL: When imatinib was used as single agent in patients with relapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a haematological response rate of 30% (9% complete) and a major cytogenetic response rate of 23%. (Of note, out of the 411 patients, 353 were treated in an expanded access program without primary response data collected.) The median time to progression in the overall population of 411 patients with relapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the 401 evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to include only those patients age 55 or older. Clinical studies in MDS/MPD Experience with imatinib in this indication is very limited and is based on haematological and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit or increased survival. One open label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD who were treated with imatinib 400 mg daily. Three patients presented a complete haematological response (CHR) and one patient experienced a partial haematological response (PHR). At the time of the original analysis, three of the four patients with detected PDGFR gene rearrangements developed haematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years. An observational registry (study L2401) was conducted to collect long-term safety and efficacy data in patients suffering from myeloproliferative neoplasms with PDGFR- β rearrangement and who were treated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily dose of 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due to the observational nature of this registry, haematologic, cytogenetic and molecular assessment data were available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assuming conservatively that patients with missing data were non-responders, CHR was observed in 20/23 (87%) patients, CCyR in 9/23 (39.1%) patients, and MR in 11/23 (47.8%) patients, respectively. When the response rate is calculated from patients with at least one valid assessment, the response rate for CHR, CCyR and MR was 20/22 (90.9%), 9/9 (100%) and 11/17 (64.7%), respectively. In addition a further 24 patients with MDS/MPD were reported in 13 publications. 21 patients were treated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients PDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR. The age of these patients ranged from 2 to 79 years. In a recent publication updated information from 6 of these 11 patients revealed that all these patients remained in cytogenetic remission (range 32-38 months). The same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR gene rearrangements (5 patients from study B2225). These patients received imatinib for a median of 47 months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease or disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic responses have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59), 48 respectively. The overall survival is 65 months since diagnosis (range 25-234). Imatinib administration to patients without the genetic translocation generally results in no improvement. There are no controlled trials in paediatric patients with MDS/MPD. Five (5) patients with MDS/MPD associated with PDGFR gene re-arrangements were reported in 4 publications. The age of these patients ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses ranging from 92.5 to 340 mg/m2 daily. All patients achieved complete haematological response, cytogenetic response and/or clinical response. Clinical studies in HES/CEL One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL were treated with 100 mg to 1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published case reports and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogenetic abnormalities were evaluated in 117 of the total population of 176 patients. In 61 of these 117 patients FIP1L1-PDGFRα fusion kinase was identified. An additional four HES patients were found to be FIP1L1-PDGFRα-positive in other 3 published reports. All 65 FIP1L1-PDGFRα fusion kinase positive patients achieved a CHR sustained for months (range from 1+ to 44+ months censored at the time of the reporting). As reported in a recent publication 21 of these 65 patients also achieved complete molecular remission with a median follow-up of 28 months (range 13-67 months). The age of these patients ranged from 25 to 72 years. Additionally, improvements in symptomatology and other organ dysfunction abnormalities were reported by the investigators in the case reports. Improvements were reported in cardiac, nervous, skin/subcutaneous tissue, respiratory/thoracic/mediastinal, musculoskeletal/connective tissue/vascular, and gastrointestinal organ systems. There are no controlled trials in paediatric patients with HES/CEL. Three (3) patients with HES and CEL associated with PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from 2 to 16 years and imatinib was given at dose 300 mg/m2 daily or doses ranging from 200 to 400 mg daily. All patients achieved complete haematological response, complete cytogenetic response and/or complete molecular response. Clinical studies in DFSP One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients with DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to 75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered amenable to further resective surgery at the time of study entry. The primary evidence of efficacy was based on objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and 8 partially. Three of the partial responders were subsequently rendered disease free by surgery. The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. A further 6 DFSP patients treated with imatinib were reported in 5 published case reports, their ages ranging from 18 months to 49 years. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. 5 patients responded, 3 completely and 2 partially. The median duration of therapy in the published literature ranged between 4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, was present in nearly all responders to imatinib treatment. There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from newborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to 520 mg/m2 daily. All patients achieved partial and/or complete response. 5.2 Pharmacokinetic properties Pharmacokinetics of imatinib 49 The pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg. Plasma pharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma concentrations had reached steady state. Absorption Mean absolute bioavailability for imatinib is 98%. There was high between-patient variability in plasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior gastrointestinal surgery on drug absorption has not been investigated. Distribution At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein. Biotransformation The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound. Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating radioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor metabolites. The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V) only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of imatinib metabolism which could have clinical relevance. Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/L, respectively. Maximal plasma concentrations of imatinib in patients are 2–4 μmol/L, consequently an inhibition of CYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did not interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a result of competitive inhibition of CYP2C8 (Ki - 34.7 µM). This Ki value is far higher than the expected plasma levels of imatinib in patients, consequently no interaction is expected upon co- administration of either 5-fluorouracil or paclitaxel and imatinib. Elimination Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites. Plasma pharmacokinetics Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when dosed once daily. Population pharmacokinetics Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on the volume of distribution (12% increase in patients > 65 years old). This change is not thought to be clinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient 50 weighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the clearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment based on kg bodyweight. There is no effect of gender on the kinetics of imatinib. Pharmacokinetics in paediatric population As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same exposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after repeated once-daily dosing. Based on pooled population pharmacokinetic analysis in paediatric patients with haematological disorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily. Organ function impairment Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4). Although the results of pharmacokinetic analysis showed that there is considerable inter-subject variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8). 5.3 Preclinical safety data The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits. Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and monkeys, accompanied by bone marrow changes in rats and dogs. The liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. No histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal papilla and in the urinary bladder was observed at doses ≥ 6 mg/kg in the 13-week study, without changes in serum or urinary parameters. An increased rate of opportunistic infections was observed with chronic imatinib treatment. In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the lowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on body surface. Treatment resulted in worsening of normally suppressed malarial infections in these animals. 51 Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post- implantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg. In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn pups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not affected, while an increased number of resorptions and a decreased number of viable foetuses was noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. These effects were not seen at doses ≤ 30 mg/kg. No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 postpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, effects upon growth, delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at approximately 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥ 30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non- glandular stomach. Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 30 mg/kg/day. 52 The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet clarified. Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. The active substance imatinib demonstrates an environmental risk for sediment organisms. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Cellulose microcrystalline Copovidone Crospovidone Sodium stearyl fumarate Silica, hydrophobic colloidal Silica, colloidal anhydrous Tablet coat Polyvinyl alchol part. hydrolised Talc Iron oxide yellow (E172) Titanium dioxide (E171) Iron oxide red (E172) Lecithin (soya) (E322) Xanthan gum (E415) 6.2 Incompatibilities Not applicable. 6.3 Shelf life Imatinib Actavis 100 mg film-coated tablets 2 years Imatinib Actavis 400 mg film-coated tablets 21 month 6.4 Special precautions for storage Do not store above 30°C. Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Al/PVC/Aclar blister. One blister contains 10 tablets. Imatinib Actavis 100 mg film-coated tablets Pack containing either 10, 20, 30, 60, 90, 120 or 180 film-coated tablets Imatinib Actavis 400 mg film-coated tablets Pack containing either 10, 30, 60 or 90 film-coated tablets 53 Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. Reykjavíkurvegur 76-78 IS-220 Hafnarfjörður Iceland 8. MARKETING AUTHORISATION NUMBER(S) Imatinib Actavis 100 mg film-coated tablets EU/1/13/825/008 EU/1/13/825/009 EU/1/13/825/010 EU/1/13/825/011 EU/1/13/825/012 EU/1/13/825/013 EU/1/13/825/014 Imatinib Actavis 400 mg film-coated tablets EU/1/13/825/015 EU/1/13/825/016 EU/1/13/825/017 EU/1/13/825/018 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 17 April 2013 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 54 http://www.ema.europa.eu/ ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 55 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release S.C. Sindan-Pharma S.R.L. 11th Ion Mihalache Ave, The 1st district, RO-011171 Bucharest Romania B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports At the time of granting the marketing authorisation, the submission of periodic safety update reports is not required for this medicinal product. However, the marketing authorisation holder shall submit periodic safety update reports for this medicinal product if the product is included in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) Not applicable. 56 ANNEX III LABELLING AND PACKAGE LEAFLET 57 A. LABELLING 58 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 50 mg hard capsules imatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 50 mg of imatinib (as mesilate). 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 30 hard capsules 90 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Use only as directed by a doctor. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 59 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/825/001 30 capsules EU/1/13/825/002 90 capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imatinib Actavis 50 mg 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: {number} SN: {number} NN: {number} 60 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 100 mg hard capsules imatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 100 mg of imatinib (as mesilate). 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 24 hard capsules 48 hard capsules 60 hard capsules 96 hard capsules 120 hard capsules 180 hard capsules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Use only as directed by a doctor. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Store in the original package in order to protect from moisture. 61 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/825/003 24 capsules EU/1/13/825/004 48 capsules EU/1/13/825/019 60 capsules EU/1/13/825/005 96 capsules EU/1/13/825/006 120 capsules EU/1/13/825/007 180 capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imatinib Actavis 100 mg 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: {number} SN: {number} NN: {number} 62 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 400 mg hard capsules imatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains 400 mg of imatinib (as mesilate). 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 10 hard capsules 30 hard capsules 60 hard capsules 90 hard capusles 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Use only as directed by a doctor. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. Store in the original package in order to protect from moisture. 63 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/825/020 10 capsules EU/1/13/825/021 30 capsules EU/1/13/825/022 60 capsules EU/1/13/825/023 90 capsules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imatinib Actavis 400 mg 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: {number} SN: {number} NN: {number} 64 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 50 mg capsules imatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER [Actavis logo] 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 65 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 100 mg capsules imatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER [Actavis logo] 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 66 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 400 mg capsules imatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER [Actavis logo] 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 67 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 100 mg film-coated tablets imatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 100 mg of imatinib (as mesilate). 3. LIST OF EXCIPIENTS Contains lecithin (soya) (E322). See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 10 film-coated tablets 20 film-coated tablets 30 film-coated tablets 60 film-coated tablets 90 film-coated tablets 120 film-coated tablets 180 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Use only as directed by a doctor. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 68 Do not store above 30°C. Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/825/008 10 tablets EU/1/13/825/009 20 tablets EU/1/13/825/010 30 tablets EU/1/13/825/011 60 tablets EU/1/13/825/012 90 tablets EU/1/13/825/013 120 tablets EU/1/13/825/014 180 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imatinib Actavis 100 mg 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: {number} SN: {number} NN: {number} 69 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 400 mg film-coated tablets imatinib 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 400 mg of imatinib (as mesilate). 3. LIST OF EXCIPIENTS Contains lecithin (soya) (E322). See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 10 film-coated tablets 30 film-coated tablets 60 film-coated tablets 90 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Use only as directed by a doctor. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. Store in the original package in order to protect from moisture. 70 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/13/825/015 10 tablets EU/1/13/825/016 30 tablets EU/1/13/825/017 60 tablets EU/1/13/825/018 90 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Imatinib Actavis 400 mg 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: {number} SN: {number} NN: {number} 71 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 100 mg tablets imatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER [Actavis logo] 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 72 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Imatinib Actavis 400 mg tablets imatinib 2. NAME OF THE MARKETING AUTHORISATION HOLDER [Actavis logo] 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 73 B. PACKAGE LEAFLET 74 Package leaflet: Information for the user Imatinib Actavis 50 mg hard capsules imatinib Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Imatinib Actavis is and what it is used for 2. What you need to know before you take Imatinib Actavis 3. How to take Imatinib Actavis 4. Possible side effects 5. How to store Imatinib Actavis 6. Contents of the pack and other information 1. What Imatinib Actavis is and what it is used for Imatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer. Imatinib Actavis is a treatment for: - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia in which certain abnormal white cells (named myeloid cells) start growing out of control. In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease (chronic, accelerated phase and blast crisis). - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the growth of these cells. Imatinib Actavis is also a treatment for adults for: - Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. - Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. 75 - Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Actavis inhibits the growth of these cells. In the rest of this leaflet, we will use the abbreviations when talking about these diseases. If you have any questions about how Imatinib Actavis works or why this medicine has been prescribed for you, ask your doctor. 2. What you need to know before you take Imatinib Actavis Imatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. Follow all your doctor’s instructions carefully, even if they differ from the general information contained in this leaflet. Do not take Imatinib Actavis: - if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor without taking Imatinib Actavis. If you think you may be allergic but are not sure, ask your doctor for advice. Warnings and precautions Talk to your doctor before taking Imatinib Actavis: - if you have or have ever had a liver, kidney or heart problem. - if you are taking the medicine levothyroxine because your thyroid has been removed. - if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started. - if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, contact your doctor. This may be a sign of damage to blood vessels known as thrombotic microangiopathy (TMA). If any of these apply to you, tell your doctor before taking Imatinib Actavis. You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun- exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are also applicable to children. During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly. Children and adolescents Imatinib Actavis is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP and HES/CEL. Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The doctor will monitor the growth at regular visits. Other medicines and Imatinib Actavis 76 Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do the same to some other medicines. Tell your doctor if you are using medicines that prevent the formation of blood clots. Pregnancy, breast-feeding and fertility - If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. - Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis during pregnancy. - Women who might become pregnant are advised to use effective contraception during treatment. - Do not breast-feed during the treatment with Imatinib Actavis. - Patients who are concerned about their fertility while taking Imatinib Actavis are advised to consult with their doctor. Driving and using machines You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not drive or use any tools or machines until you are feeling well again. Imatinib Actavis contains sodium This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially ‘sodium-free’. 3. How to take Imatinib Actavis Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib Actavis can help you to fight this condition. However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or pharmacist if you are not sure. Do not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away. How much Imatinib Actavis to take Use in adults Your doctor will tell you exactly how many capsules of Imatinib Actavis to take. - If you are being treated for CML: The usual starting dose is 600 mg to be taken as 12 capsules once a day. Your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg (16 capsules), you should take 8 capsules in the morning and 8 capsules in the evening. - If you are being treated for Ph-positive ALL: The starting dose is 600 mg to be taken as 12 capsules once a day. 77 - If you are being treated for MDS/MPD: The starting dose is 400 mg, to be taken as 8 capsules once a day. - If you are being treated for HES/CEL: The starting dose is 100 mg, to be taken as 2 capsules once a day. Your doctor may decide to increase the dose to 400 mg, to be taken as 8 capsules once a day, depending on how you respond to treatment. - If you are being treated for DFSP: The dose is 800 mg per day (16 capsules), to be taken as 8 capsules in the morning and 8 capsules in the evening. Use in children and adolescents The doctor will tell you how many capsules of Imatinib Actavis to give to your child. The amount of Imatinib Actavis given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). When and how to take Imatinib Actavis - Take Imatinib Actavis with a meal. This will help protect you from stomach problems when taking Imatinib Actavis. - Swallow the capsules whole with a large glass of water. Do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children). - If you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice. - If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. You should wash your hands immediately after opening the capsules. How long to take Imatinib Actavis Keep taking Imatinib Actavis every day for as long as your doctor tells you. If you take more Imatinib Actavis than you should If you have accidentally taken too many capsules, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you. If you forget to take Imatinib Actavis - If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose. - Then continue with your normal schedule. - Do not take a double dose to make up a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate. Some side effects may be serious. Tell your doctor straight away if you get any of the following: Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): - Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid retention). 78 - Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can reduce the number of white blood cells, so you might get infections more easily. - Unexpected bleeding or bruising (when you have not hurt yourself). Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): - Chest pain, irregular heart rhythm (signs of heart problems). - Cough, having difficulty breathing or painful breathing (signs of lung problems). - Feeling light-headed, dizzy or fainting (signs of low blood pressure). - Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). - Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). - Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). - Severely decreased urine output, feeling thirsty (signs of kidney problems). - Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). - Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). - Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). - Eye pain or deterioration in vision, bleeding in the eyes. - Pain in your hips or difficulty walking. - Numb or cold toes and fingers (signs of Raynaud’s syndrome). - Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). - Difficulty hearing. - Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). - Bruising. - Stomach pain with feeling sick (nausea). - Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). - Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). - Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood). - Blood clots in small blood vessels (thrombotic microangiopathy). Not known (frequency cannot be estimated from the available data): - Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). - Chronic renal failure. - Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a liver infection). If you get any of the above, tell your doctor straight away. Other side effects may include: Very common (may affect more than 1 in 10 people): - Headache or feeling tired. - Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. - Rash. 79 - Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have stopped taking imatinib. - Swelling such as round your ankles or puffy eyes. - Weight gain. If any of these affect you severely, tell your doctor. Common (may affect up to 1 in 10 people): - Anorexia, weight loss or a disturbed sense of taste. - Feeling dizzy or weak. - Difficulty in sleeping (insomnia). - Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. - Nose bleeds. - Pain or swelling in your abdomen, flatulence, heartburn or constipation. - Itching. - Unusual hair loss or thinning. - Numbness of the hands or feet. - Mouth ulcers. - Joint pain with swelling. - Dry mouth, dry skin or dry eye. - Decreased or increased skin sensitivity. - Hot flushes, chills or night sweats. If any of these affect you severely, tell your doctor. Not known (frequency cannot be estimated from the available data): - Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. - Painful and/or blistering skin lesions. - Slowing of growth in children and adolescents. - If any of these affect you severely, tell your doctor. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Imatinib Actavis Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month. Do not store above 25°C. Store in the original package in order to protect from moisture. Do not use any pack that is damaged or shows signs of tampering. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Imatinib Actavis contains - The active substance is imatinib (as mesilate). Each capsule contains 50 mg imatinib (as mesilate). - The other ingredients are: Capsule content: cellulose microcrystalline, copovidone, crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous). 80 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc Capsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172). Printing ink: shellac, black iron oxide (E172), propylene glycol, ammonia solution, potassium hydroxide. What Imatinib Actavis looks like and contents of the pack Hard capsule with light yellow cap and light yellow body imprinted with 50 mg in black ink. The capsule contains light yellow powder. Pack sizes: The capsules are supplied in aluminium blister packs of 30 or 90 capsules. Not all pack sizes may be marketed. Marketing Authorisation Holder Actavis Group PTC ehf. Reykjavíkurvegur 76-78, Hafnarfjörður Iceland Manufacturer S.C. Sindan-Pharma S.R.L. 11 Ion Mihalache Blvd Bucharest Romania For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Actavis Group PTC ehf. IJsland/Islande/Island Tél/Tel: +354 5503300 Lietuva UAB Sicor Biotech Tel: +370 52660203 България Актавис ЕАД Teл: +359 24899585 Luxembourg/Luxemburg Actavis Group PTC ehf. Islande/Island Tél/Tel: +354 5503300 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251007111 Magyarország Teva Gyógyszergyár Zrt. Tel: +36 12886400 Danmark Teva Denmark A/S Tlf: +45 44985511 Malta Actavis Ltd. Tel: +356 21693533 Deutschland Actavis Group PTC ehf. Island Tel: +354 5503300 Nederland Actavis Group PTC ehf. IJsland Tel: +354 5503300 Eesti UAB Sicor Biotech Eesti filiaal Tel: +372 6610801 Norge Teva Norway AS Tlf: +47 66775590 81 Ελλάδα Specifar ABEE Τηλ: +30 2105401500 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1970070 España Actavis Group PTC ehf. Islandia Tel: +354 5503300 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel: +48 223459300 France Actavis Group PTC ehf. Islande Tél: +354 5503300 Portugal Actavis Group PTC ehf. Islândia Tel: +354 5503300 Hrvatska Pliva Hrvatska d.o.o. Tel: +385 13720000 România Teva Pharmaceuticals S.R.L. Tel: +40 212306524 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)19630330 Slovenija Pliva Ljubljana d.o.o. Tel: +386 15890390 Ísland Actavis Group PTC ehf. Sími: +354 5503300 Slovenská republika TEVA Pharmaceuticals Slovakia s.r.o. Tel: +421 257267911 Italia Actavis Group PTC ehf. Islanda Tel: +354 5503300 Suomi/Finland ratiopharm Oy Puh/Tel: +358 201805900 Κύπρος Specifar ABEE Ελλάδα Τηλ: +30 2105401500 Sverige Teva Sweden AB Tel: +46 42121100 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 67323666 United Kingdom Actavis UK Limited Tel: +44 1271385257 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu 82 http://www.ema.europa.eu/ Package leaflet: Information for the user Imatinib Actavis 100 mg hard capsules imatinib Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Imatinib Actavis is and what it is used for 2. What you need to know before you take Imatinib Actavis 3. How to take Imatinib Actavis 4. Possible side effects 5. How to store Imatinib Actavis 6. Contents of the pack and other information 1. What Imatinib Actavis is and what it is used for Imatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer. Imatinib Actavis is a treatment for: - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia in which certain abnormal white cells (named myeloid cells) start growing out of control. In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease (chronic, accelerated phase and blast crisis). - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the growth of these cells. Imatinib Actavis is also a treatment for adults for: - Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. - Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. 83 - Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Actavis inhibits the growth of these cells. In the rest of this leaflet, we will use the abbreviations when talking about these diseases. If you have any questions about how Imatinib Actavis works or why this medicine has been prescribed for you, ask your doctor. 2. What you need to know before you take Imatinib Actavis Imatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. Follow all your doctor’s instructions carefully, even if they differ from the general information contained in this leaflet. Do not take Imatinib Actavis: - if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor without taking Imatinib Actavis. If you think you may be allergic but are not sure, ask your doctor for advice. Warnings and precautions Talk to your doctor before taking Imatinib Actavis: - if you have or have ever had a liver, kidney or heart problem. - if you are taking the medicine levothyroxine because your thyroid has been removed. - if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started. - if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, contact your doctor. This may be a sign of damage to blood vessels known as thrombotic microangiopathy (TMA). If any of these apply to you, tell your doctor before taking Imatinib Actavis. You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun- exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are also applicable to children. During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly. Children and adolescents Imatinib Actavis is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP and HES/CEL. Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The doctor will monitor the growth at regular visits. Other medicines and Imatinib Actavis 84 Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do the same to some other medicines. Tell your doctor if you are using medicines that prevent the formation of blood clots. Pregnancy, breast-feeding and fertility - If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. - Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis during pregnancy. - Women who might become pregnant are advised to use effective contraception during treatment. - Do not breast-feed during the treatment with Imatinib Actavis. - Patients who are concerned about their fertility while taking Imatinib Actavis are advised to consult with their doctor. Driving and using machines You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not drive or use any tools or machines until you are feeling well again. Imatinib Actavis contains sodium This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially ‘sodium-free’. 3. How to take Imatinib Actavis Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib Actavis can help you to fight this condition. However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or pharmacist if you are not sure. Do not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away. How much Imatinib Actavis to take Use in adults Your doctor will tell you exactly how many capsules of Imatinib Actavis to take. - If you are being treated for CML: The usual starting dose is 600 mg to be taken as 6 capsules once a day. Your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg (8 capsules), you should take 4 capsules in the morning and 4 capsules in the evening. - If you are being treated for Ph-positive ALL: The starting dose is 600 mg to be taken as 6 capsules once a day. 85 - If you are being treated for MDS/MPD: The starting dose is 400 mg to be taken as 4 capsules once a day. - If you are being treated for HES/CEL: The starting dose is 100 mg, to be taken as one capsule once a day. Your doctor may decide to increase the dose to 400 mg, to be taken as 4 capsules once a day, depending on how you respond to treatment. - If you are being treated for DFSP: The dose is 800 mg per day (8 capsules), to be taken as 4 capsules in the morning and 4 capsules in the evening. Use in children and adolescents The doctor will tell you how many capsules of Imatinib Actavis to give to your child. The amount of Imatinib Actavis given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). When and how to take Imatinib Actavis - Take Imatinib Actavis with a meal. This will help protect you from stomach problems when taking Imatinib Actavis. - Swallow the capsules whole with a large glass of water. Do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children). - If you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice. - If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. You should wash your hands immediately after opening the capsules. How long to take Imatinib Actavis Keep taking Imatinib Actavis every day for as long as your doctor tells you. If you take more Imatinib Actavis than you should If you have accidentally taken too many capsules, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you. If you forget to take Imatinib Actavis - If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose. - Then continue with your normal schedule. - Do not take a double dose to make up a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate. Some side effects may be serious. Tell your doctor straight away if you get any of the following: Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): - Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid retention). 86 - Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can reduce the number of white blood cells, so you might get infections more easily. - Unexpected bleeding or bruising (when you have not hurt yourself). Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): - Chest pain, irregular heart rhythm (signs of heart problems). - Cough, having difficulty breathing or painful breathing (signs of lung problems). - Feeling light-headed, dizzy or fainting (signs of low blood pressure). - Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). - Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). - Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). - Severely decreased urine output, feeling thirsty (signs of kidney problems). - Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). - Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). - Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). - Eye pain or deterioration in vision, bleeding in the eyes. - Pain in your hips or difficulty walking. - Numb or cold toes and fingers (signs of Raynaud’s syndrome). - Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). - Difficulty hearing. - Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). - Bruising. - Stomach pain with feeling sick (nausea). - Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). - Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). - Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood). - Blood clots in small blood vessels (thrombotic microangiopathy). Not known (frequency cannot be estimated from the available data): - Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). - Chronic renal failure. - Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a liver infection). If you get any of the above, tell your doctor straight away. Other side effects may include: Very common (may affect more than 1 in 10 people): - Headache or feeling tired. - Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. - Rash. 87 - Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have stopped taking imatinib. - Swelling such as round your ankles or puffy eyes. - Weight gain. If any of these affect you severely, tell your doctor. Common (may affect up to 1 in 10 people): - Anorexia, weight loss or a disturbed sense of taste. - Feeling dizzy or weak. - Difficulty in sleeping (insomnia). - Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. - Nose bleeds. - Pain or swelling in your abdomen, flatulence, heartburn or constipation. - Itching. - Unusual hair loss or thinning. - Numbness of the hands or feet. - Mouth ulcers. - Joint pain with swelling. - Dry mouth, dry skin or dry eye. - Decreased or increased skin sensitivity. - Hot flushes, chills or night sweats. If any of these affect you severely, tell your doctor. Not known (frequency cannot be estimated from the available data): - Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. - Painful and/or blistering skin lesions. - Slowing of growth in children and adolescents. - If any of these affect you severely, tell your doctor. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Imatinib Actavis Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month. Do not store above 25°C. Store in the original package in order to protect from moisture. Do not use any pack that is damaged or shows signs of tampering. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Imatinib Actavis contains - The active substance is imatinib (as mesilate). Each capsule contains 100 mg imatinib (as mesilate). - The other ingredients are: Capsule content: cellulose microcrystalline, copovidone, crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous). 88 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc Capsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172). Printing ink: shellac, black iron oxide (E172), propylene glycol, ammonia solution, potassium hydroxide. What Imatinib Actavis looks like and contents of the pack Hard capsule with light orange cap and light orange body imprinted with 100 mg in black ink. The capsule contains light yellow powder. Pack sizes: The capsules are supplied in aluminium blister packs of 24, 48, 60, 96, 120 or 180 capsules. Not all pack sizes may be marketed. Marketing Authorisation Holder Actavis Group PTC ehf. Reykjavíkurvegur 76-78, Hafnarfjörður Iceland Manufacturer S.C. Sindan-Pharma S.R.L. 11 Ion Mihalache Blvd Bucharest Romania For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Actavis Group PTC ehf. IJsland/Islande/Island Tél/Tel: +354 5503300 Lietuva UAB Sicor Biotech Tel: +370 52660203 България Актавис ЕАД Teл: +359 24899585 Luxembourg/Luxemburg Actavis Group PTC ehf. Islande/Island Tél/Tel: +354 5503300 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251007111 Magyarország Teva Gyógyszergyár Zrt. Tel: +36 12886400 Danmark Teva Denmark A/S Tlf: +45 44985511 Malta Actavis Ltd. Tel: +356 21693533 Deutschland Actavis Group PTC ehf. Island Tel: +354 5503300 Nederland Actavis Group PTC ehf. IJsland Tel: +354 5503300 Eesti UAB Sicor Biotech Eesti filiaal Tel: +372 6610801 Norge Teva Norway AS Tlf: +47 66775590 89 Ελλάδα Specifar ABEE Τηλ: +30 2105401500 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1970070 España Actavis Group PTC ehf. Islandia Tel: +354 5503300 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel: +48 223459300 France Actavis Group PTC ehf. Islande Tél: +354 5503300 Portugal Actavis Group PTC ehf. Islândia Tel: +354 5503300 Hrvatska Pliva Hrvatska d.o.o. Tel: +385 13720000 România Teva Pharmaceuticals S.R.L. Tel: +40 212306524 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)19630330 Slovenija Pliva Ljubljana d.o.o. Tel: +386 15890390 Ísland Actavis Group PTC ehf. Sími: +354 5503300 Slovenská republika TEVA Pharmaceuticals Slovakia s.r.o. Tel: +421 257267911 Italia Actavis Group PTC ehf. Islanda Tel: +354 5503300 Suomi/Finland ratiopharm Oy Puh/Tel: +358 201805900 Κύπρος Specifar ABEE Ελλάδα Τηλ: +30 2105401500 Sverige Teva Sweden AB Tel: +46 42121100 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 67323666 United Kingdom Actavis UK Limited Tel: +44 1271385257 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu 90 http://www.ema.europa.eu/ Package leaflet: Information for the user Imatinib Actavis 400 mg hard capsules imatinib Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Imatinib Actavis is and what it is used for 2. What you need to know before you take Imatinib Actavis 3. How to take Imatinib Actavis 4. Possible side effects 5. How to store Imatinib Actavis 6. Contents of the pack and other information 1. What Imatinib Actavis is and what it is used for Imatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer. Imatinib Actavis is a treatment for: - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia in which certain abnormal white cells (named myeloid cells) start growing out of control. In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease (chronic, accelerated phase and blast crisis). - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the growth of these cells. Imatinib Actavis is also a treatment for adults for: - Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. - Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. 91 - Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Actavis inhibits the growth of these cells. In the rest of this leaflet, we will use the abbreviations when talking about these diseases. If you have any questions about how Imatinib Actavis works or why this medicine has been prescribed for you, ask your doctor. 2. What you need to know before you take Imatinib Actavis Imatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. Follow all your doctor’s instructions carefully, even if they differ from the general information contained in this leaflet. Do not take Imatinib Actavis: - if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor without taking Imatinib Actavis. If you think you may be allergic but are not sure, ask your doctor for advice. Warnings and precautions Talk to your doctor before taking Imatinib Actavis: - if you have or have ever had a liver, kidney or heart problem. - if you are taking the medicine levothyroxine because your thyroid has been removed. - if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started. - if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, contact your doctor. This may be a sign of damage to blood vessels known as thrombotic microangiopathy (TMA). If any of these apply to you, tell your doctor before taking Imatinib Actavis. You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun- exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are also applicable to children. During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly. Children and adolescents Imatinib Actavis is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP and HES/CEL. Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The doctor will monitor the growth at regular visits. Other medicines and Imatinib Actavis 92 Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do the same to some other medicines. Tell your doctor if you are using medicines that prevent the formation of blood clots. Pregnancy, breast-feeding and fertility - If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. - Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis during pregnancy. - Women who might become pregnant are advised to use effective contraception during treatment. - Do not breast-feed during the treatment with Imatinib Actavis. - Patients who are concerned about their fertility while taking Imatinib Actavis are advised to consult with their doctor. Driving and using machines You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not drive or use any tools or machines until you are feeling well again. Imatinib Actavis contains sodium This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially ‘sodium-free’. 3. How to take Imatinib Actavis Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib Actavis can help you to fight this condition. However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or pharmacist if you are not sure. Do not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away. How much Imatinib Actavis to take Use in adults Your doctor will tell you exactly how many capsules of Imatinib Actavis to take. - If you are being treated for CML: The usual starting dose is 600 mg to be taken as one capsule of 400 mg plus 2 capsules of 100 mg once a day. Your doctor may prescribe a higher or lower dose depending on how you respond to the treatment. If your daily dose is 800 mg (2 capsules), you should take one capsule in the morning and a second capsule in the evening. - If you are being treated for Ph-positive ALL: 93 The starting dose is 600 mg to be taken as one capsule of 400 mg plus 2 capsules of 100 mg once a day. - If you are being treated for MDS/MPD: The starting dose is 400 mg to be taken as one capsule once a day. - If you are being treated for HES/CEL: The starting dose is 100 mg, to be taken as one capsule of 100 mg once a day. Your doctor may decide to increase the dose to 400 mg, to be taken as one capsule of 400 mg once a day, depending on how you respond to treatment. - If you are being treated for DFSP: The dose is 800 mg per day (2 capsules), to be taken as one capsule in the morning and a second capsule in the evening. Use in children and adolescents The doctor will tell you how many capsules of Imatinib Actavis to give to your child. The amount of Imatinib Actavis given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). When and how to take Imatinib Actavis - Take Imatinib Actavis with a meal. This will help protect you from stomach problems when taking Imatinib Actavis. - Swallow the capsules whole with a large glass of water. Do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children). - If you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice. - If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. You should wash your hands immediately after opening the capsules. How long to take Imatinib Actavis Keep taking Imatinib Actavis every day for as long as your doctor tells you. If you take more Imatinib Actavis than you should If you have accidentally taken too many capsules, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you. If you forget to take Imatinib Actavis - If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose. - Then continue with your normal schedule. - Do not take a double dose to make up a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate. Some side effects may be serious. Tell your doctor straight away if you get any of the following: 94 Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): - Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid retention). - Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can reduce the number of white blood cells, so you might get infections more easily. - Unexpected bleeding or bruising (when you have not hurt yourself). Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): - Chest pain, irregular heart rhythm (signs of heart problems). - Cough, having difficulty breathing or painful breathing (signs of lung problems). - Feeling light-headed, dizzy or fainting (signs of low blood pressure). - Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). - Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). - Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). - Severely decreased urine output, feeling thirsty (signs of kidney problems). - Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). - Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). - Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). - Eye pain or deterioration in vision, bleeding in the eyes. - Pain in your hips or difficulty walking. - Numb or cold toes and fingers (signs of Raynaud’s syndrome). - Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). - Difficulty hearing. - Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). - Bruising. - Stomach pain with feeling sick (nausea). - Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). - Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). - Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood). - Blood clots in small blood vessels (thrombotic microangiopathy). Not known (frequency cannot be estimated from the available data): - Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). - Chronic renal failure. - Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a liver infection). If you get any of the above, tell your doctor straight away. Other side effects may include: Very common (may affect more than 1 in 10 people): - Headache or feeling tired. 95 - Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. - Rash. - Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have stopped taking imatinib. - Swelling such as round your ankles or puffy eyes. - Weight gain. If any of these affect you severely, tell your doctor. Common (may affect up to 1 in 10 people): - Anorexia, weight loss or a disturbed sense of taste. - Feeling dizzy or weak. - Difficulty in sleeping (insomnia). - Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. - Nose bleeds. - Pain or swelling in your abdomen, flatulence, heartburn or constipation. - Itching. - Unusual hair loss or thinning. - Numbness of the hands or feet. - Mouth ulcers. - Joint pain with swelling. - Dry mouth, dry skin or dry eye. - Decreased or increased skin sensitivity. - Hot flushes, chills or night sweats. If any of these affect you severely, tell your doctor. Not known (frequency cannot be estimated from the available data): - Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. - Painful and/or blistering skin lesions. - Slowing of growth in children and adolescents. - If any of these affect you severely, tell your doctor. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Imatinib Actavis Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month. Do not store above 25°C. Store in the original package in order to protect from moisture. Do not use any pack that is damaged or shows signs of tampering. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Imatinib Actavis contains - The active substance is imatinib (as mesilate). Each capsule contains 400 mg imatinib (as mesilate). 96 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc - The other ingredients are: Capsule content: cellulose microcrystalline, copovidone, crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobic and colloidal anhydrous). Capsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172), black iron oxide (E172). Printing ink: shellac glaze-45%, black iron oxide (E172), propylene glycol, ammonium Hydroxide 28%. What Imatinib Actavis looks like and contents of the pack Hard capsule with orange opaque cap and body imprinted with 400 mg in black ink. The capsule contains light yellow powder. Pack sizes: The capsules are supplied in aluminium blister packs of 10, 30, 60, or 90 capsules. Not all pack sizes may be marketed. Marketing Authorisation Holder Actavis Group PTC ehf. Reykjavíkurvegur 76-78, Hafnarfjörður Iceland Manufacturer S.C. Sindan-Pharma S.R.L. 11 Ion Mihalache Blvd Bucharest Romania For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Actavis Group PTC ehf. IJsland/Islande/Island Tél/Tel: +354 5503300 Lietuva UAB Sicor Biotech Tel: +370 52660203 България Актавис ЕАД Teл: +359 24899585 Luxembourg/Luxemburg Actavis Group PTC ehf. Islande/Island Tél/Tel: +354 5503300 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251007111 Magyarország Teva Gyógyszergyár Zrt. Tel: +36 12886400 Danmark Teva Denmark A/S Tlf: +45 44985511 Malta Actavis Ltd. Tel: +356 21693533 Deutschland Actavis Group PTC ehf. Island Tel: +354 5503300 Nederland Actavis Group PTC ehf. IJsland Tel: +354 5503300 97 Eesti UAB Sicor Biotech Eesti filiaal Tel: +372 6610801 Norge Teva Norway AS Tlf: +47 66775590 Ελλάδα Specifar ABEE Τηλ: +30 2105401500 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1970070 España Actavis Group PTC ehf. Islandia Tel: +354 5503300 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel: +48 223459300 France Actavis Group PTC ehf. Islande Tél: +354 5503300 Portugal Actavis Group PTC ehf. Islândia Tel: +354 5503300 Hrvatska Pliva Hrvatska d.o.o. Tel: +385 13720000 România Teva Pharmaceuticals S.R.L. Tel: +40 212306524 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)19630330 Slovenija Pliva Ljubljana d.o.o. Tel: +386 15890390 Ísland Actavis Group PTC ehf. Sími: +354 5503300 Slovenská republika TEVA Pharmaceuticals Slovakia s.r.o. Tel: +421 257267911 Italia Actavis Group PTC ehf. Islanda Tel: +354 5503300 Suomi/Finland ratiopharm Oy Puh/Tel: +358 201805900 Κύπρος Specifar ABEE Ελλάδα Τηλ: +30 2105401500 Sverige Teva Sweden AB Tel: +46 42121100 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 67323666 United Kingdom Actavis UK Limited Tel: +44 1271385257 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu 98 http://www.ema.europa.eu/ Package leaflet: Information for the user Imatinib Actavis 100 mg film-coated tablets imatinib Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Imatinib Actavis is and what it is used for 2. What you need to know before you take Imatinib Actavis 3. How to take Imatinib Actavis 4. Possible side effects 5. How to store Imatinib Actavis 6. Contents of the pack and other information 1. What Imatinib Actavis is and what it is used for Imatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer. Imatinib Actavis is a treatment for: - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia in which certain abnormal white cells (named myeloid cells) start growing out of control. In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease (chronic, accelerated phase and blast crisis). - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the growth of these cells. Imatinib Actavis is also a treatment for adults for: - Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. - Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. 99 - Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Actavis inhibits the growth of these cells. In the rest of this leaflet, we will use the abbreviations when talking about these diseases. If you have any questions about how Imatinib Actavis works or why this medicine has been prescribed for you, ask your doctor. 2. What you need to know before you take Imatinib Actavis Imatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. Follow all your doctor’s instructions carefully, even if they differ from the general information contained in this leaflet. Do not take Imatinib Actavis: - if you are allergic to imatinib, soya, peanut or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor without taking Imatinib Actavis. If you think you may be allergic but are not sure, ask your doctor for advice. Warnings and precautions Talk to your doctor before taking Imatinib Actavis: - if you have or have ever had a liver, kidney or heart problem. - if you are taking the medicine levothyroxine because your thyroid has been removed. - if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started. - if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, contact your doctor. This may be a sign of damage to blood vessels known as thrombotic microangiopathy (TMA). If any of these apply to you, tell your doctor before taking Imatinib Actavis. You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun- exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are also applicable to children. During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly. Children and adolescents Imatinib Actavis is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP and HES/CEL. Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The doctor will monitor the growth at regular visits. Other medicines and Imatinib Actavis 100 Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do the same to some other medicines. Tell your doctor if you are using medicines that prevent the formation of blood clots. Pregnancy, breast-feeding and fertility - If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. - Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis during pregnancy. - Women who might become pregnant are advised to use effective contraception during treatment. - Do not breast-feed during the treatment with Imatinib Actavis. - Patients who are concerned about their fertility while taking Imatinib Actavis are advised to consult with their doctor. Driving and using machines You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not drive or use any tools or machines until you are feeling well again. Imatinib Actavis contains lecithin (soya) If you are allergic to peanut or soya, do not use this medicinal product. Imatinib Actavis contains sodium This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’. 3. How to take Imatinib Actavis Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib Actavis can help you to fight this condition. However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or pharmacist if you are not sure. Do not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away. How much Imatinib Actavis to take Use in adults Your doctor will tell you exactly how many tablets of Imatinib Actavis to take. - If you are being treated for CML: The usual starting dose is 600 mg to be taken as 6 tablets once a day. Your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg (8 tablets), you should take 4 tablets in the morning and 4 tablets in the evening. 101 - If you are being treated for Ph-positive ALL: The starting dose is 600 mg to be taken as 6 tablets once a day. - If you are being treated for MDS/MPD: The starting dose is 400 mg to be taken as 4 tablets once a day. - If you are being treated for HES/CEL: The starting dose is 100 mg, to be taken as one tablet once a day. Your doctor may decide to increase the dose to 400 mg, to be taken as 4 tablets once a day, depending on how you respond to treatment. - If you are being treated for DFSP: The dose is 800 mg per day (8 tablets), to be taken as 4 tablets in the morning and 4 tablets in the evening. Use in children and adolescents The doctor will tell you how many tablets of Imatinib Actavis to give to your child. The amount of Imatinib Actavis given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). When and how to take Imatinib Actavis - Take Imatinib Actavis with a meal. This will help protect you from stomach problems when taking Imatinib Actavis. - Swallow the tablets whole with a large glass of water. The tablet can be divided into equal doses. If you are unable to swallow the tablets, you can dissolve them in a glass of still or mineral water or apple juice: - Use about 50 ml for each 100 mg tablet. - Stir with a spoon until the tablets have completely dissolved. - Once the tablet has dissolved, drink everything in the glass straight away. Traces of the dissolved tablets may be left behind in the glass. How long to take Imatinib Actavis Keep taking Imatinib Actavis every day for as long as your doctor tells you. If you take more Imatinib Actavis than you should If you have accidentally taken too many tablets, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you. If you forget to take Imatinib Actavis - If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose. - Then continue with your normal schedule. - Do not take a double dose to make up a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate. 102 Some side effects may be serious. Tell your doctor straight away if you get any of the following: Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): - Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid retention). - Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can reduce the number of white blood cells, so you might get infections more easily. - Unexpected bleeding or bruising (when you have not hurt yourself). Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): - Chest pain, irregular heart rhythm (signs of heart problems). - Cough, having difficulty breathing or painful breathing (signs of lung problems). - Feeling light-headed, dizzy or fainting (signs of low blood pressure). - Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). - Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). - Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). - Severely decreased urine output, feeling thirsty (signs of kidney problems). - Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). - Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). - Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). - Eye pain or deterioration in vision, bleeding in the eyes. - Pain in your hips or difficulty walking. - Numb or cold toes and fingers (signs of Raynaud’s syndrome). - Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). - Difficulty hearing. - Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). - Bruising. - Stomach pain with feeling sick (nausea). - Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). - Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). - Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood). - Blood clots in small blood vessels (thrombotic microangiopathy). Not known (frequency cannot be estimated from the available data): - Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). - Chronic renal failure. - Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a liver infection). If you get any of the above, tell your doctor straight away. Other side effects may include: 103 Very common (may affect more than 1 in 10 people): - Headache or feeling tired. - Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. - Rash. - Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have stopped taking imatinib. - Swelling such as round your ankles or puffy eyes. - Weight gain. If any of these affect you severely, tell your doctor. Common (may affect up to 1 in 10 people): - Anorexia, weight loss or a disturbed sense of taste. - Feeling dizzy or weak. - Difficulty in sleeping (insomnia). - Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. - Nose bleeds. - Pain or swelling in your abdomen, flatulence, heartburn or constipation. - Itching. - Unusual hair loss or thinning. - Numbness of the hands or feet. - Mouth ulcers. - Joint pain with swelling. - Dry mouth, dry skin or dry eye. - Decreased or increased skin sensitivity. - Hot flushes, chills or night sweats. If any of these affect you severely, tell your doctor. Not known (frequency cannot be estimated from the available data): - Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. - Painful and/or blistering skin lesions - Slowing of growth in children and adolescents. If any of these affect you severely, tell your doctor. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Imatinib Actavis Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month. Do not store above 30°C. Store in the original package in order to protect from moisture. Do not use any pack that is damaged or shows signs of tampering. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information 104 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc What Imatinib Actavis contains - The active substance is imatinib (as mesilate). Each tablet contains 100 mg imatinib (as mesilate). - The other ingredients are cellulose microcrystalline, copovidone, crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous), polyvinyl alcohol partly hydrolysed, talc, yellow iron oxide (E172), titanium dioxide (E171), red iron oxide (E172), lecithin (soya) (E322), xanthan gum (E415). What Imatinib Actavis looks like and contents of the pack Round, biconvex dark yellow to brownish film-coated tablet, embossed with company logo on one side and “36” with score line on the other side. Pack sizes: The tablets are supplied in aluminium blister packs of 10, 20, 30, 60, 90, 120 or 180 film-coated tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder Actavis Group PTC ehf. Reykjavíkurvegur 76-78, Hafnarfjörður Iceland Manufacturer S.C. Sindan-Pharma S.R.L. 11 Ion Mihalache Blvd Bucharest Romania For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Actavis Group PTC ehf. IJsland/Islande/Island Tél/Tel: +354 5503300 Lietuva UAB Sicor Biotech Tel: +370 52660203 България Актавис ЕАД Teл: +359 24899585 Luxembourg/Luxemburg Actavis Group PTC ehf. Islande/Island Tél/Tel: +354 5503300 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251007111 Magyarország Teva Gyógyszergyár Zrt. Tel: +36 12886400 Danmark Teva Denmark A/S Tlf: +45 44985511 Malta Actavis Ltd. Tel: +356 21693533 Deutschland Actavis Group PTC ehf. Island Tel: +354 5503300 Nederland Actavis Group PTC ehf. IJsland Tel: +354 5503300 105 Eesti UAB Sicor Biotech Eesti filiaal Tel: +372 6610801 Norge Teva Norway AS Tlf: +47 66775590 Ελλάδα Specifar ABEE Τηλ: +30 2105401500 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1970070 España Actavis Group PTC ehf. Islandia Tel: +354 5503300 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel: +48 223459300 France Actavis Group PTC ehf. Islande Tél: +354 5503300 Portugal Actavis Group PTC ehf. Islândia Tel: +354 5503300 Hrvatska Pliva Hrvatska d.o.o. Tel: +385 13720000 România Teva Pharmaceuticals S.R.L. Tel: +40 212306524 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)19630330 Slovenija Pliva Ljubljana d.o.o. Tel: +386 15890390 Ísland Actavis Group PTC ehf. Sími: +354 5503300 Slovenská republika TEVA Pharmaceuticals Slovakia s.r.o. Tel: +421 257267911 Italia Actavis Group PTC ehf. Islanda Tel: +354 5503300 Suomi/Finland ratiopharm Oy Puh/Tel: +358 201805900 Κύπρος Specifar ABEE Ελλάδα Τηλ: +30 2105401500 Sverige Teva Sweden AB Tel: +46 42121100 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 67323666 United Kingdom Actavis UK Limited Tel: +44 1271385257 This leaflet was last revised in Other source of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu 106 http://www.ema.europa.eu/ Package leaflet: Information for the user Imatinib Actavis 400 mg film-coated tablets imatinib Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Imatinib Actavis is and what it is used for 2. What you need to know before you take Imatinib Actavis 3. How to take Imatinib Actavis 4. Possible side effects 5. How to store Imatinib Actavis 6. Contents of the pack and other information 1. What Imatinib Actavis is and what it is used for Imatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer. Imatinib Actavis is a treatment for: - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia in which certain abnormal white cells (named myeloid cells) start growing out of control. In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease (chronic, accelerated phase and blast crisis). - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the growth of these cells. Imatinib Actavis is also a treatment for adults for: - Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. - Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. 107 - Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Actavis inhibits the growth of these cells. In the rest of this leaflet, we will use the abbreviations when talking about these diseases. If you have any questions about how Imatinib Actavis works or why this medicine has been prescribed for you, ask your doctor. 2. What you need to know before you take Imatinib Actavis Imatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. Follow all your doctor’s instructions carefully, even if they differ from the general information contained in this leaflet. Do not take Imatinib Actavis: - if you are allergic to imatinib, soya, peanut or any of the other ingredients of this medicine (listed in section 6). If this applies to you, tell your doctor without taking Imatinib Actavis. If you think you may be allergic but are not sure, ask your doctor for advice. Warnings and precautions Talk to your doctor before taking Imatinib Actavis: - if you have or have ever had a liver, kidney or heart problem. - if you are taking the medicine levothyroxine because your thyroid has been removed. - if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started. - if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, contact your doctor. This may be a sign of damage to blood vessels known as thrombotic microangiopathy (TMA). If any of these apply to you, tell your doctor before taking Imatinib Actavis. You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun- exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are also applicable to children. During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly. Children and adolescents Imatinib Actavis is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP and HES/CEL. Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The doctor will monitor the growth at regular visits. Other medicines and Imatinib Actavis 108 Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do the same to some other medicines. Tell your doctor if you are using medicines that prevent the formation of blood clots. Pregnancy, breast-feeding and fertility - If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. - Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis during pregnancy. - Women who might become pregnant are advised to use effective contraception during treatment. - Do not breast-feed during the treatment with Imatinib Actavis. - Patients who are concerned about their fertility while taking Imatinib Actavis are advised to consult with their doctor. Driving and using machines You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not drive or use any tools or machines until you are feeling well again. Imatinib Actavis contains lecithin (soya) If you are allergic to peanut or soya, do not use this medicinal product. Imatinib Actavis contains sodium This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’. 3. How to take Imatinib Actavis Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib Actavis can help you to fight this condition. However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or pharmacist if you are not sure. Do not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away. How much Imatinib Actavis to take Use in adults Your doctor will tell you exactly how many tablets of Imatinib Actavis to take. - If you are being treated for CML: The recommended starting dose is 600 mg to be taken as one tablet of 400 mg plus 2 tablets of 100 mg once a day. 109 Your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg (2 tablets), you should take one tablet in the morning and a second in the evening. - If you are being treated for Ph-positive ALL: The starting dose is 600 mg to be taken as one tablet of 400 mg plus 2 tablets of 100 mg once a day. - If you are being treated for MDS/MPD: The starting dose is 400 mg to be taken as one tablet once a day. - If you are being treated for HES/CEL: The starting dose is 100 mg, to be taken as one tablet of 100 mg once a day. Your doctor may decide to increase the dose to 400 mg, to be taken as one tablet of 400 mg once a day, depending on how you respond to treatment. - If you are being treated for DFSP: The dose is 800 mg per day (2 tablets), to be taken as one tablet in the morning and a second tablet in the evening. Use in children and adolescents The doctor will tell you how many tablets of Imatinib Actavis to give to your child. The amount of Imatinib Actavis given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). When and how to take Imatinib Actavis - Take Imatinib Actavis with a meal. This will help protect you from stomach problems when taking Imatinib Actavis. - Swallow the tablets whole with a large glass of water. The score line is not intended for breaking the tablet. If you are unable to swallow the tablets, you can dissolve them in a glass of still or mineral water or apple juice: Use about 200 ml for each 400 mg tablet. - Stir with a spoon until the tablets have completely dissolved. - Once the tablet has dissolved, drink everything in the glass straight away. Traces of the dissolved tablets may be left behind in the glass. How long to take Imatinib Actavis Keep taking Imatinib Actavis every day for as long as your doctor tells you. If you take more Imatinib Actavis than you should If you have accidentally taken too many tablets, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you. If you forget to take Imatinib Actavis - If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose. - Then continue with your normal schedule. - Do not take a double dose to make up a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 110 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate. Some side effects may be serious. Tell your doctor straight away if you get any of the following: Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): - Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid retention). - Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can reduce the number of white blood cells, so you might get infections more easily. - Unexpected bleeding or bruising (when you have not hurt yourself). Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): - Chest pain, irregular heart rhythm (signs of heart problems). - Cough, having difficulty breathing or painful breathing (signs of lung problems). - Feeling light-headed, dizzy or fainting (signs of low blood pressure). - Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). - Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). - Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). - Severely decreased urine output, feeling thirsty (signs of kidney problems). - Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). - Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). - Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). - Eye pain or deterioration in vision, bleeding in the eyes. - Pain in your hips or difficulty walking. - Numb or cold toes and fingers (signs of Raynaud’s syndrome). - Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). - Difficulty hearing. - Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). - Bruising. - Stomach pain with feeling sick (nausea). - Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). - Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). - Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood). - Blood clots in small blood vessels (thrombotic microangiopathy). Not known (frequency cannot be estimated from the available data): - Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). - Chronic renal failure. - Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a liver infection). 111 If you get any of the above, tell your doctor straight away. Other side effects may include: Very common (may affect more than 1 in 10 people): - Headache or feeling tired. - Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. - Rash. - Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have stopped taking imatinib. - Swelling such as round your ankles or puffy eyes. - Weight gain. If any of these affect you severely, tell your doctor. Common (may affect up to 1 in 10 people): - Anorexia, weight loss or a disturbed sense of taste. - Feeling dizzy or weak. - Difficulty in sleeping (insomnia). - Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. - Nose bleeds. - Pain or swelling in your abdomen, flatulence, heartburn or constipation. - Itching. - Unusual hair loss or thinning. - Numbness of the hands or feet. - Mouth ulcers. - Joint pain with swelling. - Dry mouth, dry skin or dry eye. - Decreased or increased skin sensitivity. - Hot flushes, chills or night sweats. If any of these affect you severely, tell your doctor. Not known (frequency cannot be estimated from the available data): - Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. - Painful and/or blistering skin lesions - Slowing of growth in children and adolescents. If any of these affect you severely, tell your doctor. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Imatinib Actavis Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month. Do not store above 30°C. Store in the original package in order to protect from moisture. Do not use any pack that is damaged or shows signs of tampering. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 112 http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 6. Contents of the pack and other information What Imatinib Actavis contains - The active substance is imatinib (as mesilate). Each tablet contains 400 mg imatinib (as mesilate). - The other ingredients are cellulose microcrystalline, copovidone, crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous), polyvinyl alcohol partly hydrolysed, talc, yellow iron oxide (E172), titanium dioxide (E171), red iron oxide (E172), lecithin (soya) (E322), xanthan gum (E415). What Imatinib Actavis looks like and contents of the pack Oval-shape, biconvex dark yellow to brownish film-coated tablet, embossed with company logo on one side and “37” with score line on the other side. Pack sizes: The tablets are supplied in aluminium blister packs of 10, 30, 60 or 90 film-coated tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder Actavis Group PTC ehf. Reykjavíkurvegur 76-78, Hafnarfjörður Iceland Manufacturer S.C. Sindan-Pharma S.R.L. 11 Ion Mihalache Blvd Bucharest Romania For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Actavis Group PTC ehf. IJsland/Islande/Island Tél/Tel: +354 5503300 Lietuva UAB Sicor Biotech Tel: +370 52660203 България Актавис ЕАД Teл: +359 24899585 Luxembourg/Luxemburg Actavis Group PTC ehf. Islande/Island Tél/Tel: +354 5503300 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251007111 Magyarország Teva Gyógyszergyár Zrt. Tel: +36 12886400 Danmark Teva Denmark A/S Tlf: +45 44985511 Malta Actavis Ltd. Tel: +356 21693533 113 Deutschland Actavis Group PTC ehf. Island Tel: +354 5503300 Nederland Actavis Group PTC ehf. IJsland Tel: +354 5503300 Eesti UAB Sicor Biotech Eesti filiaal Tel: +372 6610801 Norge Teva Norway AS Tlf: +47 66775590 Ελλάδα Specifar ABEE Τηλ: +30 2105401500 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1970070 España Actavis Group PTC ehf. Islandia Tel: +354 5503300 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel: +48 223459300 France Actavis Group PTC ehf. Islande Tél: +354 5503300 Portugal Actavis Group PTC ehf. Islândia Tel: +354 5503300 Hrvatska Pliva Hrvatska d.o.o. Tel: +385 13720000 România Teva Pharmaceuticals S.R.L. Tel: +40 212306524 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)19630330 Slovenija Pliva Ljubljana d.o.o. Tel: +386 15890390 Ísland Actavis Group PTC ehf. Sími: +354 5503300 Slovenská republika TEVA Pharmaceuticals Slovakia s.r.o. Tel: +421 257267911 Italia Actavis Group PTC ehf. Islanda Tel: +354 5503300 Suomi/Finland ratiopharm Oy Puh/Tel: +358 201805900 Κύπρος Specifar ABEE Ελλάδα Τηλ: +30 2105401500 Sverige Teva Sweden AB Tel: +46 42121100 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 67323666 United Kingdom Actavis UK Limited Tel: +44 1271385257 This leaflet was last revised in Other source of information Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu 114 http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you take imatinib actavis', 'Section_Content': "imatinib actavis will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. follow all your doctor's instructions carefully, even if they differ from the general information contained in this leaflet. do not take imatinib actavis: - if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6). if this applies to you, tell your doctor without taking imatinib actavis. if you think you may be allergic but are not sure, ask your doctor for advice. warnings and precautions talk to your doctor before taking imatinib actavis: - if you have or have ever had a liver, kidney or heart problem. - if you are taking the medicine levothyroxine because your thyroid has been removed. - if you have ever had or might now have a hepatitis b infection. this is because imatinib actavis could cause hepatitis b to become active again, which can be fatal in some cases. patients will be carefully checked by their doctor for signs of this infection before treatment is started. - if you experience bruising, bleeding, fever, fatigue and confusion when taking imatinib actavis, contact your doctor. this may be a sign of damage to blood vessels known as thrombotic microangiopathy (tma). if any of these apply to you, tell your doctor before taking imatinib actavis. you may become more sensitive to the sun while taking imatinib actavis. it is important to cover sun- exposed areas of skin and use sunscreen with high sun protection factor (spf). these precautions are also applicable to children. during treatment with imatinib actavis, tell your doctor straight away if you put on weight very quickly. imatinib actavis may cause your body to retain water (severe fluid retention). while you are taking imatinib actavis, your doctor will regularly check whether the medicine is working. you will also have blood tests and be weighed regularly. children and adolescents imatinib actavis is also a treatment for children with cml. there is no experience in children with cml below 2 years of age. there is limited experience in children with ph-positive all and very limited experience in children with mds/mpd, dfsp and hes/cel. some children and adolescents taking imatinib actavis may have slower than normal growth. the doctor will monitor the growth at regular visits. other medicines and imatinib actavis 76 tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as st. john's wort). some medicines can interfere with the effect of imatinib actavis when taken together. they may increase or decrease the effect of imatinib actavis, either leading to increased side effects or making imatinib actavis less effective. imatinib actavis may do the same to some other medicines. tell your doctor if you are using medicines that prevent the formation of blood clots. pregnancy, breast-feeding and fertility - if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. - imatinib actavis is not recommended during pregnancy unless clearly necessary as it may harm your baby. your doctor will discuss with you the possible risks of taking imatinib actavis during pregnancy. - women who might become pregnant are advised to use effective contraception during treatment. - do not breast-feed during the treatment with imatinib actavis. - patients who are concerned about their fertility while taking imatinib actavis are advised to consult with their doctor. driving and using machines you may feel dizzy or drowsy or get blurred vision while taking this medicine. if this happens, do not drive or use any tools or machines until you are feeling well again. imatinib 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{'Title': '3. how to take imatinib actavis', 'Section_Content': "your doctor has prescribed imatinib actavis because you suffer from a serious condition. imatinib actavis can help you to fight this condition. however, always take this medicine exactly as your doctor or pharmacist has told you. it is important that you do this as long as your doctor or pharmacist tells you to. check with your doctor or pharmacist if you are not sure. do not stop taking imatinib actavis unless your doctor tells you to. if you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away. how much imatinib actavis to take use in adults your doctor will tell you exactly how many capsules of imatinib actavis to take. - if you are being treated for cml: the usual starting dose is 600 mg to be taken as 12 capsules once a day. your doctor may prescribe a higher or lower dose depending on how you respond to treatment. if your daily dose is 800 mg (16 capsules), you should take 8 capsules in the morning and 8 capsules in the evening. - if you are being treated for ph-positive all: the starting dose is 600 mg to be taken as 12 capsules once a day. - if you are being treated for mds/mpd: the starting dose is 400 mg, to be taken as 8 capsules once a day. - if you are being treated for hes/cel: the starting dose is 100 mg, to be taken as 2 capsules once a day. your doctor may decide to increase the dose to 400 mg, to be taken as 8 capsules once a day, depending on how you respond to treatment. - if you are being treated for dfsp: the dose is 800 mg per day (16 capsules), to be taken as 8 capsules in the morning and 8 capsules in the evening. use in children and adolescents the doctor will tell you how many capsules of imatinib actavis to give to your child. the amount of imatinib actavis given will depend on your child's condition, body weight and height. the total daily dose in children must not exceed 800 mg with cml and 600 mg with ph+all. the treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). when and how to take imatinib actavis - take imatinib actavis with a meal. this will help protect you from stomach problems when taking imatinib actavis. - swallow the capsules whole with a large glass of water. do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children). - if you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice. - if you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. you should wash your hands immediately after opening the capsules. how long to take imatinib actavis keep taking imatinib actavis every day for as long as your doctor 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. they are usually mild to moderate. some side effects may be serious. tell your doctor straight away if you get any of the following: very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): - rapid weight gain. imatinib actavis may cause your body to retain water (severe fluid retention). - signs of infection such as fever, severe chills, sore throat or mouth ulcers. imatinib actavis can reduce the number of white blood cells, so you might get infections more easily. - unexpected bleeding or bruising (when you have not hurt yourself). uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): - chest pain, irregular heart rhythm (signs of heart problems). - cough, having difficulty breathing or painful breathing (signs of lung problems). - feeling light-headed, dizzy or fainting (signs of low blood pressure). - feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). - rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). - severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). - severely decreased urine output, feeling thirsty (signs of kidney problems). - feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). - severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). - pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). - eye pain or deterioration in vision, bleeding in the eyes. - pain in your hips or difficulty walking. - numb or cold toes and fingers (signs of raynaud's syndrome). - sudden swelling and redness of the skin (signs of a skin infection called cellulitis). - difficulty hearing. - muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). - bruising. - stomach pain with feeling sick (nausea). - muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). - pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). - nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood). - blood clots in small blood vessels (thrombotic microangiopathy). not known (frequency cannot be estimated from the available data): - combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). - chronic renal failure. - recurrence (reactivation) of hepatitis b infection when you have had hepatitis b in the past (a liver infection). if you get any of the above, tell your doctor straight away. other side effects may include: very common (may affect more than 1 in 10 people): - headache or feeling tired. - feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. - rash. - muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have stopped taking imatinib. - swelling such as round your ankles or puffy eyes. - weight gain. if any of these affect you severely, tell your doctor. common (may affect up to 1 in 10 people): - anorexia, weight loss or a disturbed sense of taste. - feeling dizzy or weak. - difficulty in sleeping (insomnia). - discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. - nose bleeds. - pain or swelling in your abdomen, flatulence, heartburn or constipation. - itching. - unusual hair loss or thinning. - numbness of the hands or feet. - mouth ulcers. - joint pain with swelling. - dry mouth, dry skin or dry eye. - decreased or increased skin sensitivity. - hot flushes, chills or night sweats. if any of these affect you severely, tell your doctor. not known (frequency cannot be estimated from the available data): - reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. - painful and/or blistering skin lesions. - slowing of growth in children and adolescents. - if any of these affect 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'EndOffset': 4679}, {'Id': 269, 'BeginOffset': 4687, 'EndOffset': 4695, 'Score': 0.9932510256767273, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9387004971504211}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9693210124969482, 'RelationshipScore': 0.9999004602432251, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 218, 'BeginOffset': 4703, 'EndOffset': 4708, 'Text': 'palms', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9971327781677246, 'RelationshipScore': 0.9999752044677734, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 219, 'BeginOffset': 4716, 'EndOffset': 4721, 'Text': 'hands', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.7187588810920715, 'RelationshipScore': 0.9990079998970032, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 220, 'BeginOffset': 4726, 'EndOffset': 4731, 'Text': 'soles', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 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sensation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9336411356925964}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9693210124969482, 'RelationshipScore': 0.7658096551895142, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 218, 'BeginOffset': 4703, 'EndOffset': 4708, 'Text': 'palms', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 271, 'BeginOffset': 4795, 'EndOffset': 4807, 'Score': 0.674065351486206, 'Text': 'burning pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9513130187988281}]}, {'Id': 272, 'BeginOffset': 4811, 'EndOffset': 4818, 'Score': 0.8429285883903503, 'Text': 'painful', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.89154052734375}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9939926266670227, 'RelationshipScore': 0.5585448741912842, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 222, 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{'Title': '5. how to store imatinib actavis', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and blister after exp. the expiry date refers to the last day of that month. do not store above 25. store in the original package in order to protect from moisture. do not use any pack that is damaged or shows signs of tampering. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'imatinib actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '25.', 'Type': 'NUMBER', 'BeginOffset': 232, 'EndOffset': 235}, {'Text': 'any pack', 'Type': 'TREATMENT', 'BeginOffset': 312, 'EndOffset': 320}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what imatinib actavis contains - the active substance is imatinib (as mesilate). each capsule contains 50 mg imatinib (as mesilate). - the other ingredients are: capsule content: cellulose microcrystalline, copovidone, crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous). capsule shell: hypromellose, titanium dioxide (e171), yellow iron oxide (e172). printing ink: shellac, black iron oxide (e172), propylene glycol, ammonia solution, potassium hydroxide. what imatinib actavis looks like and contents of the pack hard capsule with light yellow cap and light yellow body imprinted with 50 mg in black ink. the capsule contains light yellow powder. pack sizes: the capsules are supplied in aluminium blister packs of 30 or 90 capsules. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'imatinib actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 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'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 367, 'EndOffset': 384, 'Score': 0.3831613063812256, 'Text': 'yellow iron oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'black iron oxide (e', 'Type': 'TREATMENT', 'BeginOffset': 416, 'EndOffset': 435}, {'Id': 19, 'BeginOffset': 441, 'EndOffset': 457, 'Score': 0.9944520592689514, 'Text': 'propylene glycol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 20, 'BeginOffset': 459, 'EndOffset': 475, 'Score': 0.9333324432373047, 'Text': 'ammonia solution', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 21, 'BeginOffset': 477, 'EndOffset': 496, 'Score': 0.9982799291610718, 'Text': 'potassium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'what imatinib actavis', 'Type': 'PROBLEM', 'BeginOffset': 498, 'EndOffset': 519}, {'Text': 'the pack hard capsule', 'Type': 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1DA298606E59612D832FFC82E504F91D

https://www.ema.europa.eu/documents/product-information/anagrelide-mylan-epar-product-information_en.pdf

Anagrelide Mylan

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Anagrelide Mylan 0.5 mg hard capsules Anagrelide Mylan 1 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Anagrelide Mylan 0.5 mg hard capsules Each hard capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide. Excipients with known effect Each capsule contains approximately 59.5 mg lactose. Anagrelide Mylan 1 mg hard capsules Each hard capsule contains anagrelide hydrochloride monohydrate equivalent to 1 mg anagrelide. Excipients with known effect Each capsule contains approximately 119 mg lactose. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule (capsule). Anagrelide Mylan 0.5 mg hard capsules A capsule size 4 (approximately 14.3 x 5.3 mm) with an opaque white body and cap. The capsule is filled with white to off-white powder. Anagrelide Mylan 1 mg hard capsules A capsule size 4 (approximately 14.3 x 5.3 mm) with a grey body and cap. The capsule is filled with white to off-white powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Anagrelide is indicated for the reduction of elevated platelet counts in at risk essential thrombocythaemia (ET) patients who are intolerant to their current therapy or whose elevated platelet counts are not reduced to an acceptable level by their current therapy. An at-risk patient An at-risk essential thrombocythaemia patient is defined by one or more of the following features: • > 60 years of age or • a platelet count >1,000 x 109/l or • a history of thrombo-haemorrhagic events. 3 4.2 Posology and method of administration Treatment with anagrelide should be initiated by a clinician with experience in the management of essential thrombocythaemia. Posology The recommended starting dose of anagrelide is 1 mg/day, which should be administered orally in two divided doses (0.5 mg/dose). The starting dose should be maintained for at least one week. After one week the dose may be titrated, on an individual basis, to achieve the lowest effective dose required to reduce and/or maintain a platelet count below 600 x 109/l and ideally at levels between 150 x 109/l and 400 x 109/l. The dose increment must not exceed more than 0.5 mg/day in any one week and the recommended maximum single dose should not exceed 2.5 mg (see section 4.9). During clinical development doses of 10 mg/day have been used. The effects of treatment with anagrelide must be monitored on a regular basis (see section 4.4). If the starting dose is > 1 mg/day, platelet counts should be performed every two days during the first week of treatment and at least weekly thereafter until a stable maintenance dose is reached. Typically, a fall in the platelet count will be observed within 14 to 21 days of starting treatment and in most patients an adequate therapeutic response will be observed and maintained at a dose of 1 to 3 mg/day (for further information on the clinical effects refer, to section 5.1). Elderly The observed pharmacokinetic differences between elderly and young patients with ET (see section 5.2) do not warrant using a different starting regimen or different dose titration step to achieve an individual patient-optimised anagrelide regimen. During clinical development, approximately 50% of the patients treated with anagrelide were over 60 years of age and no age specific alterations in dose were required in these patients. However, as expected, patients in this age group had twice the incidence of serious adverse events (mainly cardiac). Renal impairment There are limited pharmacokinetic data for this patient population. The potential risks and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed before treatment is commenced (see section 4.3). Hepatic impairment There are limited pharmacokinetic data for this patient population. However, hepatic metabolism represents the major route of anagrelide clearance and liver function may therefore be expected to influence this process. Therefore, it is recommended that patients with moderate or severe hepatic impairment are not treated with anagrelide. The potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepatic function should be assessed before treatment is commenced (see sections 4.3 and 4.4). Paediatric population The safety and efficacy of anagrelide in children have not been established. The experience in children and adolescents is very limited; anagrelide should be used in this patient group with caution. In the absence of specific paediatric guidelines, WHO diagnostic criteria for adult diagnosis of ET are considered to be of relevance to the paediatric population. Diagnostic guidelines for essential thrombocythaemia should be followed carefully and diagnosis reassessed periodically in cases of uncertainty, with effort made to distinguish from hereditary or secondary thrombocytosis, which may include genetic analysis and bone marrow biopsy. Typically, cytoreductive therapy is considered in high-risk paediatric patients. 4 Anagrelide treatment should only be initiated when the patient shows signs of disease progression or suffers from thrombosis. If treatment is initiated, the benefits and risks of treatment with anagrelide must be monitored regularly and the need for ongoing treatment evaluated periodically. Platelet targets are assigned on an individual patient basis by the treating physician. Discontinuation of treatment should be considered in paediatric patients who do not have a satisfactory treatment response after approximately 3 months. Currently available data are described in sections 4.4, 4.8, 5.1 and 5.2, but no recommendation on a posology can be made. Method of administration For oral use. The capsules must be swallowed whole. The contents of the capsules should not be crushed or diluted in a liquid. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with moderate or severe hepatic impairment. Patients with moderate or severe renal impairment (creatinine clearance <50 ml/min). 4.4 Special warnings and precautions for use Hepatic impairment The potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepatic function should be assessed before treatment is commenced. It is not recommended in patients with elevated transaminases (>5 times the upper limit of normal) (see sections 4.2 and 4.3). Renal impairment The potential risks and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed before treatment is commenced (see sections 4.2 and 4.3). Monitoring Therapy requires close clinical supervision of the patient which will include a full blood count (haemoglobin and white blood cell and platelet counts), assessment of liver function (ALT and AST), renal function (serum creatinine and urea) and electrolytes (potassium, magnesium and calcium). Platelets The platelet count will increase within 4 days of stopping treatment with anagrelide and will return to pre-treatment levels within 10 to 14 days, possibly rebounding above baseline values. Therefore, platelets should be monitored frequently. Cardiovascular Serious cardiovascular adverse reactions including cases of torsade de pointes, ventricular tachycardia, cardiomyopathy, cardiomegaly and congestive heart failure have been reported (see section 4.8). Caution should be taken when using anagrelide in patients with known risk factors for prolongation of the QT interval, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalaemia. 5 Care should also be taken in populations that may have a higher maximum plasma concentration (Cmax) of anagrelide or its active metabolite, 3-hydroxy anagrelide, e.g., hepatic impairment or use with CYP1A2 inhibitors (see section 4.5). Close monitoring for an effect on the QTc interval is advisable. A pre-treatment cardiovascular examination, including a baseline ECG and echocardiography is recommended for all patients prior to initiating therapy with anagrelide. All patients should be monitored regularly during treatment (e.g., ECG or echocardiography) for evidence of cardiovascular effects that may require further cardiovascular examination and investigation. Hypokalaemia or hypomagnesaemia must be corrected prior to anagrelide administration and should be monitored periodically during therapy. Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III and because of its positive inotropic and chronotropic effects, anagrelide should be used with caution in patients of any age with known or suspected heart disease. Moreover, serious cardiovascular adverse events have also occurred in patients without suspected heart disease and with normal pre-treatment cardiovascular examination. Anagrelide should only be used if the potential benefits of therapy outweigh the potential risks. Pulmonary hypertension Cases of pulmonary hypertension have been reported in patients treated with anagrelide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during anagrelide therapy. Paediatric population Very limited data are available on the use of anagrelide in the paediatric population and anagrelide should be used in this patient group with caution (see sections 4.2, 4.8, 5.1 and 5.2). As with the adult population, a full blood count and assessment of cardiac, hepatic and renal function should be undertaken before treatment and regularly during treatment. The disease may progress to myelofibrosis or AML. Although the rate of such progression is not known, children have a longer disease course and may, therefore, be at increased risk for malignant transformation, relative to adults. Children should be monitored regularly for disease progression according to standard clinical practices, such as physical examination, assessment of relevant disease markers and bone marrow biopsy. Any abnormalities should be evaluated promptly and appropriate measures taken, which may also include dose reduction, interruption or discontinuation. Clinically relevant interactions Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III (PDE III). Concomitant use of anagrelide with other PDE III inhibitors such as milrinone, amrinone, enoximone, olprinone and cilostazol is not recommended. Use of concomitant anagrelide and acetylsalicylic acid has been associated with major haemorrhagic events (see section 4.5). Excipients Anagrelide Mylan contains lactose. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Anagrelide Mylan contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 6 ‘sodium-free’. 4.5 Interaction with other medicinal products and other forms of interaction Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between anagrelide and other medicinal products have been conducted. Effects of other active substances on anagrelide • In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic properties of anagrelide. CYP1A2 inhibitors • Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine and enoxacin, and such medicinal products could theoretically adversely influence the clearance of anagrelide. CYP1A2 inducers • CYP1A2 inducers (such as omeprazole) could decrease the exposure of anagrelide increasing its main active metabolite. The consequences on the safety and efficacy profile of anagrelide are not established. Therefore, clinical and biological monitoring is recommended in patients taking concomitant CYP1A2 inducers. If needed, anagrelide dose adjustment could be made. Effects of anagrelide on other active substances • Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other co-administered medicinal products sharing that clearance mechanism e.g., theophylline. • Anagrelide is an inhibitor of PDE III. The effects of medicinal products with similar properties such as the inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide. • In vivo interaction studies in humans have demonstrated that anagrelide does not affect the pharmacokinetic properties of digoxin or warfarin. • At the doses recommended for use in the treatment of essential thrombocythaemia, anagrelide may potentiate the effects of other medicinal products that inhibit or modify platelet function e.g., acetylsalicylic acid. • A clinical interaction study performed in healthy subjects showed that co-administration of repeat-dose anagrelide 1 mg once daily and acetylsalicylic acid 75 mg once daily may enhance the anti-platelet aggregation effects of each active substance compared with administration of acetylsalicylic acid alone. In some patients with ET concomitantly treated by acetylsalicylic acid and anagrelide, major haemorrhages occurred. Therefore, the potential risks of the concomitant use of anagrelide with acetylsalicylic acid should be assessed, particularly in patients with a high-risk profile for haemorrhage before treatment is initiated. • Anagrelide may cause intestinal disturbance in some patients and compromise the absorption of hormonal oral contraceptives. Food interactions • Food delays the absorption of anagrelide, but does not significantly alter systemic exposure. • The effects of food on bioavailability are not considered clinically relevant to the use of anagrelide. Paediatric population 7 Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Women of child-bearing potential Women of child-bearing potential should use adequate birth-control measures during treatment with anagrelide. Pregnancy There are no adequate data from the use of anagrelide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, anagrelide is not recommended during pregnancy. If anagrelide is used during pregnancy, or if the patient becomes pregnant while using the medicinal product, she should be advised of the potential risk to the foetus. Breast-feeding It is unknown whether anagrelide/metabolites are excreted in human milk. Available data in animals have shown excretion of anagrelide/metabolites in milk. A risk to the newborn/infant cannot be excluded. Breast-feeding should be discontinued during treatment with anagrelide. Fertility No human data on the effect of anagrelide on fertility are available. In male rats, there was no effect on fertility or reproductive performance with anagrelide. In female rats, using doses in excess of the therapeutic range, anagrelide disrupted implantation (see section 5.3). 4.7 Effects on ability to drive and use machines In clinical development, dizziness was commonly reported. Patients are advised not to drive or operate machinery while taking anagrelide if dizziness is experienced. 4.8 Undesirable effects Summary of the safety profile The safety of anagrelide has been examined in 4 open label clinical studies. In 3 of the studies 942 patients who received anagrelide at a mean dose of approximately 2 mg/day were assessed for safety. In these studies, 22 patients received anagrelide for up to 4 years. In the later study 3,660 patients who received anagrelide at a mean dose of approximately 2 mg/day were assessed for safety. In this study 34 patients received anagrelide for up to 5 years. The most commonly reported adverse reactions associated with anagrelide were headache occurring at approximately 14%, palpitations occurring at approximately 9%, fluid retention and nausea both occurring at approximately 6% and diarrhoea occurring at 5%. These adverse drug reactions are expected based on the pharmacology of anagrelide (inhibition of PDE III). Gradual dose titration may help diminish these effects (see section 4.2). Tabulated list of adverse reactions 8 Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous reports are presented in the table below. Within the system organ classes they are listed under the following headings: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. MedDRA System Organ Class Frequency of adverse reactions Very common Common Uncommon Rare Not known Blood and lymphatic system disorders Anaemia Pancytopenia Thrombocytopenia Haemorrhage Ecchymosis Metabolism and nutrition disorders Fluid retention Oedema Weight loss Weight gain Nervous system disorders Headache Dizziness Depression Amnesia Confusion Insomnia Paraesthesia Hypoaesthesia Nervousness Dry mouth Migraine Dysarthria Somnolence Abnormal coordination Eye disorders Diplopia Vision abnormal Ear and labyrinth disorders Tinnitus Cardiac disorders Tachycardia Palpitations Ventricular tachycardia Congestive heart failure Atrial fibrillation Supraventricular tachycardia Arrhythmia Hypertension Syncope Myocardial infarction Cardiomyopathy Cardiomegaly Pericardial effusion Angina pectoris Postural hypotension Vasodilation Prinzmetal angina Torsade de pointes Respiratory, thoracic and mediastinal disorders Pulmonary hypertension Pneumonia Pleural effusion Dyspnoea Epistaxis Pulmonary infiltrates Interstitial lung disease including pneumonitis and allergic alveolitis Gastrointestina l disorders Diarrhoea Vomiting Abdominal pain Nausea Flatulence Gastrointestinal haemorrhage Pancreatitis Anorexia Dyspepsia Constipation Gastrointestinal disorder Colitis Gastritis Gingival bleeding 9 MedDRA System Organ Class Frequency of adverse reactions Very common Common Uncommon Rare Not known Hepatobiliary disorders Hepatic enzymes increased Hepatitis Skin and subcutaneous tissue disorders Rash Alopecia Pruritus Skin discolouration Dry skin Musculoskeleta l and connective tissue disorders Arthralgia Myalgia Back pain Renal and urinary disorders Impotence Renal failure Nocturia Tubulointerstitial nephritis General disorders and administration site conditions Fatigue Chest pain Fever Chills Malaise Weakness Flu-like syndrome Pain Asthenia Investigations Blood creatinine increased Paediatric population 48 patients aged 6 through17 years (19 children and 29 adolescents) have received anagrelide for up to 6.5 years either in clinical studies or as part of a disease registry (see section 5.1). The majority of adverse events observed were among those listed in the SmPC. However, safety data are limited and do not allow a meaningful comparison between adult and paediatric patients to be made (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Post-marketing case reports of intentional overdose with anagrelide have been received. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative management. Anagrelide, at higher than recommended doses, has been shown to produce reductions in blood pressure with occasional instances of hypotension. A single 5-mg dose of anagrelide can lead to a fall in blood pressure usually accompanied by dizziness. A specific antidote for anagrelide has not been identified. In case of overdose, close clinical supervision of the patient is required; this includes monitoring of the platelet count for thrombocytopenia. Dose should be decreased or stopped, as appropriate, until the platelet count returns to within the normal range. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 10 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX35. Mechanism of action The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production. In vitro studies of human megakaryocytopoiesis established that anagrelide’s inhibitory actions on platelet formation in man are mediated via retardation of maturation of megakaryocytes, and reducing their size and ploidy. Evidence of similar in vivo actions was observed in bone marrow biopsy samples from treated patients. Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III. Clinical efficacy and safety The safety and efficacy of anagrelide as a platelet lowering agent have been evaluated in four open- label, non-controlled clinical trials (study numbers 700-012, 700-014, 700-999 and 13970-301) including more than 4,000 patients with myeloproliferative neoplasms (MPNs). In patients with essential thrombocythaemia complete response was defined as a decrease in platelet count to ≤600 x 109/l or a ≥50% reduction from baseline and maintenance of the reduction for at least 4 weeks. In studies 700-012, 700-014, 700-999 and study 13970-301 the time to complete response ranged from 4 to 12 weeks. Clinical benefit in terms of thrombohaemorrhagic events has not been convincingly demonstrated. Effects on heart rate and QTc interval The effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval was evaluated in a double-blind, randomised, placebo- and active-controlled, cross-over study in healthy adult men and women. A dose-related increase in heart rate was observed during the first 12 hours, with the maximum increase occurring around the time of maximal concentrations. The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg. A transient increase in mean QTc was observed for both doses during periods of increasing heart rate and the maximum change in mean QTcF (Fridericia correction) was +5.0 msec occurring at 2 hours for 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg. Paediatric population In an open-label clinical study in 8 children and 10 adolescents (including patients who were anagrelide treatment naïve or who had been receiving anagrelide for up to 5 years pre-study), median platelet counts were decreased to controlled levels after 12 weeks of treatment. The average daily dose tended to be higher in adolescents. In a paediatric registry study, median platelet counts were reduced from diagnosis and maintained for up to 18 months in 14 paediatric patients with ET (4 children, 10 adolescents) with anagrelide treatment. In earlier, open-label studies, median platelet count reductions were observed in 7 children and 9 adolescents treated for between 3 months and 6.5 years. 11 The average total daily dose of anagrelide across all studies in paediatric patients with ET was highly variable, but overall the data suggest that adolescents could follow similar starting and maintenance doses to adults and that a lower starting dose of 0.5 mg/day would be more appropriate for children over 6 years (see sections 4.2, 4.4, 4.8, 5.2). In all paediatric patients, careful titration to a patient- specific daily dose is needed. 5.2 Pharmacokinetic properties Absorption Following oral administration of anagrelide in man, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects, peak plasma levels occur about 1 hour after administration. Pharmacokinetic data from healthy subjects established that food decreases the Cmax of anagrelide by 14%, but increases the AUC by 20%. Food also decreased the Cmax of the active metabolite, 3-hydroxy anagrelide, by 29%, although it had no effect on the AUC. Biotransformation Anagrelide is primarily metabolised by CYP1A2 to form, 3-hydroxy anagrelide, which is further metabolised via CYP1A2 to the inactive metabolite, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline. Elimination The plasma half-life of anagrelide is short, approximately 1.3 hours and as expected from its half-life, there is no evidence for anagrelide accumulation in the plasma. Less than 1% is recovered in the urine as anagrelide. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine is approximately 18-35% of the administered dose. Additionally these results show no evidence of auto-induction of the anagrelide clearance. Linearity Dose proportionality has been found in the dose range 0.5 mg to 2 mg. Paediatric population Pharmacokinetic data from exposed fasting children and adolescents (age range 7 through 16 years) with essential thrombocythaemia indicate that dose normalised exposure, Cmax and AUC, of anagrelide tended to be higher in children/adolescents compared with adults. There was also a trend to higher dose-normalised exposure to the active metabolite. Elderly Pharmacokinetic data from fasting elderly patients with ET (age range 65 through 75 years) compared to fasting adult patients (age range 22 through 50 years) indicate that the Cmax and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients. These differences were likely to be caused by lower presystemic metabolism of anagrelide to 3-hydroxy anagrelide in the elderly patients. 5.3 Preclinical safety data Repeated dose toxicity Following repeated oral administration of anagrelide in dogs, subendocardial haemorrhage and focal myocardial necrosis was observed at 1 mg/kg/day or higher in males and females with males being 12 more sensitive. The no observed effect level (NOEL) for male dogs (0.3 mg/kg/day) corresponds to 0.1-, 0.1-, and 1.6-fold the AUC in humans for anagrelide at 2 mg/day, and the metabolites BCH24426 and RL603, respectively. Reproductive toxicology Fertility In male rats, anagrelide at oral doses up to 240 mg/kg/day (>1,000 times a 2-mg/day dose, based on body surface area) was found to have no effect on fertility and reproductive performance. In female rats increases in pre- and post-implantation losses and a decrease in the mean number of live embryos was observed at 30 mg/kg/day. The NOEL (10 mg/kg/day) to this effect was 143-, 12- and 11-fold higher than the AUC in humans administered a dose of anagrelide 2 mg/day, and the metabolites BCH24426 and RL603, respectively. Embryofoetal development studies Maternally toxic doses of anagrelide in rats and rabbits were associated with increased embryo resorption and foetal mortality. In a pre- and post-natal development study in female rats, anagrelide at oral doses of ≥10 mg/kg produced a non-adverse increase in gestational duration. At the NOEL dose (3 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 14-, 2- and 2-fold higher than the AUC in humans administered an oral dose of anagrelide 2 mg/day. Anagrelide at ≥ 60 mg/kg increased parturition time and mortality in the dam and foetus, respectively. At the NOEL dose (30 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 425-, 31- and 13-fold higher than the AUC in humans administered an oral dose of anagrelide 2 mg/day, respectively. Mutagenic and carcinogenic potential Studies on the genotoxic potential of anagrelide did not identify any mutagenic or clastogenic effects. In a two-year rat carcinogenicity study, non-neoplastic and neoplastic findings were observed and related or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenal phaeochromocytomas was increased relative to control in males at all dose levels (≥3 mg/kg/day) and in females receiving 10 mg/kg/day and above. The lowest dose in males (3 mg/kg/day) corresponds to 37 times the human AUC exposure after a 1 mg twice daily dose. Uterine adenocarcinomas, of epigenetic origin, could be related to an enzyme induction of CYP1 family. They were observed in females receiving 30 mg/kg/day, corresponding to 572 times the human AUC exposure after a 1-mg twice daily dose. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule contents Lactose Lactose monohydrate Croscarmellose sodium Povidone (K29/32) Microcrystalline cellulose Magnesium stearate Capsule shell 13 Anagrelide Mylan 0.5 mg hard capsules Gelatin Titanium dioxide (E171) Anagrelide Mylan 1 mg hard capsules Gelatin Titanium dioxide (E171) Iron oxide black (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Anagrelide 0.5 mg hard capsules Store in the original package in order to protect from light and moisture. This medicinal product does not require any special temperature storage conditions. Anagrelide 1 mg hard capsules Store in the original package in order to protect from moisture. This medicinal product does not require any special temperature storage conditions. 6.5 Nature and contents of container High-density polyethylene (HDPE) bottle of 30 ml or 75 ml with a tamper evident, child-resistant polypropylene (PP) closure with a desiccant. Pack size: 100 hard capsules. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Mylan S.A.S 117 Allée des Parcs Saint-Priest 69800, France 8. MARKETING AUTHORISATION NUMBER EU/1/17/1256/001 EU/1/17/1256/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 14 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 15 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 16 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release SYNTHON HISPANIA, S.L. C/ Castello, nº1, Pol. Las Salinas Sant Boi de Llobregat Barcelona, 08830 Spain Synthon BV Microweg 22 6545 CM Nijmegen NETHERLANDS The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 17 ANNEX III LABELLING AND PACKAGE LEAFLET 18 A. LABELLING 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING CARTON AND BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Anagrelide Mylan 0.5 mg hard capsules anagrelide 2. STATEMENT OF ACTIVE SUBSTANCE Each hard capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 100 hard capsules 5. METHOD AND ROUTE OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORE OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from light and moisture. 20 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S 117 Allée des Parcs, Saint-Priest, 69800, France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/17/1256/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Carton only: anagrelide mylan 0.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE Carton only: 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA Carton only: PC SN NN 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING CARTON AND BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT Anagrelide Mylan 1 mg hard capsules anagrelide 2. STATEMENT OF ACTIVE SUBSTANCE Each hard capsule contains anagrelide hydrochloride monohydrate equivalent to 1 mg anagrelide. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule 100 hard capsules 5. METHOD AND ROUTE OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORE OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 22 Store in the original package in order to protect from moisture. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Mylan S.A.S 117 Allée des Parcs, Saint-Priest, 69800, France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/17/1256/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Carton only: anagrelide mylan 1 mg 17. UNIQUE IDENTIFIER – 2D BARCODE Carton only: 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA Carton only: PC SN NN 23 B. PACKAGE LEAFLET 24 Package leaflet: Information for the patient Anagrelide Mylan 0.5 mg hard capsules anagrelide Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Anagrelide Mylan is and what it is used for 2. What you need to know before you take Anagrelide Mylan 3. How to take Anagrelide Mylan 4. Possible side effects 5. How to store Anagrelide Mylan 6. Contents of the pack and other information 1. What Anagrelide Mylan is and what it is used for Anagrelide Mylan contains the active substance, anagrelide. Anagrelide is a medicine which interferes with the development of platelets. It reduces the number of platelets produced by the bone marrow, which results in a decrease in the platelet count in the blood towards a more normal level. For this reason, it is used to treat patients with essential thrombocythaemia. Essential thrombocythaemia is a condition which occurs when the bone marrow produces too many of the blood cells known as platelets. Large numbers of platelets in the blood can cause serious problems with blood circulation and clotting. 2. What you need to know before you take Anagrelide Mylan Do not take Anagrelide Mylan • If you are allergic to anagrelide or any of the other ingredients of this medicine (listed in section 6). An allergic reaction may be recognised as a rash, itching, swollen face or lips, or shortness of breath; • If you have moderate or severe liver problems; • If you have moderate or severe kidney problems. Warnings and precautions Talk to your doctor before taking Anagrelide Mylan: • If you have or think you might have a problem with your heart; • If you were born with or have family history of prolonged QT interval (seen on ECG, electrical recording of the heart), or you are taking other medicines that result in abnormal ECG changes or if you have low levels of electrolytes e.g., potassium, magnesium or calcium (see section “Other medicines and Anagrelide Mylan”); • If you have any problems with your liver or kidneys. In combination with acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever, as well as to prevent blood clotting, also known as aspirin), there is an increased risk 25 of major haemorrhages (bleeding) (see section “Other medicines and Anagrelide Mylan”). Children and adolescents There is limited information on the use of anagrelide in children and adolescents and therefore this medicine should be used with caution. Other medicines and Anagrelide Mylan Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines. Tell your doctor if you are taking any of the following medicines: • Medicines that can alter your heart rhythm e.g., sotalol, amiodarone; • Fluvoxamine, used to treat depression; • Certain types of antibiotic, such as enoxacin, used to treat infections; • Theophylline, used to treat severe asthma and breathing problems; • Medicines used to treat heart disorders, for example, milrinone, enoximone, amrinone, olprinone and cilostazol; • Acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever, as well as to prevent blood clotting, also known as aspirin); • Other medicines used to treat conditions affecting the platelets in your blood, e.g., clopidogrel; • Omeprazole, used to reduce the amount of acid produced in the stomach; • Oral contraceptives: If you experience bad diarrhoea whilst taking this medicine, it may reduce how well the oral contraceptive works and use of an extra method of contraception is recommended (e.g., condom). See the instructions in the patient leaflet of the contraceptive pill you are taking. Anagrelide or these medicines may not work properly if taken together. If you are not sure, speak to your doctor or pharmacist for advice. Pregnancy and breast-feeding Tell your doctor if you are pregnant or are planning to become pregnant. Anagrelide Mylan should not be taken by pregnant women. Women who are at risk of becoming pregnant should make sure that they are using effective contraception when taking anagrelide. Speak to your doctor if you need advice with contraception. Tell your doctor if you are breast-feeding or if you are planning to breast-feed your baby. Anagrelide Mylan should not be taken while breast-feeding. You must stop breast-feeding if you are taking Anagrelide Mylan. Driving and using machines Dizziness has been reported by some patients taking anagrelide. Do not drive or use machines if you feel dizzy. Anagrelide Mylan contains lactose and sodium This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’. 3. How to take Anagrelide Mylan Always take Anagrelide Mylan exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. 26 The amount of anagrelide that people take can be different, and this depends on your condition. Your doctor will prescribe the best dose for you. The usual starting dose of this medicine is 1 mg. You take this dose as one capsule of 0.5 mg twice a day, for at least a week. After this time, your doctor may either increase or decrease the number of capsules that you take to find the dose best suited to you and which treats your condition most effectively. Your capsules should be swallowed whole with a glass of water. Do not crush the capsules or dilute the contents in a liquid. You can take the capsules with food or after a meal or on an empty stomach. It is best to take the capsule(s) at the same time every day. Do not take more capsules than your doctor has recommended. Your doctor will ask you to have blood tests at regular intervals to check that your medicine is working effectively and that your liver and kidneys are working well. If you take more Anagrelide Mylan than you should If you take more Anagrelide Mylan than you should or if someone else has taken your medicine, tell a doctor or pharmacist immediately. Show them the pack of Anagrelide Mylan. If you forget to take Anagrelide Mylan Take your capsules as soon as you remember. Take your next dose at the usual time. Do not take a double dose to make up for a forgotten dose. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. If you are worried, speak to your doctor. Serious side effects Uncommon: Heart failure (signs include shortness of breath, chest pain, swelling of the legs due to fluid build-up), severe problem with the rate or rhythm of the heartbeat (ventricular tachycardia, supraventricular tachycardia or atrial fibrillation), inflammation of the pancreas which causes severe abdominal and back pain (pancreatitis), vomiting blood or passing bloody or black stools, severe reduction in blood cells which can cause weakness, bruising, bleeding or infections (pancytopenia), increased pressure in the lung arteries (signs include shortness of breath, swelling in legs or ankles and lips and skin can turn bluish colour). Rare: Kidney failure (when you pass little or no urine), heart attack. If you notice any of these side effects, contact your doctor immediately. Very common side effects: may affect more than 1 in 10 people Headache. Common side effects: may affect up to 1 in 10 people Dizziness, tiredness, rapid heartbeat, irregular or strong heartbeat (palpitations), feeling sick (nausea), diarrhoea, stomach pain, wind, being sick (vomiting), reduction in red blood cell count (anaemia), fluid retention or rash. Uncommon side effects: may affect up to 1 in 100 people A feeling of weakness or feeling unwell, high blood pressure, irregular heartbeat, fainting, chills or fever, indigestion, loss of appetite, constipation, bruising, bleeding, swelling (oedema), weight loss, muscle aches, painful joints, back pain, decreased or loss of feeling or sensation such as numbness, especially in the skin, abnormal feeling or sensation such as tingling and ‘pins and needles’, 27 sleeplessness, depression, confusion, nervousness, dry mouth, loss of memory, breathlessness, nosebleed, serious lung infection with fever, shortness of breath, cough, phlegm; hair loss, skin itching or discolouration, impotence, chest pain, reduction in blood platelets, which increases the risk of bleeding or bruising (thrombocytopenia), accumulation of fluid around the lungs or an increase in liver enzymes. Your doctor may do a blood test which may show an increase in your liver enzymes. Rare side effects: may affect up to 1 in 1,000 people Bleeding gums, weight gain, severe chest pain (angina pectoris), heart muscle disease, (signs include fatigue, chest pain and palpitations), enlarged heart, accumulation of fluid around the heart, painful spasm of the blood vessels on the heart (while resting, usually at night or early morning) (Prinzmetal angina), loss of coordination, difficulty in speaking, dry skin, migraine, visual disturbances or double vision, ringing in the ears, dizziness on standing up (especially when getting up from a sitting or lying position), increased need to pass water at night, pain, ‘flu-like’ symptoms, sleepiness, widening of blood vessels, inflammation of the large bowel (signs include: diarrhoea, usually with blood and mucus, stomach pain, fever), inflammation of the stomach (signs include: pain, nausea, vomiting), area of abnormal density in the lung, increased creatinine level in blood tests, which may be a sign of kidney problems. The following side effects have been reported but it is not known exactly how often they occur: • Potentially life-threatening, irregular heartbeat (Torsade de pointes); • Inflammation of the liver, symptoms include nausea, vomiting, itching, yellowing of the skin and eyes, discoloration of stool and urine (hepatitis); • Lung inflammation (signs include fever, coughing, difficulty breathing, wheezing; which causes scaring of the lungs) (allergic alveolitis, including interstitial lung disease, pneumonitis); • Inflammation of the kidneys (tubulointerstitial nephritis). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Anagrelide Mylan Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and bottle label after EXP. The expiry date refers to the last day of that month. Store in the original package in order to protect from light and moisture. This medicinal product does not require any special temperature storage conditions. If your doctor stops your medicine, do not keep any leftover capsules unless your doctor tells you to. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Anagrelide Mylan contains The active substance is anagrelide. Each capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide. The other ingredients are lactose, croscarmellose sodium, povidone, microcrystalline cellulose, magnesium stearate, gelatin and titanium dioxide(E171). See section 2 ‘Anagrelide Mylan contains lactose and sodium’. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 28 What Anagrelide Mylan looks like and contents of the pack Anagrelide Mylan 0.5 mg hard capsules have a white body and cap. The capsule is filled with a white to off-white powder. The capsule size is approximately 14.3 x 5.3 mm. Anagrelide Mylan is available in plastic bottles of 30 ml or 75 ml with a tamper evident, child-resistant closure and a desiccant. Each bottle contains 100 hard capsules. Marketing Authorisation Holder Mylan S.A.S 117 Allée des Parcs Saint-Priest 69800, France Manufacturer Synthon Hispania SL C/ Castelló no1 POL. Las Salinas Sant Boi de Llobregat 08830 Barcelona Spain Synthon BV Microweg 22 6545 CM Nijmegen The Netherlands For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Mylan bvba/sprl Tél/Tel: + 32 (0)2 658 61 00 Lietuva BGP Products UAB Tel: +370 5 205 1288 България Майлан ЕООД Тел: +359 2 44 55 400 Luxembourg/Luxemburg Mylan bvba/sprl Tel: + 32 (0)2 658 61 00 (Belgique/Belgien) Česká republika Mylan Healthcare CZ.s.r.o. Tel: +420 222 004 400 Magyarország Mylan EPD Kft Tel: + 36 1 465 2100 Danmark Mylan Denmark ApS Tel: +45 28 11 69 32 Malta V.J. Salomone Pharma Ltd Tel: + 356 21 22 01 74 Deutschland Mylan Healthcare GmbH Tel: +49 800 0700 800 Nederland Mylan BV Tel: +31 (0)20 426 3300 Eesti BGP Products Switzerland GmbH Eesti filiaal Tel: + 372 6363 052 Norge Mylan Healthcare Norge AS Tel: + 47 66 75 33 00 29 Ελλάδα Generics Pharma Hellas ΕΠΕ Τηλ: +30 210 993 6410 Österreich Arcana Arzneimittel GmbH Tel: +43 1 416 2418 España Mylan Pharmaceuticals, S.L Tel: + 34 900 102 712 Polska Mylan Healthcare Sp. z o.o. Tel: + 48 22 546 64 00 France Mylan S.A.S Tel: +33 4 37 25 75 00 Portugal Mylan, Lda. Tel: + 351 21 412 72 56 Hrvatska Mylan Hrvatska d.o.o. Tel: +385 1 23 50 599 România BGP Products SRL Tel: +40 372 579 000 Ireland Mylan Ireland Limited Tel: +353 (0) 87 1694982 Slovenija Mylan Healthcare d.o.o. Tel: + 386 1 23 63 180 Ísland Icepharma hf Tel: +354 540 8000 Slovenská republika Mylan s.r.o. Tel: ++421 2 32 199 100 Italia Mylan Italia S.r.l. Tel: + 39 02 612 46921 Suomi/Finland Mylan Finland OY Puh/Tel: +358 20 720 9555 Κύπρος Varnavas Hadjipanayis Ltd Τηλ: +357 2220 7700 Sverige Mylan AB Tel: + 46 855 522 750 Latvija Mylan Healthcare SIA Tel: +371 676 055 80 United Kingdom Generics [UK] Ltd Tel: +44 1707 853000 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. http://www.ema.europa.eu/ 30 Package leaflet: Information for the patient Anagrelide Mylan 1 mg hard capsules anagrelide Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Anagrelide Mylan is and what it is used for 2. What you need to know before you take Anagrelide Mylan 3. How to take Anagrelide Mylan 4. Possible side effects 5. How to store Anagrelide Mylan 6. Contents of the pack and other information 1. What Anagrelide Mylan is and what it is used for Anagrelide Mylan contains the active substance, anagrelide. Anagrelide is a medicine which interferes with the development of platelets. It reduces the number of platelets produced by the bone marrow, which results in a decrease in the platelet count in the blood towards a more normal level. For this reason, it is used to treat patients with essential thrombocythaemia. Essential thrombocythaemia is a condition which occurs when the bone marrow produces too many of the blood cells known as platelets. Large numbers of platelets in the blood can cause serious problems with blood circulation and clotting. 2. What you need to know before you take Anagrelide Mylan Do not take Anagrelide Mylan • If you are allergic to anagrelide or any of the other ingredients of this medicine (listed in section 6). An allergic reaction may be recognised as a rash, itching, swollen face or lips, or shortness of breath; • If you have moderate or severe liver problems; • If you have moderate or severe kidney problems. Warnings and precautions Talk to your doctor before taking Anagrelide Mylan: • If you have or think you might have a problem with your heart; • If you were born with or have family history of prolonged QT interval (seen on ECG, electrical recording of the heart), or you are taking other medicines that result in abnormal ECG changes or if you have low levels of electrolytes e.g., potassium, magnesium or calcium (see section “Other medicines and Anagrelide Mylan”); • If you have any problems with your liver or kidneys. In combination with acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever, as well as to prevent blood clotting, also known as aspirin), there is an increased risk 31 of major haemorrhages (bleeding) (see section “Other medicines and Anagrelide Mylan”). Children and adolescents There is limited information on the use of anagrelide in children and adolescents and therefore this medicine should be used with caution. Other medicines and Anagrelide Mylan Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines. Tell your doctor if you are taking any of the following medicines: • Medicines that can alter your heart rhythm e.g., sotalol, amiodarone; • Fluvoxamine, used to treat depression; • Certain types of antibiotic, such as enoxacin, used to treat infections; • Theophylline, used to treat severe asthma and breathing problems; • Medicines used to treat heart disorders, for example, milrinone, enoximone, amrinone, olprinone and cilostazol; • Acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever, as well as to prevent blood clotting, also known as aspirin); • Other medicines used to treat conditions affecting the platelets in your blood, e.g., clopidogrel; • Omeprazole, used to reduce the amount of acid produced in the stomach; • Oral contraceptives: If you experience bad diarrhoea whilst taking this medicine, it may reduce how well the oral contraceptive works and use of an extra method of contraception is recommended (e.g., condom). See the instructions in the patient leaflet of the contraceptive pill you are taking. Anagrelide or these medicines may not work properly if taken together. If you are not sure, speak to your doctor or pharmacist for advice. Pregnancy and breast-feeding Tell your doctor if you are pregnant or are planning to become pregnant. Anagrelide Mylan should not be taken by pregnant women. Women who are at risk of becoming pregnant should make sure that they are using effective contraception when taking anagrelide. Speak to your doctor if you need advice with contraception. Tell your doctor if you are breast-feeding or if you are planning to breast-feed your baby. Anagrelide Mylan should not be taken while breast-feeding. You must stop breast-feeding if you are taking Anagrelide Mylan. Driving and using machines Dizziness has been reported by some patients taking anagrelide. Do not drive or use machines if you feel dizzy. Anagrelide Mylan contains lactose and sodium This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. This medicine contains less than 1mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’. 3. How to take Anagrelide Mylan Always take Anagrelide Mylan exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. 32 The amount of anagrelide that people take can be different, and this depends on your condition. Your doctor will prescribe the best dose for you. The usual starting dose of anagrelide is 1 mg. You take this dose as one capsule of 0.5 mg twice a day, for at least a week. After this time, your doctor may either increase or decrease the number of capsules that you take to find the dose best suited to you and which treats your condition most effectively. Your capsules should be swallowed whole with a glass of water. Do not crush the capsules or dilute the contents in a liquid. You can take the capsules with food or after a meal or on an empty stomach. It is best to take the capsule(s) at the same time every day. Do not take more capsules than your doctor has recommended. Your doctor will ask you to have blood tests at regular intervals to check that your medicine is working effectively and that your liver and kidneys are working well. If you take more Anagrelide Mylan than you should If you take more Anagrelide Mylan than you should or if someone else has taken your medicine, tell a doctor or pharmacist immediately. Show them the pack of Anagrelide Mylan. If you forget to take Anagrelide Mylan Take your capsules as soon as you remember. Take your next dose at the usual time. Do not take a double dose to make up for a forgotten dose. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. If you are worried, speak to your doctor. Serious side effects: Uncommon: Heart failure (signs include shortness of breath, chest pain, swelling of the legs due to fluid build-up), severe problem with the rate or rhythm of the heartbeat (ventricular tachycardia, supraventricular tachycardia or atrial fibrillation), inflammation of the pancreas which causes severe abdominal and back pain (pancreatitis), vomiting blood or passing bloody or black stools, severe reduction in blood cells which can cause weakness, bruising, bleeding or infections (pancytopenia), increased pressure in the lung arteries (signs include shortness of breath, swelling in legs or ankles and lips and skin can turn bluish colour). Rare: Kidney failure (when you pass little or no urine), heart attack. If you notice any of these side effects, contact your doctor immediately. Very common side effects: may affect more than 1 in 10 people Headache. Common side effects: may affect up to 1 in 10 people Dizziness, tiredness, rapid heartbeat, irregular or strong heartbeat (palpitations), feeling sick (nausea), diarrhoea, stomach pain, wind, being sick (vomiting), reduction in red blood cell count (anaemia), fluid retention or rash. Uncommon side effects: may affect up to 1 in 100 people A feeling of weakness or feeling unwell, high blood pressure, irregular heartbeat, fainting, chills or fever, indigestion, loss of appetite, constipation, bruising, bleeding, swelling (oedema), weight loss, muscle aches, painful joints, back pain, decreased or loss of feeling or sensation such as numbness, especially in the skin, abnormal feeling or sensation such as tingling and ‘pins and needles’, sleeplessness, depression, confusion, nervousness, dry mouth, loss of memory, breathlessness, 33 nosebleed, serious lung infection with fever, shortness of breath, cough, phlegm; hair loss, skin itching or discolouration, impotence, chest pain, reduction in blood platelets, which increases the risk of bleeding or bruising (thrombocytopenia), accumulation of fluid around the lungs or an increase in liver enzymes. Your doctor may do a blood test which may show an increase in your liver enzymes. Rare side effects: may affect up to 1 in 1,000 people Bleeding gums, weight gain, severe chest pain (angina pectoris), heart muscle disease, (signs include fatigue, chest pain and palpitations), enlarged heart, accumulation of fluid around the heart, painful spasm of the blood vessels on the heart (while resting, usually at night or early morning) (Prinzmetal angina), loss of coordination, difficulty in speaking, dry skin, migraine, visual disturbances or double vision, ringing in the ears, dizziness on standing up (especially when getting up from a sitting or lying position), increased need to pass water at night, pain, ‘flu-like’ symptoms, sleepiness, widening of blood vessels, inflammation of the large bowel (signs include: diarrhoea, usually with blood and mucus, stomach pain, fever), inflammation of the stomach (signs include: pain, nausea, vomiting), area of abnormal density in the lung, increased creatinine level in blood tests, which may be a sign of kidney problems. The following side effects have been reported but it is not known exactly how often they occur: • Potentially life-threatening, irregular heartbeat (Torsade de pointes); • Inflammation of the liver, symptoms include nausea, vomiting, itching, yellowing of the skin and eyes, discoloration of stool and urine (hepatitis); • Lung inflammation (signs include fever, coughing, difficulty breathing, wheezing; which causes scaring of the lungs) (allergic alveolitis, including interstitial lung disease, pneumonitis); • Inflammation of the kidneys (tubulointerstitial nephritis). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Anagrelide Mylan Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and bottle label after EXP. The expiry date refers to the last day of that month. Store in the original package in order to protect from moisture. This medicinal product does not require any special temperature storage conditions. If your doctor stops your medicine, do not keep any leftover capsules unless your doctor tells you to. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Anagrelide Mylan contains The active substance is anagrelide. Each capsule contains anagrelide hydrochloride monohydrate equivalent to 1 mg anagrelide. The other ingredients are lactose, croscarmellose sodium, povidone, microcrystalline cellulose, magnesium stearate, gelatin, titanium dioxide (E171) and iron oxide black (E172). See section 2 ‘Anagrelide Mylan contains lactose and sodium’. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 34 What Anagrelide Mylan looks like and contents of the pack Anagrelide Mylan 1 mg hard capsules have a grey body and cap. The capsule is filled with a white to off-white powder. The capsule size is approximately 14.3 x 5.3 mm. Anagrelide Mylan is available in plastic bottles of 30 ml or 75 ml with a tamper evident, child-resistant closure and a desiccant. Each bottle contains 100 hard capsules. Marketing Authorisation Holder Mylan S.A.S 117 Allée des Parcs, Saint-Priest, 69800, France Manufacturer Synthon Hispania SL, C/ Castelló no1, POL. Las Salinas, Sant Boi de Llobregat, 08830 Barcelona, Spain. Synthon BV Microweg 22 6545 CM Nijmegen The Netherlands For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Mylan bvba/sprl Tél/Tel: + 32 (0)2 658 61 00 Lietuva BGP Products UAB Tel: +370 5 205 1288 България Майлан ЕООД Тел: +359 2 44 55 400 Luxembourg/Luxemburg Mylan bvba/sprl Tel: + 32 (0)2 658 61 00 (Belgique/Belgien) Česká republika Mylan Healthcare CZ.s.r.o. Tel: +420 222 004 400 Magyarország Mylan EPD Kft Tel: + 36 1 465 2100 Danmark Mylan Denmark ApS Tel: +45 28 11 69 32 Malta V.J. Salomone Pharma Ltd Tel: + 356 21 22 01 74 Deutschland Mylan Healthcare GmbH Tel: +49 800 0700 800 Nederland Mylan BV Tel: + 31 (0)20 426 3300 Eesti BGP Products Switzerland GmbH Eesti filiaal Tel: + 372 6363 052 Norge Mylan Healthcare Norge AS Tel: + 47 66 75 33 00 35 Ελλάδα Generics Pharma Hellas ΕΠΕ Τηλ: +30 210 993 6410 Österreich Arcana Arzneimittel GmbH Tel: +43 1 416 2418 España Mylan Pharmaceuticals, S.L Tel: + 34 900 102 712 Polska Mylan Healthcare Sp. z o.o. Tel: + 48 22 546 64 00 France Mylan S.A.S Tel: +33 4 37 25 75 00 Portugal Mylan, Lda. Tel: + 351 21 412 72 56 Hrvatska Mylan Hrvatska d.o.o. Tel: +385 1 23 50 599 România BGP Products SRL Tel: +40 372 579 000 Ireland Mylan Ireland Limited Tel: +353 (0) 87 1694982 Slovenija Mylan Healthcare d.o.o. Tel: + 386 1 23 63 180 Ísland Icepharma hf Tel: +354 540 8000 Slovenská republika Mylan s.r.o. Tel: ++421 2 32 199 100 Italia Mylan Italia S.r.l. Tel: + 39 02 612 46921 Suomi/Finland Mylan Finland OY Puh/Tel: +358 20 720 9555 Κύπρος Varnavas Hadjipanayis Ltd Τηλ: +357 2220 7700 Sverige Mylan AB Tel: + 46 855 522 750 Latvija Mylan Healthcare SIA Tel: +371 676 055 80 United Kingdom Generics [UK] Ltd Tel: +44 1707 853000 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. http://www.ema.europa.eu/ SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to take anagrelide mylan', 'Section_Content': 'always take anagrelide mylan exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. the amount of anagrelide that people take can be different, and this depends on your condition. your doctor will prescribe the best dose for you. the usual starting dose of this medicine is 1 mg. you take this dose as one capsule of 0.5 mg twice a day, for at least a week. after this time, your doctor may either increase or decrease the number of capsules that you take to find the dose best suited to you and which treats your condition most effectively. your capsules should be swallowed whole with a glass of water. do not crush the capsules or dilute the contents in a liquid. you can take the capsules with food or after a meal or on an empty stomach. it is best to take the capsule(s) at the same time every day. do not take more capsules than your doctor has recommended. your doctor will ask you to have blood tests at regular intervals to check that your medicine is working effectively and that your liver and kidneys are working well. if you take more anagrelide mylan than you should if you take more anagrelide mylan than you should or if someone else has taken your medicine, tell a doctor or pharmacist immediately. show them the pack of anagrelide mylan. if you forget to take anagrelide mylan take your capsules as soon as you remember. take your next dose at the usual time. do not take a double dose to make up for a forgotten dose.', 'Entity_Recognition': [{'Text': 'anagrelide mylan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 28}, {'Id': 4, 'BeginOffset': 138, 'EndOffset': 148, 'Score': 0.9815389513969421, 'Text': 'anagrelide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 297, 'EndOffset': 310}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 314, 'EndOffset': 315}, {'Text': 'this dose', 'Type': 'TREATMENT', 'BeginOffset': 329, 'EndOffset': 338}, {'Text': '0.5', 'Type': 'NUMBER', 'BeginOffset': 357, 'EndOffset': 360}, {'Text': 'capsules', 'Type': 'TREATMENT', 'BeginOffset': 473, 'EndOffset': 481}, {'Text': 'your capsules', 'Type': 'TREATMENT', 'BeginOffset': 582, 'EndOffset': 595}, {'Text': 'the capsules', 'Type': 'TREATMENT', 'BeginOffset': 658, 'EndOffset': 670}, {'Id': 0, 'BeginOffset': 774, 'EndOffset': 781, 'Score': 0.7369526028633118, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 18, 'BeginOffset': 938, 'EndOffset': 949, 'Score': 0.8616014122962952, 'Text': 'blood tests', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'your medicine', 'Type': 'TREATMENT', 'BeginOffset': 985, 'EndOffset': 998}, {'Id': 1, 'BeginOffset': 1036, 'EndOffset': 1041, 'Score': 0.9812946319580078, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 2, 'BeginOffset': 1046, 'EndOffset': 1053, 'Score': 0.9717195630073547, 'Text': 'kidneys', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 1089, 'EndOffset': 1105}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 1139, 'EndOffset': 1155}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 1279, 'EndOffset': 1295}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 1319, 'EndOffset': 1335}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 1431, 'EndOffset': 1444}]}

{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. if you are worried, speak to your doctor. serious side effects uncommon: heart failure (signs include shortness of breath, chest pain, swelling of the legs due to fluid build-up), severe problem with the rate or rhythm of the heartbeat (ventricular tachycardia, supraventricular tachycardia or atrial fibrillation), inflammation of the pancreas which causes severe abdominal and back pain (pancreatitis), vomiting blood or passing bloody or black stools, severe reduction in blood cells which can cause weakness, bruising, bleeding or infections (pancytopenia), increased pressure in the lung arteries (signs include shortness of breath, swelling in legs or ankles and lips and skin can turn bluish colour). rare: kidney failure (when you pass little or no urine), heart attack. if you notice any of these side effects, contact your doctor immediately. very common side effects: may affect more than 1 in 10 people headache. common side effects: may affect up to 1 in 10 people dizziness, tiredness, rapid heartbeat, irregular or strong heartbeat (palpitations), feeling sick (nausea), diarrhoea, stomach pain, wind, being sick (vomiting), reduction in red blood cell count (anaemia), fluid retention or rash. uncommon side effects: may affect up to 1 in 100 people a feeling of weakness or feeling unwell, high blood pressure, irregular heartbeat, fainting, chills or fever, indigestion, loss of appetite, constipation, bruising, bleeding, swelling (oedema), weight loss, muscle aches, painful joints, back pain, decreased or loss of feeling or sensation such as numbness, especially in the skin, abnormal feeling or sensation such as tingling and 'pins and needles', 27 sleeplessness, depression, confusion, nervousness, dry mouth, loss of memory, breathlessness, nosebleed, serious lung infection with fever, shortness of breath, cough, phlegm; hair loss, skin itching or discolouration, impotence, chest pain, reduction in blood platelets, which increases the risk of bleeding or bruising (thrombocytopenia), accumulation of fluid around the lungs or an increase in liver enzymes. your doctor may do a blood test which may show an increase in your liver enzymes. rare side effects: may affect up to 1 in 1,000 people bleeding gums, weight gain, severe chest pain (angina pectoris), heart muscle disease, (signs include fatigue, chest pain and palpitations), enlarged heart, accumulation of fluid around the heart, painful spasm of the blood vessels on the heart (while resting, usually at night or early morning) (prinzmetal angina), loss of coordination, difficulty in speaking, dry skin, migraine, visual disturbances or double vision, ringing in the ears, dizziness on standing up (especially when getting up from a sitting or lying position), increased need to pass water at night, pain, 'flu-like' symptoms, sleepiness, widening of blood vessels, inflammation of the large bowel (signs include: diarrhoea, usually with blood and mucus, stomach pain, fever), inflammation of the stomach (signs include: pain, nausea, vomiting), area of abnormal density in the lung, increased creatinine level in blood tests, which may be a sign of kidney problems. the following side effects have been reported but it is not known exactly how often they occur: potentially life-threatening, irregular heartbeat (torsade de pointes); inflammation of the liver, symptoms include nausea, vomiting, itching, yellowing of the skin and eyes, discoloration of stool and urine (hepatitis); lung inflammation (signs include fever, coughing, difficulty breathing, wheezing; which causes scaring of the lungs) (allergic alveolitis, including interstitial lung disease, pneumonitis); inflammation of the kidneys (tubulointerstitial nephritis). reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'anagrelide mylan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 21, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9649376273155212, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7221900820732117}]}, {'Text': 'serious side effects', 'Type': 'PROBLEM', 'BeginOffset': 134, 'EndOffset': 154}, {'Id': 23, 'BeginOffset': 165, 'EndOffset': 178, 'Score': 0.9784269332885742, 'Text': 'heart failure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 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creatinine level', 'Type': 'PROBLEM', 'BeginOffset': 3166, 'EndOffset': 3192}, {'Id': 209, 'BeginOffset': 3196, 'EndOffset': 3207, 'Score': 0.9526177644729614, 'Text': 'blood tests', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.5954373478889465, 'RelationshipScore': 0.9898957014083862, 'RelationshipType': 'TEST_VALUE', 'Id': 207, 'BeginOffset': 3166, 'EndOffset': 3175, 'Text': 'increased', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 180, 'BeginOffset': 3232, 'EndOffset': 3247, 'Score': 0.8959571123123169, 'Text': 'kidney problems', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7591543197631836}]}, {'Id': 181, 'BeginOffset': 3263, 'EndOffset': 3275, 'Score': 0.856843888759613, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7589234113693237}]}, {'Text': 'irregular heartbeat 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{'Title': '5. how to store anagrelide mylan', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and bottle label after exp. the expiry date refers to the last day of that month. store in the original package in order to protect from light and moisture. this medicinal product does not require any special temperature storage conditions. if your doctor stops your medicine, do not keep any leftover capsules unless your doctor tells you to. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what anagrelide mylan contains the active substance is anagrelide. each capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide. the other ingredients are lactose, croscarmellose sodium, povidone, microcrystalline cellulose, magnesium stearate, gelatin and titanium dioxide(e171). see section 2 'anagrelide mylan contains lactose and sodium'. what anagrelide mylan looks like and contents of the pack anagrelide mylan 0.5 mg hard capsules have a white body and cap. the capsule is filled with a white to off-white powder. the capsule size is approximately 14.3 x 5.3 mm. anagrelide mylan is available in plastic bottles of 30 ml or 75 ml with a tamper evident, child-resistant closure and a desiccant. each bottle contains 100 hard capsules.", 'Entity_Recognition': [{'Text': 'anagrelide mylan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 21}, {'Id': 2, 'BeginOffset': 55, 'EndOffset': 65, 'Score': 0.9853469133377075, 'Text': 'anagrelide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.6096318364143372, 'RelationshipScore': 0.9952360987663269, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 72, 'EndOffset': 79, 'Text': 'capsule', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'anagrelide hydrochloride monohydrate equivalent', 'Type': 'TREATMENT', 'BeginOffset': 89, 'EndOffset': 136}, {'Text': '0.5', 'Type': 'NUMBER', 'BeginOffset': 140, 'EndOffset': 143}, {'Id': 6, 'BeginOffset': 147, 'EndOffset': 157, 'Score': 0.9950590133666992, 'Text': 'anagrelide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9190890789031982, 'RelationshipScore': 0.9793552756309509, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 140, 'EndOffset': 146, 'Text': '0.5 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'lactose', 'Type': 'TREATMENT', 'BeginOffset': 185, 'EndOffset': 192}, {'Id': 7, 'BeginOffset': 194, 'EndOffset': 215, 'Score': 0.9704983234405518, 'Text': 'croscarmellose sodium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 217, 'EndOffset': 225, 'Score': 0.8732883334159851, 'Text': 'povidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 227, 'EndOffset': 253, 'Score': 0.9962660670280457, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 255, 'EndOffset': 273, 'Score': 0.9933165311813354, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'gelatin and titanium dioxide', 'Type': 'TREATMENT', 'BeginOffset': 275, 'EndOffset': 303}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 323, 'EndOffset': 324}, {'Id': 12, 'BeginOffset': 326, 'EndOffset': 342, 'Score': 0.5562722086906433, 'Text': 'anagrelide mylan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'lactose', 'Type': 'TREATMENT', 'BeginOffset': 352, 'EndOffset': 359}, {'Text': 'sodium', 'Type': 'TREATMENT', 'BeginOffset': 364, 'EndOffset': 370}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 378, 'EndOffset': 394}, {'Text': 'the pack anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 422, 'EndOffset': 447}, {'Text': '0.5', 'Type': 'NUMBER', 'BeginOffset': 448, 'EndOffset': 451}, {'Text': 'the capsule', 'Type': 'TREATMENT', 'BeginOffset': 496, 'EndOffset': 507}, {'Text': 'white powder', 'Type': 'TREATMENT', 'BeginOffset': 538, 'EndOffset': 550}, {'Text': 'the capsule size', 'Type': 'TEST', 'BeginOffset': 552, 'EndOffset': 568}, {'Text': '14.3', 'Type': 'NUMBER', 'BeginOffset': 586, 'EndOffset': 590}, {'Text': '5.3', 'Type': 'NUMBER', 'BeginOffset': 593, 'EndOffset': 596}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 601, 'EndOffset': 617}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 653, 'EndOffset': 655}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 662, 'EndOffset': 664}, {'Text': 'child-resistant closure', 'Type': 'TREATMENT', 'BeginOffset': 691, 'EndOffset': 714}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 753, 'EndOffset': 756}]}

1B231D72EFCF1289444C70AA9FE3F436

https://www.ema.europa.eu/documents/product-information/zoely-epar-product-information_en.pdf

Zoely

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Zoely 2.5 mg/1.5 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION White active film-coated tablets: Each film-coated tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate). Yellow placebo film-coated tablets: The tablet does not contain active substances. Excipients with known effect Each white active film-coated tablet contains 57.71 mg of lactose monohydrate. Each yellow placebo film-coated tablet contains 61.76 mg of lactose monohydrate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Active film-coated tablets: white, round and coded ‘ne’ on both sides. Placebo film-coated tablets: yellow, round and coded ‘p’ on both sides. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Oral contraception. The decision to prescribe Zoely should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Zoely compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4). 4.2 Posology and method of administration Posology One tablet is to be taken daily for 28 consecutive days. Each pack starts with 24 white active tablets, followed by 4 yellow placebo tablets. A subsequent pack is started immediately after finishing the previous pack, without a break in daily tablet intake and irrespective of presence or absence of withdrawal bleeding. Withdrawal bleeding usually starts on day 2-3 after intake of the last white tablet and may not have finished before the next pack is started. See ‘Cycle control’ in section 4.4. Special populations Renal impairment Although data in renal impaired patients are not available, renal impairment is unlikely to affect the elimination of nomegestrol acetate and estradiol. 3 Hepatic impairment No clinical studies have been performed in patients with hepatic insufficiency. Since the metabolism of steroid hormones might be impaired in patients with severe hepatic disease, the use of Zoely in these women is not indicated as long as liver function values have not returned to normal (see section 4.3). Method of administration Oral use. How to take Zoely Tablets must be taken every day at about the same time without regard to meals. Tablets should be taken with some liquid as needed, and in the order as directed on the blister. Stickers marked with the 7 days of the week are provided. The woman should choose the sticker that starts with the day she begins taking the tablets and stick it on the blister. How to start Zoely No preceding hormonal contraceptive use (in the past month) Tablet-taking has to start on day 1 of the woman’s natural cycle (i.e. the first day of her menstrual bleeding). When doing so, no additional contraceptive measures are necessary. Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring or transdermal patch) The woman should start with Zoely preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Zoely preferably on the day of removal, but at the latest when the next application would have been due. Changing from a progestogen-only-method (minipill, implant, injectable) or from a hormone-medicated intra uterine system (IUS) The woman may switch any day from the minipill and Zoely should be started on the next day. An implant or IUS may be removed any day, and Zoely should be started on the day of its removal. When changing from an injectable, Zoely should be started on the day when the next injection would have been due. In all of these cases, the woman should be advised to additionally use a barrier method until she has completed 7 days of uninterrupted white active tablet-taking. Following first-trimester abortion The woman may start immediately. When doing so, no additional contraceptive measures are necessary. Following delivery or second-trimester abortion Women should be advised to start between day 21 and 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method until she has completed 7 days of uninterrupted white active tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period. For breast-feeding women see section 4.6. Management of missed tablets The following advice only refers to missed white active tablets: If the woman is less than 24 hours late in taking any active tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time. 4 If she is 24 or more hours late in taking any active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:  7 days of uninterrupted ‘white active tablet’-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.  The more ‘white active tablets’ are missed and the closer the missed tablets are to the 4 yellow placebo tablets, the higher the risk of a pregnancy. Day 1-7 The user should take the last missed white tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used until she has completed 7 days of uninterrupted white tablet- taking. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. Day 8-17 The user should take the last missed white tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if she has missed more than 1 tablet, the woman should be advised to use extra precautions until she has completed 7 days of uninterrupted white tablet-taking. Day 18-24 The risk of reduced reliability is imminent because of the forthcoming yellow placebo tablet phase. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, she should follow the first of these two options and use extra precautions for the next 7 days as well. 1. The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time until the active tablets are used up. The 4 placebo tablets from the last row must be discarded. The next blister pack must be started right away. The user is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but she may experience spotting or breakthrough bleeding on tablet-taking days. 2. The woman may also be advised to discontinue active tablet-taking from the current blister pack. She should then take placebo tablets from the last row for a maximum of 3 days such that the total number of placebo plus missed white active tablets is not more than 4, and subsequently continue with the next blister pack. If the woman missed tablets and subsequently has no withdrawal bleed in the placebo tablet phase, the possibility of a pregnancy should be considered. Please note: If the user is not sure about the number or colour of tablets missed and what advice to follow, a barrier method should be used until she has completed 7 days of uninterrupted white active tablet-taking. Yellow placebo tablets missed Contraceptive protection is not reduced. Yellow tablets from the last (4th) row of the blister can be disregarded. However, the missed tablets should be discarded to avoid unintentionally prolonging the placebo tablet phase. Advice in case of gastro-intestinal disturbances In case of severe gastro-intestinal disturbance (e.g., vomiting or diarrhoea), absorption of the active substances may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after white tablet-taking, the tablet should be considered as missed and a new tablet should be taken as soon as possible. The new tablet should be taken within 24 hours 5 of the usual time of tablet-taking if possible. The next tablet should then be taken at the usual time. If 24 or more hours have passed since last tablet intake, the advice concerning missed tablets, as given in section 4.2 "Management of missed tablets", is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra white tablet(s) from another pack. How to shift periods or how to delay a period To delay a period the woman should continue with another blister pack of Zoely without taking the yellow placebo tablets from her current pack. The extension can be carried on for as long as wished until the end of the white active tablets in the second pack. Regular intake of Zoely is then resumed after the yellow placebo tablets have been taken of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming yellow placebo tablet phase with a maximum of 4 days. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and may experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period). 4.3 Contraindications Combined hormonal contraceptives (CHCs) must not be used in the following conditions. As no epidemiological data are yet available with 17β-estradiol containing CHCs, the contraindications for ethinylestradiol containing CHCs are considered applicable to the use of Zoely. Should any of the conditions appear for the first time during Zoely use, the medicinal product should be stopped immediately.  Presence or risk of venous thromboembolism (VTE) o Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]). o Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency. o Major surgery with prolonged immobilisation (see section 4.4). o A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4).  Presence or risk of arterial thromboembolism (ATE) o Arterial thromboembolism - current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris). o Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA). o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant). o History of migraine with focal neurological symptoms. o A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence of one serious risk factor such as:  diabetes mellitus with vascular symptoms  severe hypertension  severe dyslipoproteinaemia.  Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia.  Presence or history of severe hepatic disease as long as liver function values have not returned to normal.  Presence or history of liver tumours (benign or malignant).  Known or suspected sex steroid-influenced malignancies (e.g., of the genital organs or the breasts). 6  Presence or history of meningioma.  Undiagnosed vaginal bleeding.  Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Warnings If any of the conditions or risk factors mentioned below is present, the suitability of Zoely should be discussed with the woman. In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of Zoely should be discontinued. All data presented below are based upon epidemiological data obtained with CHCs containing ethinylestradiol. Zoely contains 17β-estradiol. As no epidemiological data are yet available with estradiol containing-CHCs, the warnings are considered applicable to the use of Zoely. Risk of venous thromboembolism (VTE)  The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. It is not yet known how the risk with Zoely compares with these lower risk products. The decision to use any product other than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.  In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman, the risk may be far higher, depending on her underlying risk factors (see below).  Epidemiological studies in women who use low dose (< 50 µg ethinylestradiol) combined hormonal contraceptives have found that out of 10,000 women between 6 and 12 will develop a VTE in one year.  It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 61 will develop a VTE in one year.  It is not yet known how the risk of VTE with CHCs that contain nomegestrol acetate in combination with estradiol compares with the risk with low dose levonorgestrel-containing CHCs.  The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.  VTE may be fatal in 1-2 % of cases.  Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, or retinal veins and arteries. Risk factors for VTE The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table). Zoely is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative, a CHC should not be prescribed (see section 4.3). 1 Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6 7 Table: Risk factors for VTE Risk factor Comment Obesity (body mass index over 30 kg/m²) Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present. Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma Note: Temporary immobilisation including air travel > 4 hours can also be a risk factor for VTE, particularly in women with other risk factors. In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Zoely has not been discontinued in advance. Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age, e.g., before 50) If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use. Other medical conditions associated with VTE Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease Increasing age Particularly above 35 years  There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.  The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on "Pregnancy and lactation" see section 4.6). Symptoms of VTE (deep vein thrombosis and pulmonary embolism) In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC. Symptoms of deep vein thrombosis (DVT) can include: - unilateral swelling of the leg and/or foot or along a vein in the leg; - pain or tenderness in the leg which may be felt only when standing or walking; - increased warmth in the affected leg; red or discoloured skin on the leg. Symptoms of pulmonary embolism (PE) can include: - sudden onset of unexplained shortness of breath or rapid breathing; - sudden coughing which may be associated with haemoptysis; - sharp chest pain; - severe light headedness or dizziness; - rapid or irregular heartbeat. Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections). Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity. If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately. 8 Risk of arterial thromboembolism (ATE) Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g., transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal. Risk factors for ATE The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Zoely is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3). Table: Risk factors for ATE Risk factor Comment Increasing age Particularly above 35 years Smoking Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception. Hypertension Obesity (body mass index over 30 kg/m2) Risk increases substantially as BMI increases. Particularly important in women with additional risk factors Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age, e.g., below 50) If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use. Migraine An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation. Other medical conditions associated with adverse vascular events Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus Symptoms of ATE In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC. Symptoms of a cerebrovascular accident can include: - sudden numbness or weakness of the face, arm or leg, especially on one side of the body; - sudden trouble walking, dizziness, loss of balance or coordination; - sudden confusion, trouble speaking or understanding; - sudden trouble seeing in one or both eyes; - sudden, severe or prolonged headache with no known cause; - loss of consciousness or fainting with or without seizure. Temporary symptoms suggest the event is a transient ischaemic attack (TIA). 9 Symptoms of a myocardial infarction (MI) can include: - pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone; - discomfort radiating to the back, jaw, throat, arm, stomach; - feeling of being full, having indigestion or choking; - sweating, nausea, vomiting or dizziness; - extreme weakness, anxiety, or shortness of breath; - rapid or irregular heartbeats. Tumours  An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV). No epidemiological data on the risk of cervical cancer in users of Zoely are available.  With the use of the higher-dosed COCs (50 g ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to 17β-estradiol-containing COCs remains to be confirmed.  A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both.  In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. Therefore, a hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs. Meningioma The occurrence of meningioma (single and multiple) has been reported with prolonged use (several years) of nomegestrol monotherapy at doses of 3.75 mg or 5 mg daily and higher. If a meningioma is diagnosed in a patient treated with Zoely, treatment should be stopped (see section 4.3). Hepatitis C  During clinical trials with the Hepatitis C virus (HCV) combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medications such as CHCs. Women using medications containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir. See section 4.5. Other conditions  Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.  Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. A relationship between COC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a COC, then it is prudent for the physician to suspend the intake of the tablets and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy. 10  The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss.  In women with hereditary angioedema, exogenous oestrogens may induce or exacerbate symptoms of angioedema.  Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.  Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing  0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking a COC, especially in the first months of use.  Crohn’s disease, ulcerative colitis, and worsening of depression have been associated with COC use.  Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.  Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.  Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment. Medical examination/consultation Prior to the initiation or reinstitution of Zoely use a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Zoely compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman. Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases. Reduced efficacy The efficacy of COCs may be reduced in the event of e.g., missed tablets (see section 4.2), gastro-intestinal disturbances during active tablet-taking (see section 4.2) or use of concomitant medicinal products that decrease the plasma concentrations of nomegestrol acetate and/or estradiol (see section 4.5). Cycle control With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about 3 cycles. The percentage of women using Zoely experiencing intracyclic bleeding after this adaptation period ranged from 15-20 %. If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage. 11 The duration of the withdrawal bleeding in women using Zoely is on average 3-4 days. Users of Zoely may also miss their withdrawal bleeding although not being pregnant. During clinical trials, absence of withdrawal bleeding ranged over the cycles 1-12 from 18 % to 32 %. In such cases, absence of withdrawal bleeding was not associated with a higher occurrence of breakthrough bleeding/spotting in the subsequent cycles. 4.6 % of the women did not have a withdrawal bleeding in the first three cycles of use and the occurrences of absence of withdrawal bleeding in the later cycles of use were high in this subgroup, ranging from 76 % to 87 % of women. 28 % of the women experienced absence of withdrawal bleeding in at least one of the cycles 2, 3 and 4, associated with higher occurrences of absence of withdrawal bleeding in the later cycles of use, ranging from 51 % to 62 %. If absence of withdrawal bleeding occurs and Zoely has been taken according to the instructions as described in section 4.2, it is unlikely that the woman is pregnant. However, pregnancy must be ruled out before Zoely use is continued, if Zoely has not been taken as directed or if two consecutive withdrawal bleedings are missed. Paediatric population It is unknown whether the amount of estradiol in Zoely is sufficient to maintain adequate levels of estradiol in adolescents, especially for bone mass accrual (see section 5.2). Laboratory tests The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range. 4.5 Interaction with other medicinal products and other forms of interaction Interactions Note: The prescribing information of concomitant medications should be consulted to identify potential interactions. Influence of other medicinal products on Zoely Interactions between oral contraceptives and enzyme-inducing medicinal products may lead to breakthrough bleeding and/or contraceptive failure. Hepatic metabolism: Interactions can occur with substances that induce CYP450 enzymes, resulting in reduced concentrations of sex hormones and decreased effectiveness of combined oral contraceptives, including Zoely. These substances are represented mostly with anticonvulsants (e.g. carbamazepine, topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine, felbamate); anti-infective drugs (e.g. rifampicin, rifabutin, griseofulvin); St. John’s wort; bosentan and HIV or Hepatitis C virus (HCV) protease inhibitors (e.g. ritonavir, boceprevir, telaprevir) and non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz). Enzyme induction can occur after a few days of treatment. Maximal enzyme induction is generally observed within a few weeks. After drug therapy is discontinued, enzyme induction can last for about 28 days. A barrier contraceptive method should also be used during the concomitant use of an enzyme inducer, and for 28 days after its discontinuation. In case of long-term treatment with hepatic enzyme-inducing substances another method of contraception should be considered. If concomitant drug administration runs beyond the end of the active tablets in the current blister pack, the next blister pack should be started right away without the usual placebo tablet interval. 12 Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g. fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations of oestrogens or progestogens. Medicinal product interaction studies were not performed with Zoely, but two studies with rifampicin and ketoconazole, respectively, were performed with a higher dosed nomegestrol acetate-estradiol combination (nomegestrol acetate 3.75 mg + 1.5 mg estradiol) in post-menopausal women. Concomitant use of rifampicin decreases the AUC0-∞ of nomegestrol acetate by 95 % and increases the AUC0-tlast of estradiol by 25 %. Concomitant use of ketoconazole (200 mg single dose) does not modify estradiol metabolism whereas increases in the peak concentration (85 %) and AUC0-∞ (115 %) of nomegestrol acetate were observed, which were of no clinical relevance. Similar conclusions are expected in women of childbearing potential. Influence of Zoely on other medicinal products Contraceptives containing ethinylestradiol may decrease the concentrations of lamotrigine by approximately 50%. Attention should be paid, notably when introducing a combined contraceptive, even with estradiol, in a well-equilibrated woman given lamotrigine. Other interactions During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medications such as CHCs. Women using medications containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir. 4.6 Fertility, pregnancy and lactation Pregnancy Zoely is not indicated during pregnancy. If pregnancy occurs while taking Zoely, further intake should be stopped. Most epidemiological studies have revealed neither an increased risk of birth defects in infants born to women who used ethinylestradiol-containing COCs prior to pregnancy, nor a teratogenic effect when ethinylestradiol-containing COCs were taken inadvertently during early pregnancy. Clinical data on a limited number of exposed pregnancies indicate no adverse effect of Zoely on the foetus or neonate. In animal studies, reproductive toxicity has been observed with the nomegestrol acetate / estradiol combination (see preclinical safety data in section 5.3). The increased risk of VTE during the postpartum period should be considered when re-starting Zoely (see section 4.2 and 4.4). Breast-feeding Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the breast milk, but there is no evidence that this adversely affects infant health. Breastfeeding may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should not be recommended until the breast- feeding mother has completely weaned her child and an alternative contraceptive method should be proposed to women wishing to breastfeed. 13 Fertility Zoely is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1. 4.7 Effects on ability to drive and use machines Zoely has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Six multi-centre clinical trials of up to one year duration were used to evaluate safety of Zoely. In total 3,434 women, aged 18-50, were enrolled and completed 33,828 cycles. Tabulated list of adverse reactions Possibly related adverse reactions that have been reported in clinical trials or during postmarketing use with Zoely are listed in the table below. All adverse reactions are listed by system organ class and frequency; very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100) and rare ( 1/10,000 to < 1/1,000). System organ class Adverse reaction in MedDRA Term1 Very common Common Uncommon Rare Metabolism and nutrition disorders increased appetite, fluid retention decreased appetite Psychiatric disorders decreased libido, depression/ depressed mood, mood altered increased libido Nervous system disorders headache, migraine cerebrovascular accident, transient ischaemic attack, disturbance in attention Eye disorders contact lens intolerance/dry eye Vascular disorders hot flush venous thromboembolism Gastrointestinal disorders nausea abdominal distension dry mouth Hepatobiliary disorders cholelithiasis, cholecystitis Skin and subcutaneous tissue disorders acne hyperhydrosis, alopecia, pruritus, dry skin, seborrhea chloasma, hypertrichosis Musculoskeletal and connective tissue disorders sensation of heaviness 14 System organ class Adverse reaction in MedDRA Term1 Very common Common Uncommon Rare Reproductive system and breast disorders abnormal withdrawal bleeding metrorrhagia, menorrhagia, breast pain, pelvic pain hypomenorrhoea, breast swelling, galactorrhoea, uterine spasm, premenstrual syndrome, breast mass, dyspareunia, vulvovaginal dryness vaginal odour, vulvovaginal discomfort General disorders and administration site conditions irritability, oedema hunger Investigations weight increased hepatic enzyme increased 1The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well. In addition to the above mentioned adverse reactions, hypersensitivity reactions have been reported in Zoely users (frequency unknown). Description of selected adverse reactions An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Multiple doses up to five times the daily dose of Zoely and single doses up to 40 times the daily dose of nomegestrol acetate alone have been used in women without safety concern. On the basis of general experience with combined oral contraceptives, symptoms that may occur are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens and oestrogens, fixed combinations, ATC code: G03AA14. Mechanism of action Nomegestrol acetate is a highly selective progestogen derived from the naturally occurring steroid hormone, progesterone. Nomegestrol acetate has a strong affinity for the human progesterone receptor and has an anti-gonadotropic activity, a progesterone receptor-mediated anti-oestrogenic activity, a moderate anti-androgenic activity, and is devoid of any oestrogenic, androgenic, glucocorticoid or mineralocorticoid activity. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 15 The oestrogen contained in Zoely is 17β-estradiol, a natural oestrogen identical to the endogenous human 17β-estradiol. The contraceptive effect of Zoely is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion. Clinical efficacy and safety In two randomized, open-label, comparative efficacy-safety trials, more than 3,200 women have been treated for up to 13 consecutive cycles with Zoely and more than 1,000 women with drospirenone 3 mg – ethinylestradiol 30 μg (21/7 regimen). In the Zoely group, acne was reported by 15.4 % of the women (versus 7.9 % in the comparator group), weight increased was reported by 8.6 % of the women (versus 5.7 % in the comparator group), and abnormal withdrawal bleeding (predominantly absence of withdrawal bleeding) was reported by 10.5 % of the women (versus 0.5 % in the comparator group). In the clinical trial performed with Zoely in the European Union the following Pearl Indices for the age class 18-35 years were calculated: Method failure: 0.40 (upper limit 95 % confidence interval 1.03) Method and user failure: 0.38 (upper limit 95 % confidence interval 0.97) In the clinical trial performed with Zoely in the United States the following Pearl Indices for the age class 18-35 years were calculated: Method failure: 1.22 (upper limit 95 % confidence interval 2.18) Method and user failure: 1.16 (upper limit 95 % confidence interval 2.08) In a randomized, open label trial, 32 women were treated for 6 cycles with Zoely. After discontinuation of Zoely, return to ovulation in the first 28 days after last tablet intake was observed in 79 % of the women. Endometrial histology was investigated in a subgroup of women (n=32) in one clinical study after 13 cycles of treatment. There were no abnormal results. Paediatric population No data on efficacy and safety are available in adolescents below 18 years. Available pharmacokinetic data are described in section 5.2. 5.2 Pharmacokinetic properties Nomegestrol acetate Absorption Orally administered nomegestrol acetate is rapidly absorbed. Maximum plasma concentrations of nomegestrol acetate of about 7 ng/mL are reached at 2 h after single administration. The absolute bioavailability of nomegestrol acetate after a single dose is 63 %. No clinically relevant effect of food was observed on the bioavailability of nomegestrol acetate. Distribution Nomegestrol acetate is extensively bound to albumin (97-98 %), but does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). The apparent volume of distribution of nomegestrol acetate at steady-state is 1,645  576 L. Biotransformation Nomegestrol acetate is metabolized into several inactive hydroxylated metabolites by liver cytochrome P450 enzymes, mainly CYP3A4 and CYP3A5 with possible contribution of CYP2C19 and CYP2C8. Nomegestrol acetate and its hydroxylated metabolites undergo extensive phase 2 16 metabolism to form glucuronide- and sulphate conjugates. The apparent clearance at steady state is 26 L/h. Elimination The elimination half-life (t1/2) is 46 h (ranging from 28-83 h) at steady state. The elimination half-life of metabolites was not determined. Nomegestrol acetate is excreted via urine and faeces. Approximately 80 % of the dose is excreted in urine and faeces within 4 days. Excretion of nomegestrol acetate was nearly complete after 10 days and amounts excreted were higher in faeces than in urine. Linearity Dose-linearity was observed in the range 0.625-5 mg (assessed in fertile and post-menopausal women). Steady-state conditions The pharmacokinetics of nomegestrol acetate are not influenced by SHBG. Steady-state is achieved after 5 days. Maximum plasma concentrations of nomegestrol acetate of about 12 ng/mL are reached 1.5 h after dosing. Average steady state plasma concentrations are 4 ng/mL. Drug drug interactions Nomegestrol acetate causes in vitro no notable induction or inhibition of any cytochrome P450 enzymes and has no clinically relevant interaction with the P-gp transporter. Estradiol Absorption Estradiol is subject to a substantial first-pass effect after oral administration. The absolute bioavailability is about 1 %. No clinically relevant effect of food was observed on the bioavailability of estradiol. Distribution The distribution of exogenous and endogenous estradiol is similar. Oestrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37 %) and to albumin (61 %), while only approximately 1-2 % is unbound. Biotransformation Oral exogenous estradiol is extensively metabolized. The metabolism of exogenous and endogenous estradiol is similar. Estradiol is rapidly transformed in the gut and the liver in several metabolites, mainly estrone, which are subsequently conjugated and undergo entero-hepatic circulation. There is a dynamic equilibrium between estradiol, estrone and estrone-Sulfate due to various enzymatic activities including estradiol-dehydrogenases, sulfotransferases and aryl sulfatases. Oxidation of estrone and estradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4, CYP3A5, and CYP1B1 and CYP2C9. Elimination Estradiol is rapidly cleared from the circulation. Due to metabolism and enterohepatic circulation, a large circulating pool of oestrogen sulfates and glucuronides is present. This results in a highly variable baseline-corrected elimination half-life of estradiol, which is calculated to be 3.6 ± 1.5 h, after intravenous administration. Steady-state conditions Maximum serum concentrations of estradiol are about 90 pg/mL and are reached 6 h after dosing. Average serum concentrations are 50 pg/mL and these estradiol levels correspond with the early and late phase of a woman’s menstrual cycle. 17 Special populations Paediatric population The pharmacokinetics of nomegestrol acetate (primary objective) after single oral dosing of Zoely in healthy postmenarcheal female adolescents and adult subjects were similar. However, after single oral dosing, for the estradiol component (secondary objective), the exposure was 36 % lower in adolescents versus adult subjects. The clinical relevance of this result is unknown. Effect of renal impairment No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of Zoely. Effect of hepatic impairment No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Zoely. However, steroid hormones may be poorly metabolized in women with impaired liver function. Ethnic groups No formal studies were performed to assess pharmacokinetics in ethnic groups. 5.3 Preclinical safety data Repeat dose toxicity studies with estradiol, nomegestrol acetate or combination have indicated expected oestrogenic and gestagen effects. Reproductive toxicity studies performed with the combination have shown foetotoxicity which is consistent with estradiol exposure. Genotoxicity and carcinogenicity studies were not conducted with the combination. Nomegestrol acetate is not genotoxic. However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core (white active and yellow placebo film-coated tablets) Lactose monohydrate Microcrystalline cellulose (E460) Crospovidone (E1201) Talc (E553b) Magnesium stearate (E572) Colloidal anhydrous silica Tablet coat (white active film-coated tablets) Poly(vinyl alcohol) (E1203) Titanium dioxide (E171) Macrogol 3350 Talc (E553b) Tablet coating (yellow placebo film-coated tablets) Poly(vinyl alcohol) (E1203) Titanium dioxide (E171) Macrogol 3350 Talc (E553b) Iron oxide yellow (E172) Iron oxide black (E172) 18 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container PVC/aluminium blister containing 28 film-coated tablets (24 white film-coated tablets and 4 yellow film-coated tablets). Pack sizes: 28, 84, 168 and 364 film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal COC tablets (including Zoely tablets) no longer required should not be disposed via wastewater or the municipal sewage system. The hormonal active compounds in the tablet may have harmful effects if reaching the aquatic environment. The tablets should be returned to a pharmacy or disposed of in another safe way according to local requirements. These measures will help to protect the environment. 7. MARKETING AUTHORISATION HOLDER Theramex Ireland Limited 3rd Floor, Kilmore House, Park Lane, Spencer Dock, Dublin 1 D01 YE64 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/11/690/001 EU/1/11/690/002 EU/1/11/690/003 EU/1/11/690/004 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 27 July 2011 Date of latest renewal: 21 April 2016 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. 19 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 20 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Delpharm Lille S.A.S. Parc d’Activités Roubaix-Est 22 Rue de Toufflers CS 50070 59452 LYS-LEZ-LANNOY France Teva Operations Poland Sp. z o.o. ul. Mogilska 80 31-546 Krakow Poland N.V. Organon Kloosterstraat 6 5349 AB Oss The Netherlands Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency; 21  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.  Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date Non-interventional post-authorisation safety study (PASS): A prospective observational study to assess in particular the risk of Venous thromboembolic events (VTE) and ATE in nomegestrol/estradiol users compared with the VTE risk in users of combined oral contraceptives containing levonorgestrel. Submission of final study report 30 April 2021 22 ANNEX III LABELLING AND PACKAGE LEAFLET 23 A. LABELLING 24 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Zoely 2.5 mg/1.5 mg film-coated tablets nomegestrol acetate/estradiol 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each white active tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate). 3. LIST OF EXCIPIENTS Contains lactose monohydrate See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets 84 film-coated tablets 168 film-coated tablets 364 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 25 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Theramex Ireland Limited 3rd Floor, Kilmore House, Park Lane, Spencer Dock, Dublin 1 D01 YE64 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/11/690/001 28 film-coated tablets EU/1/11/690/002 84 film-coated tablets EU/1/11/690/003 168 film-coated tablets EU/1/11/690/004 364 film-coated tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE zoely 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 26 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Zoely 2.5 mg/1.5 mg tablets nomegestrol acetate/estradiol 2. NAME OF THE MARKETING AUTHORISATION HOLDER Theramex Ireland Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER [Box for placing day label stating:] Place day label here [Day numbering for each individual tablet:] Start,2, ….28 [Arrows indicating the sequence of the tablets:]  27 DAY LABEL SHEET INCLUDING STICKERS PROVIDED WITH THE LEAFLET Day label sheet Choose the day label that begins with your starting day. Place the label on the blister over the words ‘Place day label here’. SUN MON TUE WED THU FRI SAT MON TUE WED THU FRI SAT SUN TUE WED THU FRI SAT SUN MON WED THU FRI SAT SUN MON TUE THU FRI SAT SUN MON TUE WED FRI SAT SUN MON TUE WED THU SAT SUN MON TUE WED THU FRI [Second day label sheet for box of 3 blisters stating, twice:] SUN MON TUE WED THU FRI SAT MON TUE WED THU FRI SAT SUN TUE WED THU FRI SAT SUN MON WED THU FRI SAT SUN MON TUE THU FRI SAT SUN MON TUE WED FRI SAT SUN MON TUE WED THU SAT SUN MON TUE WED THU FRI [In front of day labels intended for second blister:] Blister 2 [In front of day labels intended for third blister:] Blister 3 28 B. PACKAGE LEAFLET 29 Package leaflet: Information for the user Zoely 2.5 mg/1.5 mg film-coated tablets nomegestrol acetate/estradiol This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Important things to know about combined hormonal contraceptives (CHCs):  They are one of the most reliable reversible methods of contraception if used correctly.  They slightly increase the risk of having a blood clot in the veins and arteries, especially in the first year or when restarting a combined hormonal contraceptive following a break of 4 or more weeks.  Please be alert and see your doctor if you think you may have symptoms of a blood clot (see section 2 “Blood clots”). Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them. - If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Zoely is and what it is used for 2. What you need to know before you use Zoely 3. How to use Zoely 4. Possible side effects 5. How to store Zoely 6. Contents of the pack and other information 1. What Zoely is and what it is used for Zoely is a contraceptive pill that is used to prevent pregnancy.  All 24 white film-coated tablets are active tablets that contain a small amount of two different female hormones. These are nomegestrol acetate (a progestogen) and estradiol (an oestrogen).  The 4 yellow tablets are inactive tablets that do not contain hormones and are called placebo tablets.  Contraceptive pills that contain two different hormones, like Zoely, are called ‘combined pills’.  Estradiol, the oestrogen in Zoely, is identical to the hormone produced by your ovaries during a menstrual cycle.  Nomegestrol acetate, the progestogen in Zoely, is derived from the hormone progesterone. Progesterone is produced by your ovaries during a menstrual cycle. 2. What you need to know before you use Zoely General notes Before you start using Zoely you should read the information on blood clots (thrombosis) in section 2. It is particularly important to read the symptoms of a blood clot – see section 2 “Blood clots”. 30 Before you can begin taking Zoely, your doctor will ask you some questions about your personal health history and that of your close relatives. The doctor will also measure your blood pressure and, depending upon your personal situation, may also carry out some other tests. In this leaflet, several situations are described where you should stop taking the pill, or where the reliability of the pill may be decreased. In such situations you should not have sexual intercourse or you should take extra non-hormonal contraceptive precautions, e.g., use a condom or another barrier method. Do not use rhythm or temperature methods. These methods can be unreliable because the pill alters the usual changes in temperature and cervical mucus that occur during the menstrual cycle. Zoely, like other hormonal contraceptives, does not protect against HIV infection (AIDS) or any other sexually transmitted disease. Do not use Zoely You must not use Zoely if you have any of the conditions listed below. If you do have any of the conditions listed below, you must tell your doctor. Your doctor will discuss with you what other form of birth control would be more appropriate.  if you have (or have ever had) a blood clot in a blood vessel of your legs (deep vein thrombosis, DVT), your lungs (pulmonary embolus, PE) or other organs;  if you know you have a disorder affecting your blood clotting - for instance, protein C deficiency, protein S deficiency, antithrombin – III deficiency, Factor V Leiden or antiphospholipid antibodies;  if you need an operation or if you are off your feet for a long time (see section ‘Blood clots);  if you have ever had a heart attack or a stroke;  if you have (or have ever had) angina pectoris (a condition that causes severe chest pain and may be a first sign of a heart attack) or transient ischaemic attack (TIA – temporary stroke symptoms);  if you have any of the following diseases that may increase your risk of a clot in the arteries: – severe diabetes with blood vessel damage – very high blood pressure – a very high level of fat in the blood (cholesterol or triglycerides); – a condition known as hyperhomocysteinaemia  if you have (or have ever had) a type of migraine called ‘migraine with aura’;  if you have (had) inflammation of the pancreas (pancreatitis) associated with high levels of fat in your blood;  if you have (had) severe liver disease and your liver is not yet working normally;  if you have (had) a benign or malignant tumour in the liver;  if you have (had), or if you may have, cancer of the breast or the genital organs;  in case of presence or history of meningioma (generally benign tumour of the tissue located between the brain and the skull). In case of doubt, contact your doctor.  if you have any unexplained bleeding from the vagina;  if you are allergic to estradiol or nomegestrol acetate, or any of the other ingredients of this medicine (listed in section 6). If any of these conditions appear for the first time while using Zoely, stop taking it at once and tell your doctor. In the meantime, use a non-hormonal contraceptive. See also ‘General Notes’ in section 2 above. 31 When to take special care with Zoely When should you contact your doctor? Seek urgent medical attention  if you notice possible signs of a blood clot that may mean you are suffering from a blood clot in the leg (i.e., deep vein thrombosis), a blood clot in the lung (i.e., pulmonary embolism), a heart attack or a stroke (see “Blood clots” section below). For a description of the symptoms of these serious side effects please go to “How to recognise a blood clot”.  if you notice any changes in your own health, especially involving any of the items mentioned in this leaflet (see also in section 2 ‘Do not use Zoely’; do not forget about the changes in the health of your immediate family);  if you feel a lump in your breast;  if you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives together with difficulty breathing;  if you are going to use other medicines (see also in section 2 ‘Other medicines and Zoely’);  if you are to be immobilised or are to have surgery (tell your doctor at least four weeks in advance);  if you have unusual, heavy vaginal bleeding;  if you forgot one or more tablets in the first week of the blister pack and had unprotected intercourse in the seven days before (see also in section 3 ‘If you forget to take Zoely’);  if you have severe diarrhoea or experience severe vomiting;  if you miss periods and suspect you may be pregnant (do not start the next blister pack until your doctor tells you, see also in section 3 ‘If you have missed one or more periods’). Tell your doctor if any of the following conditions apply to you. If the condition develops, or gets worse while you are using Zoely, you should also tell your doctor.  if you have hereditary angioedema. Consult your doctor immediately if you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing. Products containing oestrogens may induce or worsen symptoms of angioedema;  if a close relative has or has ever had breast cancer;  if you have epilepsy (see in section 2 ‘Other medicines and Zoely’);  if you have liver disease (for instance jaundice) or gallbladder disease (for instance gallstones);  if you have diabetes;  if you have depression;  if you have Crohn’s disease or ulcerative colitis (chronic inflammatory bowel disease);  if you have systemic lupus erythematosus (SLE - a disease affecting your natural defence system);  if you have haemolytic uraemic syndrome (HUS - a disorder of blood clotting causing failure of the kidneys);  if you have sickle cell anaemia (an inherited disease of the red blood cells);  if you have elevated levels of fat in the blood (hypertriglyceridaemia) or a positive family history for this condition. Hypertriglyceridaemia has been associated with an increased risk of developing pancreatitis (inflammation of the pancreas);  if you need an operation or if you are off your feet for a long time (see in section 2 ‘Blood clots).  if you have just given birth you are at an increased risk of blood clots. You should ask your doctor how soon after delivery you can start taking Zoely.  if you have an inflammation in the veins under the skin (superficial thrombophlebitis);  if you have varicose veins.  if you have a condition that occurred for the first time or worsened during pregnancy or previous use of sex hormones (e.g. hearing loss, porphyria [a disease of the blood], herpes 32 gestationis [skin rash with vesicles during pregnancy], Sydenham’s chorea [a disease of the nerves in which sudden movements of the body occur] (see in section 2 ‘When should you contact your doctor’);  if you have (or have ever had) chloasma [yellowish-brown pigment patches, so called ‘pregnancy patches’, particularly on the face]. If so, avoid too much exposure to the sun or ultraviolet light; BLOOD CLOTS Using a combined hormonal contraceptive such as Zoely increases your risk of developing a blood clot compared with not using one. In rare cases a blood clot can block blood vessels and cause serious problems. Blood clots can develop  in veins (referred to as ‘venous thrombosis’, ‘venous thromboembolism’ or VTE)  in the arteries (referred to as an ‘arterial thrombosis’, ‘arterial thromboembolism’ or ATE). Recovery from blood clots is not always complete. Rarely, there may be serious lasting effects or, very rarely, they may be fatal. It is important to remember that the overall risk of a harmful blood clot due to Zoely is small. HOW TO RECOGNISE A BLOOD CLOT Seek urgent medical attention if you notice any of the following signs or symptoms. Are you experiencing any of these signs? What are you possibly suffering from?  swelling of one leg or along a vein in the leg or foot especially when accompanied by:  pain or tenderness in the leg which may be felt only when standing or walking  increased warmth in the affected leg  change in colour of the skin on the leg e.g. turning pale, red or blue Deep vein thrombosis  sudden unexplained breathlessness or rapid breathing;  sudden cough without an obvious cause, which may bring up blood;  sharp chest pain which may increase with deep breathing;  severe light headedness or dizziness;  rapid or irregular heartbeat;  severe pain in your stomach; If you are unsure, talk to a doctor as some of these symptoms such as coughing or being short of breath may be mistaken for a milder condition such as a respiratory tract infection (e.g., a ‘common cold’). Pulmonary embolism Symptoms most commonly occur in one eye:  immediate loss of vision or  painless blurring of vision which can progress to loss of vision Retinal vein thrombosis (blood clot in the eye) 33  chest pain, discomfort, pressure, heaviness  sensation of squeezing or fullness in the chest, arm or below the breastbone;  fullness, indigestion or choking feeling;  upper body discomfort radiating to the back, jaw, throat, arm and stomach;  sweating, nausea, vomiting or dizziness;  extreme weakness, anxiety, or shortness of breath;  rapid or irregular heartbeats Heart attack  sudden weakness or numbness of the face, arm or leg, especially on one side of the body;  sudden confusion, trouble speaking or understanding;  sudden trouble seeing in one or both eyes;  sudden trouble walking, dizziness, loss of balance or coordination;  sudden, severe or prolonged headache with no known cause;  loss of consciousness or fainting with or without seizure. Sometimes the symptoms of stroke can be brief with an almost immediate and full recovery, but you should still seek urgent medical attention as you may be at risk of another stroke. Stroke  swelling and slight blue discolouration of an extremity;  severe pain in your stomach (acute abdomen). Blood clots blocking other blood vessels BLOOD CLOTS IN A VEIN What can happen if a blood clot forms in a vein?  The use of combined hormonal contraceptives has been connected with an increase in the risk of blood clots in the vein (venous thrombosis). However, these side effects are rare. Most frequently, they occur in the first year of use of a combined hormonal contraceptive.  If a blood clot forms in a vein in the leg or foot it can cause a deep vein thrombosis (DVT).  If a blood clot travels from the leg and lodges in the lung it can cause a pulmonary embolism.  Very rarely a clot may form in a vein in another organ such as the eye (retinal vein thrombosis). When is the risk of developing a blood clot in a vein highest? The risk of developing a blood clot in a vein is highest during the first year of taking a combined hormonal contraceptive for the first time. The risk may also be higher if you restart taking a combined hormonal contraceptive (the same product or a different product) after a break of 4 weeks or more. After the first year, the risk gets smaller but is always slightly higher than if you were not using a combined hormonal contraceptive. When you stop Zoely your risk of a blood clot returns to normal within a few weeks. What is the risk of developing a blood clot? The risk depends on your natural risk of VTE and the type of combined hormonal contraceptive you are taking. The overall risk of a blood clot in the leg or lung (DVT or PE) with Zoely is small.  Out of 10,000 women who are not using any combined hormonal contraceptive and are not pregnant, about 2 will develop a blood clot in a year.  Out of 10,000 women who are using a combined hormonal contraceptive that contains levonorgestrel, norethisterone, or norgestimate, about 5-7 will develop a blood clot in a year. 34  It is not yet known how the risk of a blood clot with Zoely compares to the risk with a combined hormonal contraceptive that contains levonorgestrel.  The risk of having a blood clot will vary according to your personal medical history (see “Factors that increase your risk of a blood clot” below). Risk of developing a blood clot in a year Women who are not using a combined hormonal pill and are not pregnant About 2 out of 10,000 women Women using a combined hormonal contraceptive pill containing levonorgestrel, norethisterone or norgestimate About 5-7 out of 10,000 women Women using Zoely Not yet known Factors that increase your risk of a blood clot in a vein The risk of a blood clot with Zoely is small but some conditions will increase the risk. Your risk is higher:  if you are very overweight (body mass index or BMI over 30 kg/m2);  if one of your immediate family has had a blood clot in the leg, lung or other organ at a young age (e.g., below the age of about 50). In this case you could have a hereditary blood clotting disorder;  if you need to have an operation, or if you are off your feet for a long time because of an injury or illness, or you have your leg in a cast. The use of Zoely may need to be stopped several weeks before surgery or while you are less mobile. If you need to stop Zoely ask your doctor when you can start using it again.  as you get older (particularly above about 35 years);  if you gave birth less than a few weeks ago The risk of developing a blood clot increases the more conditions you have. Air travel (> 4 hours) may temporarily increase your risk of a blood clot, particularly if you have some of the other factors listed. It is important to tell your doctor if any of these conditions apply to you, even if you are unsure. Your doctor may decide that Zoely needs to be stopped. If any of the above conditions change while you are using Zoely, for example a close family member experiences a thrombosis for no known reason or you gain a lot of weight, tell your doctor. BLOOD CLOTS IN AN ARTERY What can happen if a blood clot forms in an artery? Like a blood clot in a vein, a clot in an artery can cause serious problems. For example, it can cause a heart attack or a stroke. Factors that increase your risk of a blood clot in an artery It is important to note that the risk of a heart attack or stroke from using Zoely is very small but can increase:  with increasing age (beyond about 35 years);  if you smoke. When using a combined hormonal contraceptive like Zoely you are advised to stop smoking. If you are unable to stop smoking and are older than 35 your doctor may advise you to use a different type of contraceptive;  if you are overweight;  if you have high blood pressure;  if a member of your immediate family has had a heart attack or stroke at a young age (less than about 50). In this case you could also have a higher risk of having a heart attack or stroke; 35  if you, or someone in your immediate family, have a high level of fat in the blood (cholesterol or triglycerides);  if you get migraines, especially migraines with aura;  if you have a problem with your heart (valve disorder, disturbance of the rhythm called atrial fibrillation)  if you have diabetes. If you have more than one of these conditions or if any of them are particularly severe, the risk of developing a blood clot may be increased even more. If any of the above conditions change while you are using Zoely, for example, you start smoking, a close family member experiences a thrombosis for no known reason or you gain a lot of weight, tell your doctor. Cancer Breast cancer has been found slightly more often in women using combined pills, but it is not known whether this is caused by the combined pills. For example, it may be that tumours are found more in women on combined pills because they are examined by the doctor more often. After stopping the combined pill, the increased risk gradually reduces. It is important to check your breasts regularly and you should contact your doctor if you feel any lump. You should also tell your doctor if a close relative has, or ever had breast cancer (see section 2 “When to take special care with Zoely”). In rare cases, benign (noncancerous) liver tumours, and in even fewer cases malignant (cancerous) liver tumours have been reported in pill users. Contact your doctor if you have unusual severe abdominal pain. Cervical cancer is caused by an infection with the human papilloma virus (HPV). It has been reported to occur more often in women using the pill for more than 5 years. It is unknown if this finding is due to the use of hormonal contraceptives or to other factors, such as difference in sexual behaviour. Meningiomas Cases of meningioma (generally benign tumours of the brain) have been reported with prolonged use (several years) of nomegestrol monotherapy (without estradiol) at higher doses of 3.75 and 5 mg and more (see section ‘Do not use Zoely’). If a meningioma is diagnosed, treatment with Zoely should be stopped. Psychiatric disorders Some women using hormonal contraceptives including Zoely have reported depression or depressed mood. Depression can be serious and may sometimes lead to suicidal thoughts. If you experience mood changes and depressive symptoms contact your doctor for further medical advice as soon as possible. Laboratory tests If you are having any blood or urinary test, tell your doctor that you are using Zoely as it may affect the results of some tests. Children and adolescents No data on efficacy and safety are available in adolescents below 18 years. Other medicines and Zoely Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription and herbal medicines. Also tell any other doctor or dentist who prescribes another medicine (or the dispensing pharmacist) that you use Zoely.  There are medicines that can make Zoely less effective in preventing pregnancy, or can cause unexpected bleeding. These include medicines used to treat: 36 – epilepsy (e.g. primidone, phenytoin, phenobarbital, carbamazepine, oxcarbazepine, topiramate, felbamate); – tuberculosis (e.g. rifampicin); – HIV infections (e.g. rifabutin, ritonavir, efavirenz); – Hepatitis C virus (HCV) infection (e.g. boceprevir, telaprevir); – other infectious diseases (e.g. griseofulvin); – high blood pressure in the blood vessels in the lungs (bosentan).  The herbal product St. John’s wort may also stop Zoely from working properly. If you want to use herbal products containing St. John’s wort while you are already using Zoely you should consult your doctor first.  If you are taking medicines or herbal products that might make Zoely less effective, a barrier contraceptive method should also be used. Since the effect of another medicine on Zoely may last up to 28 days after stopping the medicine, it is necessary to use the additional barrier contraceptive method for that long.  Some medicines can increase the levels of the active substances of Zoely in the blood. The effectiveness of the pill is maintained, but tell your doctor if you are using anti-fungal medicines containing ketoconazole.  Zoely may also interfere with the working of other medicines – such as the anti-epileptic lamotrigine.  The Hepatitis C virus (HCV) combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir may cause increases in liver function blood test results (increase in ALT liver enzyme) in women using CHCs containing ethinylestradiol. Zoely contains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using Zoely with this HCV combination drug regimen. Your doctor will advise you. Pregnancy and breast-feeding Zoely must not be used by women who are pregnant, or who think they may be pregnant. If you get pregnant while using Zoely you should stop using Zoely and contact your doctor. If you want to stop Zoely because you want to get pregnant, see in section 3 ‘If you stop taking Zoely’. Zoely is not usually recommended for use during breast-feeding. If you wish to use the pill while breast-feeding, please seek the advice of your doctor. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Zoely has no or negligible effect on your ability to drive and use machines. Zoely contains lactose Zoely contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. 3. How to use Zoely When and how to take the tablets The Zoely blister contains 28 tablets: 24 white tablets with the active substances (number 1-24) and 4 yellow tablets without active substances (number 25-28). Each time you start a new blister of Zoely, take the number 1 white active tablet in the left-hand top corner (see ‘Start’). Choose from the 7 stickers with day indicators the one in the grey column that begins with your starting day. For example, if you start on a Wednesday, use the day label sticker that starts with ‘WED’. Stick it on the blister, just above the row of white active tablets where it reads ‘Place day label here’. This allows you to check whether you took your daily tablet. Take one tablet each day at about the same time, with some water if necessary. Follow the direction of the arrows on the blister, so use the white active tablets first and then the yellow placebo tablets. 37 Your period will start during the 4 days that you use the yellow placebo tablets (so-called withdrawal bleeding). Usually it will start 2-3 days after the last white active tablet and may not have finished before the next blister is started. Start taking your next blister immediately after the last yellow tablet, even if your period hasn’t finished. This means that you will always start a new blister on the same day of the week, and also that you have your period on roughly the same days each month. Some users may not have their period every month during the intake of the yellow tablets. If you have taken Zoely every day according to these directions, it is unlikely that you are pregnant (see also section 3 ‘If you have missed one or more periods’). Starting your first pack of Zoely When no hormonal contraceptive has been used in the past month Start taking Zoely on the first day of your cycle (i.e. the first day of your menstrual bleeding). Zoely will work immediately. You do not need to use an additional contraceptive method. When changing from another combined hormonal contraceptive (combined pill, vaginal ring, or transdermal patch) You can start taking Zoely the day after you have taken the last tablet from your present pill blister (this means no tablet-free break). If your present pill blister also contains inactive (placebo) tablets you can start Zoely on the day after taking the last active tablet (if you are not sure which this is, ask your doctor or pharmacist). You can also start later, but never later than the day following the tablet-free break of your present pill (or the day after the last inactive tablet of your present pill). In case you use a vaginal ring or transdermal patch, it is best to start using Zoely on the day you remove the ring or patch. You can also start, at the latest, on the day you would have started using the next ring or patch. If you follow these instructions, it is not necessary to use an additional contraceptive method. When changing from a progestogen-only pill (minipill) You can stop taking the minipill any day and start taking Zoely the next day. But if you are having intercourse, make sure you also use a barrier method of contraception for the first 7 days that you are taking Zoely. When changing from a progestogen-only injectable, implant or a hormone-medicated intrauterine system (IUS) Start using Zoely when your next injection is due or on the day that your implant or IUS is removed. But if you are having intercourse, make sure you also use a barrier method of contraception for the first 7 days that you are taking Zoely. After having a baby You can start Zoely between 21 and 28 days after having a baby. If you start later than day 28, you should also use a barrier method of contraception during the first 7 days of Zoely use. If, after having a baby, you have had sexual intercourse before starting Zoely, be sure that you are not pregnant or wait until the next menstrual period. If you want to start Zoely after having a baby and are breast-feeding, see also section 2 ‘Pregnancy and Breast-feeding’. Ask your doctor what to do if you are not sure when to start. After a miscarriage or an abortion Follow the advice of your doctor. If you take more Zoely than you should There have been no reports of serious harmful effects from taking too many Zoely tablets at one time. If you have taken several tablets at a time, you may have nausea, vomiting or vaginal bleeding. If you discover that a child has taken Zoely, ask your doctor for advice. 38 If you forget to take Zoely The following advice only refers to missed white active tablets.  if you are less than 24 hours late in taking a tablet, the reliability of the pill is maintained. Take the tablet as soon as you remember and take the next tablets at the usual time.  if you are 24 or more hours late in taking any tablet, the reliability of the pill may be reduced. The more consecutive tablets you have missed, the higher the risk that the contraceptive efficacy is decreased. There is a particularly high risk of becoming pregnant if you miss white active tablets at the beginning or at the end of the blister. Therefore you should follow the rules given below. Day 1-7 of white active tablet intake (see picture and schedule) Take the last white active missed tablet as soon as you remember (even if this means taking two tablets at the same time) and take the next tablet at the usual time. However, use a barrier method such as a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row. If you had sexual intercourse in the week before missing the tablets, there is a possibility of becoming or being pregnant. So contact your doctor immediately. Day 8-17 of white active tablet intake (see picture and schedule) Take the last missed tablet as soon as you remember (even if this means taking two tablets at the same time) and take the next tablets at the usual time. If you have taken your tablets correctly in the 7 days prior to the missed tablet, the protection against pregnancy is not reduced, and you do not need to use extra precautions. However, if you have missed more than 1 tablet, use a barrier method such as a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row. Day 18-24 of white active tablet intake (see picture and schedule) There is a particularly high risk of becoming pregnant if you miss white active tablets close to the yellow placebo tablet interval. By adjusting your intake schedule this higher risk can be prevented. The following two options can be followed. You do not need to use extra precautions if you have taken your tablets correctly in the 7 days prior to the missed tablet. If this is not the case, you should follow the first of these two options and use a barrier method such as a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row. Option 1) Take the last missed white active tablet as soon as you remember (even if this means taking two tablets at the same time) and take the next tablets at the usual time. Start the next blister as soon as the white active tablets in the current blister are finished, so skip the yellow placebo tablets. You may not have your period until you take the yellow placebo tablets at the end of the second blister, but you may have spotting (drops or flecks of blood) or breakthrough bleeding while taking the white active tablets. Option 2) Stop taking the white active tablets and start taking the yellow placebo tablets for a maximum of 3 days so that the total number of placebo plus missed white active tablets is not more than 4. At the end of the placebo tablet interval, start the next blister. If you cannot remember how many white active tablets you have missed, follow the first option, use a barrier method such as a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row, and contact your doctor (as you may not have been protected from being pregnant). If you have forgotten to take white active tablets in a blister, and you do not have the expected monthly period while taking the yellow placebo tablets from the same blister, you may be pregnant. Consult your doctor before you start with the next blister. Yellow placebo tablets missed The last 4 yellow tablets of the fourth row are placebo tablets which do not contain active substances. If you forgot to take one of these tablets the reliability of Zoely is maintained. Throw away the yellow placebo tablet(s) you missed and continue taking the next tablets at the usual time. 39 Picture Schedule: if you are 24 or more hours late taking white tablets If you vomit or have severe diarrhoea If you vomit within 3-4 hours of taking a white active tablet, or you have severe diarrhoea, the active ingredients of your Zoely tablet may not have been completely absorbed into your body. The situation is similar to if you forget a white active tablet. After vomiting or diarrhoea, you must take another white active tablet from a reserve blister as soon as possible. If possible take it within 24 hours of when you normally take your pill. Take the next tablet at the usual time. If this is not possible or 24 or more hours have passed, you should follow the advice given under "If you forget to take Zoely". If you have severe diarrhoea, please tell your doctor. The yellow tablets are placebo tablets which do not contain active substances. If you vomit or have severe diarrhoea within 3-4 hours of taking a yellow tablet, the reliability of Zoely is maintained. If you want to delay your period You can delay your period by not taking the yellow placebo tablets and going straight to a new blister of Zoely. You may experience light or menstruation-like bleeding while using this second blister. When you wish your period to begin during the second blister, stop taking the white active tablets and start taking the yellow placebo tablets. After finishing the 4 yellow placebo tablets from the second blister, start with the next (third) blister. 40 If you want to change the starting day of your period If you take the tablets according to the instructions, then your period will begin during the placebo days. If you have to change this day, reduce the number of placebo days – when you take the yellow placebo tablets – (but never increase them – 4 is the maximum). For example, if you start taking the placebo tablets on Friday, and you want to change this to a Tuesday (3 days earlier) you must start a new blister 3 days earlier than usual. You may not have any bleeding during the shortened period of yellow placebo tablet intake. While using the next blister you may have some spotting (drops or flecks of blood) or breakthrough bleeding on white active tablet-taking days. If you are not sure what to do, consult your doctor. If you have unexpected bleeding With all combined pills, for the first few months, you can have some irregular vaginal bleeding (spotting or breakthrough bleeding) between your periods. You may need to use sanitary protection, but keep taking your tablets as usual. Irregular vaginal bleeding usually stops once your body has adjusted to the pill (usually after about 3 months). If bleeding continues, becomes heavy or starts again, contact your doctor. If you have missed one or more periods Clinical trials with Zoely have shown that you may occasionally miss your regular monthly period after Day 24.  If you have taken all the tablets correctly, and you have not vomited or had severe diarrhoea, or used other medicines, then it is very unlikely that you are pregnant. Keep taking Zoely as usual. See also in section 3 ‘If you vomit or have severe diarrhoea’ or in section 2 ‘Other medicines and Zoely’.  If you have not taken all the tablets correctly, or if your expected period does not happen twice in a row, you may be pregnant. Contact your doctor immediately. Do not start the next blister of Zoely until your doctor has checked that you are not pregnant. If you stop taking Zoely You can stop taking Zoely at any time. If you do not want to become pregnant, first ask your doctor about other methods of birth control. If you stop taking Zoely because you want to get pregnant, you are recommended to wait until you have had a natural period before trying to conceive. This will help you to determine when the baby will be due. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. If you get any side effect, particularly if severe or persistent, or have any change to your health that you think may be due to Zoely, please talk to your doctor. An increased risk of blood clots in your veins (venous thromboembolism (VTE)) or blood clots in your arteries (arterial thromboembolism (ATE)) is present for all women taking combined hormonal contraceptives. For more detailed information on the different risks from taking combined hormonal contraceptives, please see section 2, “What you need to know before you use Zoely”. The following side effects have been linked with the use of Zoely: Very common (may affect more than 1 in 10 people):  acne  changes to menstrual periods (e.g. absence or irregularity) Common (may affect up to 1 in 10 people):  decreased interest in sex; depression/depressed mood; mood changes  headache or migraine 41  feeling sick (nausea)  heavy menstrual periods; breast pain; pelvic pain  weight gain Uncommon (may affect up to 1 in 100 people):  increased appetite; fluid retention (oedema)  hot flush  swollen abdomen  increased sweating; hair loss; itching; dry skin; oily skin  heaviness in limbs  regular but scanty periods; larger breasts; breast lump; milk production while not pregnant; premenstrual syndrome; pain during intercourse; dryness in the vagina or vulva; spasm of the uterus  irritability  increased liver enzymes Rare (may affect up to 1 in 1,000 people):  harmful blood clots in a vein or artery, for example: o in a leg or foot (i.e., DVT) o in a lung (i.e., PE) o heart attack o stroke o mini-stroke or temporary stroke-like symptoms known as a transient ischaemic attack (TIA) o blood clots in the liver, stomach/intestine, kidneys or eye. The chance of having a blood clot may be higher if you have any other conditions that increase this risk. (See section 2 for more information on the conditions that increase risk for blood clots and the symptoms of a blood clot.)  decreased appetite  increased interest in sex  disturbance in attention  dry eye; contact lens intolerance  dry mouth  golden brown pigment patches, mostly in the face; excessive hair growth  vaginal smell; discomfort in the vagina or vulva  hunger  disease of the gallbladder Allergic (hypersensitive) reactions have been reported in users of Zoely, but the frequency cannot be estimated from the available data. Further information on the possible side effect changes to menstrual periods (e.g. absence or irregular) during the use of Zoely is described in section 3 ‘When and how to take the tablets’, ‘If you have unexpected bleeding’ and ‘If you have missed one or more periods’). Reporting of side effects If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Zoely Keep this medicine out of the sight and reach of children. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2009/10/WC500004368.pdf 42 Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Combined pills (including Zoely tablets) no longer required should not be disposed via wastewater or the municipal sewage system. The hormonal active ingredients in the tablet may have harmful effects if they reach the aquatic environment. Return them to a pharmacy or dispose them in another safe way according to local requirements. These measures will help to protect the environment. 6. Contents of the pack and other information What Zoely contains - The active substances are: nomegestrol acetate and estradiol White active film-coated tablets: Each tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate). Yellow placebo film-coated tablets: The tablet does not contain active substances. - The other ingredients are: Tablet core (white active and yellow placebo film-coated tablets): Lactose monohydrate (see section 2 ‘Zoely contains lactose’), microcrystalline cellulose (E460), crospovidone (E1201), talc (E553b), magnesium stearate (E572) and colloidal anhydrous silica Tablet coat (white active film-coated tablets): Poly(vinyl alcohol) (E1203), titanium dioxide (E171), macrogol 3350 and talc (E553b) Tablet coat (yellow placebo film-coated tablets): Poly(vinyl alcohol) (E1203), titanium dioxide (E171), macrogol 3350, talc (E553b), iron oxide yellow (E172) and iron oxide black (E172) What Zoely looks like and contents of the pack The active film-coated tablets (tablets) are white and round. They are coded ‘ne’ on both sides. The placebo film-coated tablets are yellow and round. They are coded ‘p’ on both sides. Zoely comes in blisters of 28 film-coated tablets (24 white active film-coated tablets and 4 yellow placebo film-coated tablets) packed in a ply carton. Pack sizes: 28, 84, 168 and 364 film-coated tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder Theramex Ireland Limited 3rd Floor, Kilmore House, Park Lane, Spencer Dock, Dublin 1 D01 YE64 Ireland Manufacturer Delpharm Lille S.A.S. Parc d’Activités Roubaix-Est 22 Rue de Toufflers CS 50070 59452 LYS-LEZ-LANNOY France Teva Operations Poland Sp. z o.o. ul. Mogilska 80 31-546 Krakow 43 Poland N.V. Organon Kloosterstraat 6 5349 AB Oss The Netherlands Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands This leaflet was last revised in. Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. if you get any side effect, particularly if severe or persistent, or have any change to your health that you think may be due to zoely, please talk to your doctor. an increased risk of blood clots in your veins (venous thromboembolism (vte)) or blood clots in your arteries (arterial thromboembolism (ate)) is present for all women taking combined hormonal contraceptives. for more detailed information on the different risks from taking combined hormonal contraceptives, please see section 2, "what you need to know before you use zoely". the following side effects have been linked with the use of zoely: very common (may affect more than 1 in 10 people): acne changes to menstrual periods (e.g. absence or irregularity) common (may affect up to 1 in 10 people): decreased interest in sex; depression/depressed mood; mood changes headache or migraine 41 feeling sick (nausea) heavy menstrual periods; breast pain; pelvic pain weight gain uncommon (may affect up to 1 in 100 people): increased appetite; fluid retention (oedema) hot flush swollen abdomen increased sweating; hair loss; itching; dry skin; oily skin heaviness in limbs regular but scanty periods; larger breasts; breast lump; milk production while not pregnant; premenstrual syndrome; pain during intercourse; dryness in the vagina or vulva; spasm of the uterus irritability increased liver enzymes rare (may affect up to 1 in 1,000 people): harmful blood clots in a vein or artery, for example: o in a leg or foot (i.e., dvt) o in a lung (i.e., pe) o heart attack o stroke o mini-stroke or temporary stroke-like symptoms known as a transient ischaemic attack (tia) o blood clots in the liver, stomach/intestine, kidneys or eye. the chance of having a blood clot may be higher if you have any other conditions that increase this risk. (see section 2 for more information on the conditions that increase risk for blood clots and the symptoms of a blood clot.) decreased appetite increased interest in sex disturbance in attention dry eye; contact lens intolerance dry mouth golden brown pigment patches, mostly in the face; excessive hair growth vaginal smell; discomfort in the vagina or vulva hunger disease of the gallbladder allergic (hypersensitive) reactions have been reported in users of zoely, but the frequency cannot be estimated from the available data. further information on the possible side effect changes to menstrual periods (e.g. absence or irregular) during the use of zoely is described in section 3 \'when and how to take the tablets\', \'if you have unexpected bleeding\' and \'if you have missed one or more periods\'). reporting of side effects if you get any side effects talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 25, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9638739824295044, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6608428359031677}]}, {'Id': 26, 'BeginOffset': 107, 'EndOffset': 118, 'Score': 0.953026533126831, 'Text': 'side effect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7657597064971924}], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.6739284992218018, 'RelationshipScore': 0.9940265417098999, 'RelationshipType': 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'oily skin heaviness in limbs', 'Type': 'PROBLEM', 'BeginOffset': 1198, 'EndOffset': 1226}, {'Text': 'scanty periods', 'Type': 'PROBLEM', 'BeginOffset': 1239, 'EndOffset': 1253}, {'Text': 'larger breasts', 'Type': 'PROBLEM', 'BeginOffset': 1255, 'EndOffset': 1269}, {'Id': 62, 'BeginOffset': 1271, 'EndOffset': 1282, 'Score': 0.8482788801193237, 'Text': 'breast lump', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8815745115280151}]}, {'Id': 63, 'BeginOffset': 1284, 'EndOffset': 1299, 'Score': 0.4695127606391907, 'Text': 'milk production', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7217336893081665}]}, {'Id': 64, 'BeginOffset': 1310, 'EndOffset': 1318, 'Score': 0.9875698685646057, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5059759616851807}, {'Name': 'DIAGNOSIS', 'Score': 0.49425217509269714}, {'Name': 'NEGATION', 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'stroke-like symptoms', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7151503562927246}]}, {'Text': 'a transient ischaemic attack (tia)', 'Type': 'PROBLEM', 'BeginOffset': 1689, 'EndOffset': 1723}, {'Text': 'blood clots in the liver, stomach/intestine, kidneys or eye', 'Type': 'PROBLEM', 'BeginOffset': 1726, 'EndOffset': 1785}, {'Text': 'a blood clot', 'Type': 'PROBLEM', 'BeginOffset': 1808, 'EndOffset': 1820}, {'Text': 'any other conditions', 'Type': 'PROBLEM', 'BeginOffset': 1847, 'EndOffset': 1867}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 1906, 'EndOffset': 1907}, {'Id': 91, 'BeginOffset': 1970, 'EndOffset': 1981, 'Score': 0.9674990773200989, 'Text': 'blood clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.4640992283821106}]}, {'Text': 'the symptoms', 'Type': 'PROBLEM', 'BeginOffset': 1986, 'EndOffset': 1998}, {'Text': 'a blood clot', 'Type': 'PROBLEM', 'BeginOffset': 2002, 'EndOffset': 2014}, {'Id': 93, 'BeginOffset': 2017, 'EndOffset': 2035, 'Score': 0.8833324313163757, 'Text': 'decreased appetite', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8968445062637329}]}, {'Id': 94, 'BeginOffset': 2046, 'EndOffset': 2073, 'Score': 0.8733799457550049, 'Text': 'interest in sex disturbance', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6856048703193665}]}, {'Text': 'attention dry eye', 'Type': 'PROBLEM', 'BeginOffset': 2077, 'EndOffset': 2094}, {'Id': 96, 'BeginOffset': 2096, 'EndOffset': 2120, 'Score': 0.7204893231391907, 'Text': 'contact lens intolerance', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8705934286117554}]}, {'Id': 97, 'BeginOffset': 2121, 'EndOffset': 2130, 'Score': 0.36732736229896545, 'Text': 'dry mouth', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7689099311828613}]}, {'Text': 'golden brown pigment patches', 'Type': 'PROBLEM', 'BeginOffset': 2131, 'EndOffset': 2159}, {'Id': 85, 'BeginOffset': 2175, 'EndOffset': 2179, 'Score': 0.9913578033447266, 'Text': 'face', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'excessive hair growth vaginal smell', 'Type': 'PROBLEM', 'BeginOffset': 2181, 'EndOffset': 2216}, {'Text': 'discomfort in the vagina', 'Type': 'PROBLEM', 'BeginOffset': 2218, 'EndOffset': 2242}, {'Text': 'vulva hunger disease', 'Type': 'PROBLEM', 'BeginOffset': 2246, 'EndOffset': 2266}, {'Text': 'the gallbladder allergic (hypersensitive) reactions', 'Type': 'PROBLEM', 'BeginOffset': 2270, 'EndOffset': 2321}, {'Id': 105, 'BeginOffset': 2368, 'EndOffset': 2377, 'Score': 0.3646351099014282, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 106, 'BeginOffset': 2459, 'EndOffset': 2478, 'Score': 0.7895448803901672, 'Text': 'side effect changes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 107, 'BeginOffset': 2482, 'EndOffset': 2499, 'Score': 0.8038774728775024, 'Text': 'menstrual periods', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8744324445724487}]}, {'Text': 'irregular)', 'Type': 'PROBLEM', 'BeginOffset': 2517, 'EndOffset': 2527}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 2576, 'EndOffset': 2577}, {'Text': "unexpected bleeding'", 'Type': 'PROBLEM', 'BeginOffset': 2627, 'EndOffset': 2647}, {'Id': 109, 'BeginOffset': 2708, 'EndOffset': 2720, 'Score': 0.9357881546020508, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8145287036895752}]}, {'Id': 110, 'BeginOffset': 2736, 'EndOffset': 2748, 'Score': 0.7736654877662659, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7222959399223328}]}, {'Id': 111, 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{'Title': '5. how to store zoely', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. combined pills (including zoely tablets) no longer required should not be disposed via wastewater or the municipal sewage system. the hormonal active ingredients in the tablet may have harmful effects if they reach the aquatic environment. return them to a pharmacy or dispose them in another safe way according to local requirements. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'combined pills (including zoely tablets', 'Type': 'TREATMENT', 'BeginOffset': 276, 'EndOffset': 315}, {'Text': 'the hormonal active ingredients', 'Type': 'TREATMENT', 'BeginOffset': 406, 'EndOffset': 437}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 611, 'EndOffset': 625}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what zoely contains - the active substances are: nomegestrol acetate and estradiol white active film-coated tablets: each tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate). yellow placebo film-coated tablets: the tablet does not contain active substances. - the other ingredients are: tablet core (white active and yellow placebo film-coated tablets): lactose monohydrate (see section 2 'zoely contains lactose'), microcrystalline cellulose (e460), crospovidone (e1201), talc (e553b), magnesium stearate (e572) and colloidal anhydrous silica tablet coat (white active film-coated tablets): poly(vinyl alcohol) (e1203), titanium dioxide (e171), macrogol 3350 and talc (e553b) tablet coat (yellow placebo film-coated tablets): poly(vinyl alcohol) (e1203), titanium dioxide (e171), macrogol 3350, talc (e553b), iron oxide yellow (e172) and iron oxide black (e172) what zoely looks like and contents of the pack the active film-coated tablets (tablets) are white and round. they are coded 'ne' on both sides. the placebo film-coated tablets are yellow and round. they are coded 'p' on both sides. zoely comes in blisters of 28 film-coated tablets (24 white active film-coated tablets and 4 yellow placebo film-coated tablets) packed in a ply carton. pack sizes: 28, 84, 168 and 364 film-coated tablets. not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 49, 'EndOffset': 68, 'Score': 0.9857524037361145, 'Text': 'nomegestrol acetate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.60157310962677, 'RelationshipScore': 0.967195451259613, 'RelationshipType': 'FORM', 'Id': 6, 'BeginOffset': 96, 'EndOffset': 100, 'Text': 'film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.4473790228366852, 'RelationshipScore': 0.9590766429901123, 'RelationshipType': 'FORM', 'Id': 7, 'BeginOffset': 101, 'EndOffset': 115, 'Text': 'coated tablets', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.330194354057312, 'RelationshipScore': 0.9712560176849365, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 8, 'BeginOffset': 117, 'EndOffset': 128, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'estradiol white active film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 73, 'EndOffset': 115}, {'Text': '2.5 mg nomegestrol acetate', 'Type': 'TREATMENT', 'BeginOffset': 138, 'EndOffset': 164}, {'Text': '1.5 mg estradiol', 'Type': 'TREATMENT', 'BeginOffset': 169, 'EndOffset': 185}, {'Id': 13, 'BeginOffset': 190, 'EndOffset': 201, 'Score': 0.3320384621620178, 'Text': 'hemihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'yellow placebo film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 204, 'EndOffset': 238}, {'Text': 'white active and yellow placebo film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 329, 'EndOffset': 380}, {'Text': 'lactose monohydrate', 'Type': 'TREATMENT', 'BeginOffset': 383, 'EndOffset': 402}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 416, 'EndOffset': 417}, {'Id': 18, 'BeginOffset': 445, 'EndOffset': 471, 'Score': 0.9941098690032959, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 19, 'BeginOffset': 480, 'EndOffset': 492, 'Score': 0.9925359487533569, 'Text': 'crospovidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 20, 'BeginOffset': 516, 'EndOffset': 534, 'Score': 0.9947722554206848, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'colloidal anhydrous silica tablet coat (white active film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 546, 'EndOffset': 618}, {'Text': 'poly(vinyl alcohol', 'Type': 'TREATMENT', 'BeginOffset': 621, 'EndOffset': 639}, {'Id': 26, 'BeginOffset': 650, 'EndOffset': 666, 'Score': 0.9973969459533691, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 27, 'BeginOffset': 675, 'EndOffset': 688, 'Score': 0.9858148097991943, 'Text': 'macrogol 3350', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.19511118531227112, 'RelationshipScore': 0.9964963793754578, 'RelationshipType': 'STRENGTH', 'Id': 28, 'BeginOffset': 699, 'EndOffset': 705, 'Text': 'e553b)', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7072492837905884, 'RelationshipScore': 0.9991820454597473, 'RelationshipType': 'FORM', 'Id': 29, 'BeginOffset': 706, 'EndOffset': 712, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.3511063754558563, 'RelationshipScore': 0.9712590575218201, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 32, 'BeginOffset': 756, 'EndOffset': 760, 'Text': 'poly', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'yellow placebo film', 'Type': 'TEST', 'BeginOffset': 719, 'EndOffset': 738}, {'Text': 'poly(vinyl alcohol', 'Type': 'TREATMENT', 'BeginOffset': 756, 'EndOffset': 774}, {'Id': 34, 'BeginOffset': 785, 'EndOffset': 801, 'Score': 0.9972566962242126, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 35, 'BeginOffset': 810, 'EndOffset': 823, 'Score': 0.9868867993354797, 'Text': 'macrogol 3350', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.2565423250198364, 'RelationshipScore': 0.5023862719535828, 'RelationshipType': 'STRENGTH', 'Id': 36, 'BeginOffset': 831, 'EndOffset': 836, 'Text': 'e553b', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'iron oxide yellow', 'Type': 'TREATMENT', 'BeginOffset': 839, 'EndOffset': 856}, {'Id': 38, 'BeginOffset': 868, 'EndOffset': 884, 'Score': 0.9927268028259277, 'Text': 'iron oxide black', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8648754954338074, 'RelationshipScore': 0.5189847350120544, 'RelationshipType': 'FORM', 'Id': 40, 'BeginOffset': 971, 'EndOffset': 978, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the active film-coated tablets (tablets', 'Type': 'TREATMENT', 'BeginOffset': 939, 'EndOffset': 978}, {'Id': 1, 'BeginOffset': 1029, 'EndOffset': 1034, 'Score': 0.8893989324569702, 'Text': 'sides', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the placebo film', 'Type': 'TREATMENT', 'BeginOffset': 1036, 'EndOffset': 1052}, {'Id': 3, 'BeginOffset': 1117, 'EndOffset': 1122, 'Score': 0.9071109294891357, 'Text': 'sides', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '28 film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 1151, 'EndOffset': 1173}, {'Text': 'white active film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 1178, 'EndOffset': 1210}, {'Text': '4 yellow placebo film-coated tablets)', 'Type': 'TREATMENT', 'BeginOffset': 1215, 'EndOffset': 1252}, {'Text': 'a ply carton', 'Type': 'TREATMENT', 'BeginOffset': 1263, 'EndOffset': 1275}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 1289, 'EndOffset': 1291}, {'Text': '84', 'Type': 'NUMBER', 'BeginOffset': 1293, 'EndOffset': 1295}, {'Text': '168', 'Type': 'NUMBER', 'BeginOffset': 1297, 'EndOffset': 1300}, {'Text': '364', 'Type': 'NUMBER', 'BeginOffset': 1305, 'EndOffset': 1308}, {'Text': 'film', 'Type': 'TEST', 'BeginOffset': 1309, 'EndOffset': 1313}]}

C89FAB3627FDCF11CEF85ABB09623E6A

https://www.ema.europa.eu/documents/product-information/eklira-genuair-epar-product-information_en.pdf

Eklira Genuair

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Eklira Genuair 322 micrograms inhalation powder 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each delivered dose (the dose leaving the mouthpiece) contains 375 µg aclidinium bromide equivalent to 322 µg of aclidinium. This corresponds to a metered dose of 400 µg aclidinium bromide equivalent to 343 µg aclidinium. Excipients with known effect Each delivered dose contains approximately 12 mg lactose (as monohydrate). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Inhalation powder. White or almost white powder in a white inhaler with an integral dose indicator and a green dosage button. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Eklira Genuair is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD) (see section 5.1). 4.2 Posology and method of administration Posology The recommended dose is one inhalation of 322 micrograms aclidinium twice daily. If a dose is missed the next dose should be taken as soon as possible. However, if it is nearly time for the next dose, the missed dose should be skipped. Elderly No dose adjustments are required for elderly patients (see section 5.2). Renal impairment No dose adjustments are required for patients with renal impairment (see section 5.2). Hepatic impairment No dose adjustments are required for patients with hepatic impairment (see section 5.2). Paediatric population There is no relevant use of Eklira Genuair in children and adolescents (under 18 years of age) for the indication of COPD. 3 Method of administration For inhalation use. Patients should be instructed on how to administer the product correctly as the Genuair inhaler may work differently from inhalers the patients may have used previously. It is important to instruct the patients to carefully read the Instructions for Use in the Package Leaflet, which is packed together with each inhaler. For Instructions for Use, see section 6.6. 4.3 Contraindications Hypersensitivity to aclidinium bromide or to the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Paradoxical bronchospasm: Administration of Eklira Genuair may cause paradoxical bronchospasm. If this occurs, treatment with Eklira Genuair should be stopped and other treatments considered. Deterioration of disease: Aclidinium bromide is a maintenance bronchodilator and should not be used for the relief of acute episodes of bronchospasm, i.e. as a rescue therapy. In the event of a change in COPD intensity while the patient is being treated with aclidinium bromide so that the patient considers additional rescue medication is required, a re-evaluation of the patient and the patients’ treatment regimen should be conducted. Cardiovascular effects: Eklira Genuair should be used with caution in patients who had a myocardial infarction during the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV as per the “New York Heart Association”. Experience in patients with cardiovascular comorbidities in clinical trials is limited (see section 5.1). These conditions may be affected by the anticholinergic mechanism of action. Anticholinergic activity: Dry mouth, which has been observed with anticholinergic treatment, may in the long term be associated with dental caries. Consistent with its anticholinergic activity, aclidinium bromide should be used with caution in patients with symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma (even though direct contact of the product with the eyes is very unlikely). Excipients: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Co-administration of aclidinium bromide with other anticholinergic-containing medicinal products has not been studied and is not recommended. Although no formal in vivo drug interaction studies have been performed, inhaled aclidinium bromide has been used concomitantly with other COPD medicinal products including sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids without clinical evidence of drug interactions. 4 In vitro studies have shown that aclidinium bromide or the metabolites of aclidinium bromide at the therapeutic dose are not expected to cause interactions with active substances that are substrates of P-glycoprotein (P-gp), or active substances metabolised by cytochrome P450 (CYP450) enzymes and esterases (see section 5.2). 4.6 Fertility, pregnancy and lactation Pregnancy There are no data available on the use of aclidinium bromide in pregnant women. Studies in animals have shown foetotoxicity only at dose levels much higher than the maximum human exposure to aclidinium bromide (see section 5.3). Aclidinium bromide should only be used during pregnancy if the expected benefits outweigh the potential risks. Breast-feeding It is unknown whether aclidinium bromide/metabolites are excreted in human milk. Animal studies have shown excretion of small amounts of aclidinium bromide/metabolites into milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Eklira Genuair therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Studies in rats have shown slight reductions in fertility only at dose levels much higher than the maximum human exposure to aclidinium bromide (see section 5.3). It is considered unlikely that aclidinium bromide administered at the recommended dose will affect fertility in humans. 4.7 Effects on ability to drive and use machines Aclidinium bromide may have minor influence on the ability to drive and use machines. The occurrence of headache, dizziness or blurred vision following administration of aclidinium bromide (see section 4.8) may influence the ability to drive or to use machinery. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions with Eklira Genuair were headache (6.6%) and nasopharyngitis (5.5%). Tabulated summary of adverse reactions The frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse reactions (i.e. events attributed to Eklira Genuair) observed with Eklira Genuair 322 µg (636 patients) in the pooled analysis of one 6-month and two 3-month randomised, placebo-controlled clinical trials. A placebo-controlled trial in 1791 patients with moderate to very severe COPD treated with Eklira Genuair up to 36 months did not identify other adverse reactions. The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). System organ class Preferred term Frequency Infections and infestations Sinusitis Common Nasopharyngitis Common Immune system disorders Hypersensitivity Rare Angioedema Not known 5 Anaphylactic reaction Not known Nervous system disorders Headache Common Dizziness Uncommon Eye disorders Blurred vision Uncommon Cardiac disorders Tachycardia Uncommon Palpitations Uncommon Respiratory, thoracic and mediastinal disorders Cough Common Dysphonia Uncommon Gastrointestinal disorders Diarrhoea Common Nausea Common Dry mouth Uncommon Stomatitis Uncommon Skin and subcutaneous tissue disorders Rash Uncommon Pruritus Uncommon Renal and urinary disorders Urinary retention Uncommon Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose High doses of aclidinium bromide may lead to anticholinergic signs and symptoms. However, single inhaled doses up to 6,000 µg aclidinium bromide have been administered to healthy subjects without systemic anticholinergic adverse reactions. Additionally, no clinically relevant adverse reactions were observed following 7-day twice daily dosing of up to 800 µg aclidinium bromide in healthy subjects. Acute intoxication by inadvertent medicinal product ingestion of aclidinium bromide is unlikely, due to its low oral bioavailability and the breath-actuated dosing mechanism of the Genuair inhaler. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs for obstructive airway diseases, anticholinergics; ATC Code: R03BB05. Mechanism of action Aclidinium bromide is a competitive, selective muscarinic receptor antagonist (also known as an anticholinergic), with a longer residence time at the M3 receptors than the M2 receptors. M3 receptors mediate contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs to antagonise M3 receptors of airway smooth muscle and induce bronchodilation. Nonclinical in vitro and in vivo studies showed rapid, dose-dependent and long-lasting inhibition by aclidinium of acetylcholine-induced bronchoconstriction. Aclidinium bromide is quickly broken down in plasma, the level of systemic anticholinergic side effects is therefore low. Pharmacodynamic effects Clinical efficacy studies showed that Eklira Genuair provided clinically meaningful improvements in lung function (as measured by the forced expiratory volume in 1 second [FEV1]) over 12 hours following morning and evening administration, which were evident within 30 minutes of the first dose (increases from baseline of 124-133 mL). Maximal bronchodilation was achieved within 1-3 hours after dosing with mean peak improvements in FEV1 relative to baseline of 227-268 mL at steady-state. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc?_sm_au_=iWHNfPk6pL272dJN 6 Cardiac electrophysiology No effects on QT interval (corrected using either the Fridericia or Bazett method or individually- corrected) were observed when aclidinium bromide (200 µg or 800 µg) was administered once daily for 3 days to healthy subjects in a thorough QT study. In addition, no clinically significant effects of Eklira Genuair on cardiac rhythm were observed on 24-hour Holter monitoring after 3 months treatment of 336 patients (of whom 164 received Eklira Genuair 322 µg twice daily). Clinical efficacy and safety The Eklira Genuair Phase III clinical development programme included 269 patients treated with Eklira Genuair 322 µg twice daily in one 6-month randomised, placebo-controlled study and 190 patients treated with Eklira Genuair 322 µg twice daily in one 3-month randomised, placebo- controlled study. Efficacy was assessed by measures of lung function and symptomatic outcomes such as breathlessness, disease-specific health status, use of rescue medication and occurrence of exacerbations. In the long-term safety studies, Eklira Genuair was associated with bronchodilatory efficacy when administered over a 1-year treatment period. Bronchodilation In the 6-month study, patients receiving Eklira Genuair 322 µg twice daily experienced a clinically meaningful improvement in their lung function (as measured by FEV1). Maximal bronchodilatory effects were evident from day one and were maintained over the 6-month treatment period. After 6 months treatment, the mean improvement in morning pre-dose (trough) FEV1 compared to placebo was 128 mL (95% CI=85-170; p<0.0001). Similar observations were made with Eklira Genuair in the 3 month study. Disease-Specific Health Status and Symptomatic Benefits Eklira Genuair provided clinically meaningful improvements in breathlessness (assessed using the Transition Dyspnoea Index [TDI]) and disease-specific health status (assessed using the St. George’s Respiratory Questionnaire [SGRQ]). The Table below shows symptom relief obtained after 6 months treatment with Eklira Genuair. Variable Treatment Improvement over placebo p-value Eklira Genuair Placebo TDI Percentage of Patients who achieved MCIDa 56.9 45.5 1.68-foldc increase in likelihood 0.004 Mean Change from baseline 1.9 0.9 1.0 unit <0.001 SGRQ Percentage of Patients who achieved MCIDb 57.3 41.0 1.87-foldc increase in likelihood <0.001 Mean Change from baseline -7.4 -2.8 - 4.6 units <0.0001 a Minimum clinically important difference (MCID) of at least 1 unit change in TDI. b MCID of at least - 4 units change in SGRQ. c Odds ratio, increase in the likelihood of achieving the MCID compared to placebo. Patients treated with Eklira Genuair required less rescue medication than patients treated with placebo (a reduction of 0.95 puffs per day at 6 months [p=0.005]). Eklira Genuair also improved daily symptoms of COPD (dyspnoea, cough and sputum production) and night-time and early morning symptoms. Pooled efficacy analysis of the 6-month and 3-month placebo controlled studies demonstrated a statistically significant reduction in the rate of moderate to severe exacerbations (requiring treatment with antibiotics or corticosteroids or resulting in hospitalisations) with aclidinium 322 µg twice daily compared to placebo (rate per patient per year: 0.31 vs 0.44 respectively; p=0.0149). 7 Long Term Safety and Efficacy Trial up to 3 years The effect of aclidinium bromide on the occurrence of major adverse cardiovascular events (MACE) was assessed in a randomised, double-blind, placebo-controlled, parallel-group study in 3630 adult patients between 40 and 91 years of age with moderate to very severe COPD, treated for up to 36 months. 58.7% were male and 90.7% were Caucasian, with a mean postbronchodilator FEV1 of 47.9% of predicted value and a mean CAT (COPD Assessment Test) of 20.7. All patients had a history of cardiovascular or cerebrovascular disease and/or significant cardiovascular risk factors. 59.8% of patients had at least one COPD exacerbation within the past 12 months from the screening visit. Approximately 48% of enrolled patients had a prior history of at least 1 documented previous cardiovascular event; cerebrovascular disease (13.1%), coronary artery disease (35.4%), peripheral vascular disease or history of claudication (13.6%). The study had an event-driven design and was terminated once sufficient MACE events for the primary safety analysis were observed. Patients discontinued treatment if they experienced a MACE event and entered into the post-treatment follow-up period during the study. 70.7% of patients completed the study per investigator assessment. The median time on-treatment in the Eklira Genuair and placebo groups was 1.1 and 1 year, respectively. The median time on-study in the Eklira Genuair and placebo groups was approximately 1.4 and 1.3 years, respectively. The primary safety endpoint was the time to first occurrence of MACE, defined as any of the following adjudicated events: cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal ischemic stroke. The frequency of patients with at least one MACE was 3.85% vs. 4.23% patients in the aclidinium and placebo groups, respectively. Eklira Genuair did not increase the MACE risk in patients with COPD compared to placebo when added to current background therapy (hazard ratio (HR) 0.89; 95% CI: 0.64, 1.23). The upper bound of the confidence interval excluded a pre-defined risk margin of 1.8. The rate of moderate or severe COPD exacerbations per patient per year during the first year of treatment was evaluated as the primary efficacy endpoint in the study. Patients treated with Eklira Genuair showed a statistically significant reduction of 22% compared to placebo (rate ratio [RR] 0.78; 95% CI 0.68 to 0.89; p<0.001). In addition, Eklira Genuair showed a statistically significant reduction of 35% in the rate of hospitalisations due to COPD exacerbations while on-treatment during the first year compared with placebo (RR 0.65; 95% CI 0.48 to 0.89; p=0.006). The Eklira Genuair group showed a statistically significant delay in the time to first moderate or severe exacerbation while on-treatment compared to the placebo group. Patients in the aclidinium bromide group had a 18% relative reduction of the risk of an exacerbation (HR 0.82; 95% CI [0.73, 0.92], p<0.001). Exercise tolerance In a 3-week crossover, randomised, placebo-controlled clinical study Eklira Genuair was associated with a statistically significant improvement in exercise endurance time in comparison to placebo of 58 seconds (95% CI=9-108; p=0.021; pre-treatment value: 486 seconds). Eklira Genuair statistically significantly reduced lung hyperinflation at rest (functional residual capacity [FRC]=0.197 L [95% CI=0.321, 0.072; p=0.002]; residual volume [RV]=0.238 L [95% CI=0.396, 0.079; p=0.004]) and also improved trough inspiratory capacity (by 0.078 L; 95% CI=0.01, 0.145; p=0.025) and reduced dyspnoea during exercise (Borg scale) (by 0.63 Borg units; 95% CI=1.11, 0.14; p=0.012). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Eklira Genuair in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use). 8 5.2 Pharmacokinetic properties Absorption Aclidinium bromide is rapidly absorbed from the lung, achieving maximum plasma concentrations within 5 minutes of inhalation in healthy subjects, and normally within the first 15 minutes in COPD patients. The fraction of the inhaled dose that reaches the systemic circulation as unchanged aclidinium is very low at less than 5%. Steady state peak plasma concentrations achieved after dry powder inhalation by COPD patients of 400 µg aclidinium bromide were approximately 224 pg/mL. Steady-state plasma levels were attained within seven days of twice daily dosing. Distribution Whole lung deposition of inhaled aclidinium bromide via the Genuair inhaler averaged approximately 30% of the metered dose. The plasma protein binding of aclidinium bromide determined in vitro most likely corresponded to the protein binding of the metabolites due to the rapid hydrolysis of aclidinium bromide in plasma; plasma protein binding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The main plasma protein that binds aclidinium bromide is albumin. Biotransformation Aclidinium bromide is rapidly and extensively hydrolysed to its pharmacologically inactive alcohol- and carboxylic acid-derivatives. The hydrolysis occurs both chemically (non-enzymatically) and enzymatically by esterases, butyrylcholinesterase being the main human esterase involved in the hydrolysis. Plasma levels of the acid metabolite are approximately 100-fold greater than those of the alcohol metabolite and the unchanged active substance following inhalation. The low absolute bioavailability of inhaled aclidinium bromide (<5%) is because aclidinium bromide undergoes extensive systemic and pre-systemic hydrolysis whether deposited in the lung or swallowed. Biotransformation via CYP450 enzymes plays a minor role in the total metabolic clearance of aclidinium bromide. In vitro studies have shown that aclidinium bromide at the therapeutic dose or its metabolites do not inhibit or induce any of the cytochrome P450 (CYP450) enzymes and do not inhibit esterases (carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro studies have shown that aclidinium bromide or the metabolites of aclidinium bromide are not substrates or inhibitors of P-glycoprotein. Elimination The terminal elimination half-life and effective half-life of aclidinium bromide are approximately 14 hours and 10 hours, respectively, following inhalation of twice daily 400 µg doses in COPD patients. Following intravenous administration of 400 µg radiolabelled aclidinium bromide to healthy subjects, approximately 1% of the dose was excreted as unchanged aclidinium bromide in the urine. Up to 65% of the dose was eliminated as metabolites in the urine and up to 33% as metabolites in the faeces. Following inhalation of 200 µg and 400 µg of aclidinium bromide by healthy subjects or COPD patients, the urinary excretion of unchanged aclidinium was very low at about 0.1% of the administered dose, indicating that renal clearance plays a minor role in the total aclidinium clearance from plasma. Linearity/non-linearity 9 Aclidinium bromide demonstrated kinetic linearity and a time-independent pharmacokinetic behaviour in the therapeutic range. Special populations Elderly patients The pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPD appear to be similar in patients aged 40–59 years and in patients aged ≥70 years. Therefore, no dose adjustment is required for elderly COPD patients. Hepatically-impaired patients No studies have been performed on hepatically-impaired patients. As aclidinium bromide is metabolised mainly by chemical and enzymatic cleavage in the plasma, hepatic dysfunction is very unlikely to alter its systemic exposure. No dose adjustment is required for hepatically-impaired COPD patients. Renally-impaired patients No significant pharmacokinetic differences were observed between subjects with normal renal function and subjects with renal impairment. Therefore, no dose adjustment and no additional monitoring are required for renally-impaired COPD patients. Race Following repeated inhalations, the systemic exposure of aclidinium bromide has been observed to be similar in Japanese and Caucasian patients. Pharmacokinetic/pharmacodynamic relationship Because aclidinium bromide acts locally in the lungs and is quickly broken down in plasma there is no direct relationship between pharmacokinetics and pharmacodynamics. 5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. Effects in nonclinical studies with respect to cardiovascular parameters (increased heart rates in dogs), reproductive toxicity (foetotoxic effects), and fertility (slight decreases in conception rate, number of corpora lutea, and pre- and post-implantation losses) were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. The low toxicity observed in nonclinical toxicity studies is in part due to rapid metabolism of aclidinium bromide in plasma and the lack of significant pharmacological activity of the major metabolites. The safety margins for human systemic exposure with 400 µg twice daily over the no observed adverse effect levels in these studies ranged from 7- to 73-fold. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 10 3 years. To be used within 90 days of opening the pouch. 6.4 Special precautions for storage Keep the inhaler inside the pouch until the administration period starts. 6.5 Nature and contents of container The inhaler device is a multicomponent device made of polycarbonate, acrylonitrile-butadiene-styrene, polyoxymethylene, polyester-butylene-terephthalate, polypropylene, polystyrene and stainless steel. It is white-coloured with an integral dose indicator and a green dosage button. The mouthpiece is covered with a removable green protective cap. The inhaler is supplied in a plastic laminate pouch, placed in a cardboard carton. Carton containing 1 inhaler with 30 doses. Carton containing 1 inhaler with 60 doses. Carton containing 3 inhalers each with 60 doses. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Instructions for Use Getting Started Read these Instructions for Use before you start using the medicine. Become familiar with the parts of your Genuair inhaler. Figure A Before use: a) Before first use, tear open the sealed bag and remove the inhaler. Throw away the bag. b) Do not press the green button until you are ready to take a dose. c) Pull off the cap by lightly squeezing the arrows marked on each side (Figure B). Control window Red = confirms correct inhalation Green button Dose indicator Mouthpiece Protective Cap Control window Green = inhaler ready to use 11 STEP 1: Prepare your dose 1.1 Look in the opening of the mouthpiece and make sure nothing is blocking it (Figure C). 1.2 Look at the control window (should be red, Figure C). Figure C 1.3 Hold the inhaler horizontally with the mouthpiece facing you and the green button on top (Figure D). Figure D 1.4 Press the green button all the way down to load your dose (Figure E). When you press the button all the way down, the control window changes from red to green. Make sure the green button is on top. Do not tilt. 1.5 Release the green button (Figure F). Make sure you release the button so the inhaler can work correctly. Figure B Squeeze here and pull RED Check mouthpiece opening 12 Figure E Figure F Stop and Check: 1.6 Make sure the control window is now green (Figure G). Your medicine is ready to be inhaled. Go to ‘STEP 2: Inhale your medicine’. Figure G What to do if the control window is still red after pressing the button (Figure H). Figure H The dose is not prepared. Go back to ‘STEP 1 Prepare your dose’ and repeat steps 1.1 to 1.6. STEP 2: Inhale your medicine Read steps 2.1 to 2.7 fully before use. Do not tilt. 2.1 Hold the inhaler away from your mouth, and breathe out completely. Never breathe out into the inhaler (Figure I). GREEN 13 Figure I 2.2 Hold your head upright, put the mouthpiece between your lips, and close your lips tightly around it (Figure J). Do not hold the green button down while inhaling. Figure J 2.3 Take a strong, deep breath through your mouth. Keep breathing in for as long as possible. A ‘click’ will let you know that you are inhaling correctly. Keep breathing in as long as possible after you hear the ‘click’. Some patients may not hear the ‘click’. Use the control window to ensure you have inhaled correctly. 2.4 Take the inhaler out of your mouth. 2.5 Hold your breath for as long as possible. 2.6 Slowly breathe out away from the inhaler. Some patients may experience a grainy sensation in their mouth, or a slightly sweet or bitter taste. Do not take an extra dose even if you do not taste or feel anything after inhaling. Stop and Check: 2.7 Make sure the control window is now red (Figure K). This means you have inhaled your medicine correctly. 14 Figure K What to do if the control window is still green after inhalation (Figure L). Figure L This means you have not inhaled your medicine correctly. Go back to ‘STEP 2 Inhale your medicine’ and repeat steps 2.1 to 2.7. If the control window still does not change to red, you may have forgotten to release the green button before inhaling, or you may not have inhaled strongly enough. If this happens, try again. Make sure you have released the green button, and you have breathed out completely. Then take a strong, deep breath through the mouthpiece. Please contact your doctor if the control window is still green after repeated attempts. Push the protective cap back onto the mouthpiece after each use (Figure M), to prevent contamination of the inhaler with dust or other materials. You should discard your inhaler if you lose the cap. Additional information What should you do if you accidently prepare a dose? Figure M RED 15 Store your inhaler with the protective cap in place until it is time to inhale your medicine, then remove the cap and start at Step 1.6. How does the dose indicator work?  The dose indicator shows the total number of doses left in the inhaler (Figure N).  On first use, every inhaler contains at least 60 doses, or at least 30 doses, depending on the pack size.  Each time you load a dose by pressing the green button, the dose indicator moves by a small amount towards the next number (50, 40, 30, 20, 10, or 0). When should you get a new inhaler? You should get a new inhaler:  If your inhaler appears to be damaged or if you lose the cap, or  When a red band appears in the dose indicator, this means you are nearing your last dose (Figure N), or  If your inhaler is empty (Figure O). Figure N How do you know that your inhaler is empty? When the green button will not return to its full upper position and is locked in a middle position, you have reached the last dose (Figure O). Even though the green button is locked, your last dose may still be inhaled. After that, the inhaler cannot be used again and you should start using a new inhaler. How should you clean the inhaler? Figure O Locked Dose indicator Red band Dose indicator moves slowly from 60 to 0: 60, 50, 40, 30, 20, 10, 0. 16 NEVER use water to clean the inhaler, as this may damage your medicine. If you wish to clean your inhaler, just wipe the outside of the mouthpiece with a dry tissue or paper towel. 7. MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden 8. MARKETING AUTHORISATION NUMBER(S) EU/1/12/778/001 EU/1/12/778/002 EU/1/12/778/003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 20 July 2012 Date of last renewal: 20 April 2017 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.ema.europa.eu/ 17 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 18 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Industrias Farmacéuticas Almirall, S.A. Ctra. Nacional II, Km. 593 08740 Sant Andreu de la Barca Barcelona Spain B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION Pharmacovigilance system The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the Marketing Authorisation is in place and functioning before and whilst the medicinal product is on the market. Risk Management Plan (RMP) The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in the Risk Management Plan presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the Committee for Medicinal Products for Human Use (CHMP). As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR). In addition, an updated RMP should be submitted  When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities  Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached  At the request of the European Medicines Agency. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date Submission of the results of the agreed post-authorisation safety study (PASS) for aclidinium bromide to evaluate the overall mortality and the proposed cardiovascular safety endpoints (with an additional endpoint of cardiac arrhythmia) among patients with COPD using aclidinium, according to a protocol agreed by the PRAC. 2023 19 ANNEX III LABELLING AND PACKAGE LEAFLET 20 A. LABELLING 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Eklira Genuair 322 micrograms inhalation powder aclidinium (aclidinium bromide) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each delivered dose contains 375 micrograms aclidinium bromide equivalent to 322 micrograms of aclidinium. 3. LIST OF EXCIPIENTS Also contains: Lactose 4. PHARMACEUTICAL FORM AND CONTENTS 1 inhaler containing 30 doses 1 inhaler containing 60 doses 3 inhalers each containing 60 doses 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use Inhalation use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP To be used within 90 days of opening the pouch 9. SPECIAL STORAGE CONDITIONS Keep the Genuair inhaler inside the pouch until the administration period starts. 22 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AstraZeneca AB SE-151 85 Södertälje Sweden AstraZeneca (AstraZeneca logo) 12. MARKETING AUTHORISATION NUMBER(S) EU/1/12/778/001 30 doses EU/1/12/778/002 60 doses EU/1/12/778/003 3 inhalers each containing 60 doses 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE eklira genuair 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 23 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Inhaler label 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Eklira Genuair 322 mcg inhalation powder aclidinium (aclidinium bromide) Inhalation use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP To be used within 90 days of opening the pouch. 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 30 doses 60 doses 6. OTHER AstraZeneca (AstraZeneca logo) 24 B. PACKAGE LEAFLET 25 Package leaflet: Information for the patient Eklira Genuair 322 micrograms inhalation powder Aclidinium (aclidinium bromide) This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What Eklira Genuair is and what it is used for 2. What you need to know before you use Eklira Genuair 3. How to use Eklira Genuair 4. Possible side effects 5. How to store Eklira Genuair 6. Contents of the pack and other information Instructions for Use 1. What Eklira Genuair is and what it is used for What Eklira Genuair is The active ingredient of Eklira Genuair is aclidinium bromide, which belongs to a group of medicines called bronchodilators. Bronchodilators relax airways and help keep bronchioles open. Eklira Genuair is a dry powder inhaler that uses your breath to deliver the medicine directly into your lungs. This makes it easier for chronic obstructive pulmonary disease (COPD) patients to breathe. What Eklira Genuair is used for Eklira Genuair is indicated to help open the airways and relieve symptoms of COPD, a serious, long- term lung disease characterised by breathing difficulties. Regular use of Eklira Genuair can help you when you have ongoing shortness of breath related to your disease to help you minimise the effects of the disease on your everyday life and reduce the number of flare-ups (the worsening of your COPD symptoms for several days). 2. What you need to know before you use Eklira Genuair Do not use Eklira Genuair - if you are allergic to aclidinium bromide or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor, pharmacist or nurse before using Eklira Genuair: - if you have had heart problems recently. - if you see halos around lights or coloured images (glaucoma). - if you have an enlarged prostate, problems passing urine, or a blockage in your bladder. 26 Eklira Genuair is indicated for maintenance treatment and should not be used to treat a sudden attack of breathlessness or wheezing. If your COPD symptoms (breathlessness, wheezing, cough) do not improve or get worse you should contact your doctor for advice as soon as possible. Dry mouth, which has been observed with medicines like Eklira Genuair, may after using your medicine for a long time, be associated with tooth decay. Therefore, please remember to pay attention to oral hygiene. Stop taking Eklira Genuair and seek medical help immediately: - if you get tightness of the chest, coughing, wheezing or breathlessness immediately after using the medicine. These may be signs of a condition called bronchospasm. Children and adolescents Eklira Genuair is not for use in children or adolescents below 18 years of age. Other medicines and Eklira Genuair Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Inform your doctor if you have been or are using similar medicines for breathing problems, such as medicines containing tiotropium, ipratropium. Ask your doctor or pharmacist if you are not sure. The use of Eklira Genuair with these medicines is not recommended. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. You should not use Eklira Genuair if you are pregnant or are breast-feeding unless your doctor tells you so. Driving and using machines Eklira Genuair may have minor influence on the ability to drive and use machines. This medicine may cause headache, dizziness or blurred vision. If you are affected by any of these side effects do not drive or use machinery until the headache has cleared, the feeling of dizziness has passed and your vision has returned to normal. Eklira Genuair contains lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. 3. How to use Eklira Genuair Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The recommended dose is one inhalation twice a day in the morning and evening. The effects of Eklira Genuair last for 12 hours; therefore, you should try to use your Eklira Genuair inhaler at the same time every morning and evening. This ensures that there is always enough medicine in your body to help you breathe more easily throughout the day and night. It will also help you to remember to use it. The recommended dose can be used for elderly patients and for patients with kidney or liver problems. No dose adjustments are necessary. COPD is a long-term disease; therefore, it is recommended that Eklira Genuair is used every day, twice a day and not only when breathing problems or other symptoms of COPD are experienced. Route of administration 27 The medicine is for inhalation use. Refer to the Instructions for Use for instructions on how to use the Genuair inhaler. If you are not sure of how to use Eklira Genuair, contact your doctor or pharmacist. You can use Eklira Genuair any time before or after food or drink. If you use more Eklira Genuair than you should If you think you may have used more Eklira Genuair than you should, contact your doctor or pharmacist. If you forget to use Eklira Genuair If you forget a dose of Eklira Genuair, inhale the dose as soon as you remember. However, if it is nearly time for your next dose, skip the missed dose. Do not take a double dose to make up for a forgotten dose. If you stop using Eklira Genuair This medicine is for long-term use. If you want to stop treatment, first talk to your doctor, as your symptoms may worsen. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Allergic reactions may rarely occur (may affect up to 1 in 1,000 people). Stop using the medicine and contact your doctor immediately if you develop swelling of your face, throat, lips or tongue (with or without difficulty breathing or swallowing), dizziness or fainting, faster heart rate or if you get raised severely itchy bumps on your skin (hives) as these may be symptoms of an allergic reaction. The following side effects may occur whilst using Eklira Genuair: Common: may affect up to 1 in 10 people - Headache - Inflammation of the sinuses (sinusitis) - Common cold (nasopharyngitis) - Cough - Diarrhoea - Nausea Uncommon: may affect up to 1 in 100 people - Dizziness - Dry mouth - Inflammation of the mouth (stomatitis) - Hoarseness (dysphonia) - Faster heart beat (tachycardia) - Sensation of heart beating (palpitations) - Difficulty passing urine (urinary retention) - Blurred vision - Rash - Itching of the skin Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting 28 system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Eklira Genuair Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the inhaler label and carton after “EXP”. The expiry date refers to the last day of that month. Keep the inhaler inside the pouch until the administration period starts. To be used within 90 days of opening the pouch. Do not use the Eklira Genuair if you notice that the pack is damaged or shows signs of tampering. After you have taken the last dose, the inhaler has to be disposed of. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Eklira Genuair contains - The active substance is aclidinium bromide. Each delivered dose contains 375 micrograms aclidinium bromide equivalent to 322 micrograms of aclidinium. - The other ingredient is lactose monohydrate (refer to Section 2 “Eklira Genuair contains lactose”). What Eklira Genuair looks like and contents of the pack Eklira Genuair is a white or almost white powder. The Genuair inhaler device is white coloured with an integral dose indicator and a green dosage button. The mouthpiece is covered with a removable green protective cap. It is supplied in a plastic pouch. Pack sizes supplied: Carton containing 1 inhaler with 30 doses. Carton containing 1 inhaler with 60 doses. Carton containing 3 inhalers each with 60 doses. Not all pack sizes may be marketed. Marketing Authorisation Holder AstraZeneca AB SE-151 85 Södertälje Sweden Manufacturer Industrias Farmacéuticas Almirall, S.A. Ctra. Nacional II, Km. 593 08740 Sant Andreu de la Barca, Barcelona Spain For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc?_sm_au_=iWHNfPk6pL272dJN 29 België/Belgique/Belgien AstraZeneca S.A./N.V. Tel: +32 2 370 48 11 Lietuva UAB AstraZeneca Lietuva Tel: +370 5 2660550 България АстраЗенека България ЕООД Тел.: +359 (2) 44 55 000 Luxembourg/Luxemburg AstraZeneca S.A./N.V. Tél/Tel: +32 2 370 48 11 Česká republika AstraZeneca Czech Republic s.r.o. Tel: +420 222 807 111 Magyarország AstraZeneca Kft. Tel.: +36 1 883 6500 Danmark AstraZeneca A/S Tlf: +45 43 66 64 62 Malta Associated Drug Co. Ltd Tel: +356 2277 8000 Deutschland AstraZeneca GmbH Tel: +49 41 03 7080 Nederland AstraZeneca BV Tel: +31 79 363 2222 Eesti AstraZeneca Tel: +372 6549 600 Norge AstraZeneca AS Tlf: +47 21 00 64 00 Ελλάδα AstraZeneca A.E. Τηλ: +30 2 106871500 Österreich AstraZeneca Österreich GmbH Tel: +43 1 711 31 0 España AstraZeneca Farmacéutica Spain, S.A. Tel: +34 91 301 91 00 Polska AstraZeneca Pharma Poland Sp. z o.o. Tel.: +48 22 245 73 00 France AstraZeneca Tél: +33 1 41 29 40 00 Portugal AstraZeneca Produtos Farmacêuticos, Lda. Tel: +351 21 434 61 00 Hrvatska AstraZeneca d.o.o. Tel: +385 1 4628 000 România AstraZeneca Pharma SRL Tel: +40 21 317 60 41 Ireland A. Menarini Pharmaceuticals Ireland Ltd Tel: +353 1 284 6744 Slovenija AstraZeneca UK Limited Tel: +386 1 51 35 600 Ísland Vistor hf. Sími: +354 535 70 00 Slovenská republika AstraZeneca AB, o.z. Tel: +421 2 5737 7777 Italia AstraZeneca S.p.A. Tel: +39 02 9801 1 Suomi/Finland AstraZeneca Oy Puh/Tel: +358 10 23 010 Κύπρος Αλέκτωρ Φαρµακευτική Λτδ Τηλ: +357 22490305 Sverige AstraZeneca AB Tel: +46 8 553 26 000 30 Latvija SIA AstraZeneca Latvija Tel: +371 67377100 United Kingdom AstraZeneca UK Ltd Tel: +44 1582 836 836 This leaflet was last revised in <{month YYYY}>. Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. http://www.ema.europa.eu/ 31 Instructions for Use This section contains information on how to use your Genuair inhaler. It is important that you read this information as the Genuair may work differently from inhalers you have used previously. If you have any questions about how to use your inhaler, please ask your doctor, pharmacist or nurse for assistance. The Instructions for Use is divided into the following sections: - Getting started - Step 1: Prepare your dose - Step 2: Inhale your medicine - Additional information Getting Started Read these Instructions for Use before you start using the medicine. Become familiar with the parts of your Genuair inhaler. Figure A Before use: a) Before first use, tear open the sealed bag and remove the inhaler. Throw away the bag. b) Do not press the green button until you are ready to take a dose. c) Pull off the cap by lightly squeezing the arrows marked on each side (Figure B). Control window Red = confirms correct inhalation Green button Dose indicator Mouthpiece Protective Cap Control window Green = inhaler ready to use 32 Figure B STEP 1: Prepare your dose 1.1 Look in the opening of the mouthpiece and make sure nothing is blocking it (Figure C). 1.2 Look at the control window (should be red, Figure C). Figure C 1.3 Hold the inhaler horizontally with the mouthpiece facing you and the green button on top (Figure D). Figure D 1.4 Press the green button all the way down to load your dose (Figure E). When you press the button all the way down, the control window changes from red to green. Make sure the green button is on top. Do not tilt. 1.5 Release the green button (Figure F). Make sure you release the button so the inhaler can work correctly. Squeeze here and pull RED Check mouthpiece opening 33 Figure E Figure F Stop and Check: 1.6 Make sure the control window is now green (Figure G). Your medicine is ready to be inhaled. Go to ‘STEP 2: Inhale your medicine’. Figure G What to do if the control window is still red after pressing the button (Figure H). Figure H The dose is not prepared. Go back to ‘STEP 1 Prepare your dose’ and repeat steps 1.1 to 1.6. STEP 2: Inhale your medicine Read steps 2.1 to 2.7 fully before use. Do not tilt. GREEN 34 2.1 Hold the inhaler away from your mouth, and breathe out completely. Never breathe out into the inhaler (Figure I). Figure I 2.2 Hold your head upright, put the mouthpiece between your lips, and close your lips tightly around it (Figure J). Do not hold the green button down while inhaling. 2.3 Take a strong, deep breath through your mouth. Keep breathing in for as long as possible. A ‘click’ will let you know that you are inhaling correctly. Keep breathing in as long as possible after you hear the ‘click’. Some patients may not hear the ‘click’. Use the control window to ensure you have inhaled correctly. 2.4 Take the inhaler out of your mouth. 2.5 Hold your breath for as long as possible. 2.6 Slowly breathe out away from the inhaler. Some patients may experience a grainy sensation in their mouth, or a slightly sweet or bitter taste. Do not take an extra dose even if you do not taste or feel anything after inhaling. Stop and Check: 2.7 Make sure the control window is now red (Figure K). This means you have inhaled your medicine correctly. Figure J 35 Figure K What to do if the control window is still green after inhalation (Figure L). Figure L This means you have not inhaled your medicine correctly. Go back to ‘STEP 2 Inhale your medicine’ and repeat steps 2.1 to 2.7. If the control window still does not change to red, you may have forgotten to release the green button before inhaling, or you may not have inhaled strongly enough. If this happens, try again. Make sure you have released the green button, and you have breathed out completely. Then take a strong, deep breath through the mouthpiece. Please contact your doctor if the control window is still green after repeated attempts. Push the protective cap back onto the mouthpiece after each use (Figure M), to prevent contamination of the inhaler with dust or other materials. You should discard your inhaler if you lose the cap. Additional information What should you do if you accidently prepare a dose? Store your inhaler with the protective cap in place until it is time to inhale your medicine, then remove the cap and start at Step 1.6. How does the dose indicator work? Figure M RED 36  The dose indicator shows the total number of doses left in the inhaler (Figure N).  On first use, every inhaler contains at least 60 doses, or at least 30 doses, depending on the pack size.  Each time you load a dose by pressing the green button, the dose indicator moves by a small amount towards the next number (50, 40, 30, 20, 10, or 0). When should you get a new inhaler? You should get a new inhaler:  If your inhaler appears to be damaged or if you lose the cap, or  When a red band appears in the dose indicator, this means you are nearing your last dose (Figure N), or  If your inhaler is empty (Figure O). Figure N How do you know that your inhaler is empty? When the green button will not return to its full upper position and is locked in a middle position, you have reached the last dose (Figure O). Even though the green button is locked, your last dose may still be inhaled. After that, the inhaler cannot be used again and you should start using a new inhaler. How should you clean the inhaler? Figure O Locked Dose indicator moves slowly from 60 to 0: 60, 50, 40, 30, 20, 10, 0. Dose indicator Red band 37 NEVER use water to clean the inhaler, as this may damage your medicine. If you wish to clean your inhaler, just wipe the outside of the mouthpiece with a dry tissue or paper towel. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what eklira genuair is and what it is used for', 'Section_Content': 'what eklira genuair is the active ingredient of eklira genuair is aclidinium bromide, which belongs to a group of medicines called bronchodilators. bronchodilators relax airways and help keep bronchioles open. eklira genuair is a dry powder inhaler that uses your breath to deliver the medicine directly into your lungs. this makes it easier for chronic obstructive pulmonary disease (copd) patients to breathe. what eklira genuair is used for eklira genuair is indicated to help open the airways and relieve symptoms of copd, a serious, long- term lung disease characterised by breathing difficulties. regular use of eklira genuair can help you when you have ongoing shortness of breath related to your disease to help you minimise the effects of the disease on your everyday life and reduce the number of flare-ups (the worsening of your copd symptoms for several days).', 'Entity_Recognition': [{'Text': 'eklira genuair', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 2, 'BeginOffset': 48, 'EndOffset': 62, 'Score': 0.4634452164173126, 'Text': 'eklira genuair', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 66, 'EndOffset': 84, 'Score': 0.9800098538398743, 'Text': 'aclidinium bromide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 114, 'EndOffset': 123}, {'Id': 4, 'BeginOffset': 131, 'EndOffset': 146, 'Score': 0.6538960337638855, 'Text': 'bronchodilators', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'bronchodilators relax', 'Type': 'TREATMENT', 'BeginOffset': 148, 'EndOffset': 169}, {'Text': 'a dry powder inhaler', 'Type': 'TREATMENT', 'BeginOffset': 228, 'EndOffset': 248}, {'Text': 'your breath', 'Type': 'PROBLEM', 'BeginOffset': 259, 'EndOffset': 270}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 282, 'EndOffset': 294}, {'Id': 0, 'BeginOffset': 314, 'EndOffset': 319, 'Score': 0.9913123250007629, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'chronic obstructive pulmonary disease (copd) patients to breathe', 'Type': 'PROBLEM', 'BeginOffset': 346, 'EndOffset': 410}, {'Text': 'eklira genuair', 'Type': 'TREATMENT', 'BeginOffset': 444, 'EndOffset': 458}, {'Text': 'symptoms', 'Type': 'PROBLEM', 'BeginOffset': 509, 'EndOffset': 517}, {'Id': 10, 'BeginOffset': 521, 'EndOffset': 525, 'Score': 0.9824708104133606, 'Text': 'copd', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9334064722061157}]}, {'Text': 'a serious, long- term lung disease', 'Type': 'PROBLEM', 'BeginOffset': 527, 'EndOffset': 561}, {'Id': 12, 'BeginOffset': 579, 'EndOffset': 601, 'Score': 0.9247609972953796, 'Text': 'breathing difficulties', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5004227757453918}, {'Name': 'DIAGNOSIS', 'Score': 0.5339895486831665}]}, {'Id': 6, 'BeginOffset': 618, 'EndOffset': 632, 'Score': 0.27717605233192444, 'Text': 'eklira genuair', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ongoing shortness of breath', 'Type': 'PROBLEM', 'BeginOffset': 660, 'EndOffset': 687}, {'Text': 'your disease', 'Type': 'PROBLEM', 'BeginOffset': 699, 'EndOffset': 711}, {'Id': 15, 'BeginOffset': 737, 'EndOffset': 759, 'Score': 0.5072214007377625, 'Text': 'effects of the disease', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8473764061927795}], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.6003620624542236, 'RelationshipScore': 0.8430910110473633, 'RelationshipType': 'ACUITY', 'Id': 17, 'BeginOffset': 854, 'EndOffset': 870, 'Text': 'for several days', 'Category': 'MEDICAL_CONDITION', 'Traits': []}]}, {'Text': 'your copd symptoms', 'Type': 'PROBLEM', 'BeginOffset': 835, 'EndOffset': 853}]}

{'Title': '2. what you need to know before you use eklira genuair', 'Section_Content': 'do not use eklira genuair - if you are allergic to aclidinium bromide or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor, pharmacist or nurse before using eklira genuair: - if you have had heart problems recently. - if you see halos around lights or coloured images (glaucoma). - if you have an enlarged prostate, problems passing urine, or a blockage in your bladder. eklira genuair is indicated for maintenance treatment and should not be used to treat a sudden attack of breathlessness or wheezing. if your copd symptoms (breathlessness, wheezing, cough) do not improve or get worse you should contact your doctor for advice as soon as possible. dry mouth, which has been observed with medicines like eklira genuair, may after using your medicine for a long time, be associated with tooth decay. therefore, please remember to pay attention to oral hygiene. stop taking eklira genuair and seek medical help immediately: - if you get tightness of the chest, coughing, wheezing or breathlessness immediately after using the medicine. these may be signs of a condition called bronchospasm. children and adolescents eklira genuair is not for use in children or adolescents below 18 years of age. other medicines and eklira genuair tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. inform your doctor if you have been or are using similar medicines for breathing problems, such as medicines containing tiotropium, ipratropium. ask your doctor or pharmacist if you are not sure. the use of eklira genuair with these medicines is not recommended. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. you should not use eklira genuair if you are pregnant or are breast-feeding unless your doctor tells you so. driving and using machines eklira genuair may have minor influence on the ability to drive and use machines. this medicine may cause headache, dizziness or blurred vision. if you are affected by any of these side effects do not drive or use machinery until the headache has cleared, the feeling of dizziness has passed and your vision has returned to normal. eklira genuair contains lactose if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.', 'Entity_Recognition': [{'Text': 'eklira genuair', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 7, 'BeginOffset': 11, 'EndOffset': 25, 'Score': 0.3066582977771759, 'Text': 'eklira genuair', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.7793554663658142}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 39, 'EndOffset': 47}, {'Id': 8, 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{'Title': '3. how to use eklira genuair', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose is one inhalation twice a day in the morning and evening. the effects of eklira genuair last for 12 hours; therefore, you should try to use your eklira genuair inhaler at the same time every morning and evening. this ensures that there is always enough medicine in your body to help you breathe more easily throughout the day and night. it will also help you to remember to use it. the recommended dose can be used for elderly patients and for patients with kidney or liver problems. no dose adjustments are necessary. copd is a long-term disease; therefore, it is recommended that eklira genuair is used every day, twice a day and not only when breathing problems or other symptoms of copd are experienced. route of administration 27 the medicine is for inhalation use. refer to the instructions for use for instructions on how to use the genuair inhaler. if you are not sure of how to use eklira genuair, contact your doctor or pharmacist. you can use eklira genuair any time before or after food or drink. if you use more eklira genuair than you should if you think you may have used more eklira genuair than you should, contact your doctor or pharmacist. if you forget to use eklira genuair if you forget a dose of eklira genuair, inhale the dose as soon as you remember. however, if it is nearly time for your next dose, skip the missed dose. do not take a double dose to make up for a forgotten dose. if you stop using eklira genuair this medicine is for long-term use. if you want to stop treatment, first talk to your doctor, as your symptoms may worsen. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'eklira genuair', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Id': 4, 'BeginOffset': 228, 'EndOffset': 242, 'Score': 0.36421290040016174, 'Text': 'eklira genuair', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DURATION', 'Score': 0.4599418640136719, 'RelationshipScore': 0.6085618138313293, 'RelationshipType': 'DURATION', 'Id': 5, 'BeginOffset': 252, 'EndOffset': 260, 'Text': '12 hours', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 252, 'EndOffset': 254}, {'Text': 'your eklira genuair inhaler', 'Type': 'TREATMENT', 'BeginOffset': 295, 'EndOffset': 322}, {'Id': 16, 'BeginOffset': 613, 'EndOffset': 637, 'Score': 0.46534207463264465, 'Text': 'kidney or liver problems', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5544891357421875}, {'Name': 'DIAGNOSIS', 'Score': 0.7322047352790833}]}, {'Id': 1, 'BeginOffset': 623, 'EndOffset': 628, 'Score': 0.9917090535163879, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'dose adjustments', 'Type': 'TREATMENT', 'BeginOffset': 642, 'EndOffset': 658}, {'Id': 17, 'BeginOffset': 674, 'EndOffset': 678, 'Score': 0.8811670541763306, 'Text': 'copd', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8865282535552979}]}, {'Text': 'a long-term disease', 'Type': 'PROBLEM', 'BeginOffset': 682, 'EndOffset': 701}, {'Text': 'eklira genuair', 'Type': 'TREATMENT', 'BeginOffset': 737, 'EndOffset': 751}, {'Id': 19, 'BeginOffset': 801, 'EndOffset': 819, 'Score': 0.5084285140037537, 'Text': 'breathing problems', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6326615214347839}]}, {'Text': 'other symptoms', 'Type': 'PROBLEM', 'BeginOffset': 823, 'EndOffset': 837}, {'Id': 20, 'BeginOffset': 841, 'EndOffset': 845, 'Score': 0.9707489013671875, 'Text': 'copd', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8472395539283752}]}, {'Text': '27', 'Type': 'NUMBER', 'BeginOffset': 887, 'EndOffset': 889}, {'Text': 'the genuair inhaler', 'Type': 'TREATMENT', 'BeginOffset': 991, 'EndOffset': 1010}, {'Id': 14, 'BeginOffset': 1374, 'EndOffset': 1388, 'Score': 0.3284434378147125, 'Text': 'eklira genuair', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 1515, 'EndOffset': 1528}, {'Id': 15, 'BeginOffset': 1580, 'EndOffset': 1586, 'Score': 0.19798091053962708, 'Text': 'eklira', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 1651, 'EndOffset': 1660}, {'Text': 'your symptoms', 'Type': 'PROBLEM', 'BeginOffset': 1692, 'EndOffset': 1705}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1766, 'EndOffset': 1779}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. allergic reactions may rarely occur (may affect up to 1 in 1,000 people). stop using the medicine and contact your doctor immediately if you develop swelling of your face, throat, lips or tongue (with or without difficulty breathing or swallowing), dizziness or fainting, faster heart rate or if you get raised severely itchy bumps on your skin (hives) as these may be symptoms of an allergic reaction. the following side effects may occur whilst using eklira genuair: common: may affect up to 1 in 10 people - headache - inflammation of the sinuses (sinusitis) - common cold (nasopharyngitis) - cough - diarrhoea - nausea uncommon: may affect up to 1 in 100 people - dizziness - dry mouth - inflammation of the mouth (stomatitis) - hoarseness (dysphonia) - faster heart beat (tachycardia) - sensation of heart beating (palpitations) - difficulty passing urine (urinary retention) - blurred vision - rash - itching of the skin reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting 28 system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': None}

{'Title': '5. how to store eklira genuair', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the inhaler label and carton after "exp". the expiry date refers to the last day of that month. keep the inhaler inside the pouch until the administration period starts. to be used within 90 days of opening the pouch. do not use the eklira genuair if you notice that the pack is damaged or shows signs of tampering. after you have taken the last dose, the inhaler has to be disposed of. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information instructions for use', 'Section_Content': 'what eklira genuair contains - the active substance is aclidinium bromide. each delivered dose contains 375 micrograms aclidinium bromide equivalent to 322 micrograms of aclidinium. - the other ingredient is lactose monohydrate (refer to section 2 "eklira genuair contains lactose"). what eklira genuair looks like and contents of the pack eklira genuair is a white or almost white powder. the genuair inhaler device is white coloured with an integral dose indicator and a green dosage button. the mouthpiece is covered with a removable green protective cap. it is supplied in a plastic pouch. pack sizes supplied: carton containing 1 inhaler with 30 doses. carton containing 1 inhaler with 60 doses. carton containing 3 inhalers each with 60 doses. not all pack sizes may be marketed.', 'Entity_Recognition': None}

528B762D4619412DFD587388A74F39C1

https://www.ema.europa.eu/documents/product-information/refixia-epar-product-information_en.pdf

Refixia

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Refixia 500 IU powder and solvent for solution for injection Refixia 1000 IU powder and solvent for solution for injection Refixia 2000 IU powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Refixia 500 IU powder and solvent for solution for injection Each vial contains nominally 500 IU nonacog beta pegol*. After reconstitution, 1 ml of Refixia contains approximately 125 IU nonacog beta pegol. Refixia 1000 IU powder and solvent for solution for injection Each vial contains nominally 1000 IU nonacog beta pegol*. After reconstitution, 1 ml of Refixia contains approximately 250 IU nonacog beta pegol. Refixia 2000 IU powder and solvent for solution for injection Each vial contains nominally 2000 IU nonacog beta pegol*. After reconstitution, 1 ml of Refixia contains approximately 500 IU nonacog beta pegol. *recombinant human factor IX, produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology, covalently conjugated to a 40 kDa polyethylene-glycol (PEG). The potency (International Units) is determined using the European Pharmacopeia one-stage clotting test. The specific activity of Refixia is approximately 152 IU/mg protein. Refixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG) selectively attached to specific N-linked glycans in the rFIX activation peptide. Upon activation of Refixia, the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activated factor IX molecule. The primary amino acid sequence of the rFIX in Refixia is identical to the Ala148 allelic form of human plasma-derived factor IX. No additives of human or animal origin are used in the cell culture, purification, conjugation, or formulation of Refixia. Excipient with known effect Less than 1 mmol sodium (23 mg) per vial. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. The powder is white to off-white. The solvent is clear and colourless. pH: 6.4. Osmolality: 272 mOsmol/kg. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment and prophylaxis of bleeding in patients 12 years and above with haemophilia B (congenital factor IX deficiency). 4.2 Posology and method of administration Treatment should be under the supervision of a physician experienced in the treatment of haemophilia. Previously untreated patients The safety and efficacy of Refixia in previously untreated patients have not yet been established. Treatment monitoring Routine monitoring of factor IX activity levels for the purpose of dose adjustment is not necessary. In the clinical trial programme, dose adjustment was not performed. Mean steady state factor IX trough levels above 15% were observed for all age groups, see section 5.2 for details. Due to the interference of polyethylene glycol (PEG) in the one-stage clotting assay with various aPTT reagents, it is recommended to use a chromogenic assay (e.g. Rox Factor IX or Biophen) when monitoring is needed. If a chromogenic assay is not available, it is recommended to use a one-stage clotting assay with an aPTT reagent (e.g. Cephascreen) qualified for use with Refixia. For modified long-acting factor products it is known that the one-stage clotting assay results are highly dependent on the aPTT reagent and reference standard used. For Refixia some reagents will cause underestimation (30–50%), while most silica containing reagents will cause severe overestimation of the factor IX activity (more than 400%). Therefore, silica based reagents should be avoided. Use of a reference laboratory is recommended when a chromogenic assay or a qualified one-stage clotting assay is not available locally. Posology The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor IX in plasma). Prophylaxis 40 IU/kg body weight once weekly. Adjustments of doses and administration intervals may be considered based on achieved FIX levels and individual bleeding tendency. The trough levels achieved with the weekly 40 IU/kg dosing regimen are summarised in section 5.2. Patients on prophylaxis who forget a dose are advised to take their dose upon discovery and thereafter continue with the usual once weekly dosing schedule. A double dose should be avoided. On-demand treatment Dose and duration of the substitution therapy depend on the location and severity of the bleeding, see Table 1 for dosing guidance in bleeding episodes. Table 1 Treatment of bleeding episodes with Refixia Degree of haemorrhage Recommended dose IU/kg of Refixia Dosing recommendations 4 Early haemarthrosis, muscle bleeding or oral bleeding. More extensive haemarthrosis, muscle bleeding or haematoma. 40 A single dose is recommended. Severe or life threatening haemorrhages. 80 Additional doses of 40 IU/kg can be given. Surgery The dose level and dosing intervals for surgery depend on the procedure and local practice. General recommendations are provided in Table 2. Table 2 Treatment in surgery with Refixia Type of surgical procedure Recommended dose IU/kg body weight Dosing recommendations Minor surgery including tooth extraction. 40 Additional doses can be given if needed. Major surgery. 80 Pre-operative dose. 40 Consider two repeated doses of 40 IU/kg (in 1–3 day intervals) within the first week after surgery. Due to the long half-life of Refixia, the frequency of dosing in the post-surgical period may be extended to once weekly after the first week until bleeding stops and healing is achieved. Paediatric population The dose recommendations in adolescents (12–18 years) are the same as for adults: 40 IU/kg body weight. The long-term safety of Refixia in children below 12 years has not yet been established. Method of administration Intravenous use. Refixia is administered by intravenous bolus injection over several minutes after reconstitution of the powder for injection with the histidine solvent. The rate of administration should be determined by the patient’s comfort level up to a maximum injection rate of 4 ml/min. For instructions on reconstitution of the medicinal product before administration, see section 6.6. In case of self-administration or administration by caregiver appropriate training is needed. 4.3 Contraindications 5 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Known allergic reaction to hamster protein. 4.4 Special warnings and precautions for use Hypersensitivity Allergic type hypersensitivity reactions are possible with Refixia. The product contains traces of hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. In case of shock, standard medical treatment for shock should be implemented. Inhibitors After repeated treatment with human coagulation factor IX (rDNA) products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing. There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX. Because of the risk of allergic reactions with factor IX products, the initial administrations of factor IX should, according to the treating physician’s judgement, be performed under medical observation where proper medical care for allergic reactions could be provided. In case of residual FIX activity levels, there is a risk of interference when performing the Nijmegen modified Bethesda assay for inhibitor testing. Therefore a pre-heating step or a wash-out is recommended in order to ensure detection of low-titre inhibitors. Thromboembolism Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with Refixia should be weighed against the risk of these complications. Cardiovascular event In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk. Catheter-related complications If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered. Paediatric population Refixia is not indicated for use in children (below 12 years). The listed warnings and precautions apply both to adults and adolescents (12–18 years). Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially “sodium-free”. 6 Record of use It is strongly recommended that every time that Refixia is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction No interactions of human coagulation factor IX (rDNA) products with other medicinal products have been reported. 4.6 Fertility, pregnancy and lactation Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breastfeeding is not available. Therefore, factor IX should be used during pregnancy and lactation only if clearly indicated. 4.7 Effects on ability to drive and use machines Refixia has no influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely with recombinant factor IX products and may in some cases progress to severe anaphylaxis (including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also section 4.4). Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction. Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed. Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre is contacted. There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX products like Refixia is rarely associated with such adverse reactions. Tabulated list of adverse reactions The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. A total of 115 previously treated male patients with moderate or severe haemophilia B have been exposed to Refixia for a total of 170 patient years in the completed clinical trials. 7 Table 3 Frequency of adverse reactions in clinical trials System Organ Class Adverse reaction Frequency Immune system disorders Hypersensitivity Anaphylaxis Inhibitors Uncommon Unknown Unknown Cardiac disorders Palpitations Uncommon Gastrointestinal disorders Nausea Common Skin and subcutaneous tissue disorders Pruritus* Common General disorders and administration site conditions Fatigue Hot flush Injection site reactions** Common Uncommon Common *Pruritus includes the terms pruritus and ear pruritus **Injection site reactions include injection site pain, infusion site pain, injection site swelling, injection site erythema and injection site rash. Description of selected adverse reactions In an ongoing trial in previously untreated patients, anaphylaxis has occurred in close temporal association with development of factor IX inhibitors following treatment with Refixia. There are insufficient data to provide information on inhibitor incidence in previously untreated patients. Paediatric population Refixia is indicated for patients 12 years and above. No difference in the safety profile of Refixia was observed between previously treated adolescent (12–18 years) and adult patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Overdoses up to 169 IU/kg have been reported in clinical trials. No symptoms associated with overdoses have been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX, ATC code: B02BD04. Mechanism of action Refixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG) conjugated to the protein. The average molecular weight of Refixia is approximately 98 kDa and the molecular weight of the protein moiety alone is 56 kDa. Upon activation of Refixia, the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activated factor IX molecule. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 8 Factor IX is a single chain glycoprotein. It is a vitamin-K dependent coagulation factor and it is synthesised in the liver. Factor IX is activated by factor XIa and by factor VII/tissue factor complex. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in profuse bleeding into joints, muscles, or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies. Clinical efficacy The completed clinical trial programme included one phase 1 trial and four phase 3 multicentre, non- controlled trials. Prophylaxis Fifty-four of the patients across all age-groups were treated with a weekly prophylactic dose of 40 IU/kg where 23 (43%) of these patients had no bleeding episodes. Pivotal trial The pivotal trial included 74 adolescent (13–17 years) and adult (18–65 years) previously treated patients. The trial included one open-label on-demand arm with treatment for approximately 28 weeks and two prophylaxis treatment arms with single-blind randomisation to either 10 IU/kg or 40 IU/kg once-weekly for approximately 52 weeks. When comparing the 10 IU/kg and 40 IU/kg treatments, the annualised bleeding rate for patients in the 40 IU/kg arm was found to be 49% lower than the bleeding rate (95% CI: 5%;73%) for patients in the 10 IU/kg arm (p<0.05). The median (IQR) overall annual bleeding rate (ABR) in patients (13–65 years) treated with a prophylactic dose of 40 IU/kg once weekly was 1.04 (0.00; 4.01) whereas the traumatic ABR was 0.00 (0.00; 2.05), joint ABR was 0.97 (0.00; 2.07) and spontaneous ABR was 0.00 (0.00; 0.99). Of note, ABR is not comparable between different factor concentrates and between different clinical studies. In this pivotal trial in adolescent and adult patients, there were 70 breakthrough bleeding episodes for 16 out of 29 patients in the 40 IU/kg prophylaxis arm. The overall success rate for treatment of breakthrough bleeds was 97.1% (67 out of 69 evaluated bleeds). A total of 69 (98.6%) of the 70 bleeding episodes were treated with one injection. Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds. In 29 adult and adolescent patients treated, 13 patients with 20 target joints were treated for one year with a weekly prophylactic dose of 40 IU/kg. Eighteen out of these 20 joints (90%) were no longer considered target joints at the end of the trial. On-demand treatment In the pivotal trial there was a non-randomised arm where 15 patients were treated in an on-demand regimen with 40 IU/kg for mild or moderate bleeds and 80 IU/kg for severe bleeds. The overall success rate (defined as excellent or good) for treatment of bleeds was 95% with 98% of the bleeds treated with one or two injections. Paediatric population The use of Refixia in children below 12 years is not indicated (see section 4.2 for information on paediatric use). A trial including 25 paediatric previously treated patients (ages 0–12 years) who received a prophylactic dose 40 IU/kg once weekly was performed. In children aged 0–12 years, the median (IQR) annualised bleeding rate was 1.0 (0.00; 2.06) and the spontaneous bleeding rate was 0.00 (0.00; 0.00). 9 For treatment of bleeds in paediatrics, the overall success rate (defined as excellent or good) was 93% (39 out of 42 bleeds), where 36 (86 %) of the bleeds were resolved with 1 injection, and 5 (12%) of the bleeds were resolved with 2 injections of Refixia. The European Medicines Agency has deferred the completion of the study with Refixia in previously untreated patients (see section 4.2 for information on paediatric use). Overall haemostatic efficacy Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds or 80 IU/kg for severe bleeds, where one bleed was evaluated as severe. An overall assessment of haemostatic efficacy was performed by the patient or caretaker (for home treatment) or study site investigator (for treatment under health care professional supervision) using a 4-point scale of excellent, good, moderate, or poor. The overall success rate (defined as excellent or good) for treatment of bleeds was 93% (551 out of 591). Of the 597 treated bleeds observed in 79 (75%) of the 105 patients, 521 (87%) of the bleeds were resolved with 1 injection and 60 (10%) of the bleeds were resolved with 2 injections of Refixia. The success rate and dose needed for treatment of the bleeding episodes were independent of the localisation of the bleed. The success rate for treatment of bleeding episodes was also independent of whether the bleed was traumatic or spontaneous of nature. Surgery Three trials of which one trial was a dedicated surgery trial included in total 15 major and 26 minor surgery procedures (patients aged 13 to 56 years). Haemostatic effect of Refixia during surgery was confirmed with a success rate of 100% in the 15 major surgeries in the trials. All evaluated minor surgeries were performed successfully. In a dedicated surgery trial, the efficacy analysis included 13 major surgical procedures performed in 13 previously treated adult and adolescent patients. The procedures included 9 orthopaedic, 1 gastrointestinal, and 3 surgeries in the oral cavity. The patients received 1 pre-operative injection of 80 IU/kg on the day of surgery, and post-operatively, injections of 40 IU/kg. A pre-operative dose of 80 IU/kg Refixia was effective and no patients required additional doses on the day of surgery. In the post-surgery period Day 1 to 6 and Day 7 to 13, the median number of additional 40 IU/kg doses administered was 2.0 and 1.5, respectively. The mean total consumption of Refixia during and after surgery was 241 IU/kg (range: 81–460 IU/kg). 5.2 Pharmacokinetic properties Refixia has a prolonged half-life compared to unmodified factor IX. All pharmacokinetic studies with Refixia were conducted in previously treated patients with haemophilia B (factor IX ≤2%). The analysis of plasma samples was conducted using the one-stage clotting assay. Steady state pharmacokinetic parameters for adolescents and adults are shown in Table 4 Table 4 Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescents and adults (geometric mean (CV%)) PK Parameter 13–17 years N=3 ≥18 years N=6 Half-life (t1/2) (hours) 103 (14) 115 (10) Incremental Recovery (IR) (IU/ml per IU/kg) 0.018 (28) 0.019 (20) Area under the curve (AUC)0-168h (IU*hours/ml) 91 (22) 93 (15) Clearance (CL) (ml/hour/kg) 0.4 (17) 0.4 (11) Mean residence time (MRT) (hours) 144 (15) 158 (10) 10 Volume of distribution (Vss) (ml/kg) 61 (31) 66 (12) Factor IX activity 168 h post dosing (IU/ml) 0.29 (19) 0.32 (17) Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of distribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation. All patients assessed in the steady state pharmacokinetic session had factor IX activity levels above 0.24 IU/ml at 168 hours post dosing with a weekly dose of 40 IU/kg. Single-dose pharmacokinetic parameters of Refixia are listed by age in Table 5. The use of Refixia in children below 12 years is not indicated. Table 5 Single-dose pharmacokinetic parameters of Refixia (40 IU/kg) by age (geometric mean (CV%)) PK Parameter 0–6 years N=12 7–12 years N=13 13–17 years N=3 ≥18 years N=6 Half-life (t1/2) (hours) 70 (16) 76 (26) 89 (24) 83 (23) Incremental Recovery (IR) (IU/ml per IU/kg) 0.015 (7) 0.016 (16) 0.020 (15) 0.023 (11) Area under the curve (AUC)inf (IU*hours/ml) 46 (14) 56 (19) 80 (35) 91 (16) Clearance CL (ml/hour/kg) 0.8 (13) 0.6 (22) 0.5 (30) 0.4 (15) Mean residence time (MRT) (hours) 95 (15) 105 (24) 124 (24) 116 (22) Volume of distribution (Vss) (ml/kg) 72 (15) 68 (22) 59 (8) 47 (16) Factor IX activity 168 h post dosing (IU/ml) 0.08 (16) 0.11 (19) 0.15 (60) 0.17 (31) Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of distribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation. As expected, body weight adjusted clearance in paediatric and adolescent patients was higher compared to adults. No dose adjustment was required for paediatric or adolescent patients in clinical trials. The mean trough levels at steady state are presented in Table 6; based on all pre-dose measurements taken every 8 weeks at steady state for all patients on once weekly dosing of 40 IU/kg. The use of Refixia in children below 12 years is not indicated. Table 6 Mean of trough levels* of Refixia (40 IU/kg) at steady state 0–6 years 7–12 years 13–17 years 18–65 years 11 N=12 N=13 N=9 N=20 Estimated mean factor IX trough levels IU/ml (95% CI) 0.15 (0.13;0.18) 0.19 (0.16;0.22) 0.24 (0.20;0.28) 0.29 (0.26;0.33) * Factor IX trough levels = factor IX activity measured prior to next weekly dose (5 to 10 days post dosing) at steady state. Pharmacokinetics were investigated in 16 adult and adolescent patients of which 6 were normal weight (BMI 18.5–24.9 kg/m2) and 10 were overweight (BMI 25–29.9 kg/m2). There were no apparent differences in the pharmacokinetic profiles between normal weight and overweight patients. 5.3 Preclinical safety data In a repeat dose toxicity study in monkeys, mild and transient body tremors were seen 3 hours post dosing and abated within 1 hour. These body tremors were seen at doses of Refixia (3,750 IU/kg), which were more than 90 times higher than the recommended dose for humans (40 IU/kg). No mechanism behind the tremors was identified. Tremors have not been reported in the clinical trials. Non-clinical data reveal no concern for humans based on conventional safety pharmacology and repeated dose toxicity studies in rats and monkeys. In repeat dose toxicity studies in rats and monkeys, 40 kDa polyethylene-glycol (PEG) was detected by immunohistochemical staining in epithelial cells of choroid plexus in the brain. This finding was not associated with tissue damage or abnormal clinical signs. In distribution and excretion studies in mice and rats, the 40 kDa polyethylene-glycol (PEG) moiety of Refixia was shown to be widely distributed to and eliminated from organs, and excreted via plasma in urine (44–56%) and faeces (28–50%). Based on modelled data using observed terminal half-lives (15– 49 days) in rat tissue distribution studies, the 40 kDa polyethylene-glycol (PEG) moiety will reach steady state levels in all human tissues within 1–2 years of treatment. Long-term studies in animals to evaluate the carcinogenic potential of Refixia, or studies to determine the effects of Refixia on genotoxicity, fertility, development, or reproduction have not been performed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder Sodium chloride Histidine Sucrose Polysorbate 80 Mannitol Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Solvent Histidine Water for injections Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) 6.2 Incompatibilities 12 In the absence of compatibility studies, this medicine must not be mixed with other medicinal products or reconstituted with infusion solutions other than the provided histidine solvent. 6.3 Shelf life Unopened 2 years. During the shelf life Refixia may be stored up to 30°C for a single period not exceeding 6 months. Once the product has been taken out of the refrigerator the product must not be returned to the refrigerator. Please record the beginning of storage at room temperature on the product carton. After reconstitution Chemical and physical in-use stability have been demonstrated for 24 hours stored in a refrigerator (2°C – 8°C) and 4 hours stored at room temperature (≤ 30°C). From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the users and would normally not be recommended for longer than 4 hours stored at room temperature (≤ 30°C) or 24 hours in a refrigerator (2°C – 8°C), unless reconstitution has taken place under controlled and validated aseptic conditions. 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect from light. For storage at room temperature and storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Each pack contains: – 1 glass vial (type I) with powder and chlorobutyl rubber stopper – 1 sterile vial adapter for reconstitution – 1 pre-filled syringe of 4 ml histidine solvent with backstop (polypropylene), a rubber plunger (bromobutyl) and a tip cap with a stopper (bromobutyl) – 1 plunger rod (polypropylene). Pack size of 1. 6.6 Special precautions for disposal and other handling Refixia is to be administered intravenously after reconstitution of the powder with the solvent supplied in the syringe. After reconstitution the solution appears as a clear and colourless liquid free of visible particles. Reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior to administration. Do not use solutions that are cloudy or have deposits. For instructions on reconstitution of the medicinal product before administration, see the package leaflet. The rate of administration should be determined by the patient’s comfort level up to a maximum injection rate of 4 ml/min. An infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters will also be needed. These devices are not included in the Refixia package. Always use an aseptic technique. 13 Disposal After injection, safely dispose of the syringe with the infusion set and the vial with the vial adapter. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 8. MARKETING AUTHORISATION NUMBERS EU/1/17/1193/001 EU/1/17/1193/002 EU/1/17/1193/003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 14 ANNEX II A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 15 A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers of the biological active substance Novo Nordisk A/S Brennum Park 25K DK-3400 Hillerød Denmark Novo Nordisk A/S Hagedornsvej 1 DK-2820 Gentofte Denmark Name and address of the manufacturer responsible for batch release Novo Nordisk A/S Novo Alle DK-2880 Bagsværd Denmark B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Obligation to conduct post-authorisation measures 16 The MAH shall complete, within the stated timeframe, the below measures: Description Due date Non-interventional post-authorisation safety study (PASS): In order to investigate the potential effects of PEG accumulation in the choroid plexus of the brain and other tissues/organs, the MAH should conduct and submit the results of a non- interventional post-authorisation safety study deriving from a registry of Haemophilia patients according to an agreed protocol. Submission of study results: Q2-2028 17 ANNEX III LABELLING AND PACKAGE LEAFLET 18 A. LABELLING 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT Refixia 500 IU powder and solvent for solution for injection nonacog beta pegol (recombinant coagulation factor IX) 2. STATEMENT OF ACTIVE SUBSTANCE Powder: 500 IU nonacog beta pegol (approx. 125 IU/ml after reconstitution), 3. LIST OF EXCIPIENTS Powder: sodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide, hydrochloric acid Solvent: Histidine, water for injections, sodium hydroxide, hydrochloric acid 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in a pre-filled syringe, 1 plunger rod and 1 vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Read the package leaflet before use Intravenous use, after reconstitution 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 20 Store in a refrigerator. Do not freeze Can be stored at room temperature (up to 30°C) for a single period up to 6 months. Must not be returned to refrigerator after storage at room temperature Date removed from refrigerator: ____________ Store in the original package to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBER EU/1/17/1193/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Refixia 500 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 21 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Refixia 500 IU powder for solution for injection nonacog beta pegol IV 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 500 IU 6. OTHER Novo Nordisk A/S 22 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT Refixia 1000 IU powder and solvent for solution for injection nonacog beta pegol (recombinant coagulation factor IX) 2. STATEMENT OF ACTIVE SUBSTANCE Powder: 1000 IU nonacog beta pegol (approx. 250 IU/ml after reconstitution), 3. LIST OF EXCIPIENTS Powder: sodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide, hydrochloric acid Solvent: Histidine, water for injections, sodium hydroxide, hydrochloric acid 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in a pre-filled syringe, 1 plunger rod and 1 vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Read the package leaflet before use Intravenous use, after reconstitution 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 23 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze Can be stored at room temperature (up to 30°C) for a single period up to 6 months. Must not be returned to refrigerator after storage at room temperature Date removed from refrigerator: ____________ Store in the original package to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBER EU/1/17/1193/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Refixia 1000 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 24 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Refixia 1000 IU powder for solution for injection nonacog beta pegol IV 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1000 IU 6. OTHER Novo Nordisk A/S 25 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT Refixia 2000 IU powder and solvent for solution for injection nonacog beta pegol (recombinant coagulation factor IX) 2. STATEMENT OF ACTIVE SUBSTANCE Powder: 2000 IU nonacog beta pegol (approx. 500 IU/ml after reconstitution), 3. LIST OF EXCIPIENTS Powder: sodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide, hydrochloric acid Solvent: Histidine, water for injections, sodium hydroxide, hydrochloric acid 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in a pre-filled syringe, 1 plunger rod and 1 vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Read the package leaflet before use Intravenous use, after reconstitution 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 26 Store in a refrigerator. Do not freeze Can be stored at room temperature (up to 30°C) for a single period up to 6 months. Must not be returned to refrigerator after storage at room temperature Date removed from refrigerator: ____________ Store in the original package to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBER EU/1/17/1193/003 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Refixia 2000 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 27 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Refixia 2000 IU powder for solution for injection nonacog beta pegol IV 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2000 IU 6. OTHER Novo Nordisk A/S 28 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Pre-filled syringe 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Solvent for Refixia Histidine solution 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 4 ml 6. OTHER Novo Nordisk A/S 29 B. PACKAGE LEAFLET 30 Package leaflet: Information for the user Refixia 500 IU powder and solvent for solution for injection Refixia 1000 IU powder and solvent for solution for injection Refixia 2000 IU powder and solvent for solution for injection nonacog beta pegol This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Refixia is and what it is used for 2. What you need to know before you use Refixia 3. How to use Refixia 4. Possible side effects 5. How to store Refixia 6. Contents of the pack and other information 1. What Refixia is and what it is used for What Refixia is Refixia contains the active substance nonacog beta pegol and is a long-acting recombinant coagulation factor IX product. Factor IX is a protein naturally found in the blood that helps to stop bleeding. What Refixia is used for Refixia is used to treat and prevent bleeding in patients 12 years and above with haemophilia B (inborn factor IX deficiency). In patients with haemophilia B, factor IX is missing or does not work properly. Refixia replaces this faulty or missing factor IX and helps blood to form clots at the site of bleeding. When you bleed, Refixia is activated in the blood to form factor IX. 2. What you need to know before you use Refixia Do not use Refixia: • if you are allergic to the active substance or any of the other ingredients of this medicine (listed in section 6). • if you are allergic to hamster proteins. If you are not sure if either of the above applies to you, talk to your doctor before using this medicine. Warnings and precautions 31 Allergic reactions and development of inhibitors There is a rare risk that you may experience a sudden and severe allergic reaction (e.g. anaphylactic reaction) to Refixia. Stop the injection and contact your doctor or an emergency unit immediately if you have signs of an allergic reaction such as rash, hives, weals, itching on large areas of skin, redness and/or swelling of lips, tongue, face or hands, difficulty in swallowing or breathing, shortness of breath, wheezing, tightness of the chest, pale and cold skin, fast heartbeat, and/or dizziness. Your doctor may need to treat you promptly for these reactions. Your doctor may also do a blood test to check if you have developed factor IX inhibitors (neutralising antibodies) against your medicine, as inhibitors may develop together with allergic reactions. If you have such antibodies, you may be at an increased risk of sudden and severe allergic reactions (e.g. anaphylactic reaction) during future treatment with factor IX. Because of the risk of allergic reactions with factor IX, your initial treatment with Refixia should be given in a medical clinic or in the presence of health care professionals where proper medical care for allergic reactions can be provided if needed. Talk to your doctor immediately if your bleeding does not stop as expected or if you have to significantly increase your usage of Refixia in order to stop a bleed. Your doctor will do a blood test to check if you have developed inhibitors (neutralising antibodies) against Refixia. The risk for developing inhibitors is highest if you have not been treated with factor IX medicines before i.e. for small children. Blood clots Tell your doctor, if any of the following apply to you as there is an increased risk of blood clots during treatment with Refixia: • you have recently had surgery • you suffer from other serious illness e.g. liver disease, heart disease, or cancer • you have risk factors for heart disease e.g high blood pressure, obesity, or smoking. Kidney disorder (nephrotic syndrome) There is a rare risk of developing a specific kidney disorder called “nephrotic syndrome” following high doses of factor IX in haemophilia B patients with factor IX inhibitors and a history of allergic reactions. Catheter-related problems If you have a central venous access device (CVAD), you may develop infections or blood clots at the site of the catheter. Other medicines and Refixia Tell your doctor if you are taking, have recently taken or might take any other medicines. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using Refixia. Driving and using machines Refixia has no influence on the ability to drive and use machines. Refixia contains sodium This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially “sodium-free”. 3. How to use Refixia 32 Treatment with Refixia will be started by a doctor who is experienced in the care of patients with haemophilia B. Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure about how to use Refixia. Your doctor will calculate your dose for you. The dose will depend on your weight and what the medicine is being used for. Prevention of bleeding The dose of Refixia is 40 international units (IU) per kg of body weight. This is given as one injection every week. Your doctor may choose another dose or how often the injections should be given, based on your need. Treatment of bleeding The dose of Refixia is 40 international units (IU) per kg of body weight. Depending on the location and the severity of bleeding you may need a higher dose (80 IU per kg) or extra injections. Discuss with your doctor the dose and number of injections you need. Use in children and adolescents Refixia can be used only in adolescents (12 years and above). The dose in adolescents is also calculated according to body weight and is the same dose as for adults. How Refixia is given Refixia is given as an injection into a vein. See “Instructions on how to use Refixia” for more information. If you use more Refixia than you should If you use more Refixia than you should, contact your doctor. If you have to significantly increase your usage of Refixia to stop a bleed, talk to your doctor immediately. For further information, see section 2 “Allergic reactions and development of inhibitors”. If you forget to use Refixia If you forget a dose, inject the missed dose as soon as you remember. Do not inject a double dose to make up for a forgotten dose. If you are in doubt contact your doctor. If you stop using Refixia If you stop using Refixia you may no longer be protected against bleeding or a current bleed may not stop. Do not stop using Refixia without talking to your doctor. If you have any further questions on the use of this medicine, ask your doctor. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Allergic reactions are possible with this medicine. If sudden and severe allergic reactions (e.g. anaphylactic reactions) occur, the injection must be stopped immediately. You must contact your doctor or an emergency unit immediately if you have early signs of an allergic reaction such as: • difficulty in swallowing or breathing • shortness of breath or wheezing • chest tightness • redness and/or swelling of the lips, tongue, face or hands • rash, hives, weals or itching • pale and cold skin, fast heartbeat, and/or dizziness (low blood pressure). 33 The following side effects have been observed with Refixia: Common side effects (may affect up to 1 in 10 people) • itching (pruritus) • skin reactions at the site of injection • feeling sick (nausea) • feeling very tired. Uncommon side effects (may affect up to 1 in 100 people) • allergic reactions (hypersensitivity). This may become severe and could be life-threatening (anaphylactic reactions) • heart palpitations • hot flush. Side effects with unknown frequency (frequency cannot be estimated from the available data) • neutralising antibodies (inhibitors). Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Refixia Keep this medicine out of the sight and reach of children. Do not use Refixia after the expiry date which is stated after “EXP” on the carton and on the vial and the pre-filled syringe labels. The expiry date refers to the last day of that month. Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect from light. Refixia may be taken out of the refrigerator for a maximum period of 6 months and stored at room temperature (up to 30°C). Please record on the carton the date Refixia is removed from the refrigerator and placed at room temperature. This new expiry date should never exceed the one initially mentioned on the outer carton. If the medicine has not been used before the new expiry date, it should be disposed of. After storage at room temperature the medicine must not be put back in the refrigerator. Use the injection immediately after reconstitution. If it cannot be used immediately, use within 24 hours if stored in a refrigerator at 2°C – 8°C or within 4 hours if stored out of the refrigerator at a maximum temperature of 30°C. The powder in the vial appears as a white to off-white powder. Do not use the powder if the colour has changed. The reconstituted solution will be clear and colourless. Do not use the reconstituted solution if you notice any particles or discolouration. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Refixia contains http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 34 • The active substance is nonacog beta pegol (pegylated human coagulation factor IX (rDNA)). Each vial of Refixia contains nominally 500 IU, 1000 IU or 2000 IU nonacog beta pegol corresponding to approximately 125 IU/ml, 250 IU/ml or 500 IU/ml respectively after reconstitution with histidine solvent. • The other ingredients in the powder are sodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide and hydrochloric acid. • The ingredients in the sterilised solvent are histidine, water for injections, sodium hydroxide and hydrochloric acid. What Refixia looks like and contents of the pack • Refixia is provided as a powder and solvent for solution for injection (500 IU, 1000 IU or 2000 IU powder in a vial and 4 ml solvent in a pre-filled syringe, a plunger rod with a vial adapter – pack size of 1). • The powder is white to off-white and the solvent is clear and colourless. Marketing Authorisation Holder and Manufacturer Novo Nordisk A/S Novo Allé DK-2880 Bagsværd, Denmark This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ 35 Instructions on how to use Refixia Read these instructions carefully before using Refixia. Refixia is supplied as a powder. Before injection it must be reconstituted with the solvent supplied in the syringe. The solvent is a histidine solution. The reconstituted product must be injected into your vein (intravenous (IV) injection). The equipment in this package is designed to reconstitute and inject Refixia. You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters. These items are not included in the Refixia package. Do not use the equipment without proper training from your doctor or nurse. Always wash your hands and ensure that the area around you is clean. When you prepare and inject medicine directly into the veins, it is important to use a clean and germ free (aseptic) technique. Incorrect technique can introduce germs that can infect the blood. Do not open the equipment until you are ready to use it. Do not use the equipment if it has been dropped, or if it is damaged. Use a new package instead. Do not use the equipment if it has expired. Use a new package instead. The expiry date is printed on the outer carton, on the vial, on the vial adapter, and on the pre-filled syringe. Do not use the equipment if you suspect it is contaminated. Use a new package instead. Do not dispose of any of the items until after you have injected the reconstituted solution. The equipment is for single use only. Contents The package contains: • 1 vial with Refixia powder • 1 vial adapter • 1 pre-filled syringe with solvent • 1 plunger rod (placed under the syringe) 36 Vial with Refixia powder Plastic cap Rubber stopper (under plastic cap) Overview Vial adapter Protective cap Spike (under protective paper) Protective paper Pre-filled syringe with solvent Syringe tip (under syringe cap) Scale Plunger Syringe cap 37 Plunger rod Thread Wide top end 1. Prepare the vial and the syringe • Take out the number of Refixia packages you need. • Check the expiry date. • Check the name, strength and colour of the package, to make sure it contains the correct product. • Wash your hands and dry them properly using a clean towel or air dry. • Take the vial, the vial adapter and the pre- filled syringe out of the carton. Leave the plunger rod untouched in the carton. • Bring the vial and the pre-filled syringe to room temperature. You can do this by holding them in your hands until they feel as warm as your hands. • Do not use any other way to warm the vial and pre-filled syringe. A • Remove the plastic cap from the vial. If the plastic cap is loose or missing, do not use the vial. • Wipe the rubber stopper with a sterile alcohol swab and allow it to air dry for a few seconds before use to ensure that it is as germ free as possible. • Do not touch the rubber stopper with your fingers as this can transfer germs. B 38 2. Attach the vial adapter • Remove the protective paper from the vial adapter. If the protective paper is not fully sealed or if it is broken, do not use the vial adapter. Do not take the vial adapter out of the protective cap with your fingers. If you touch the spike on the vial adapter, germs from your fingers can be transferred. C • Place the vial on a flat and solid surface. • Turn over the protective cap, and snap the vial adapter onto the vial. Once attached, do not remove the vial adapter from the vial. D • Lightly squeeze the protective cap with your thumb and index finger as shown. Remove the protective cap from the vial adapter. Do not lift the vial adapter from the vial when removing the protective cap. E 3. Attach the plunger rod and the syringe • Grasp the plunger rod by the wide top end and take it out of the carton. Do not touch the sides or the thread of the plunger rod. If you touch the sides or the thread, germs from your fingers can be transferred. • Immediately connect the plunger rod to the syringe by turning it clockwise into the plunger inside the pre-filled syringe until resistance is felt. F • Remove the syringe cap from the pre-filled syringe by bending it down until the perforation breaks. • Do not touch the syringe tip under the syringe cap. If you touch the syringe tip, germs from your fingers can be transferred. If the syringe cap is loose or missing, do G 39 not use the pre-filled syringe. • Screw the pre-filled syringe securely onto the vial adapter until resistance is felt. H 4. Reconstitute the powder with the solvent • Hold the pre-filled syringe slightly tilted with the vial pointing downwards. • Push the plunger rod to inject all the solvent into the vial. I • Keep the plunger rod pressed down and swirl the vial gently until all the powder is dissolved. Do not shake the vial as this will cause foaming. • Check the reconstituted solution. It must be clear and colourless and no particles should be visible. If you notice particles or discolouration, do not use it. Use a new package instead. J Refixia is recommended to be used immediately after it has been reconstituted. This is because if left, the medicine may no longer be sterile and could cause infections. If you cannot use the reconstituted Refixia solution immediately, it should be used within 4 hours when stored at room temperature (up to 30°C) and within 24 hours when stored in a refrigerator (2°C – 8°C). Store the reconstituted product in the vial. Do not freeze reconstituted Refixia solution or store it in syringes. Keep reconstituted Refixia solution out of direct light. If your dose requires more than one vial, repeat steps A to J with additional vials, vial adapters and pre-filled syringes until you have reached your required dose. 40 • Keep the plunger rod pushed completely in. • Turn the syringe with the vial upside down. • Stop pushing the plunger rod and let it move back on its own while the reconstituted solution fills the syringe. • Pull the plunger rod slightly downwards to draw the reconstituted solution into the syringe. • In case you only need part of the entire vial, use the scale on the syringe to see how much reconstituted solution you withdraw, as instructed by your doctor or nurse. If, at any point, there is air in the syringe, inject the air back into the vial. • While holding the vial upside down, tap the syringe gently to let any air bubbles rise to the top. • Push the plunger rod slowly until all air bubbles are gone. K • Unscrew the vial adapter with the vial. • Do not touch the syringe tip. If you touch the syringe tip, germs from your fingers can be transferred. L 5. Inject the reconstituted solution Refixia is now ready to inject into your vein. • Inject the reconstituted solution as instructed by your doctor or nurse. • Inject slowly over 1 to 3 minutes. • Do not mix Refixia with any other intravenous infusions or medications. Injecting Refixia via needleless connectors for intravenous (IV) catheters Caution: The pre-filled syringe is made of glass and is designed to be compatible with standard luer- lock connections. Some needleless connectors with an internal spike are incompatible with the pre-filled syringe. This incompatibility may prevent administration of the drug and/or result in damage to the needleless connector. Injecting the solution via a central venous access device (CVAD) such as a central venous catheter or a subcutaneous port: • Use a clean and germ free (aseptic) technique. Follow the instructions for proper use for your connector and CVAD in consultation with your doctor or nurse. 41 • Injecting into a CVAD may require using a sterile 10 ml plastic syringe for withdrawal of the reconstituted solution. This should be done right after step J. • If the CVAD line needs to be flushed before or after Refixia injection, use sodium chloride 9 mg/ml solution for injection. Disposal • After injection, safely dispose of all unused Refixia solution, the syringe with the infusion set, the vial with the vial adapter and other waste materials as instructed by your pharmacist. Do not throw it out with the ordinary household waste. M Do not disassemble the equipment before disposal. Do not reuse the equipment. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what refixia is and what it is used for', 'Section_Content': 'what refixia is refixia contains the active substance nonacog beta pegol and is a long-acting recombinant coagulation factor ix product. factor ix is a protein naturally found in the blood that helps to stop bleeding. what refixia is used for refixia is used to treat and prevent bleeding in patients 12 years and above with haemophilia b (inborn factor ix deficiency). in patients with haemophilia b, factor ix is missing or does not work properly. refixia replaces this faulty or missing factor ix and helps blood to form clots at the site of bleeding. when you bleed, refixia is activated in the blood to form factor ix.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'refixia', 'Type': 'PROBLEM', 'BeginOffset': 16, 'EndOffset': 23}, {'Text': 'the active substance nonacog beta pegol', 'Type': 'TREATMENT', 'BeginOffset': 33, 'EndOffset': 72}, {'Text': 'a long-acting recombinant coagulation factor ix product', 'Type': 'TREATMENT', 'BeginOffset': 80, 'EndOffset': 135}, {'Text': 'factor ix', 'Type': 'PROBLEM', 'BeginOffset': 137, 'EndOffset': 146}, {'Text': 'a protein naturally', 'Type': 'PROBLEM', 'BeginOffset': 150, 'EndOffset': 169}, {'Text': 'the blood', 'Type': 'PROBLEM', 'BeginOffset': 179, 'EndOffset': 188}, {'Id': 1, 'BeginOffset': 208, 'EndOffset': 216, 'Score': 0.6613272428512573, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'refixia', 'Type': 'TREATMENT', 'BeginOffset': 243, 'EndOffset': 250}, {'Id': 2, 'BeginOffset': 280, 'EndOffset': 288, 'Score': 0.9881094098091125, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6549317240715027}]}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 301, 'EndOffset': 303}, {'Text': 'haemophilia b (inborn factor ix deficiency', 'Type': 'PROBLEM', 'BeginOffset': 325, 'EndOffset': 367}, {'Id': 5, 'BeginOffset': 387, 'EndOffset': 398, 'Score': 0.6948233842849731, 'Text': 'haemophilia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5652453303337097}]}, {'Id': 6, 'BeginOffset': 402, 'EndOffset': 422, 'Score': 0.8082478642463684, 'Text': 'factor ix is missing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.470569372177124}]}, {'Text': 'this faulty', 'Type': 'PROBLEM', 'BeginOffset': 467, 'EndOffset': 478}, {'Text': 'missing factor ix', 'Type': 'PROBLEM', 'BeginOffset': 482, 'EndOffset': 499}, {'Id': 7, 'BeginOffset': 524, 'EndOffset': 529, 'Score': 0.6403788328170776, 'Text': 'clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 545, 'EndOffset': 553, 'Score': 0.9661247134208679, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.46187978982925415}]}, {'Text': 'you bleed', 'Type': 'PROBLEM', 'BeginOffset': 560, 'EndOffset': 569}, {'Text': 'refixia', 'Type': 'PROBLEM', 'BeginOffset': 571, 'EndOffset': 578}]}

{'Title': '2. what you need to know before you use refixia', 'Section_Content': 'do not use refixia: if you are allergic to the active substance or any of the other ingredients of this medicine (listed in section 6). if you are allergic to hamster proteins. if you are not sure if either of the above applies to you, talk to your doctor before using this medicine. warnings and precautions 31 allergic reactions and development of inhibitors there is a rare risk that you may experience a sudden and severe allergic reaction (e.g. anaphylactic reaction) to refixia. stop the injection and contact your doctor or an emergency unit immediately if you have signs of an allergic reaction such as rash, hives, weals, itching on large areas of skin, redness and/or swelling of lips, tongue, face or hands, difficulty in swallowing or breathing, shortness of breath, wheezing, tightness of the chest, pale and cold skin, fast heartbeat, and/or dizziness. your doctor may need to treat you promptly for these reactions. your doctor may also do a blood test to check if you have developed factor ix inhibitors (neutralising antibodies) against your medicine, as inhibitors may develop together with allergic reactions. if you have such antibodies, you may be at an increased risk of sudden and severe allergic reactions (e.g. anaphylactic reaction) during future treatment with factor ix. because of the risk of allergic reactions with factor ix, your initial treatment with refixia should be given in a medical clinic or in the presence of health care professionals where proper medical care for allergic reactions can be provided if needed. talk to your doctor immediately if your bleeding does not stop as expected or if you have to significantly increase your usage of refixia in order to stop a bleed. your doctor will do a blood test to check if you have developed inhibitors (neutralising antibodies) against refixia. the risk for developing inhibitors is highest if you have not been treated with factor ix medicines before i.e. for small children. blood clots tell your doctor, if any of the following apply to you as there is an increased risk of blood clots during treatment with refixia: you have recently had surgery you suffer from other serious illness e.g. liver disease, heart disease, or cancer you have risk factors for heart disease e.g high blood pressure, obesity, or smoking. kidney disorder (nephrotic syndrome) there is a rare risk of developing a specific kidney disorder called "nephrotic syndrome" following high doses of factor ix in haemophilia b patients with factor ix inhibitors and a history of allergic reactions. catheter-related problems if you have a central venous access device (cvad), you may develop infections or blood clots at the site of the catheter. other medicines and refixia tell your doctor if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using refixia. driving and using machines refixia has no influence on the ability to drive and use machines. refixia contains sodium this medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially "sodium-free".', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 31, 'EndOffset': 39}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 99, 'EndOffset': 112}, {'Id': 7, 'BeginOffset': 147, 'EndOffset': 175, 'Score': 0.43315285444259644, 'Text': 'allergic to hamster proteins', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5490298271179199}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 269, 'EndOffset': 282}, {'Text': '31', 'Type': 'NUMBER', 'BeginOffset': 309, 'EndOffset': 311}, {'Id': 8, 'BeginOffset': 312, 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0.9410630464553833, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 2, 'BeginOffset': 696, 'EndOffset': 702, 'Text': 'tongue', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9980729818344116, 'RelationshipScore': 0.9741078615188599, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 3, 'BeginOffset': 704, 'EndOffset': 708, 'Text': 'face', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9988961219787598, 'RelationshipScore': 0.9684992432594299, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 4, 'BeginOffset': 712, 'EndOffset': 717, 'Text': 'hands', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'swelling of lips, tongue, face or hands', 'Type': 'PROBLEM', 'BeginOffset': 678, 'EndOffset': 717}, {'Id': 18, 'BeginOffset': 719, 'EndOffset': 756, 'Score': 0.9288513660430908, 'Text': 'difficulty in swallowing or breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 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{'Title': '3. how to use refixia', 'Section_Content': 'treatment with refixia will be started by a doctor who is experienced in the care of patients with haemophilia b. always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure about how to use refixia. your doctor will calculate your dose for you. the dose will depend on your weight and what the medicine is being used for. prevention of bleeding the dose of refixia is 40 international units (iu) per kg of body weight. this is given as one injection every week. your doctor may choose another dose or how often the injections should be given, based on your need. treatment of bleeding the dose of refixia is 40 international units (iu) per kg of body weight. depending on the location and the severity of bleeding you may need a higher dose (80 iu per kg) or extra injections. discuss with your doctor the dose and number of injections you need. use in children and adolescents refixia can be used only in adolescents (12 years and above). the dose in adolescents is also calculated according to body weight and is the same dose as for adults. how refixia is given refixia is given as an injection into a vein. see "instructions on how to use refixia" for more information. if you use more refixia than you should if you use more refixia than you should, contact your doctor. if you have to significantly increase your usage of refixia to stop a bleed, talk to your doctor immediately. for further information, see section 2 "allergic reactions and development of inhibitors". if you forget to use refixia if you forget a dose, inject the missed dose as soon as you remember. do not inject a double dose to make up for a forgotten dose. if you are in doubt contact your doctor. if you stop using refixia if you stop using refixia you may no longer be protected against bleeding or a current bleed may not stop. do not stop using refixia without talking to your doctor. if you have any further 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. allergic reactions are possible with this medicine. if sudden and severe allergic reactions (e.g. anaphylactic reactions) occur, the injection must be stopped immediately. you must contact your doctor or an emergency unit immediately if you have early signs of an allergic reaction such as: difficulty in swallowing or breathing shortness of breath or wheezing chest tightness redness and/or swelling of the lips, tongue, face or hands rash, hives, weals or itching pale and cold skin, fast heartbeat, and/or dizziness (low blood pressure). the following side effects have been observed with refixia: common side effects (may affect up to 1 in 10 people) itching (pruritus) skin reactions at the site of injection feeling sick (nausea) feeling very tired. uncommon side effects (may affect up to 1 in 100 people) allergic reactions (hypersensitivity). this may become severe and could be life-threatening (anaphylactic reactions) heart palpitations hot flush. side effects with unknown frequency (frequency cannot be estimated from the available data) neutralising antibodies (inhibitors). reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 9, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9674293398857117, 'Text': 'side effects', 'Category': 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0.9519163966178894, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6538662314414978}]}, {'Id': 51, 'BeginOffset': 1367, 'EndOffset': 1379, 'Score': 0.8601099848747253, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7099798917770386}]}, {'Id': 52, 'BeginOffset': 1433, 'EndOffset': 1444, 'Score': 0.36894774436950684, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.626948356628418}]}, {'Id': 53, 'BeginOffset': 1458, 'EndOffset': 1470, 'Score': 0.8550413250923157, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7452174425125122}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1526, 'EndOffset': 1539}]}

{'Title': '5. how to store refixia', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use refixia after the expiry date which is stated after "exp" on the carton and on the vial and the pre-filled syringe labels. the expiry date refers to the last day of that month. store in a refrigerator (2 8). do not freeze. store in the original package in order to protect from light. refixia may be taken out of the refrigerator for a maximum period of 6 months and stored at room temperature (up to 30). please record on the carton the date refixia is removed from the refrigerator and placed at room temperature. this new expiry date should never exceed the one initially mentioned on the outer carton. if the medicine has not been used before the new expiry date, it should be disposed of. after storage at room temperature the medicine must not be put back in the refrigerator. use the injection immediately after reconstitution. if it cannot be used immediately, use within 24 hours if stored in a refrigerator at 2 8 or within 4 hours if stored out of the refrigerator at a maximum temperature of 30. the powder in the vial appears as a white to off-white powder. do not use the powder if the colour has changed. the reconstituted solution will be clear and colourless. do not use the reconstituted solution if you notice any particles or discolouration. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 272, 'EndOffset': 273}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 274, 'EndOffset': 275}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 424, 'EndOffset': 425}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 471, 'EndOffset': 474}, {'Text': 'the injection', 'Type': 'TREATMENT', 'BeginOffset': 857, 'EndOffset': 870}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 950, 'EndOffset': 952}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 990, 'EndOffset': 991}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 992, 'EndOffset': 993}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 1004, 'EndOffset': 1005}, {'Text': 'a maximum temperature', 'Type': 'TEST', 'BeginOffset': 1049, 'EndOffset': 1070}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 1074, 'EndOffset': 1077}, {'Text': 'the powder in the vial', 'Type': 'TREATMENT', 'BeginOffset': 1078, 'EndOffset': 1100}, {'Text': 'white powder', 'Type': 'TREATMENT', 'BeginOffset': 1127, 'EndOffset': 1139}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 1152, 'EndOffset': 1162}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 1190, 'EndOffset': 1216}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 1258, 'EndOffset': 1284}, {'Text': 'discolouration', 'Type': 'PROBLEM', 'BeginOffset': 1316, 'EndOffset': 1330}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what refixia contains 34 the active substance is nonacog beta pegol (pegylated human coagulation factor ix (rdna)). each vial of refixia contains nominally 500 iu, 1000 iu or 2000 iu nonacog beta pegol corresponding to approximately 125 iu/ml, 250 iu/ml or 500 iu/ml respectively after reconstitution with histidine solvent. the other ingredients in the powder are sodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide and hydrochloric acid. the ingredients in the sterilised solvent are histidine, water for injections, sodium hydroxide and hydrochloric acid. what refixia looks like and contents of the pack refixia is provided as a powder and solvent for solution for injection (500 iu, 1000 iu or 2000 iu powder in a vial and 4 ml solvent in a pre-filled syringe, a plunger rod with a vial adapter pack size of 1). the powder is white to off-white and the solvent is clear and colourless.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '34', 'Type': 'NUMBER', 'BeginOffset': 22, 'EndOffset': 24}, {'Text': 'nonacog beta pegol (pegylated human coagulation factor ix', 'Type': 'TREATMENT', 'BeginOffset': 49, 'EndOffset': 106}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 156, 'EndOffset': 159}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 164, 'EndOffset': 168}, {'Text': '2000', 'Type': 'NUMBER', 'BeginOffset': 175, 'EndOffset': 179}, {'Text': 'nonacog beta pegol', 'Type': 'TREATMENT', 'BeginOffset': 183, 'EndOffset': 201}, {'Text': '125', 'Type': 'NUMBER', 'BeginOffset': 233, 'EndOffset': 236}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 244, 'EndOffset': 247}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 257, 'EndOffset': 260}, {'Id': 5, 'BeginOffset': 306, 'EndOffset': 323, 'Score': 0.34893694519996643, 'Text': 'histidine solvent', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 365, 'EndOffset': 380, 'Score': 0.9813015460968018, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 382, 'EndOffset': 391, 'Score': 0.9215745329856873, 'Text': 'histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 393, 'EndOffset': 400, 'Score': 0.7138574123382568, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 402, 'EndOffset': 416, 'Score': 0.6599057912826538, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 418, 'EndOffset': 426, 'Score': 0.9205037951469421, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 428, 'EndOffset': 444, 'Score': 0.9984684586524963, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 449, 'EndOffset': 466, 'Score': 0.9953880906105042, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 514, 'EndOffset': 523, 'Score': 0.5334805846214294, 'Text': 'histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.6046119928359985, 'RelationshipScore': 0.9995589852333069, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 535, 'EndOffset': 545, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 535, 'EndOffset': 545}, {'Id': 15, 'BeginOffset': 547, 'EndOffset': 563, 'Score': 0.9990899562835693, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.6046119928359985, 'RelationshipScore': 0.5915699005126953, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 535, 'EndOffset': 545, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 16, 'BeginOffset': 568, 'EndOffset': 585, 'Score': 0.9951306581497192, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.6918653249740601, 'RelationshipScore': 0.7129587531089783, 'RelationshipType': 'DOSAGE', 'Id': 18, 'BeginOffset': 716, 'EndOffset': 723, 'Text': '1000 iu', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the pack refixia', 'Type': 'TREATMENT', 'BeginOffset': 627, 'EndOffset': 643}, {'Text': 'a powder and solvent for solution', 'Type': 'TREATMENT', 'BeginOffset': 659, 'EndOffset': 692}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 708, 'EndOffset': 711}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 716, 'EndOffset': 720}, {'Text': '2000', 'Type': 'NUMBER', 'BeginOffset': 727, 'EndOffset': 731}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 756, 'EndOffset': 757}, {'Text': 'a pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 772, 'EndOffset': 792}, {'Text': 'a plunger rod', 'Type': 'TREATMENT', 'BeginOffset': 794, 'EndOffset': 807}, {'Text': 'a vial adapter pack size', 'Type': 'TREATMENT', 'BeginOffset': 813, 'EndOffset': 837}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 845, 'EndOffset': 855}]}

24F22F9DA3FA2ED775EDC64E4696201A

https://www.ema.europa.eu/documents/product-information/pelmeg-epar-product-information_en.pdf

Pelmeg

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Pelmeg 6 mg solution for injection in pre-filled syringe 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre-filled syringe contains 6 mg of pegfilgrastim* in 0.6 mL solution for injection. The concentration is 10 mg/mL based on protein only**. *Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with polyethylene glycol (PEG). ** The concentration is 20 mg/mL if the PEG moiety is included. The potency of this product should not be compared to the potency of another pegylated or nonpegylated protein of the same therapeutic class. For more information, see section 5.1 Excipient with known effect Each pre-filled syringe contains 30 mg sorbitol (E420). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection Clear, colourless solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes). 4.2 Posology and method of administration Pelmeg therapy should be initiated and supervised by physicians experienced in oncology and/or haematology. Posology One 6 mg dose (a single pre-filled syringe) of Pelmeg is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy. 3 Special populations Paediatric population The safety and efficacy of pegfilgrastim in children has not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made. Patients with renal impairment No dose change is recommended in patients with renal impairment, including those with end stage renal disease. Method of administration Pelmeg is injected subcutaneously. The injections should be given into the thigh, abdomen or upper arm. For instructions on handling of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biologic medicinal products, the tradename and the batch number of the administered product should be clearly recorded in the patient file. Limited clinical data suggest a comparable effect on time to recovery of severe neutropenia for pegfilgrastim to filgrastim in patients with de novo acute myeloid leukaemia (AML) (see section 5.1). However, the long-term effects of Pelmeg have not been established in AML; therefore, it should be used with caution in this patient population. Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro. The safety and efficacy of Pelmeg have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from AML. The safety and efficacy of Pelmeg administration in de novo AML patients aged < 55 years with cytogenetics t (15;17) have not been established. The safety and efficacy of Pelmeg have not been investigated in patients receiving high dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens. Pulmonary adverse events Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk (see section 4.8). The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of Acute Respiratory Distress Syndrome (ARDS). In such circumstances Pelmeg should be discontinued at the discretion of the physician and the appropriate treatment given (see section 4.8). 4 Glomerulonephritis Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended. Capillary leak syndrome Capillary leak syndrome has been reported after granulocyte-colony stimulating factor administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care (see section 4.8). Splenomegaly and splenic rupture Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see section 4.8). Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain. Thrombocytopenia and anaemia Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia. Sickle cell anaemia Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease (see section 4.8). Therefore, physicians should use caution when prescribing Pelmeg in patients with sickle cell trait or sickle cell disease, should monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of this medicinal product with splenic enlargement and vaso-occlusive crisis. Leukocytosis White blood cell (WBC) counts of 100 × 109/L or greater have been observed in less than 1 % of patients receiving pegfilgrastim therapy. No adverse events directly attributable to this degree of leukocytosis have been reported. Such elevation in white blood cells is transient, typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of this medicinal product. Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 × 109/L after the expected nadir, this medicinal product should be discontinued immediately. Hypersensitivity Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have been reported in patients treated with pegfilgrastim. Permanently discontinue Pelmeg in patients with clinically significant hypersensitivity. Do not administer Pelmeg to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. 5 Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against pegfilgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present. Aortitis Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF (see section 4.8). Other warnings The safety and efficacy of Pelmeg for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated. Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging findings. This should be considered when interpreting bone-imaging results. This medicinal product contains 30 mg sorbitol in each pre-filed syringe which is equivalent to 50 mg / mL. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. . This medicinal product contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say essentially ‘sodium-free’. 4.5 Interaction with other medicinal products and other forms of interaction Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ Pelmeg should be administered at least 24 hours after administration of cytotoxic chemotherapy. In clinical trials, pegfilgrastim has been safely administered 14 days before chemotherapy. Concomitant use of Pelmeg with any chemotherapy agent has not been evaluated in patients. In animal models concomitant administration of pegfilgrastim and 5-fluorouracil (5-FU) or other antimetabolites has been shown to potentiate myelosuppression. Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated in clinical trials. The potential for interaction with lithium, which also promotes the release of neutrophils, has not been specifically investigated. There is no evidence that such an interaction would be harmful. The safety and efficacy of Pelmeg have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression e.g., nitrosoureas. 6 Specific interaction or metabolism studies have not been performed, however, clinical trials have not indicated an interaction of pegfilgrastim with any other medicinal products. 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data from the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Pelmeg is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding There is insufficient information on the excretion of pegfilgrastim / metabolites in human milk a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Pelmeg therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 6 to 9 times higher than the recommended human dose (based on body surface area) (see section 5.3). 4.7 Effects on ability to drive and use machines Pelmeg has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and musculoskeletal pain (common). Bone pain was generally of mild to moderate severity, transient and could be controlled in most patients with standard analgesics. Hypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnoea, erythaema, flushing, and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon [≥ 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patients receiving pegfilgrastim (uncommon) (see section 4.4). Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported as uncommon (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following administration of granulocyte colony-stimulating factors; see section 4.4 and section “Description of selected adverse reactions” below. Splenomegaly, generally asymptomatic, is uncommon. Splenic rupture including some fatal cases is uncommonly reported following administration of pegfilgrastim (see section 4.4). Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly, cases have resulted in respiratory failure or Acute Respiratory Distress Syndrome (ARDS), which may be fatal (see section 4.4). Isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell disease (uncommon in sickle cell patients) (see section 4.4). 7 Tabulated list of adverse reactions The data in the table below describe adverse reactions reported from clinical trials and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. MedDRA system organ class Adverse reactions Very common Common Uncommon Rare Very rare (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1,000 to < 1/100) (≥ 1/10,000 to < 1/1,000) (< 1/10,000) Blood and lymphatic system disorders Thrombocytope nia1 Leukocytosis1 Sickle cell crisis2; Splenomegaly2; Splenic rupture2 Immune system disorders Hypersensitivity reactions; Anaphylaxis Metabolism and nutrition disorders Elevations in uric acid Nervous system disorders Headache1 Vascular disorders Capillary leak syndrome1 Aortitis Respiratory, thoracic and mediastinal disorders Acute Respiratory Distress Syndrome2; Pulmonary adverse reactions (interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis) Haemoptysis Pulmonary hemorrhage Gastrointestina l disorders Nausea1 Skin and subcutaneous tissue disorders Sweet’s syndrome (acute febrile dermatosis)1,2; Cutaneous vasculitis1,2 Stevens- Johnson syndrome Musculoskeleta l and connective tissue disorders Bone pain Musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain) 8 MedDRA system organ class Adverse reactions Very common Common Uncommon Rare Very rare (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1,000 to < 1/100) (≥ 1/10,000 to < 1/1,000) (< 1/10,000) Renal and urinary disorders Glomerulo- nephritis2 General disorders and administration site conditions Injection site pain, Non-cardiac chest pain 1 Injection site reactions2 Investigations Elevations in lactate dehydrogenase and alkaline phosphatase1; Transient elevations in LFT's for ALT or AST1 1 See section “Description of selected adverse reactions” below. 2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised, controlled clinical trials in adults that supported the marketing authorisation. The frequency category was estimated from a statistical calculation based upon 1,576 patients receiving pegfilgrastim in nine randomised clinical trials. Description of selected adverse reactions Uncommon cases of Sweet’s syndrome have been reported, although in some cases underlying haematological malignancies may play a role. Uncommon events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim. The mechanism of vasculitis in patients receiving pegfilgrastim is unknown. Injection site reactions, including injection site erythaema (uncommon) as well as injection site pain (common) have occurred on initial or subsequent treatment with pegfilgrastim. Common cases of leukocytosis (White Blood Count [WBC] > 100 × 109/L) have been reported (see section 4.4). Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical effects, were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase, with no associated clinical effects, were uncommon in patients receiving pegfilgrastim following cytotoxic chemotherapy. Nausea and headaches were very commonly observed in patients receiving chemotherapy. Uncommon elevations in liver function tests (LFTs) for ALT (alanine aminotransferase) or AST (aspartate aminotransferase), have been observed in patients after receiving pegfilgrastim following cytotoxic chemotherapy. These elevations are transient and return to baseline. Common cases of thrombocytopenia have been reported. Cases of capillary leak syndrome have been reported in the post marketing setting with granulocyte colony-stimulating factor use. These have generally occurred in patients with advanced malignant 9 diseases, sepsis, taking multiple chemotherapy medicinal products or undergoing apheresis (see section 4.4). Paediatric population The experience in children is limited. A higher frequency of serious adverse reactions in younger children aged 0-5 years (92 %) has been observed compared to older children aged 6-11 and 12-21 years respectively (80 % and 67 %) and adults. The most common adverse reaction reported was bone pain (see section 5.1 and 5.2). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Single doses of 300 μg/kg have been administered subcutaneously to a limited number of healthy volunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverse events were similar to those in subjects receiving lower doses of pegfilgrastim. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: immunostimulants, colony stimulating factor; ATC Code: L03AA13 Pelmeg is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule. Pegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Pegfilgrastim and filgrastim have been shown to have identical modes of action, causing a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes. Similarly to filgrastim, neutrophils produced in response to pegfilgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similar effects may be seen on some non-myeloid cells in vitro. In two randomised, double-blind, pivotal studies in patients with high risk stage II-IV breast cancer undergoing myelosuppressive chemotherapy consisting of doxorubicin and docetaxel, use of pegfilgrastim, as a single once per cycle dose, reduced the duration of neutropenia and the incidence of febrile neutropenia similarly to that observed with daily administrations of filgrastim (a median of 11 daily administrations). In the absence of growth factor support, this regimen has been reported to result in a mean duration of grade 4 neutropenia of 5 to7 days, and a 30-40 % incidence of febrile neutropenia. In one study (n = 157), which used a 6 mg fixed dose of pegfilgrastim the mean duration of grade 4 neutropenia for the pegfilgrastim group was 1.8 days compared with 1.6 days in the filgrastim group (difference 0.23 days, 95 % CI −0.15, 0.63). Over the entire study, the rate of febrile neutropenia was 13 % of pegfilgrastim-treated patients compared with 20 % of filgrastim-treated patients (difference 7 %, 95 % CI of −19 %, 5 %). In a second study (n = 310), which used a weight-adjusted dose (100 μg /kg), the mean duration of grade 4 neutropenia for the pegfilgrastim http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/ 10 group was 1.7 days, compared with 1.8 days in the filgrastim group (difference 0.03 days, 95 % CI −0.36, 0.30). The overall rate of febrile neutropenia was 9 % of patients treated with pegfilgrastim and 18 % of patients treated with filgrastim (difference 9 %, 95 % CI of −16.8 %,−1.1 %). In a placebo-controlled, double blind study in patients with breast cancer the effect of pegfilgrastim on the incidence of febrile neutropenia was evaluated following administration of a chemotherapy regimen associated with a febrile neutropenia rate of 10-20 % (docetaxel 100 mg/m2 every 3 weeks for 4 cycles). Nine hundred and twenty eight patients were randomised to receive either a single dose of pegfilgrastim or placebo approximately 24 hours (Day 2) after chemotherapy in each cycle. The incidence of febrile neutropenia was lower for patients randomised to receive pegfilgrastim compared with placebo (1 % versus 17 %, p < 0.001). The incidence of hospitalisations and IV anti-infective use associated with a clinical diagnosis of febrile neutropenia was lower in the pegfilgrastim group compared with placebo (1 % versus 14 %, p < 0.001; and 2 % versus 10 %, p < 0.001). A small (n = 83), Phase II, randomised, double-blind study in patients receiving chemotherapy for de novo acute myeloid leukaemia compared pegfilgrastim (single dose of 6 mg) with filgrastim, administered during induction chemotherapy. Median time to recovery from severe neutropenia was estimated as 22 days in both treatment groups. Long term outcome was not studied (see section 4.4). In a phase II (n = 37) multicentre, randomised, open-label study of paediatric sarcoma patients receiving 100 μg/kg pegfilgrastim following cycle 1 of vincristine, doxorubicin and cyclophosphamide (VAdriaC/IE) chemotherapy, a longer duration of severe neutropenia (neutrophils < 0.5 × 109) was observed in younger children aged 0-5 years (8.9 days) compared to older children aged 6-11 years and 12-21 years (6 days and 3.7 days, respectively) and adults. Additionally a higher incidence of febrile neutropenia was observed in younger children aged 0-5 years (75 %) compared to older children aged 6-11 years and 12-21 years (70 % and 33 %, respectively) and adults (see sections 4.8 and 5.2). 5.2 Pharmacokinetic properties After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim occurs at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintained during the period of neutropenia after myelosuppressive chemotherapy. The elimination of pegfilgrastim is non-linear with respect to dose; serum clearance of pegfilgrastim decreases with increasing dose. Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the serum concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery (see figure 1). Figure 1: Profile of median pegfilgrastim serum concentration and absolute neutrophil count (ANC) in chemotherapy treated patients after a single 6 mg injection M ed ia n S er um P eg fil gr as tim C on c. (n g/ m l) M ed ia n A bs ol ut e N eu tro ph il C ou nt (c el ls x 1 09 /l) Study Day 11 Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not expected to be affected by renal or hepatic impairment. In an open label, single dose study (n = 31) various stages of renal impairment, including end-stage renal disease, had no impact on the pharmacokinetics of pegfilgrastim. Elderly Limited data indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (> 65 years) is similar to that in adults. Paediatric population The pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma, who received 100 μg/kg pegfilgrastim after the completion of VAdriaC/IE chemotherapy. The youngest age group (0-5 years) had a higher mean exposure to pegfilgrastim (AUC) (± Standard Deviation) (47.9 ± 22.5 μg·hr/mL) than older children aged 6-11 years and 12-21 years (22.0 ± 13.1 μg·hr/mL and 29.3 ± 23.2 μg·hr/mL, respectively) (see section 5.1). With the exception of the youngest age group (0-5 years), the mean AUC in paediatric subjects appeared similar to that for adult patients with high-risk stage II-IV breast cancer and receiving 100 μg/kg pegfilgrastim after the completion of doxorubicin/docetaxel (see sections 4.8 and 5.1). 5.3 Preclinical safety data Preclinical data from conventional studies of repeated dose toxicity revealed the expected pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow, extramedullary haematopoiesis and splenic enlargement. There were no adverse effects observed in offspring from pregnant rats given pegfilgrastim subcutaneously, but in rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity (embryo loss) at cumulative doses approximately 4 times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose. In rat studies, it was shown that pegfilgrastim may cross the placenta. Studies in rats indicated that reproductive performance, fertility, oestrous cycling, days between pairing and coitus, and intrauterine survival were unaffected by pegfilgrastim given subcutaneously. The relevance of these findings for humans is not known. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium acetate* Sorbitol (E 420) Polysorbate 20 Water for injections Hydrochloric acid (for pH adjustment) Sodium hydroxide (for pH adjustment) *Sodium acetate is prepared by mixing sodium acetate trihydrate and acetic acid. 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products, particularly with sodium chloride solutions. 12 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in a refrigerator (2 °C – 8 °C). Pelmeg may be exposed to room temperature (not above 30º C) for a maximum single period of up to 96 hours. Pelmeg left at room temperature for more than 96 hours should be discarded. Do not freeze. Accidental exposure to freezing temperatures for two periods of less than 72 hours each does not adversely affect the stability of Pelmeg. Keep the container in the outer carton in order to protect from light. 6.5 Nature and contents of container Pre-filled syringe (Type I glass), with a bromobutyl rubber stopper and a stainless steel needle with an automatic needle guard. Each pre-filled syringe contains 0.6 mL of solution for injection. Pack size of one pre-filled syringe in a blistered packaging. 6.6 Special precautions for disposal and other handling Before administration, Pelmeg solution should be inspected visually for particulate matter. Only a solution that is clear and colourless should be injected. Excessive shaking may aggregate pegfilgrastim, rendering it biologically inactive. Allow the pre-filled syringe to reach room temperature before injecting. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Mundipharma Biologics S.L. Calle García Ximénez, nº3-1º 31002 Pamplona (Navarra), Spain 8. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1328/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 20 November 2018 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 13 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 14 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance 3P BIOPHARMACEUTICALS SL C/ Mocholi 2, Poligono Industrial Mocholi 31110 Noain Spain Name and address of the manufacturer responsible for batch release PharmaKorell GmbH Marie-Curie-Str. 8 79539 Loerrach Germany B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 15 ANNEX III LABELLING AND PACKAGE LEAFLET 16 A. LABELLING 17 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON FOR BLISTERED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Pelmeg 6 mg solution for injection in pre-filled syringe pegfilgrastim 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 mL (10 mg/mL) solution for injection. 3. LIST OF EXCIPIENTS Excipients: sodium acetate, sorbitol (E 420), polysorbate 20, and water for injections. See package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection 1 pre-filled syringe with automatic needle guard (0.6 mL). 5. METHOD AND ROUTE(S) OF ADMINISTRATION For single use only. For subcutaneous use. Important: read the package leaflet before handling pre-filled syringe 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Avoid vigorous shaking. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the container in the outer carton in order to protect from light. 18 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Mundipharma Biologics S.L. Calle García Ximénez, nº3-1º 31002 Pamplona (Navarra) Spain 12. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1328/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Pelmeg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 19 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER PACK WITH SYRINGE 1. NAME OF THE MEDICINAL PRODUCT Pelmeg 6 mg solution for injection pegfilgrastim 2. NAME OF THE MARKETING AUTHORISATION HOLDER Mundipharma 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER Logo 20 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SYRINGE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Pelmeg 6 mg pegfilgrastim SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.6 mL 6. OTHER Mundipharma 21 B. PACKAGE LEAFLET 22 Package leaflet: Information for the user Pelmeg 6 mg solution for injection in pre-filled syringe pegfilgrastim This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Pelmeg is and what it is used for 2. What you need to know before you use Pelmeg 3. How to use Pelmeg 4. Possible side effects 5. How to store Pelmeg 6. Contents of the pack and other information 1. What Pelmeg is and what it is used for Pelmeg contains the active substance pegfilgrastim. Pegfilgrastim is a protein produced by biotechnology in bacteria called E. coli. It belongs to a group of proteins called cytokines, and is very similar to a natural protein (granulocyte-colony stimulating factor) produced by your own body. Pelmeg is used in adult patients to reduce the duration of neutropenia (low white blood cell count) and the occurrence of febrile neutropenia (low white blood cell count with a fever) which can be caused by the use of cytotoxic chemotherapy (medicines that destroy rapidly growing cells). White blood cells are important as they help your body fight infection. These cells are very sensitive to the effects of chemotherapy which can cause the number of these cells in your body to decrease. If white blood cells fall to a low level there may not be enough left in the body to fight bacteria and you may have an increased risk of infection. Your doctor has given you Pelmeg to encourage your bone marrow (part of the bone which makes blood cells) to produce more white blood cells that help your body fight infection. 2. What you need to know before you use Pelmeg Do not use Pelmeg if • you are allergic to pegfilgrastim, filgrastim, E. coli derived proteins, or any of the other ingredients of this medicine. 23 Warnings and precautions Talk to your doctor, pharmacist or nurse before using Pelmeg: • if you experience an allergic reaction including weakness, drop in blood pressure, difficulty breathing, swelling of the face (anaphylaxis), redness and flushing, skin rash and areas of the skin that itch • if you experience a cough, fever and difficulty breathing. This can be a sign of Acute Respiratory Distress Syndrome (ARDS) • if you have any of the following or combination of the following side effects: - swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness These could be symptoms of condition called “Capillary Leak Syndrome” which causes blood to leak from the small blood vessels into your body. See section 4. • if you get left upper abdominal pain or pain at the tip of your shoulder. This may be a sign of a problem with your spleen (splenomegaly) • if you have recently had a serious lung infection (pneumonia), fluid in the lungs (pulmonary oedema), inflammation of the lungs (interstitial lung disease) or an abnormal chest x-ray (lung infiltration) • if you are aware of any altered blood cell counts (e.g. increase in white blood cells or anaemia) or decreased blood platelet counts, which reduces the ability of your blood to clot (thrombocytopenia). Your doctor may want to monitor you more closely. • if you have sickle cell anaemia. Your doctor may monitor your condition more closely. • if you have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing these could be signs of a severe allergic reaction. • Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported rarely in cancer patients and healthy donors. The symptoms can include fever, abdominal pain, malaise, back pain and increased inflammatory markers. Tell your doctor if you experience these symptoms. Your doctor will check your blood and urine regularly as Pelmeg can harm the tiny filters inside your kidneys (glomerulonephritis). Severe skin reactions (Stevens-Johnson syndrome) have been reported with the use of Pelmeg. Stop using Pelmeg and seek medical attention immediately if you notice any of the symptoms described in section 4. You should talk to your doctor about your risks of developing cancers of the blood. If you develop or are likely to develop cancers of the blood, you should not use Pelmeg, unless instructed by your doctor. Loss of response to pegfilgrastim If you experience a loss of response or failure to maintain a response with pegfilgrastim treatment, your doctor will investigate the reasons why including whether you have developed antibodies which neutralise pegfilgrastim’s activity. Other medicines and Pelmeg Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 24 Pregnancy and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine. Pelmeg has not been tested in pregnant women. It is important to tell your doctor if you: • are pregnant; • think you may be pregnant; or • are planning to have a baby. If you become pregnant during Pelmeg treatment, please inform your doctor. Unless your doctor directs you otherwise, you must stop breast-feeding if you use Pelmeg. Driving and using machines Pelmeg has no or negligible effect on the ability to drive or use machines. Pelmeg contains sorbitol (E 420) and sodium acetate This medicine contains 30 mg sorbitol in each pre-filed syringe which is equivalent to 50 mg / mL. This medicine contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say essentially ‘sodium-free’. 3. How to use Pelmeg Pelmeg is for use in adults aged 18 and over. Always use Pelmeg exactly as your doctor has told you. You should check with your doctor or pharmacist if you are unsure. The usual dose is one 6 mg subcutaneous injection (injection under your skin) using a pre-filled syringe and it should be given at least 24 hours after your last dose of chemotherapy at the end of each chemotherapy cycle. Do not shake Pelmeg vigorously as this may affect its activity. Injecting Pelmeg yourself Your doctor may decide that it would be more convenient for you to inject Pelmeg yourself. Your doctor or nurse will show you how to inject yourself. Do not try to inject yourself if you have not been trained. For further instructions on how to inject yourself with Pelmeg, please read the section at the end of this leaflet. If you use more Pelmeg than you should If you use more Pelmeg than you should contact your doctor, pharmacist or nurse. If you forget to inject Pelmeg If you have forgotten a dose of Pelmeg, you should contact your doctor to discuss when you should inject the next dose. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 25 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Please tell your doctor immediately if you have any of the following or combination of the following side effects: • swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. These symptoms generally develop in a rapid fashion. These could be symptoms of an uncommon (may affect up to 1 in 100 people) condition called “Capillary Leak Syndrome” which causes blood to leak from the small blood vessels into your body and needs urgent medical attention. Very common side effects (may affect more than 1 in 10 people): • bone pain. Your doctor will tell you what you can take to ease the bone pain. • nausea and headaches. Common side effects (may affect up to 1 in 10 people): • pain at the site of injection. • general aches and pains in the joints and muscles. • some changes may occur in your blood, but these will be detected by routine blood tests. Your white blood cell count may become high for a short period of time. Your platelet count may become low which might result in bruising. Uncommon side effects (may affect up to 1 in 100 people): • allergic-type reactions, including redness and flushing, skin rash, and raised areas of the skin that itch. • serious allergic reactions, including anaphylaxis (weakness, drop in blood pressure, difficulty breathing, swelling of the face). • increased spleen size. • spleen rupture. Some cases of splenic rupture were fatal. It is important that you contact your doctor immediately if you experience pain in the upper left side of the abdomen or left shoulder pain since this may relate to a problem with your spleen. • breathing problems. If you have a cough, fever and difficulty breathing please tell your doctor. • Sweet’s syndrome (plum-coloured, raised, painful lesions on the limbs and sometimes the face and neck with fever) has occurred but other factors may play a role. • cutaneous vasculitis (inflammation of the blood vessels in the skin). • damage to the tiny filters inside your kidneys (glomerulonephritis). • redness at the site of injection. • coughing up blood (haemoptysis). Rare side effects (may affect up to 1 in 1,000 people) • Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body), see section 2. • Bleeding from the lung (pulmonary haemorrhage). • Stevens-Johnson syndrome, which can appear as reddish target-like or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. Stop using Pelmeg if you develop these symptoms and contact your doctor or seek medical attention immediately. See also section 2. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 26 5. How to store Pelmeg Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the syringe label after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2 °C - 8 °C). You may take Pelmeg out of the refrigerator and keep it at room temperature (not above 30° C) for no longer than 4 days. Once a syringe has been removed from the refrigerator and has reached room temperature (not above 30° C) it must either be used within 4 days or disposed of. Do not freeze. Pelmeg may be used if it is accidentally frozen for two periods of less than 72 hours each. Keep the container in the outer carton in order to protect from light. Do not use this medicine if you notice it is cloudy or there are particles in it. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other infor mation What Pelmeg contains • The active substance is pegfilgrastim. Each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 mL of solution. • The other ingredients are sodium acetate, sorbitol (E 420), polysorbate 20 and water for injections. See section 2. What Pelmeg looks like and contents of the pack Pelmeg is a clear, colourless solution for injection in a pre-filled syringe (6 mg/0.6 mL). Each pack contains 1 pre-filled glass syringe with an attached stainless steel needle and needle cap. The syringe is provided with an automatic needle guard. Marketing Authorisation Holder Mundipharma Biologics S.L. Calle García Ximénez, nº3-1º 31002 Pamplona (Navarra) Spain Manufacturer PharmaKorell GmbH Marie-Curie-Strasse 8 D-79539 Lörrach Germany For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: 27 België/Belgique/Belgien Mundipharma Comm. VA Tél/Tel: +32 15 45 11 80 info@mundipharma.be Lietuva EGIS Pharmaceuticals PLC atstovybė Tel.:+ 370 5 231 4658 info@egis.lt България ТП„Мундифарма Гезелшафт м.б.Х.“ Teл.: + 359 2 962 13 56 mundipharma@mundipharma.bg Luxembourg/Luxemburg Mundipharma Comm. VA Tél/Tel: +32 15 45 11 80 info@mundipharma.be Česká republika Mundipharma GesmbH. Austria - organizační složka ČR Tel: + 420 222 318 221 office@mundipharma.cz Magyarország Egis Gyógyszergyár Zrt. Tel.: +36 1 803 5555 mailbox@egis.hu Danmark Mundipharma A/S Tlf: + 45 45 17 48 00 mundipharma@mundipharma.dk Malta Mundipharma Corporation (Ireland) Limited Tel: +353 1 206 3800 Deutschland Mundipharma GmbH Tel: +49 (0) 69 506029-000 info@mundipharma.de Nederland Mundipharma Pharmaceuticals B.V. Tel: + 31 (0)33 450 82 70 info@mundipharma.nl Eesti KBM Pharma OÜ Tel: +372 733 8080 Norge Mundipharma AS Tlf: + 47 67 51 89 00 post@mundipharma.no Ελλάδα Mundipharma Corporation (Ireland) Limited Τηλ: + 353 1 206 3800 Österreich Mundipharma Gesellschaft m.b.H. Tel: +43 (0)1 523 25 05-0 info@mundipharma.at España Mundipharma Pharmaceuticals, S.L. Tel: +34 91 3821870 infomed@mundipharma.es Polska Mundipharma Polska Sp. z o.o. Tel.: + (48 22) 866 87 12 biuro@mundipharma.pl France MUNDIPHARMA SAS Tél: +33 1 40 65 29 29 infomed@mundipharma.fr Portugal Mundipharma Farmacêutica Lda Tel: +351 21 901 31 62 medinfo@mundipharma.pt Hrvatska Medis Adria d.o.o Tel: + 385 (0) 1 230 34 46 info@medisadria.hr Ireland Mundipharma Pharmaceuticals Limited Tel: +353 1 206 3800 România Egis Pharmaceuticals PLC România Tel: +40 21 412 00 17 office@egis.ro Slovenija Medis, d.o.o. Tel: +386 158969 00 info@medis.si mailto:info@mundipharma.be mailto:info@egis.lt mailto:info@mundipharma.be mailto:office@mundipharma.cz mailto:mailbox@egis.hu mailto:mundipharma@mundipharma.dk mailto:info@mundipharma.nl mailto:post@mundipharma.no mailto:info@mundipharma.at mailto:infomed@mundipharma.es mailto:biuro@mundipharma.pl mailto:infomed@mundipharma.fr mailto:info@medisadria.hr mailto:office@egis.ro mailto:info@medis.si 28 Ísland Icepharma hf. Sími: + 354 540 8000 icepharma@icepharma.is Slovenská republika Mundipharma Ges.m.b.H.-o.z. Tel: + 4212 6381 1611 mundipharma@mundipharma.sk Italia Mundipharma Pharmaceuticals Srl Tel: +39 02 3182881 infomedica@mundipharma.it Suomi/Finland Mundipharma Oy Puh/Tel: + 358 (0)9 8520 2065 info@mundipharma.fi Κύπρος Mundipharma Pharmaceuticals Ltd Τηλ: +357 22 815656 info@mundipharma.com.cy Sverige Mundipharma AB Tel: + 46 (0)31 773 75 30 info@mundipharma.se Latvija EGIS Pharmaceuticals PLC parstavniecibas Tel: + 371 676 13 859 info@egis.lv United Kingdom NAPP Pharmaceuticals Limited Tel: +44(0) 1223 424444 This leaflet was last revised in . Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. QR code to be included <www.pelmeg.eu> mailto:icepharma@icepharma.is mailto:mundipharma@mundipharma.sk mailto:infomedica@mundipharma.it mailto:info@mundipharma.fi mailto:info@mundipharma.com.cy mailto:info@mundipharma.se mailto:info@egis.lv http://www.ema.europa.eu/ 29 Instructions for use Guide to parts Before use After use Before use After use Used plunger Plunger Syringe label Finger grips Used syring barrel Syringe label Syringe barrel Used needle Syringe safety guard Used needle safety spring Needle safety spring Needle cap on Needle cap off Important Before you use a Pelmeg pre-filled syringe with automatic needle guard, read this important information: • It is important that you do not try to give yourself the injection unless you have received training from your doctor or healthcare provider. • Pelmeg is given as an injection into the tissue just under the skin (subcutaneous injection). Do not remove the needle cap from the pre-filled syringe until you are ready to inject. Do not use the pre-filled syringe if it has been dropped on a hard surface. Use a new pre-filled syringe and call your doctor or healthcare provider. Do not attempt to activate the pre-filled syringe prior to injection. Do not attempt to remove the clear pre-filled syringe safety guard from the pre-filled syringe Do not attempt to remove the peelable label on the pre-filled syringe barrel before administering your injection. Call your doctor or healthcare provider if you have any questions. 30 Step 1: Prepare A Remove the pre-filled syringe tray from the package and gather the supplies needed for your injection: alcohol wipes, a cotton ball or gauze pad, a plaster and a sharps disposal container (not included). For a more comfortable injection, leave the pre-filled syringe at room temperature for about 30 minutes before injecting. Wash your hands thoroughly with soap and water. On a clean, well-lit work surface, place the new pre-filled syringe and the other supplies. Do not try to warm the syringe by using a heat source such as hot water or microwave. Do not leave the pre-filled syringe exposed to direct sunlight. Do not shake the pre-filled syringe. Keep pre-filled syringes out of the sight and reach of children. B Open the tray, peeling away the cover. Grab the pre-filled syringe safety guard to remove the pre-filled syringe from the tray. For safety reasons: Do not grasp the plunger. Do not grasp the needle cap. C Inspect the medicine and pre-filled syringe. Do not use the pre-filled syringe if: • The medicine is cloudy or there are particles in it. It must be a clear and colourless liquid. • Any part appears cracked or broken. • The needle cap is missing or not securely attached. • The expiry date printed on the label has passed the last day of the month shown. In all cases, call your doctor or healthcare provider. Grab here Medicine 31 Step 2: Get ready A Wash your hands thoroughly. Prepare and clean your injection site. Upper arm Belly Upper thigh You can use: • Upper part of your thigh. • Belly, except for a 5 cm (2-inch) area right around your belly button. • Outer area of upper arm (only if someone else is giving you the injection). Clean the injection site with an alcohol wipe. Let your skin dry. Do not touch the injection site before injecting. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. 32 B Carefully pull the needle cap straight out and away from your body. C Pinch your injection site to create a firm surface. Its important to keep the skin pinched when injecting. Step 3: Inject A Hold the pinch. INSERT the needle into skin. Do not touch the cleaned area of the skin. 33 B PUSH the plunger with slow and constant pressure until you feel or hear a “snap”. Push all the way down through the snap. It is important to push down through the “snap” to deliver your full dose. C RELEASE your thumb. Then LIFT the syringe off skin. After releasing the plunger, the pre-filled syringe safety guard will safely cover the injection needle. Do not put the needle cap back on used pre-filled syringes “SNAP” 34 Healthcare professionals only The trade name and the batch number of the administered product should be clearly recorded in the patient file. Remove and save the pre-filled syringe label Turn the plunger to move the label into a position where you can remove the syringe label 35 Step 4: Finish A Discard the used pre-filled syringe and other supplies in a sharps disposal container. Medicines should be disposed of in accordance with local requirements. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. Keep the syringe and sharps disposal container out of sight and reach of children. Do not reuse the pre-filled syringe. Do not recycle pre-filled syringes or throw them into household waste. B Examine the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply a plaster if needed. 36 ANNEX IV SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S) 37 Scientific conclusions Taking into account the PRAC Assessment Report on the PSUR(s) for pegfilgrastim, the scientific conclusions of the CHMP are as follows: Three reported cases show a causal relationship between the adverse drug reaction (ADR) Stevens- Johnson syndrome and pegfilgrastim. The number of cases is small, but because of the seriousness of the ADR, the PRAC recommends that the Product Information should be updated accordingly. The CHMP agrees with the scientific conclusions made by the PRAC. Grounds for the variation to the terms of the marketing authorisation(s) On the basis of the scientific conclusions for pegfilgrastim the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing pegfilgrastim is unchanged subject to the proposed changes to the product information. The CHMP recommends that the terms of the marketing authorisation(s) should be varied. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET ANNEX IV SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)

{'Title': '1. what pelmeg is and what it is used for', 'Section_Content': 'pelmeg contains the active substance pegfilgrastim. pegfilgrastim is a protein produced by biotechnology in bacteria called e. coli. it belongs to a group of proteins called cytokines, and is very similar to a natural protein (granulocyte-colony stimulating factor) produced by your own body. pelmeg is used in adult patients to reduce the duration of neutropenia (low white blood cell count) and the occurrence of febrile neutropenia (low white blood cell count with a fever) which can be caused by the use of cytotoxic chemotherapy (medicines that destroy rapidly growing cells). white blood cells are important as they help your body fight infection. these cells are very sensitive to the effects of chemotherapy which can cause the number of these cells in your body to decrease. if white blood cells fall to a low level there may not be enough left in the body to fight bacteria and you may have an increased risk of infection. your doctor has given you pelmeg to encourage your bone marrow (part of the bone which makes blood cells) to produce more white blood cells that help your body fight infection.', 'Entity_Recognition': [{'Text': 'pelmeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the active substance pegfilgrastim', 'Type': 'TREATMENT', 'BeginOffset': 16, 'EndOffset': 50}, {'Id': 3, 'BeginOffset': 52, 'EndOffset': 65, 'Score': 0.9634522199630737, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a protein', 'Type': 'PROBLEM', 'BeginOffset': 69, 'EndOffset': 78}, {'Text': 'bacteria', 'Type': 'PROBLEM', 'BeginOffset': 108, 'EndOffset': 116}, {'Text': 'e. coli', 'Type': 'PROBLEM', 'BeginOffset': 124, 'EndOffset': 131}, {'Id': 4, 'BeginOffset': 352, 'EndOffset': 363, 'Score': 0.9826478362083435, 'Text': 'neutropenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9310688376426697}]}, {'Text': 'low white blood cell count', 'Type': 'PROBLEM', 'BeginOffset': 365, 'EndOffset': 391}, {'Id': 5, 'BeginOffset': 415, 'EndOffset': 434, 'Score': 0.7473416924476624, 'Text': 'febrile neutropenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9294565320014954}]}, {'Id': 6, 'BeginOffset': 436, 'EndOffset': 462, 'Score': 0.4244369864463806, 'Text': 'low white blood cell count', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6309845447540283}]}, {'Text': 'a fever', 'Type': 'PROBLEM', 'BeginOffset': 468, 'EndOffset': 475}, {'Id': 14, 'BeginOffset': 511, 'EndOffset': 533, 'Score': 0.9141808152198792, 'Text': 'cytotoxic chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 535, 'EndOffset': 544}, {'Id': 15, 'BeginOffset': 582, 'EndOffset': 599, 'Score': 0.4193421006202698, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'your body fight infection', 'Type': 'PROBLEM', 'BeginOffset': 627, 'EndOffset': 652}, {'Text': 'these cells', 'Type': 'PROBLEM', 'BeginOffset': 654, 'EndOffset': 665}, {'Id': 16, 'BeginOffset': 703, 'EndOffset': 715, 'Score': 0.923709511756897, 'Text': 'chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 787, 'EndOffset': 804, 'Score': 0.3899598717689514, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.5636240243911743, 'RelationshipScore': 0.9999697208404541, 'RelationshipType': 'TEST_VALUE', 'Id': 18, 'BeginOffset': 815, 'EndOffset': 818, 'Text': 'low', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'fight bacteria', 'Type': 'PROBLEM', 'BeginOffset': 869, 'EndOffset': 883}, {'Id': 9, 'BeginOffset': 922, 'EndOffset': 931, 'Score': 0.9830544590950012, 'Text': 'infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7930824160575867}]}, {'Text': 'your bone marrow', 'Type': 'PROBLEM', 'BeginOffset': 979, 'EndOffset': 995}, {'Id': 1, 'BeginOffset': 1009, 'EndOffset': 1013, 'Score': 0.7745674848556519, 'Text': 'bone', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 20, 'BeginOffset': 1026, 'EndOffset': 1037, 'Score': 0.3161998391151428, 'Text': 'blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'white blood cells', 'Type': 'TREATMENT', 'BeginOffset': 1055, 'EndOffset': 1072}, {'Text': 'your body fight infection', 'Type': 'PROBLEM', 'BeginOffset': 1083, 'EndOffset': 1108}]}

{'Title': '2. what you need to know before you use pelmeg', 'Section_Content': 'do not use pelmeg if you are allergic to pegfilgrastim, filgrastim, e. coli derived proteins, or any of the other ingredients of this medicine. warnings and precautions talk to your doctor, pharmacist or nurse before using pelmeg: if you experience an allergic reaction including weakness, drop in blood pressure, difficulty breathing, swelling of the face (anaphylaxis), redness and flushing, skin rash and areas of the skin that itch if you experience a cough, fever and difficulty breathing. this can be a sign of acute respiratory distress syndrome (ards) if you have any of the following or combination of the following side effects: - swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness these could be symptoms of condition called "capillary leak syndrome" which causes blood to leak from the small blood vessels into your body. see section 4. if you get left upper abdominal pain or pain at the tip of your shoulder. this may be a sign of a problem with your spleen (splenomegaly) if you have recently had a serious lung infection (pneumonia), fluid in the lungs (pulmonary oedema), inflammation of the lungs (interstitial lung disease) or an abnormal chest x-ray (lung infiltration) if you are aware of any altered blood cell counts (e.g. increase in white blood cells or anaemia) or decreased blood platelet counts, which reduces the ability of your blood to clot (thrombocytopenia). your doctor may want to monitor you more closely. if you have sickle cell anaemia. your doctor may monitor your condition more closely. if you have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing these could be signs of a severe allergic reaction. inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported rarely in cancer patients and healthy donors. the symptoms can include fever, abdominal pain, malaise, back pain and increased inflammatory markers. tell your doctor if you experience these symptoms. your doctor will check your blood and urine regularly as pelmeg can harm the tiny filters inside your kidneys (glomerulonephritis). severe skin reactions (stevens-johnson syndrome) have been reported with the use of pelmeg. stop using pelmeg and seek medical attention immediately if you notice any of the symptoms described in section 4. you should talk to your doctor about your risks of developing cancers of the blood. if you develop or are likely to develop cancers of the blood, you should not use pelmeg, unless instructed by your doctor. loss of response to pegfilgrastim if you experience a loss of response or failure to maintain a response with pegfilgrastim treatment, your doctor will investigate the reasons why including whether you have developed antibodies which neutralise pegfilgrastim\'s activity. other medicines and pelmeg tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding ask your doctor or pharmacist for advice before taking any medicine. pelmeg has not been tested in pregnant women. it is important to tell your doctor if you: are pregnant; think you may be pregnant; or are planning to have a baby. if you become pregnant during pelmeg treatment, please inform your doctor. unless your doctor directs you otherwise, you must stop breast-feeding if you use pelmeg. driving and using machines pelmeg has no or negligible effect on the ability to drive or use machines. pelmeg contains sorbitol (e 420) and sodium acetate this medicine contains 30 mg sorbitol in each pre-filed syringe which is equivalent to 50 mg / ml. this medicine contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say essentially \'sodium-free\'.', 'Entity_Recognition': [{'Text': 'pelmeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 29, 'EndOffset': 37}, {'Id': 23, 'BeginOffset': 41, 'EndOffset': 54, 'Score': 0.9776966571807861, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 24, 'BeginOffset': 56, 'EndOffset': 66, 'Score': 0.9964362382888794, 'Text': 'filgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'e. coli derived proteins', 'Type': 'TREATMENT', 'BeginOffset': 68, 'EndOffset': 92}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 129, 'EndOffset': 142}, {'Text': 'an allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 249, 'EndOffset': 269}, {'Id': 26, 'BeginOffset': 280, 'EndOffset': 288, 'Score': 0.9975115060806274, 'Text': 'weakness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 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itch', 'Type': 'PROBLEM', 'BeginOffset': 417, 'EndOffset': 435}, {'Text': 'a cough', 'Type': 'PROBLEM', 'BeginOffset': 454, 'EndOffset': 461}, {'Id': 36, 'BeginOffset': 463, 'EndOffset': 468, 'Score': 0.9911235570907593, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.950127899646759}]}, {'Id': 37, 'BeginOffset': 473, 'EndOffset': 493, 'Score': 0.9879652261734009, 'Text': 'difficulty breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.953623354434967}]}, {'Text': 'acute respiratory distress syndrome', 'Type': 'PROBLEM', 'BeginOffset': 517, 'EndOffset': 552}, {'Id': 40, 'BeginOffset': 554, 'EndOffset': 558, 'Score': 0.615556001663208, 'Text': 'ards', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.968615710735321, 'RelationshipScore': 0.9726037383079529, 'RelationshipType': 'ACUITY', 'Id': 38, 'BeginOffset': 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'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5263691544532776}]}, {'Text': 'blood to leak from the small blood vessels into your body', 'Type': 'PROBLEM', 'BeginOffset': 908, 'EndOffset': 965}, {'Text': '4.', 'Type': 'NUMBER', 'BeginOffset': 979, 'EndOffset': 981}, {'Text': 'left upper abdominal pain', 'Type': 'PROBLEM', 'BeginOffset': 993, 'EndOffset': 1018}, {'Id': 52, 'BeginOffset': 1022, 'EndOffset': 1026, 'Score': 0.9951015114784241, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8278032541275024}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.964913547039032, 'RelationshipScore': 0.9660758972167969, 'RelationshipType': 'DIRECTION', 'Id': 6, 'BeginOffset': 993, 'EndOffset': 997, 'Text': 'left', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'DIRECTION', 'Score': 0.9679953455924988, 'RelationshipScore': 0.972966194152832, 'RelationshipType': 'DIRECTION', 'Id': 7, 'BeginOffset': 998, 'EndOffset': 1003, 'Text': 'upper', 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{'Title': '3. how to use pelmeg', 'Section_Content': 'pelmeg is for use in adults aged 18 and over. always use pelmeg exactly as your doctor has told you. you should check with your doctor or pharmacist if you are unsure. the usual dose is one 6 mg subcutaneous injection (injection under your skin) using a pre-filled syringe and it should be given at least 24 hours after your last dose of chemotherapy at the end of each chemotherapy cycle. do not shake pelmeg vigorously as this may affect its activity. injecting pelmeg yourself your doctor may decide that it would be more convenient for you to inject pelmeg yourself. your doctor or nurse will show you how to inject yourself. do not try to inject yourself if you have not been trained. for further instructions on how to inject yourself with pelmeg, please read the section at the end of this leaflet. if you use more pelmeg than you should if you use more pelmeg than you should contact your doctor, pharmacist or nurse. if you forget to inject pelmeg if you have forgotten a dose of pelmeg, you should contact your doctor to discuss when you should inject the next dose. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': None}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. please tell your doctor immediately if you have any of the following or combination of the following side effects: swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. these symptoms generally develop in a rapid fashion. these could be symptoms of an uncommon (may affect up to 1 in 100 people) condition called "capillary leak syndrome" which causes blood to leak from the small blood vessels into your body and needs urgent medical attention. very common side effects (may affect more than 1 in 10 people): bone pain. your doctor will tell you what you can take to ease the bone pain. nausea and headaches. common side effects (may affect up to 1 in 10 people): pain at the site of injection. general aches and pains in the joints and muscles. some changes may occur in your blood, but these will be detected by routine blood tests. your white blood cell count may become high for a short period of time. your platelet count may become low which might result in bruising. uncommon side effects (may affect up to 1 in 100 people): allergic-type reactions, including redness and flushing, skin rash, and raised areas of the skin that itch. serious allergic reactions, including anaphylaxis (weakness, drop in blood pressure, difficulty breathing, swelling of the face). increased spleen size. spleen rupture. some cases of splenic rupture were fatal. it is important that you contact your doctor immediately if you experience pain in the upper left side of the abdomen or left shoulder pain since this may relate to a problem with your spleen. breathing problems. if you have a cough, fever and difficulty breathing please tell your doctor. sweet\'s syndrome (plum-coloured, raised, painful lesions on the limbs and sometimes the face and neck with fever) has occurred but other factors may play a role. cutaneous vasculitis (inflammation of the blood vessels in the skin). damage to the tiny filters inside your kidneys (glomerulonephritis). redness at the site of injection. coughing up blood (haemoptysis). rare side effects (may affect up to 1 in 1,000 people) inflammation of the aorta (the large blood vessel which transports blood from the heart to the body), see section 2. bleeding from the lung (pulmonary haemorrhage). stevens-johnson syndrome, which can appear as reddish target-like or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. stop using pelmeg if you develop these symptoms and contact your doctor or seek medical attention immediately. see also section 2. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes 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{'Title': '5. how to store pelmeg', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': None, 'Entity_Recognition': None}

399E88688D80CED2B7C61AD85C3A1E0C

https://www.ema.europa.eu/documents/product-information/idflu-epar-product-information_en.pdf

IDflu

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Me dic ina l p rod uc t n o l on ge r a uth ori se d 2 1. NAME OF THE MEDICINAL PRODUCT IDflu 15 microgram/strain suspension for injection Influenza vaccine (split virion, inactivated) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Influenza virus (inactivated, split) of the following strains*: A/California/7/2009 (H1N1)pdm09 - like strain (A/California/7/2009, NYMC X-179A) .............................................................................................................................. 15 micrograms HA** A/Hong Kong/4801/2014 (H3N2) - like strain (A/Hong Kong/4801/2014, NYMC X-263B) .............................................................................................................................. 15 micrograms HA** B/Brisbane/60/2008 - like strain (B/Brisbane/60/2008, wild type) ..................... 15 micrograms HA** Per 0.1 ml dose * propagated in fertilised hens’ eggs from healthy chicken flocks ** haemagglutinin This vaccine complies with the WHO recommendations (Northern Hemisphere) and EU decision for the 2016/2017 season. For the full list of excipients, see section 6.1. IDflu may contain residues of eggs such as ovalbumin and residues of neomycin, formaldehyde and octoxinol 9, which are used during the manufacturing process (see section 4.3). 3. PHARMACEUTICAL FORM Suspension for injection. Colourless and opalescent suspension. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prophylaxis of influenza in individuals 60 years of age and over, especially in those who run an increased risk of associated complications. The use of IDflu should be based on official recommendations. 4.2 Posology and method of administration Posology Individuals 60 years of age and over: 0.1 ml. Paediatric population IDflu is not recommended for use in children and adolescents below 18 years due to insufficient data on safety and efficacy. Me dic ina l p rod uc t n o l on ge r a uth ori se d 3 Method of administration Immunisation should be carried out by intradermal route. The recommended site of administration is the region of the deltoid. Precautions to be taken before handling or administering the medicinal product For instructions on preparation of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substances, to any of the excipients listed in section 6.1, or to any residues such as eggs (ovalbumin, chicken proteins), neomycin, formaldehyde and octoxinol 9. Immunisation shall be postponed in subjects with febrile illness or acute infection. 4.4 Special warnings and precautions for use As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of the vaccine (see section 4.8). IDflu should under no circumstances be administered intravascularly. Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient. Very limited data in immunocompromised patients are available for IDflu. In case of presence of liquid at the injection site after vaccine administration, re-vaccination is not required. Interference with serological testing: See section 4.5. 4.5 Interaction with other medicinal products and other forms of interaction IDflu may be given at the same time as other vaccines. Immunisation should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified. The immunological response may be diminished if the patient is undergoing immunosuppressant treatment. Following influenza vaccination, false positive results in serology tests using the ELISA method to detect antibodies against HIV1, Hepatitis C and especially HTLV1 have been observed. The Western Blot technique disproves the false-positive ELISA test results. The transient false positive reactions could be due to the IgM response by the vaccine. 4.6 Fertility, pregnancy and lactation This vaccine is intended for individuals 60 years of age and over. Therefore, this information is not applicable. 4.7 Effects on ability to drive and use machines IDflu has no or negligible influence on the ability to drive and use machines. Me dic ina l p rod uc t n o l on ge r a uth ori se d 4 4.8 Undesirable effects a. Summary of the safety profile The safety of IDflu has been assessed in 3 open-label randomised clinical trials, 3,372 vaccinees received an injection of IDflu. Safety evaluation was performed for all subjects during the first 3 weeks following vaccination and serious adverse reactions were collected during six months of follow-up for 2,974 subjects (population of two out of the three clinical trials). The most common reactions occurring after vaccine administration were local reactions at injection site. Apparent local reactions after intradermal administration were more frequent than after intramuscular administration of an adjuvanted or non-adjuvanted comparator vaccine. Most reactions resolved spontaneously within 1 to 3 days after onset. Systemic safety profile of IDflu is similar to the comparator vaccine, adjuvanted or non-adjuvanted, administered intramuscularly. After repetitive yearly injections the safety profile of IDflu is similar to the previous injections. b. Tabulated summary of adverse reactions The data below summarizes the frequencies of the adverse reactions that were recorded following vaccination during clinical trials and worldwide post-marketing experience, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from available data). Me dic ina l p rod uc t n o l on ge r a uth ori se d 5 Organ class Very common Common Uncommon Rare Very rare Not known Immune system disorders Allergic reactions including generalized skin reactions such as urticaria, anaphylactic reactions, angioedema, shock Nervous system disorders Headache Paresthesia, neuritis Skin and subcutaneous tissue disorders Sweating Pruritus, rash Musculoskeletal and connective tissue disorders Myalgia Arthralgia General disorders and administration site conditions Local reactions: redness*, induration swelling, pruritus, pain Malaise, shivering, fever, Local reactions: ecchymosis Fatigue * In some cases, local redness lasted up to 7 days. c. Potential adverse events Based on the experience with trivalent inactivated influenza vaccines administered by intramuscular or deep subcutaneous injection, the following events may be reported: Blood and lymphatic system disorders Transient thrombocytopenia, transient lymphadenopathy Nervous system disorders Neuralgia, febrile convulsions, neurological disorders, such as encephalomyelitis and Guillain-Barré syndrome Vascular disorders Vasculitis associated in very rare cases with transient renal involvement Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Overdose is unlikely to have any untoward effect. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 6 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Influenza vaccines, ATC code: J07BB02 Immunogenicity Seroprotection is generally obtained within 2 to 3 weeks. The duration of postvaccinal immunity to homologous strains or to strains closely related to the vaccine strains varies but is usually 6-12 months. In a pivotal randomised comparative phase III trial, 2,606 subjects over 60 years of age received 0.1 ml of IDflu by intradermal route and 1,089 subjects over 60 years of age received 0.5 ml of a trivalent inactivated influenza vaccine administered by intramuscular route. In this comparative trial the geometric mean titres (GMTs), seroprotection rate*, seroconversion or significant increase rate** and the geometric mean titre ratio (GMTR) for anti-HA antibody (measured by HI) were assessed according to predefined criteria. Data were as follows (values in brackets show the 95% confidence intervals): Intradermal 15µg A/H1N1 A/H3N2 B A/New Caledonia/ 20/99 A/Wisconsin/ 67/2005 B/Malaysia/ 2506/2004 N = 2,585 N = 2,586 N = 2,582 Geometric mean of titre (1/dil) 81.7 (78.0 ; 85.6) 298.0 (282 ; 315) 39.9 (38.3 ; 41.6) Seroprotection rate (%) * 77.0 (75.3 ; 78.6) 93.3 (92.3 ; 94.3) 55.7 (53.8 ; 57.6) Seroconversion or significant increase rate (%) ** 38.7 (36.8 ; 40.6) 61.3 (59.3 ; 63.1) 36.4 (34.5 ; 38.3) Geometric mean of titre ratio (GMTR) 3.97 (3.77 ; 4.18) 8.19 (7.68 ; 8.74) 3.61 (3.47 ; 3.76) * Seroprotection = HI titre ≥ 40 ** Seroconversion = negative pre-vaccination HI titre and post vaccination HI titre ≥ 40, Significant increase = positive pre-vaccination HI titre and at least a 4-fold increase in post-vaccination HI titre GMTR: Geometric mean titre ratio of individual (post-/pre-vaccination titre). IDflu is at least as immunogenic as the comparator trivalent inactivated influenza vaccine administered by intramuscular route for each of the 3 influenza strains in subjects from 60 years of age and over. Across all three influenza strains, for the comparator intramuscular vaccine GMTs ranged between 34.8 (1/dil) and 181.0 (1/dil), seroprotection rates ranged between 48.9% and 87.9%, seroconversion or significant increase rates ranged between 30.0% and 46.9% and GMTRs ranged between 3.04 and 5.35-fold over baseline HI titres. In a randomised comparative phase III trial, 398 subjects over 65 years of age received 0.1 ml of IDflu by intradermal route and 397 subjects over 65 years of age received 0.5 ml of a trivalent inactivated adjuvanted (MF-59 containing) influenza vaccine at the same dosage administered by intramuscular route. Me dic ina l p rod uc t n o l on ge r a uth ori se d 7 IDflu is as immunogenic as the comparator trivalent adjuvanted (MF-59 containing) vaccine in terms of GMT for each of the 3 influenza strains with the SRH method and for 2 strains with the HI method. 5.2 Pharmacokinetic properties Not applicable 5.3 Preclinical safety data Non-clinical data revealed no special hazard for humans based on animal studies. The vaccine was immunogenic in mice and rabbits. In repeated-dose toxicity studies in rabbits there was no significant evidence of systemic toxicity. Nevertheless, single and repeated administrations led to transient local erythema and oedema. Genotoxicity and carcinogenic potential were not assessed because these studies are not appropriate for a vaccine. Fertility and toxicity studies to reproduction in females have not identified any specific potential hazard for humans. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Potassium chloride Disodium phosphate dihydrate Potassium dihydrogen phosphate Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf-life 1 year 6.4 Special precautions for storage Store in a refrigerator (2°C-8°C). Do not freeze. Keep the syringe in the outer carton in order to protect from light. 6.5 Nature and contents of container 0.1 ml of suspension in a pre-filled syringe (glass) with a Micro-Injection System, with attached micro-needle, equipped with an elastomer plunger stopper (chlorobutyl), a tip cap (thermoplastic elastomer and polypropylene) and a needle shielding system. Pack size of 1 or 10 or 20. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. The vaccine should be allowed to reach room temperature before use. Me dic ina l p rod uc t n o l on ge r a uth ori se d 8 Micro-needle Window Finger pads Vaccine Needle shield Needle cap Flange Plunger The vaccine should not be used if foreign particles are present in the suspension. It is not necessary to shake the vaccine before use. The Micro-Injection System for intradermal injection consists of a pre-filled syringe with a micro-needle (1.5 mm) and a needle shielding system. The needle shielding system is designed to cover the micro-needle after use. Micro-Injection System Me dic ina l p rod uc t n o l on ge r a uth ori se d 9 INSTRUCTION FOR USE Please read the instructions before use 1/ REMOVE NEEDLE CAP 2/ HOLD MICRO-INJECTION SYSTEM BETWEEN THUMB & MIDDLE FINGER Remove the needle cap from the Micro-Injection System. Do not purge air through the needle. Hold the system by placing the thumb and middle finger only on the finger pads; the index finger remains free. Do not place fingers on the windows. 3/ INSERT NEEDLE RAPIDLY PERPENDICULAR TO THE SKIN 4/ INJECT USING THE INDEX FINGER Insert the needle perpendicular to the skin, in the region of the deltoid, in a short, quick movement. Once the micro-needle has been inserted, maintain a light pressure on the surface of the skin and inject using the index finger to push on the plunger. The vein test is unnecessary. 5/ ACTIVATE NEEDLE SHIELD BY PUSHING FIRMLY ON PLUNGER Remove the needle from the skin. Orient the needle away from you and others. With the same hand, push very firmly with the thumb on the plunger to activate the needle shield. You hear a click and a shield comes out to cover the needle. Immediately dispose of the system in the nearest sharps collector. Injection is considered successful whether or not the presence of a wheal is observed. In case of presence of liquid at the injection site after vaccine administration, re- vaccination is not required. Activated needle shield Me dic ina l p rod uc t n o l on ge r a uth ori se d 10 7. MARKETING AUTHORISATION HOLDER Sanofi Pasteur SA, 2, avenue Pont Pasteur, F-69007 Lyon, France. 8. MARKETING AUTHORISATION NUMBER(S) EU/1/08/507/004 EU/1/08/507/005 EU/1/08/507/006 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 24 February 2009 Date of latest renewal: 24 February 2014 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. Me dic ina l p rod uc t n o l on ge r a uth ori se d 11 ANNEX II A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Me dic ina l p rod uc t n o l on ge r a uth ori se d 12 A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) of the biological active substance(s) Sanofi Pasteur Parc Industriel d’Incarville 27100 Val-de-Reuil France Name and address of the manufacturer(s) responsible for batch release Sanofi Pasteur Parc Industriel d’Incarville 27100 Val-de-Reuil France Sanofi Pasteur Campus Mérieux 1541, avenue Marcel Mérieux 69280 Marcy l’Etoile France The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. • Official batch release In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be undertaken by a state laboratory or a laboratory designated for that purpose. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. Me dic ina l p rod uc t n o l on ge r a uth ori se d 13 An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information is received that may lead to a significant change to benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. Me dic ina l p rod uc t n o l on ge r a uth ori se d 14 ANNEX III LABELLING AND PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 15 A. LABELLING Me dic ina l p rod uc t n o l on ge r a uth ori se d 16 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Pack of 1 or 10 or 20 pre-filled syringe(s) with a Micro-Injection System 1. NAME OF THE MEDICINAL PRODUCT IDflu 15 microgram/strain, suspension for injection Influenza vaccine (split virion, inactivated) Strains 2016/2017 2. STATEMENT OF ACTIVE SUBSTANCES Influenza virus (inactivated, split) of the following strains: A/California/7/2009 (H1N1)pdm09 - like strain A/Hong Kong/4801/2014 (H3N2) - like strain B/Brisbane/60/2008 - like strain 15 µg haemagglutinin per strain per 0.1 ml dose 3. LIST OF EXCIPIENTS Sodium chloride, potassium chloride, disodium phosphate dihydrate, potassium dihydrogen phosphate, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Suspension for injection 1 pre-filled syringe (0.1 ml) with a Micro-Injection System 10 pre-filled syringes (0.1 ml) with a Micro-Injection System 20 pre-filled syringes (0.1 ml) with a Micro-Injection System 5. METHOD AND ROUTE OF ADMINISTRATION Intradermal use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. Me dic ina l p rod uc t n o l on ge r a uth ori se d 17 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in refrigerator. Do not freeze. Keep the syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Sanofi Pasteur SA, 2, avenue Pont Pasteur F-69007 Lyon France 12. MARKETING AUTHORISATION NUMBER(S) EU/1/08/507/004 - pack of 1 pre-filled syringe with a Micro-Injection System EU/1/08/507/005 - pack of 10 pre-filled syringes with a Micro-Injection System EU/1/08/507/006 - pack of 20 pre-filled syringes with a Micro-Injection System 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille is accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. Me dic ina l p rod uc t n o l on ge r a uth ori se d 18 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: Me dic ina l p rod uc t n o l on ge r a uth ori se d 19 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Pre-filled syringe label text 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION IDflu 15 µg/strain 2016/2017 Influenza vaccine Intradermal use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.1 ml 6. OTHER Sanofi Pasteur SA Me dic ina l p rod uc t n o l on ge r a uth ori se d 20 B. PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 21 Package leaflet: Information for the user IDflu 15 microgram/strain suspension for injection Influenza vaccine (split virion, inactivated) Read all of this leaflet carefully before you receive this vaccine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This vaccine has been prescribed for you only. Do not pass it on to others. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What IDflu is and what it is used for 2. What you need to know before you use IDflu 3. How to use IDflu 4. Possible side effects 5. How to store IDflu 6. Contents of the pack and other information 1. What IDflu is and what it is used for IDflu is a vaccine.This vaccine is recommended to help to protect you against flu. The vaccine may be administered to individuals of 60 years of age and over, especially in those who run an increased risk of associated complications. When an injection of IDflu is given, the immune system (body's natural defences) will develop protection against flu infection. IDflu will help to protect you against the three strains of virus contained in the vaccine, or other strains closely related to them. Full effect of the vaccine is generally achieved 2-3 weeks after the vaccination. 2. What you need to know before you use IDflu Do not use IDflu: - If you are allergic to: • The active substances, • Any of the other ingredients of this vaccine (listed in section 6), • Any component that may be present in very small amounts such as eggs (ovalbumin, chicken proteins), neomycin, formaldehyde and octoxinol 9. - If you have an illness with fever or acute infection, the vaccination shall be postponed until after you have recovered. Warnings and precautions Talk to your doctor, pharmacist or nurse before using IDflu. - You should tell your doctor before vaccination if you have a poor immune response (immunosuppression) due to disease or medicines, because the vaccine may not work very well in this case. - This vaccine should under no circumstances be administered into a vein (intravascularly). Me dic ina l p rod uc t n o l on ge r a uth ori se d 22 - If, for any reason, you have a blood test within a few days following an influenza vaccination, please tell your doctor. Tests for HIV-1, hepatitis C virus and HTLV-1 may be affected. Children and adolescents IDflu is not recommended for use in children and adolescents below 18 years. Other vaccines or medicines and IDflu Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. - Other vaccines: IDflu can be given at the same time as other vaccines by using separate limbs. It should be noted that the side effects may be intensified. - Tell your doctor if you have been treated with medicines that may reduce your immune response such as corticosteroids (for example cortisone), medicines against cancer (chemotherapy), radiotherapy or other medicines affecting the immune system. In this case, the vaccine may not work very well. Pregnancy, breast-feeding and fertility This vaccine is intended for individuals 60 years of age and over. Therefore, this information is not applicable. Driving and using machines This vaccine has no or negligible influence on the ability to drive and use machines. 3. How to use IDflu Always use this vaccine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The recommended dose is 0.1 ml for individuals 60 years of age and over. IDflu is administered to you by your doctor or nurse. IDflu is given as an injection into the upper layer of the skin (preferably the muscle of the upper arm). If you have any further questions on the use of this vaccine, ask your doctor, pharmacist or nurse. 4. Possible side effects Like all medicines, this vaccine can cause side effects, although not everybody gets them. You should see your doctor immediately if you experience symptoms of angioedema, such as: • Swollen face, tongue or pharynx • Difficulty to swallow • Hives and difficulties to breathe. During clinical trials and after the vaccine came on the market, the following side effects were reported with the use of IDflu. Very common reactions (may affect more than 1 in 10 people) - At the injection site: redness, hardness, swelling, itching and pain. - Headache and muscular pain. Me dic ina l p rod uc t n o l on ge r a uth ori se d 23 Common reactions (may affect up to 1 in 10 people) - Bruising at the injection site. - Feeling generally unwell, fever (38.0°C or higher) and shivering. Uncommon reactions (may affect up to 1 in 100 people) - Tiredness, joint pain and increased sweating. Rare reactions (may affect up to 1 in 1000 people) - Tingling or numbness, inflammation of nerves, itching and rash. Reactions of not known frequency (frequency cannot be estimated from the available data) - Allergic reactions including skin reactions that may spread throughout the body such as hives, severe allergic reactions (anaphylactic reactions), swollen face, tongue or pharynx, difficulty to swallow, hives and difficulties to breathe (angioedema), failure of the circulatory system (shock) leading to medical emergency. Most of side effects listed above disappeared without treatment within 1 to 3 days after onset. In some cases, redness at the injection site lasted up to 7 days. The following side effects have been reported with other vaccines given to prevent flu. These side effects may occur with IDflu. • Temporary reduction in the number of blood particles called platelets which can result in bruising or bleeding, temporary swelling of the glands in the neck, armpit or groin. • Pain located on the nerve route, convulsions associated with fever, nervous system disorders including inflammation of the brain or spinal cord or Guillain-Barré syndrome which causes extreme weakness and paralysis. • Vessel inflammation which may result in very rare cases in temporary kidney problems. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store IDflu Keep this vaccine out of the sight and reach of children. Do not use this vaccine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the syringe in the outer carton in order to protect from light. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 24 6. Contents of the pack and other information What IDflu contains The active substances are Influenza virus (inactivated split) of the following strains*: A/California/7/2009 (H1N1)pdm09 - like strain (A/California/7/2009, NYMC X-179A) .............................................................................................................................. 15 micrograms HA** A/Hong Kong/4801/2014 (H3N2) - like strain (A/Hong Kong/4801/2014, NYMC X-263B) .............................................................................................................................. 15 micrograms HA** B/Brisbane/60/2008 - like strain (B/Brisbane/60/2008, wild type) ..................... 15 micrograms HA** Per 0.1 ml dose * propagated in fertilised hens’ eggs from healthy chicken flocks ** haemagglutinin This vaccine complies with the WHO recommendations (Northern Hemisphere) and EU decision for the 2016/2017 season. The other ingredients are: sodium chloride, potassium chloride, disodium phosphate dihydrate, potassium dihydrogen phosphate and water for injections. What IDflu looks like and contents of the pack The vaccine is a colourless and opalescent suspension. IDflu is a suspension for injection in a pre-filled syringe of 0.1 ml with a Micro-Injection System in packs of 1, 10 or 20. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: Sanofi Pasteur SA, 2, avenue Pont Pasteur, F-69007 Lyon, France. Manufacturer: Sanofi Pasteur - Parc Industriel d’Incarville - 27100 Val-de-Reuil - France Sanofi Pasteur, Campus Mérieux – 1541, avenue Marcel Mérieux – 69280 Marcy l’Etoile - France For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Sanofi Belgium tel.: +32 2 710.54.00 Lietuva Sanofi – Aventis Lietuva, UAB Tel.: +370 5 2730967 България Sanofi Bulgaria EOOD Teл.: +359 2 970 53 00 Luxembourg/Luxemburg Sanofi Belgium tel.: +32 2 710.54.00 Me dic ina l p rod uc t n o l on ge r a uth ori se d 25 Česká republika Sanofi Pasteur divize vakcín sanofi-aventis, s.r.o. Tel: +420 233 086 111 Magyarország sanofi-aventis zrt Tel.: +36 1 505 0055 Danmark sanofi-aventis Denmark A/S Tel: +45 4516 7000 Malta Cherubino Ltd Tel.: +356 21 343270 Deutschland Sanofi-Aventis Deutschland GmbH Tel.: 0800 54 54 010 Tel. aus dem Ausland: +49 69 305 21 130 Nederland sanofi-aventis Netherlands B.V. Tel: +31 182 557 755 Eesti Sanofi-Aventis Estonia OÜ Tel.: +372 627 3488 Norge Sanofi-aventis Norge AS Tel: + 47 67 10 71 00 Ελλάδα ΒΙΑΝΕΞ Α.Ε. Τηλ: +30.210.8009111 Österreich Sanofi-Aventis GmbH Tel: +43 (1) 80185-0. España sanofi-aventis, S.A. Tel: +34 93 485 94 00 Polska Sanofi Pasteur Sp. z o.o. Tel.: +48 22 280 05 00 France Sanofi Pasteur Europe Tél: 0800 42 43 46 Appel depuis l’étranger : +33 1 57 63 23 23 Portugal Sanofi – Produtos Farmacêuticos, Lda. Tel: + 351 21 35 89 400 Hrvatska sanofi-aventis Croatia d.o.o Tel: + 385 1 6003 400 România sanofi - aventis Romania SRL Tel.: +40(21) 317 31 36 Ireland sanofi-aventis Ireland T/A SANOFI Tel: + 353 (0) 1 4035 600 Slovenija ALPE s.p. Tel.: +386 (0)1 432 62 38 Ísland Vistor Tel : +354 535 7000 Slovenská republika sanofi-aventis Pharma Slovakia s.r.o. divízia vakcín Sanofi Pasteur Tel.: +421 2 33 100 100 Italia Sanofi S.p.A. Tel: 800536389 Tel dall'estero: +39 02 39394983 Suomi/Finland Sanofi Oy Tel: +358 (0) 201 200 300 Κύπρος Γ. Α. Σταμάτης & Σια Λτδ. Τηλ.: +357 - 22 76 62 76 Sverige Sanofi AB Tel: +46 8-634 50 00 Me dic ina l p rod uc t n o l on ge r a uth ori se d 26 Latvija Sanofi Aventis Latvia SIA Vakcīnu nodaļa Tel.: +371 67114978 United Kingdom Sanofi Tel: +44 845 372 7101 This leaflet was last revised in {MM/YYYY}. Other sources of information Detailed information on this vaccine is available on the European Medicines Agency web site: http://www.ema.europa.eu. --------------------------------------------------------------------------------------------------------------------------- The following information is intended for healthcare professionals only: • As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of anaphylactic event following the administration of the vaccine. • The vaccine should be allowed to reach room temperature before use. • The vaccine should not be used if foreign particles are present in the suspension. • It is not necessary to shake the vaccine before use. • The Micro-Injection System for intradermal injection consists of a pre-filled syringe with a micro-needle (1.5 mm) and a needle shielding system. The needle shielding system is designed to cover the micro-needle after use. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 27 Micro-needle Window Finger pads Vaccine Needle shield Needle cap Flange Plunger Micro-Injection System Me dic ina l p rod uc t n o l on ge r a uth ori se d 28 INSTRUCTION FOR USE Please read the instructions before use 1/ REMOVE NEEDLE CAP 2/ HOLD MICRO-INJECTION SYSTEM BETWEEN THUMB & MIDDLE FINGER Remove the needle cap from the Micro-Injection System. Do not purge air through the needle. Hold the system by placing the thumb and middle finger only on the finger pads; the index finger remains free. Do not place fingers on the windows. 3/ INSERT NEEDLE RAPIDLY PERPENDICULAR TO THE SKIN 4/ INJECT USING THE INDEX FINGER Insert the needle perpendicular to the skin, in the region of the deltoid, in a short, quick movement. Once the micro-needle has been inserted, maintain a light pressure on the surface of the skin and inject using the index finger to push on the plunger. The vein test is unnecessary. 5/ ACTIVATE NEEDLE SHIELD BY PUSHING FIRMLY ON PLUNGER Remove the needle from the skin. Orient the needle away from you and others. With the same hand, push very firmly with the thumb on the plunger to activate the needle shield. You hear a click and a shield comes out to cover the needle. Immediately dispose of the system in the nearest sharps collector. Injection is considered successful whether or not the presence of a wheal is observed. In case of presence of liquid at the injection site after vaccine administration, re- vaccination is not required. See also section 3. HOW TO USE IDflu Activated needle shield Me dic ina l p rod uc t n o l on ge r a uth ori se d SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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virus and htlv-1 may be affected. children and adolescents idflu is not recommended for use in children and adolescents below 18 years. other vaccines or medicines and idflu tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. - other vaccines: idflu can be given at the same time as other vaccines by using separate limbs. it should be noted that the side effects may be intensified. - tell your doctor if you have been treated with medicines that may reduce your immune response such as corticosteroids (for example cortisone), medicines against cancer (chemotherapy), radiotherapy or other medicines affecting the immune system. in this case, the vaccine may not work very well. pregnancy, breast-feeding and fertility this vaccine is intended for individuals 60 years of age and over. therefore, this information is not applicable. driving and using machines this vaccine has no or negligible influence on the ability to drive and use machines.', 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{'Title': '3. how to use idflu', 'Section_Content': 'always use this vaccine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose is 0.1 ml for individuals 60 years of age and over. idflu is administered to you by your doctor or nurse. idflu is given as an injection into the upper layer of the skin (preferably the muscle of the upper arm). if you have any further questions on the use of this vaccine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'idflu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 23}, {'Text': '0.1', 'Type': 'NUMBER', 'BeginOffset': 157, 'EndOffset': 160}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 180, 'EndOffset': 182}, {'Text': 'idflu', 'Type': 'TREATMENT', 'BeginOffset': 260, 'EndOffset': 265}, {'Id': 6, 'BeginOffset': 281, 'EndOffset': 290, 'Score': 0.3678901195526123, 'Text': 'injection', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 319, 'EndOffset': 323, 'Score': 0.9971106052398682, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 2, 'BeginOffset': 340, 'EndOffset': 346, 'Score': 0.8287597894668579, 'Text': 'muscle', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 4, 'BeginOffset': 360, 'EndOffset': 363, 'Score': 0.9651350975036621, 'Text': 'arm', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 414, 'EndOffset': 426}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this vaccine can cause side effects, although not everybody gets them. you should see your doctor immediately if you experience symptoms of angioedema, such as: swollen face, tongue or pharynx difficulty to swallow hives and difficulties to breathe. during clinical trials and after the vaccine came on the market, the following side effects were reported with the use of idflu. very common reactions (may affect more than 1 in 10 people) - at the injection site: redness, hardness, swelling, itching and pain. - headache and muscular pain. common reactions (may affect up to 1 in 10 people) - bruising at the injection site. - feeling generally unwell, fever (38.0 or higher) and shivering. uncommon reactions (may affect up to 1 in 100 people) - tiredness, joint pain and increased sweating. rare reactions (may affect up to 1 in 1000 people) - tingling or numbness, inflammation of nerves, itching and rash. reactions of not known frequency (frequency cannot be estimated from the available data) - allergic reactions including skin reactions that may spread throughout the body such as hives, severe allergic reactions (anaphylactic reactions), swollen face, tongue or pharynx, difficulty to swallow, hives and difficulties to breathe (angioedema), failure of the circulatory system (shock) leading to medical emergency. most of side effects listed above disappeared without treatment within 1 to 3 days after onset. in some cases, redness at the injection site lasted up to 7 days. the following side effects have been reported with other vaccines given to prevent flu. these side effects may occur with idflu. temporary reduction in the number of blood particles called platelets which can result in bruising or bleeding, temporary swelling of the glands in the neck, armpit or groin. pain located on the nerve route, convulsions associated with fever, nervous system disorders including inflammation of the brain or spinal cord or guillain-barré syndrome which causes extreme weakness and paralysis. vessel inflammation which may result in very rare cases in temporary kidney problems. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'idflu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 32}, {'Id': 25, 'BeginOffset': 43, 'EndOffset': 55, 'Score': 0.9653733372688293, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 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'Text': 'skin reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7873016595840454}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.935499370098114, 'RelationshipScore': 0.9151932001113892, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 8, 'BeginOffset': 1097, 'EndOffset': 1101, 'Text': 'body', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 8, 'BeginOffset': 1097, 'EndOffset': 1101, 'Score': 0.935499370098114, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 58, 'BeginOffset': 1110, 'EndOffset': 1115, 'Score': 0.9730337858200073, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.47093790769577026}, {'Name': 'DIAGNOSIS', 'Score': 0.6412770748138428}]}, {'Text': 'severe allergic reactions', 'Type': 'PROBLEM', 'BeginOffset': 1117, 'EndOffset': 1142}, {'Id': 60, 'BeginOffset': 1144, 'EndOffset': 1166, 'Score': 0.9657094478607178, 'Text': 'anaphylactic reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8165202140808105}]}, {'Text': 'swollen face, tongue or pharynx', 'Type': 'PROBLEM', 'BeginOffset': 1169, 'EndOffset': 1200}, {'Id': 62, 'BeginOffset': 1202, 'EndOffset': 1223, 'Score': 0.9479347467422485, 'Text': 'difficulty to swallow', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.80687016248703}]}, {'Id': 63, 'BeginOffset': 1225, 'EndOffset': 1230, 'Score': 0.9634249210357666, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7658835053443909}]}, {'Id': 64, 'BeginOffset': 1235, 'EndOffset': 1258, 'Score': 0.9395579099655151, 'Text': 'difficulties to breathe', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6853011846542358}]}, {'Id': 65, 'BeginOffset': 1260, 'EndOffset': 1270, 'Score': 0.976858913898468, 'Text': 'angioedema', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4012961983680725}, {'Name': 'DIAGNOSIS', 'Score': 0.5702536702156067}]}, {'Text': 'failure of the circulatory system', 'Type': 'PROBLEM', 'BeginOffset': 1273, 'EndOffset': 1306}, {'Id': 67, 'BeginOffset': 1308, 'EndOffset': 1313, 'Score': 0.8861271739006042, 'Text': 'shock', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5567711591720581}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.7952654361724854, 'RelationshipScore': 0.6951273083686829, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 12, 'BeginOffset': 1288, 'EndOffset': 1306, 'Text': 'circulatory system', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 68, 'BeginOffset': 1353, 'EndOffset': 1365, 'Score': 0.902076244354248, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7623190879821777}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.7952654361724854, 'RelationshipScore': 0.7058225870132446, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 12, 'BeginOffset': 1288, 'EndOffset': 1306, 'Text': 'circulatory system', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 1399, 'EndOffset': 1408}, {'Id': 89, 'BeginOffset': 1416, 'EndOffset': 1427, 'Score': 0.9085657596588135, 'Text': '1 to 3 days', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.902076244354248, 'RelationshipScore': 0.7389105558395386, 'RelationshipType': 'OVERLAP', 'Id': 68, 'BeginOffset': 1353, 'EndOffset': 1365, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7623190879821777}]}]}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 1421, 'EndOffset': 1422}, {'Text': 'redness at the injection site', 'Type': 'PROBLEM', 'BeginOffset': 1456, 'EndOffset': 1485}, {'Id': 90, 'BeginOffset': 1499, 'EndOffset': 1505, 'Score': 0.8582568168640137, 'Text': '7 days', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.9746920466423035, 'RelationshipScore': 0.7698229551315308, 'RelationshipType': 'OVERLAP', 'Id': 69, 'BeginOffset': 1456, 'EndOffset': 1463, 'Text': 'redness', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8987067341804504}]}]}, {'Id': 70, 'BeginOffset': 1521, 'EndOffset': 1533, 'Score': 0.8087397813796997, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7781603932380676}]}, {'Text': 'other vaccines', 'Type': 'TREATMENT', 'BeginOffset': 1558, 'EndOffset': 1572}, {'Id': 71, 'BeginOffset': 1590, 'EndOffset': 1593, 'Score': 0.9291086792945862, 'Text': 'flu', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6452533006668091}, {'Name': 'DIAGNOSIS', 'Score': 0.5169166326522827}]}, {'Id': 72, 'BeginOffset': 1601, 'EndOffset': 1613, 'Score': 0.8601989150047302, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7523911595344543}]}, {'Id': 73, 'BeginOffset': 1629, 'EndOffset': 1634, 'Score': 0.47610539197921753, 'Text': 'idflu', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'temporary reduction', 'Type': 'TREATMENT', 'BeginOffset': 1636, 'EndOffset': 1655}, {'Text': 'platelets', 'Type': 'TREATMENT', 'BeginOffset': 1696, 'EndOffset': 1705}, {'Id': 74, 'BeginOffset': 1726, 'EndOffset': 1734, 'Score': 0.9892262816429138, 'Text': 'bruising', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.884921133518219}]}, {'Id': 75, 'BeginOffset': 1738, 'EndOffset': 1746, 'Score': 0.996637225151062, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8898354768753052}]}, {'Text': 'temporary swelling of the glands in the neck, armpit or groin', 'Type': 'PROBLEM', 'BeginOffset': 1748, 'EndOffset': 1809}, {'Id': 77, 'BeginOffset': 1811, 'EndOffset': 1815, 'Score': 0.969804584980011, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7674415111541748}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.6986154317855835, 'RelationshipScore': 0.9992524981498718, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 18, 'BeginOffset': 1831, 'EndOffset': 1836, 'Text': 'nerve', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 18, 'BeginOffset': 1831, 'EndOffset': 1836, 'Score': 0.6986154317855835, 'Text': 'nerve', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'convulsions', 'Type': 'PROBLEM', 'BeginOffset': 1844, 'EndOffset': 1855}, {'Id': 78, 'BeginOffset': 1872, 'EndOffset': 1877, 'Score': 0.9780714511871338, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7160308361053467}]}, {'Id': 79, 'BeginOffset': 1879, 'EndOffset': 1903, 'Score': 0.9304865598678589, 'Text': 'nervous system disorders', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7693601250648499}]}, {'Text': 'inflammation of the brain', 'Type': 'PROBLEM', 'BeginOffset': 1914, 'EndOffset': 1939}, {'Id': 81, 'BeginOffset': 1943, 'EndOffset': 1981, 'Score': 0.7629947066307068, 'Text': 'spinal cord or guillain-barré syndrome', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9592407941818237}]}, {'Text': 'extreme weakness', 'Type': 'PROBLEM', 'BeginOffset': 1995, 'EndOffset': 2011}, {'Id': 83, 'BeginOffset': 2016, 'EndOffset': 2025, 'Score': 0.9925092458724976, 'Text': 'paralysis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5597049593925476}]}, {'Text': 'vessel inflammation', 'Type': 'PROBLEM', 'BeginOffset': 2027, 'EndOffset': 2046}, {'Text': 'temporary kidney problems', 'Type': 'PROBLEM', 'BeginOffset': 2086, 'EndOffset': 2111}, {'Id': 95, 'BeginOffset': 2126, 'EndOffset': 2138, 'Score': 0.9447035789489746, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.701688826084137}]}, {'Id': 96, 'BeginOffset': 2154, 'EndOffset': 2166, 'Score': 0.9064189195632935, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7201143503189087}]}, {'Id': 97, 'BeginOffset': 2237, 'EndOffset': 2249, 'Score': 0.9506289958953857, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6105943918228149}]}, {'Id': 98, 'BeginOffset': 2298, 'EndOffset': 2310, 'Score': 0.854573130607605, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6849924325942993}]}, {'Id': 99, 'BeginOffset': 2364, 'EndOffset': 2375, 'Score': 0.37086233496665955, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5928104519844055}]}, {'Id': 100, 'BeginOffset': 2389, 'EndOffset': 2401, 'Score': 0.8563477396965027, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7272924184799194}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2457, 'EndOffset': 2470}]}

{'Title': '5. how to store idflu', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what idflu contains the active substances are influenza virus (inactivated split) of the following strains*: a/california/7/2009 (h1n1)pdm09 - like strain (a/california/7/2009, nymc x-179a) .............................................................................................................................. micrograms ha** a/hong kong/4801/2014 (h3n2) - like strain (a/hong kong/4801/2014, nymc x-263b) .............................................................................................................................. micrograms ha** b/brisbane/60/2008 - like strain (b/brisbane/60/2008, wild type) ..................... micrograms ha** per 0.1 ml dose * propagated in fertilised hens' eggs from healthy chicken flocks ** haemagglutinin this vaccine complies with the who recommendations (northern hemisphere) and eu decision for the 2016/2017 season. the other ingredients are: sodium chloride, potassium chloride, disodium phosphate dihydrate, potassium dihydrogen phosphate and water for injections. what idflu looks like and contents of the pack the vaccine is a colourless and opalescent suspension. idflu is a suspension for injection in a pre-filled syringe of 0.1 ml with a micro-injection system in packs of 1, 10 or 20. not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'idflu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 6, 'BeginOffset': 46, 'EndOffset': 61, 'Score': 0.43353623151779175, 'Text': 'influenza virus', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8514743447303772}]}, {'Id': 8, 'BeginOffset': 111, 'EndOffset': 121, 'Score': 0.38800621032714844, 'Text': 'california', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'ADDRESS', 'Traits': []}, {'Id': 9, 'BeginOffset': 122, 'EndOffset': 128, 'Score': 0.9996139407157898, 'Text': '7/2009', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Text': 'pdm09', 'Type': 'PROBLEM', 'BeginOffset': 135, 'EndOffset': 140}, {'Id': 10, 'BeginOffset': 158, 'EndOffset': 168, 'Score': 0.8499430418014526, 'Text': 'california', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'ADDRESS', 'Traits': []}, {'Id': 11, 'BeginOffset': 169, 'EndOffset': 175, 'Score': 0.9991645812988281, 'Text': '7/2009', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 12, 'BeginOffset': 340, 'EndOffset': 354, 'Score': 0.2635149657726288, 'Text': 'kong/4801/2014', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 7, 'BeginOffset': 369, 'EndOffset': 375, 'Score': 0.3758178949356079, 'Text': 'strain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 384, 'EndOffset': 398, 'Score': 0.3565746545791626, 'Text': 'kong/4801/2014', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Text': 'nymc', 'Type': 'TEST', 'BeginOffset': 400, 'EndOffset': 404}, {'Text': 'micrograms ha', 'Type': 'TEST', 'BeginOffset': 540, 'EndOffset': 553}, {'Id': 14, 'BeginOffset': 567, 'EndOffset': 574, 'Score': 0.9968035221099854, 'Text': '60/2008', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 15, 'BeginOffset': 601, 'EndOffset': 608, 'Score': 0.9925596714019775, 'Text': '60/2008', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Text': '0.1', 'Type': 'NUMBER', 'BeginOffset': 663, 'EndOffset': 666}, {'Text': 'haemagglutinin this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 744, 'EndOffset': 771}, {'Id': 16, 'BeginOffset': 856, 'EndOffset': 860, 'Score': 0.643774151802063, 'Text': '2016', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 17, 'BeginOffset': 861, 'EndOffset': 865, 'Score': 0.4123981297016144, 'Text': '2017', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 0, 'BeginOffset': 901, 'EndOffset': 916, 'Score': 0.9909080266952515, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 918, 'EndOffset': 936, 'Score': 0.9980193376541138, 'Text': 'potassium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 938, 'EndOffset': 966, 'Score': 0.9843010306358337, 'Text': 'disodium phosphate dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.34031933546066284, 'RelationshipScore': 0.9608170390129089, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 4, 'BeginOffset': 1013, 'EndOffset': 1023, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 3, 'BeginOffset': 968, 'EndOffset': 998, 'Score': 0.9898550510406494, 'Text': 'potassium dihydrogen phosphate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.34031933546066284, 'RelationshipScore': 0.9999654293060303, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 4, 'BeginOffset': 1013, 'EndOffset': 1023, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 1013, 'EndOffset': 1023}, {'Text': 'the pack the vaccine', 'Type': 'TREATMENT', 'BeginOffset': 1063, 'EndOffset': 1083}, {'Text': 'opalescent suspension', 'Type': 'TREATMENT', 'BeginOffset': 1104, 'EndOffset': 1125}, {'Text': 'a pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 1166, 'EndOffset': 1186}, {'Text': '0.1', 'Type': 'NUMBER', 'BeginOffset': 1190, 'EndOffset': 1193}, {'Text': 'a micro-injection system', 'Type': 'TREATMENT', 'BeginOffset': 1202, 'EndOffset': 1226}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1239, 'EndOffset': 1240}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 1242, 'EndOffset': 1244}, {'Text': '20.', 'Type': 'NUMBER', 'BeginOffset': 1248, 'EndOffset': 1251}]}

E6A99A8422B8B26B49739D643ED1FAA0

https://www.ema.europa.eu/documents/product-information/revolade-epar-product-information_en.pdf

Revolade

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Revolade 12.5 mg film-coated tablets Revolade 25 mg film-coated tablets Revolade 50 mg film-coated tablets Revolade 75 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Revolade 12.5 mg film-coated tablets Each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. Revolade 25 mg film-coated tablets Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. Revolade 50 mg film-coated tablets Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag. Revolade 75 mg film-coated tablets Each film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Revolade 12.5 mg film-coated tablets White, round, biconvex film-coated tablet (approximately 7.9 mm in diameter) debossed with ‘GS MZ1’ and ‘12.5’ on one side. Revolade 25 mg film-coated tablets White, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS NX3’ and ‘25’ on one side. Revolade 50 mg film-coated tablets Brown, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS UFU’ and ‘50’ on one side. Revolade 75 mg film-coated tablets Pink, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS FFS’ and ‘75’ on one side. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Revolade is indicated for the treatment of patients aged 1 year and above with primary immune thrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1). Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1). Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation (see section 5.1). 4.2 Posology and method of administration Eltrombopag treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases or the management of chronic hepatitis C and its complications. Posology Eltrombopag dosing requirements must be individualised based on the patient’s platelet counts. The objective of treatment with eltrombopag should not be to normalise platelet counts. The powder for oral suspension may lead to higher eltrombopag exposure than the tablet formulation (see section 5.2). When switching between the tablet and powder for oral suspension formulations, platelet counts should be monitored weekly for 2 weeks. Immune (primary) thrombocytopenia The lowest dose of eltrombopag to achieve and maintain a platelet count ≥50,000/µl should be used. Dose adjustments are based upon the platelet count response. Eltrombopag must not be used to normalise platelet counts. In clinical studies, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag and decreased within 1 to 2 weeks after discontinuation. Adults and paediatric population aged 6 to 17 years The recommended starting dose of eltrombopag is 50 mg once daily. For patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). Paediatric population aged 1 to 5 years The recommended starting dose of eltrombopag is 25 mg once daily. 4 Monitoring and dose adjustment After initiating eltrombopag, the dose must be adjusted to achieve and maintain a platelet count ≥50,000/µl as necessary to reduce the risk for bleeding. A daily dose of 75 mg must not be exceeded. Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in Table 1. During therapy with eltrombopag full blood counts (FBCs), including platelet count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥50,000/µl for at least 4 weeks) has been achieved. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. Table 1 Dose adjustments of eltrombopag in ITP patients Platelet count Dose adjustment or response <50,000/µl following at least 2 weeks of therapy Increase daily dose by 25 mg to a maximum of 75 mg/day*. 50,000/µl to 150,000/µl Use lowest dose of eltrombopag and/or concomitant ITP treatment to maintain platelet counts that avoid or reduce bleeding. >150,000/µl to 250,000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments♦. >250,000/µl Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is ≤ 100,000/µl, reinitiate therapy at a daily dose reduced by 25 mg. * For patients taking 25 mg eltrombopag once every other day, increase dose to 25 mg once daily. ♦ For patients taking 25 mg eltrombopag once daily, consideration should be given to dosing at 12.5 mg once daily or alternatively a dose of 25 mg once every other day. Eltrombopag can be administered in addition to other ITP medicinal products. The dose regimen of concomitant ITP medicinal products should be modified, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag. It is necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient’s platelet response prior to considering another dose adjustment. The standard eltrombopag dose adjustment, either decrease or increase, would be 25 mg once daily. Discontinuation Treatment with eltrombopag should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of eltrombopag therapy at 75 mg once daily. Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician. In non-splenectomised patients this should include evaluation relative to splenectomy. The reoccurrence of thrombocytopenia is possible upon discontinuation of treatment (see section 4.4). Chronic hepatitis C (HCV) associated thrombocytopenia When eltrombopag is given in combination with antivirals reference should be made to the full summary of product characteristics of the respective coadministered medicinal products for comprehensive details of relevant safety information or contraindications. In clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag. The aim of treatment with eltrombopag should be to achieve the minimum level of platelet counts 5 needed to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviral therapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk of bleeding complications, normally around 50,000-75,000/µl. Platelet counts >75,000/µl should be avoided. The lowest dose of eltrombopag needed to achieve the targets should be used. Dose adjustments are based upon the platelet count response. Initial dose regimen Eltrombopag should be initiated at a dose of 25 mg once daily. No dosage adjustment is necessary for HCV patients of East Asian ancestry or patients with mild hepatic impairment (see section 5.2). Monitoring and dose adjustment The dose of eltrombopag should be adjusted in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Platelet counts should be monitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose adjustments should be avoided (see Table 2). During antiviral therapy, the dose of eltrombopag should be adjusted as necessary to avoid dose reductions of peginterferon due to decreasing platelet counts that may put patients at risk of bleeding (see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved, normally around 50,000-75,000/µl. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by 25 mg should be considered if platelet counts exceed the required target. It is recommended to wait for 2 weeks to assess the effects of this and any subsequent dose adjustments. A dose of 100 mg eltrombopag once daily must not be exceeded. Table 2 Dose adjustments of eltrombopag in HCV patients during antiviral therapy Platelet count Dose adjustment or response <50,000/µl following at least 2 weeks of therapy Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥50,000/µl to ≤100,000/µl Use lowest dose of eltrombopag as necessary to avoid dose reductions of peginterferon. >100,000/µl to ≤150,000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments♦. >150,000/µl Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is ≤100,000/µl, reinitiate therapy at a daily dose reduced by 25 mg*. * For patients taking 25 mg eltrombopag once daily, consideration should be given to reinitiating dosing at 25 mg every other day. ♦ On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose reductions should be avoided. Discontinuation If after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviral therapy is not achieved, eltrombopag should be discontinued. Eltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwise justified. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation. 6 Severe aplastic anaemia Initial dose regimen Eltrombopag should be initiated at a dose of 50 mg once daily. For patients of Asian ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). The treatment should not be initiated when the patients has existing cytogenetic abnormalities of chromosome 7. Monitoring and dose adjustment Haematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag (see section 5.1). The dose of eltrombopag should be adjusted in 50 mg increments every 2 weeks as necessary to achieve the target platelet count ≥50,000/µl. For patients taking 25 mg once daily, the dose should be increased to 50 mg daily before increasing the dose amount by 50 mg. A dose of 150 mg daily must not be exceeded. Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dosage regimen of eltrombopag modified based on platelet counts as outlined in Table 3. Table 3 Dose adjustments of eltrombopag in patients with severe aplastic anaemia Platelet count Dose adjustment or response <50,000/µl following at least 2 weeks of therapy Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. 50,000/µl to 150,000/µl Use lowest dose of eltrombopag to maintain platelet counts. >150,000/µl to 250,000/µl Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. >250,000/µl Stop eltrombopag; for at least one week. Once the platelet count is ≤100,000/µl, reinitiate therapy at a daily dose reduced by 50 mg. Tapering for tri-lineage (white blood cells, red blood cells, and platelets) responders For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag may be reduced by 50%. If counts remain stable after 8 weeks at the reduced dose, then eltrombopag must be discontinued and blood counts monitored. If platelet counts drop to <30,000/µl, haemoglobin drops to < 9 g/dl or absolute neutrophil count (ANC) <0.5 x 109/l, eltrombopag may be reinitiated at the previous effective dose. Discontinuation If no haematological response has occurred after 16 weeks of therapy with eltrombopag, therapy should be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate (see sections 4.4 and 4.8). Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of eltrombopag (see section 4.8). Special populations Renal impairment No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or performing urine analysis (see section 5.2). 7 Hepatic impairment Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see section 4.4). If the use of eltrombopag is deemed necessary for ITP patients with hepatic impairment the starting dose must be 25 mg once daily. After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 3 weeks should be observed before increasing the dose. No dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepatic impairment (Child-Pugh score ≤6). Chronic HCV patients and severe aplastic anaemia patients with hepatic impairment should initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 2 weeks should be observed before increasing the dose. There is an increased risk for adverse events, including hepatic decompensation and thromboembolic events, in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, either in preparation for invasive procedure or in HCV patients undergoing antiviral therapy (see sections 4.4 and 4.8). Elderly There are limited data on the use of eltrombopag in ITP patients aged 65 years and older and no clinical experience in ITP patients aged over 85 years. In the clinical studies of eltrombopag, overall no clinically significant differences in safety of eltrombopag were observed between patients aged at least 65 years and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see section 5.2). There are limited data on the use of eltrombopag in HCV and SAA patients aged over 75 years. Caution should be exercised in these patients (see section 4.4). Asian patients For patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), including those with hepatic impairment, eltrombopag should be initiated at a dose of 25 mg once daily (see section 5.2). Patient platelet count should continue to be monitored and the standard criteria for further dose modification followed. Paediatric population Revolade is not recommended for use in children under the age of one year with ITP due to insufficient data on safety and efficacy. The safety and efficacy of eltrombopag has not been established in children and adolescents (<18 years) with chronic HCV related thrombocytopenia or SAA. No data are available. Method of administration Oral use. The tablets should be taken at least two hours before or four hours after any products such as antacids, dairy products (or other calcium containing food products), or mineral supplements containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc) (see sections 4.5 and 5.2). 8 4.3 Contraindications Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as defined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when treated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of treatment in terms of the proportion achieving sustained virological response (SVR) compared with placebo were modest in these patients (especially for those with baseline albumin ≤35g/l) compared with the group overall. Treatment with eltrombopag in these patients should be initiated only by physicians experienced in the management of advanced HCV, and only when the risks of thrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered clinically indicated, close monitoring of these patients is required. Combination with direct-acting antiviral agents Safety and efficacy have not been established in combination with direct-acting antiviral agents approved for treatment of chronic hepatitis C infection. Risk of hepatotoxicity Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might be life-threatening (see section 4.8). Serum alanine aminotransferase (ALT), aspartate aminotrasferase (AST) and bilirubin should be measured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase (3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or >5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are:  progressive, or  persistent for ≥4 weeks, or  accompanied by increased direct bilirubin, or  accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. Caution is required when administering eltrombopag to patients with hepatic disease. In ITP and SAA patients a lower starting dose of eltrombopag should be used. Close monitoring is required when administering to patients with hepatic impairment (see section 4.2). Hepatic decompensation (use with interferon) Hepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients with low albumin levels (≤35 g/l) or with MELD score ≥10 at baseline. Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) occurred more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In patients with low albumin levels (≤ 35 g/l) or with a MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. In addition, the benefits of treatment in terms of the proportion 9 achieving SVR compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. The respective interferon summary of product characteristics should be referenced for discontinuation criteria. Eltrombopag should be terminated if antiviral therapy is discontinued for hepatic decompensation. Thrombotic/thromboembolic complications In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n=1,439), 38 out of 955 patients (4%) treated with eltrombopag and 6 out of 484 patients (1%) in the placebo group experienced thromboembolic events (TEEs). Reported thrombotic/thromboembolic complications included both venous and arterial events. The majority of TEEs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus <1% for placebo). No specific temporal relationship between start of treatment and event of TEE were observed. Patients with low albumin levels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients should be closely monitored for signs and symptoms of TEE. The risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treated with 75 mg eltrombopag once daily for 2 weeks in preparation for invasive procedures. Six of 143 (4%) adult patients with CLD receiving eltrombopag experienced TEEs (all of the portal venous system) and 2 of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five of the 6 patients treated with eltrombopag experienced the thrombotic complication at a platelet count >200,000/µl and within 30 days of the last dose of eltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures. In eltrombopag clinical studies in ITP thromboembolic events were observed at low and normal platelet counts. Caution should be used when administering eltrombopag to patients with known risk factors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking. Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds the target levels (see section 4.2). The risk-benefit balance should be considered in patients at risk of TEEs of any aetiology. No case of TEE was identified from a clinical study in refractory SAA, however the risk of these events cannot be excluded in this patient population due to the limited number of exposed patients. As the highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient population. Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis. When treatment is considered appropriate, caution is required when administering eltrombopag to patients with hepatic impairment (see sections 4.2 and 4.8). 10 Bleeding following discontinuation of eltrombopag Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with eltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levels within 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may lead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following discontinuation of eltrombopag. In HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatal cases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. Following discontinuation of therapy, patients should be monitored for any signs or symptoms of gastrointestinal bleeding. Bone marrow reticulin formation and risk of bone marrow fibrosis Eltrombopag may increase the risk for development or progression of reticulin fibres within the bone marrow. The relevance of this finding, as with other thrombopoietin receptor (TPO-R) agonists, has not been established yet. Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, full blood count (FBC) with white blood cell count (WBC) differential should be performed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be examined for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued and a bone marrow biopsy considered, including staining for fibrosis. Progression of existing myelodysplastic syndrome (MDS) There is a theoretical concern that TPO-R agonists may stimulate the progression of existing haematological malignancies such as MDS. TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is predominantly expressed on the surface of cells of the myeloid lineage. For TPO-R agonists there is a concern that they may stimulate the progression of existing haematopoietic malignancies such as MDS. In clinical studies with a TPO-R agonist in patients with MDS, cases of transient increases in blast cell counts were observed and cases of MDS disease progression to acute myeloid leukaemia (AML) were reported. The diagnosis of ITP or SAA in adults and elderly patients should be confirmed by the exclusion of other clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be excluded. Consideration should be given to performing a bone marrow aspirate and biopsy over the course of the disease and treatment, particularly in patients over 60 years of age, those with systemic symptoms, or abnormal signs such as increased peripheral blast cells. The effectiveness and safety of Revolade have not been established for the treatment of thrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS. 11 Cytogenetic abnormalities and progression to MDS/AML in patients with SAA Cytogenetic abnormalities are known to occur in SAA patients. It is not known whether eltrombopag increases the risk of cytogenetic abnormalities in patients with SAA. In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months. In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6. In clinical studies with eltrombopag in SAA, 4% of patients (5/133) were diagnosed with MDS. The median time to diagnosis was 3 months from the start of eltrombopag treatment. For SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bone marrow examination with aspirations for cytogenetics is recommended prior to initiation of eltrombopag, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate. Ocular changes Cataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). In controlled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1,439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the eltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, have been reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the eltrombopag group and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring of patients is recommended. QT/QTc prolongation A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically significant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical studies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of these QTc prolongation events is unknown. Loss of response to eltrombopag A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin. Paediatric population The above warnings and precautions for ITP also apply to the paediatric population. Interference with laboratory tests Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum discolouration and interference with total bilirubin and creatinine testing have been reported in patients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testing using another method may help in determining the validity of the result. 12 4.5 Interaction with other medicinal products and other forms of interaction Effects of eltrombopag on other medicinal products HMG CoA reductase inhibitors Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103% (90% confidence interval [CI]: 82%, 126%) and AUC0- 55% (90% CI: 42%, 69%). Interactions are also expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. When co-administered with eltrombopag, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see section 5.2). OATP1B1 and BCRP substrates Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution (see section 5.2). Cytochrome P450 substrates In studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe substrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected when eltrombopag and CYP450 substrates are co-administered (see section 5.2). HCV protease inhibitors Dose adjustment is not required when eltrombopag is co-administered with either telaprevir or boceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours did not alter plasma telaprevir exposure. Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did not alter plasma boceprevir AUC(0-), but increased Cmax by 20%, and decreased Cmin by 32%. The clinical relevance of the decrease in Cmin has not been established, increased clinical and laboratory monitoring for HCV suppression is recommended. Effects of other medicinal products on eltrombopag Ciclosporin A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg ciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the Cmax and the AUCinf of eltrombopag by 25% and 18%, respectively. The co-administration of 600 mg ciclosporin decreased the Cmax and the AUCinf of eltrombopag by 39% and 24%, respectively. Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient’s platelet count (see section 4.2). Platelet count should be monitored at least weekly for 2 to 3 weeks when eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increased based on these platelet counts. 13 Polyvalent cations (chelation) Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma eltrombopag AUC0- by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62%, 76%). Eltrombopag should be taken at least two hours before or four hours after any products such as antacids, dairy products or mineral supplements containing polyvalent cations to avoid significant reduction in eltrombopag absorption due to chelation (see sections 4.2 and 5.2). Lopinavir/ritonavir Co-administration of eltrombopag with lopinavir/ritonavir may cause a decrease in the concentration of eltrombopag. A study in 40 healthy volunteers showed that the co-administration of a single 100 mg dose of eltrombopag with repeat dose lopinavir/ritonavir 400/100 mg twice daily resulted in a reduction in eltrombopag plasma AUCinf by 17% (90% CI: 6.6%, 26.6%). Therefore, caution should be used when co-administration of eltrombopag with lopinavir/ritonavir takes place. Platelet count should be closely monitored in order to ensure appropriate medical management of the dose of eltrombopag when lopinavir/ritonavir therapy is initiated or discontinued. CYP1A2 and CYP2C8 inhibitors and inducers Eltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and UGT1A3 (see section 5.2). Medicinal products that inhibit or induce a single enzyme are unlikely to significantly affect plasma eltrombopag concentrations, whereas medicinal products that inhibit or induce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease (e.g. rifampicin) eltrombopag concentrations. HCV protease inhibitors Results of a drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeat doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of eltrombopag 200 mg did not alter plasma eltrombopag exposure to a clinically significant extent. Medicinal products for treatment of ITP Medicinal products used in the treatment of ITP in combination with eltrombopag in clinical studies included corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. Platelet counts should be monitored when combining eltrombopag with other medicinal products for the treatment of ITP in order to avoid platelet counts outside of the recommended range (see section 4.2). Food interaction The administration of eltrombopag tablet or powder for oral suspension formulations with a high- calcium meal (e.g. a meal that included dairy products) significantly reduced plasma eltrombopag AUC0-∞ and Cmax. In contrast, the administration of eltrombopag 2 hours before or 4 hours after a high- calcium meal or with low-calcium food [<50 mg calcium] did not alter plasma eltrombopag exposure to a clinically significant extent (see section 4.2). Administration of a single 50 mg dose of eltrombopag in tablet form with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag mean AUC0-∞ by 59% and mean Cmax by 65%. 14 Administration of a single 25 mg dose of eltrombopag as powder for oral suspension with a high- calcium, moderate-fat and moderate-calorie meal reduced plasma eltrombopag mean AUC0-∞ by 75% and mean Cmax by 79%. This decrease of exposure was attenuated when a single 25 mg dose of eltrombopag powder for oral suspension was administered 2 hours before a high-calcium meal (mean AUC0-∞ was decreased by 20% and mean Cmax by 14%). Food low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no added calcium, magnesium or iron) fruit juice, unfortified soya milk and unfortified grain, did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see sections 4.2 and 4.5). 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Revolade is not recommended during pregnancy. Women of childbearing potential / Contraception in males and females Revolade is not recommended in women of childbearing potential not using contraception. Breast-feeding It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have shown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to continue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Fertility was not affected in male or female rats at exposures that were comparable to those in humans. However a risk for humans cannot be ruled out (see section 5.3). 4.7 Effects on ability to drive and use machines Eltrombopag has negligible influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of eltrombopag, including dizziness and lack of alertness, should be borne in mind when considering the patient’s ability to perform tasks that require judgement, motor and cognitive skills. 15 4.8 Undesirable effects Summary of the safety profile Immune thrombocytopenia in adult and paediatric patients The safety of Revolade was assessed using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completed open-label studies TRA108057, TRA105325 (EXTEND) and TRA112940. Patients received study medication for up to 8 years (in EXTEND). The most important serious adverse reactions were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included nausea, diarrhoea and increased alanine aminotransferase. The safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies. PETIT2 (TRA115450) was a 2-part, double-blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study. PETIT (TRA108062) was a 3-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea. Thrombocytopenia with HCV infection in adult patients ENABLE 1 (TPL103922 n=716) and ENABLE 2 (TPL108390 n=805) were randomised, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=253). Patients are analysed according to the treatment received (total safety double-blind population, Revolade n=955 and placebo n=484). The most important serious adverse reactions identified were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included headache, anaemia, decreased appetite, cough, nausea, diarrhoea, hyperbilirubinaemia, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and oedema. Severe aplastic anaemia in adult patients The safety of eltrombopag in severe aplastic anaemia was assessed in a single-arm, open-label study (N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (21%) were treated for >1 year. The most important serious adverse reactions were febrile neutropenia and sepsis/infection. The most common adverse reactions occurring in at least 10% of patients included headache, dizziness, cough, oropharyngeal pain, nausea, diarrhoea, abdominal pain, transaminases increased, arthralgia, pain in extremity, fatigue and pyrexia. 16 List of adverse reactions The adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCV studies (N=1,520), the SAA studies (N=43) and post-marketing reports are listed below by MedDRA system organ class and by frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data). ITP study population System organ class Frequency Adverse reaction Infections and infestations Very common Nasopharyngitis♦, upper respiratory tract infection♦ Common Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, respiratory tract infection, gingivitis Uncommon Skin infection Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Rectosigmoid cancer Blood and lymphatic system disorders Common Anaemia, eosinophilia, leukocytosis, thrombocytopenia, haemoglobin decreased, white blood cell count decreased Uncommon Anisocytosis, haemolytic anaemia, myelocytosis, band neutrophil count increased, myelocyte present, platelet count increased, haemoglobin increased Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Common Hypokalaemia, decreased appetite, blood uric acid increased Uncommon Anorexia, gout, hypocalcaemia Psychiatric disorders Common Sleep disorder, depression Uncommon Apathy, mood altered, tearfulness Nervous system disorders Common Paraesthesia, hypoaesthesia, somnolence, migraine Uncommon Tremor, balance disorder, dysaesthesia, hemiparesis, migraine with aura, neuropathy peripheral, peripheral sensory neuropathy, speech disorder, toxic neuropathy, vascular headache Eye disorders Common Dry eye, vision blurred, eye pain, visual acuity reduced Uncommon Lenticular opacities, astigmatism, cataract cortical, lacrimation increased, retinal haemorrhage, retinal pigment epitheliopathy, visual impairment, visual acuity tests abnormal, blepharitis, keratoconjunctivitis sicca Ear and labyrinth disorders Common Ear pain, vertigo Cardiac disorders Uncommon Tachycardia, acute myocardial infarction, cardiovascular disorder, cyanosis, sinus tachycardia, electrocardiogram QT prolonged 17 Vascular disorders Common Deep vein thrombosis, haematoma, hot flush Uncommon Embolism, thrombophlebitis superficial, flushing Respiratory, thoracic and mediastinal disorders Very common Cough♦ Common Oropharyngeal pain, rhinorrhoea♦ Uncommon Pulmonary embolism, pulmonary infarction, nasal discomfort, oropharyngeal blistering, sinus disorder, sleep apnoea syndrome Gastrointestinal disorders Very common Nausea, diarrhoea♦ Common Mouth ulceration, toothache♦, vomiting, abdominal pain*, mouth haemorrhage, flatulence * Very common in paediatric ITP Uncommon Dry mouth, glossodynia, abdominal tenderness, faeces discoloured, food poisoning, frequent bowel movements, haematemesis, oral discomfort Hepatobiliary disorders Very common Alanine aminotransferase increased† Common Aspartate aminotransferase increased†, hyperbilirubinaemia, hepatic function abnormal Uncommon Cholestasis, hepatic lesion, hepatitis, drug-induced liver injury Skin and subcutaneous tissue disorders Common Rash, alopecia, hyperhidrosis, pruritus generalised, petechiae Uncommon Urticaria, dermatosis, cold sweat, erythema, melanosis, pigmentation disorder, skin discolouration, skin exfoliation Musculoskeletal and connective tissue disorders Common Myalgia, muscle spasm, musculoskeletal pain, bone pain, back pain Uncommon Muscular weakness Renal and urinary disorders Common Proteinuria, blood creatinine increased, thrombotic microangiopathy with renal failure‡ Uncommon Renal failure, leukocyturia, lupus nephritis, nocturia, blood urea increased, urine protein/creatinine ratio increased Reproductive system and breast disorders Common Menorrhagia General disorders and administration site conditions Common Pyrexia*, chest pain, asthenia *Very common in paediatric ITP Uncommon Feeling hot, vessel puncture site haemorrhage, feeling jittery, inflammation of wound, malaise, sensation of foreign body Investigations Common Blood alkaline phosphatase increased Uncommon Blood albumin increased, protein total increased, blood albumin decreased, pH urine increased Injury, poisoning and procedural complications Uncommon Sunburn ♦ Additional adverse reactions observed in paediatric studies (aged 1to 17 years). † Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, although at a lower frequency. ‡ Grouped term with preferred terms acute kidney injury and renal failure HCV study population (in combination with anti-viral interferon and ribavirin therapy) System organ class Frequency Adverse reaction Infections and infestations Common Urinary tract infection, upper respiratory tract infection, bronchitis, nasopharyngitis, influenza, oral herpes Uncommon Gastroenteritis, pharyngitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Hepatic neoplasm malignant 18 Blood and lymphatic system disorders Very common Anaemia Common Lymphopenia Uncommon Haemolytic anaemia Metabolism and nutrition disorders Very common Decreased appetite Common Hyperglycaemia, abnormal loss of weight Psychiatric disorders Common Depression, anxiety, sleep disorder Uncommon Confusional state, agitation Nervous system disorders Very common Headache Common Dizziness, disturbance in attention, dysgeusia, hepatic encephalopathy, lethargy, memory impairment, paraesthesia Eye disorders Common Cataract, retinal exudates, dry eye, ocular icterus, retinal haemorrhage Ear and labyrinth disorders Common Vertigo Cardiac disorders Common Palpitations Respiratory, thoracic and mediastinal disorders Very common Cough Common Dyspnoea, oropharyngeal pain, dyspnoea exertional, productive cough Gastrointestinal disorders Very common Nausea, diarrhoea Common Vomiting, ascites, abdominal pain, abdominal pain upper, dyspepsia, dry mouth, constipation, abdominal distension, toothache, stomatitis, gastrooesophagal reflux disease, haemorrhoids, abdominal discomfort, varices oesophageal Uncomon Oesophageal varices haemorrhage, gastritis, aphthous stomatitis Hepatobiliary disorders Common Hyperbilirubinaemia, jaundice, drug-induced liver injury Uncommon Portal vein thrombosis, hepatic failure Skin and subcutaneous tissue disorders Very common Pruritus Common Rash, dry skin, eczema, rash pruritic, erythema, hyperhidrosis, pruritus generalised, alopecia Uncommon Skin lesion, skin discolouration, skin hyperpigmentation, night sweats Musculoskeletal and connective tissue disorder Very common Myalgia Common Arthralgia, muscle spasms, back pain, pain in extremity, musculoskeletal pain, bone pain Renal and urinary disorders Uncommon Thrombotic microangiopathy with acute renal failure†, dysuria General disorders and administration site conditions Very common Pyrexia, fatigue, influenza-like illness, asthenia, chills Common Irritability, pain, malaise, injection site reaction, non-cardiac chest pain, oedema, oedema peripheral Uncommon Injection site pruritus, injection site rash, chest discomfort Investigations Common Blood bilirubin increased, weight decreased, white blood cell count decreased, haemoglobin decreased, neutrophil count decreased, international normalised ratio increased, activated partial thromboplastin time prolonged, blood glucose increased, blood albumin decreased Uncommon Electrocardiogram QT prolonged † Grouped term with preferred terms oliguria, renal failure and renal impairment 19 SAA study population System organ class Frequency Adverse reaction Blood and lymphatic system disorders Common Neutropenia, splenic infarction Metabolism and nutrition disorders Common Iron overload, decreased appetite, hypoglycaemia, increased appetite Psychiatric disorders Common Anxiety, depression Nervous system disorders Very common Headache, dizziness Common Syncope Eye disorders Common Dry eye, cataract, ocular icterus, vision blurred, visual impairment, vitreous floaters Respiratory, thoracic and mediastinal disorders Very common Cough, oropharyngeal pain, rhinorrhoea Common Epistaxis Gastrointestinal disorders Very common Diarrhoea, nausea, gingival bleeding, abdominal pain Common Oral mucosal blistering, oral pain, vomiting, abdominal discomfort, constipation, abdominal distension, dysphagia, faeces discoloured, swollen tongue, gastrointestinal motility disorder, flatulence Hepatobiliary disorders Very common Transaminases increased Common Blood bilirubin increased (hyperbilirubinemia), jaundice Not known Drug-induced liver injury* * Cases of drug-induced liver injury have been reported in patients with ITP and HCV Skin and subcutaneous tissue disorders Common Petechiae, rash, pruritus, urticaria, skin lesion, rash macular Not known Skin discolouration, skin hyperpigmentation Musculosketal and connective tissue disorders Very common Arthralgia, pain in extremity, muscle spasms Common Back pain, myalgia, bone pain Renal and urinary disorders Common Chromaturia General disorders and administration site conditions Very common Fatigue, pyrexia, chills Common Asthenia, oedema peripheral, malaise Investigations Common Blood creatine phosphokinase increased Description of selected adverse reactions Thrombotic/thromboembolic events (TEEs) In 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving eltrombopag (n=446), 17 patients experienced a total of 19 TEEs, which included (in descending order of occurrence) deep vein thrombosis (n=6), pulmonary embolism (n=6), acute myocardial infarction (n=2), cerebral infarction (n=2), embolism (n=1) (see section 4.4). In a placebo-controlled study (n=288, Safety population), following 2 weeks’ treatment in preparation for invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag experienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo group experienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a platelet count >200,000/µl No specific risk factors were identified in those patients who experienced a TEE with the exception of platelet counts ≥200,000/µl (see section 4.4). 20 In controlled studies in thrombocytopenic patients with HCV (n=1,439), 38 out of 955 patients (4%) treated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus < 1% for placebo) (see section 4.4). Patients with low albumin levels (≤ 35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. Hepatic decompensation (use with interferon) Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation (see section 4.4). Hepatotoxixity In the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and bilirubin were observed (see section 4.4). These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in adults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group experienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients (aged 1 to 17 years) with chronic ITP, ALT 3 x ULN was reported in 4.7% and 0% of the eltrombopag and placebo groups, respectively. In 2 controlled clinical studies in patients with HCV, ALT or AST 3 x ULN was reported in 34% and 38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag in combination with peginterferon / ribavirin therapy will experience indirect hyperbilirubinaemia. Overall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the eltrombopag and placebo groups, respectively. In the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULN with total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN occurred in 14% of patients. Thrombocytopenia following discontinuation of treatment In the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8% and 8% of the eltrombopag and placebo groups, respectively (see section 4.4). Increased bone marrow reticulin Across the programme, no patients had evidence of clinically relevant bone marrow abnormalities or clinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients, eltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4). 21 Cytogenetic abnormalities In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months. In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6. Haematologic malignancies In the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS following treatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and 1/62 (2%) patient has been diagnosed with MDS or AML in each study. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In case of an overdose, consideration should be given to oral administration of a metal cation-containing preparation, such as calcium, aluminium, or magnesium preparations to chelate eltrombopag and thus limit absorption. Platelet counts should be closely monitored. Treatment with eltrombopag should be reinitiated in accordance with dosing and administration recommendations (see section 4.2). In the clinical studies there was one report of overdose where the patient ingested 5000 mg of eltrombopag. Reported adverse reactions included mild rash, transient bradycardia, ALT and AST elevation, and fatigue. Liver enzymes measured between Days 2 and 18 after ingestion peaked at a 1.6-fold ULN in AST, a 3.9-fold ULN in ALT, and a 2.4-fold ULN in total bilirubin, The platelet counts were 672,000/µl on Day 18 after ingestion and the maximum platelet count was 929,000/µl. All events were resolved without sequelae following treatment. Because eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, haemodialysis would not be expected to be an effective method to enhance the elimination of eltrombopag. 22 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics. ATC code: B02BX 05. Mechanism of action TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates signalling cascades similar but not identical to that of endogenous thrombopoietin (TPO), inducing proliferation and differentiation from bone marrow progenitor cells. Clinical efficacy and safety Immune (primary) thrombocytopenia (ITP) studies Two phase III, randomised, double-blind, placebo-controlled studies RAISE (TRA102537) and TRA100773B and two open-label studies REPEAT (TRA108057) and EXTEND (TRA105325) evaluated the safety and efficacy of eltrombopag in adult patients with previously treated ITP. Overall, eltrombopag was administered to 277 ITP patients for at least 6 months and 202 patients for at least 1 year. Double-blind placebo-controlled studies RAISE: 197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and randomisation was stratified based upon splenectomy status, use of ITP medicinal products at baseline and baseline platelet count. The dose of eltrombopag was adjusted during the 6-month treatment period based on individual platelet counts. All patients initiated treatment with eltrombopag 50 mg. From Day 29 to the end of treatment, 15 to 28% of eltrombopag-treated patients were maintained on ≤25 mg and 29 to 53% received 75 mg. In addition, patients could taper off concomitant ITP medicinal products and receive rescue treatments as dictated by local standard of care. More than half of all patients in each treatment group had ≥3 prior ITP therapies and 36% had a prior splenectomy. Median platelet counts at baseline were 16,000/l for both treatment groups and in the eltrombopag group were maintained above 50,000/µl at all on-therapy visits starting at Day 15; in contrast, median platelet counts in the placebo group remained <30,000/µl throughout the study. Platelet count response between 50,000-400,000/l in the absence of rescue treatment was achieved by significantly more patients in the eltrombopag treated group during the 6 month treatment period, p <0.001. Fifty-four percent of the eltrombopag-treated patients and 13% of placebo-treated patients achieved this level of response after 6 weeks of treatment. A similar platelet response was maintained throughout the study, with 52% and 16% of patients responding at the end of the 6-month treatment period. 23 Table 4 Secondary efficacy results from RAISE Eltrombopag N=135 Placebo N=62 Key secondary endpoints Number of cumulative weeks with platelet counts 50,000-400,000/µl, Mean (SD) 11.3 (9.46) 2.4 (5.95) Patients with ≥75% of assessments in the target range (50,000 to 400,000/l), n (%) p-value a 51 (38) 4 (7) <0.001 Patients with bleeding (WHO Grades 1-4) at any time during 6 months, n (%) p-value a 106 (79) 56 (93) 0.012 Patients with bleeding (WHO Grades 2-4) at any time during 6 months, n (%) p-value a 44 (33) 32 (53) 0.002 Requiring rescue therapy, n (%) p-value a 24 (18) 25 (40) 0.001 Patients receiving ITP therapy at baseline (n) 63 31 Patients who attempted to reduce or discontinue baseline therapy, n (%)b p-value a 37 (59) 10 (32) 0.016 a Logistic regression model adjusted for randomisation stratification variables b 21 out of 63 (33%) patients treated with eltrombopag who were taking an ITP medicinal product at baseline permanently discontinued all baseline ITP medicinal products. At baseline, more than 70% of ITP patients in each treatment group reported any bleeding (WHO Grades 1-4) and more than 20% reported clinically significant bleeding (WHO Grades 2-4), respectively. The proportion of eltrombopag-treated patients with any bleeding (Grades 1-4) and clinically significant bleeding (Grades 2-4) was reduced from baseline by approximately 50% from Day 15 to the end of treatment throughout the 6-month treatment period. TRA100773B: The primary efficacy endpoint was the proportion of responders, defined as ITP patients who had an increase in platelet counts to 50,000/l at Day 43 from a baseline of <30,000/l; patients who withdrew prematurely due to a platelet count 200,000/l were considered responders, those that discontinued for any other reason were considered non-responders irrespective of platelet count. A total of 114 patients with previously treated ITP were randomised 2:1 eltrombopag (n=76) to placebo (n=38). Table 5 Efficacy results from TRA100773B Eltrombopag N=74 Placebo N=38 Key primary endpoints Eligible for efficacy analysis, n 73 37 Patients with platelet count 50,000/l after up to 42 days of dosing (compared to a baseline count of <30,000/l), n (%) p-valuea 43 (59) 6 (16) <0.001 Key secondary endpoints Patients with a Day 43 bleeding assessment, n 51 30 Bleeding (WHO Grades 1-4) n (%) p-valuea 20 (39) 18 (60) 0.029 a Logistic regression model adjusted for randomisation stratification variables 24 In both RAISE and TRA100773B the response to eltrombopag relative to placebo was similar irrespective of ITP medicinal product use, splenectomy status and baseline platelet count (≤15,000/µl, >15,000/µl) at randomisation. In RAISE and TRA100773B studies, in the subgroup of ITP patients with baseline platelet count ≤15,000/μl the median platelet counts did not reach the target level (>50,000/l), although in both studies 43% of these patients treated with eltrombopag responded after 6 weeks of treatment. In addition, in the RAISE study, 42% of patients with baseline platelet count ≤15,000/μl treated with eltrombopag responded at the end of the 6 month treatment period. Forty-two to 60% of the eltrombopag-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of treatment. An open-label, repeat-dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks off treatment) showed that episodic use with multiple courses of eltrombopag has demonstrated no loss of response. Eltrombopag was administered to 302 ITP patients in the open-label extension study EXTEND (TRA105325), 218 patients completed 1 year, 180 completed 2 years, 107 completed 3 years, 75 completed 4 years, 34 completed 5 years and 18 completed 6 years. The median baseline platelet count was 19,000/l prior to eltrombopag administration. Median platelet counts at 1, 2, 3, 4, 5, 6 and 7 years on study were 85,000/l, 85,000/l, 105,000/l, 64,000/l, 75,000/l, 119,000/l and 76,000/l, respectively. Clinical studies comparing eltrombopag to other treatment options (e.g. splenectomy) have not been conducted. The long-term safety of eltrombopag should be considered prior to starting therapy. Paediatric population (aged 1 to 17 years) The safety and efficacy of eltrombopag in paediatric patients have been investigated in two studies. TRA115450 (PETIT2): The primary endpoint was a sustained response, defined as the proportion of patients receiving eltrombopag, compared to placebo, achieving platelet counts ≥50,000/µl for at least 6 out of 8 weeks (in the absence of rescue therapy), between weeks 5 to 12 during the double-blind randomised period. Patients were diagnosed with chronic ITP for at least 1 year and were refractory or relapsed to at least one prior ITP therapy or unable to continue other ITP treatments for a medical reason and had platelet count <30,000/µl. Ninety-two patients were randomised by three age cohort strata (2:1) to eltrombopag (n=63) or placebo (n=29). The dose of eltrombopag could be adjusted based on individual platelet counts. Overall, a significantly greater proportion of eltrombopag patients (40%) compared with placebo patients (3%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9] p <0.001) which was similar across the three age cohorts (Table 6). Table 6 Sustained platelet response rates by age cohort in paediatric patients with chronic ITP Eltrombopag n/N (%) [95% CI] Placebo n/N (%) [95% CI] Cohort 1 (12 to 17 years) Cohort 2 (6 to 11 years) Cohort 3 (1 to 5 years) 9/23 (39%) [20%, 61%] 11/26 (42%) [23%, 63%] 5/14 (36%) [13%, 65%] 1/10 (10%) [0%, 45%] 0/13 (0%) [N/A] 0/6 (0%) [N/A] 25 Statistically fewer eltrombopag patients required rescue treatment during the randomised period compared to placebo patients (19% [12/63] vs. 24% [7/29], p=0.032). At baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported any bleeding (WHO Grades 1-4). At Week 12, the proportion of eltrombopag patients reporting any bleeding was decreased to half of baseline (36%). In comparison, at Week 12, 55% of placebo patients reported any bleeding. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the study and 53% (8/15) of patients were able to reduce (n=1) or discontinue (n=7) baseline ITP therapy, mainly corticosteroids, without needing rescue therapy. TRA108062 (PETIT): The primary endpoint was the proportion of patients achieving platelet counts ≥50,000/µl at least once between weeks 1 and 6 of the randomised period. Patients were diagnosed with ITP for at least 6 months and were refractory or relapsed to at least one prior ITP therapy with a platelet count <30,000/µl (n=67). During the randomised period of the study, patients were randomised by three age cohort strata (2:1) to eltrombopag (n=45) or placebo (n=22). The dose of eltrombopag could be adjusted based on individual platelet counts. Overall, a significantly greater proportion of eltrombopag patients (62%) compared with placebo patients (32%) met the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3] p=0.011). Sustained response was seen in 50% of the initial responders during 20 out of 24 weeks in the PETIT 2 study and 15 out of 24 weeks in the PETIT study. Chronic hepatitis C associated thrombocytopenia studies The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV infection were evaluated in two randomised, double-blind, placebo-controlled studies. ENABLE 1 utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilised peginterferon alfa-2b plus ribavirin. Patients did not receive direct acting antiviral agents. In both studies, patients with a platelet count of <75,000/µl were enrolled and stratified by platelet count (<50,000/µl and ≥50,000/µl to <75,000/µl), screening HCV RNA (<800,000 IU/ml and ≥800,000 IU/ml), and HCV genotype (genotype 2/3, and genotype 1/4/6). Baseline disease characteristics were similar in both studies and were consistent with compensated cirrhotic HCV patient population. The majority of patients were HCV genotype 1 (64%) and had bridging fibrosis/cirrhosis. Thirty-one percent of patients had been treated with prior HCV therapies, primarily pegylated interferon plus ribavirin. The median baseline platelet count was 59,500/µl in both treatment groups: 0.8%, 28% and 72% of the patients recruited had platelet counts <20,000/µl, <50.000/µl and ≥50,000/µl respectively. The studies consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to ≥90,000/µl for ENABLE 1 and ≥100,000/µl for ENABLE 2. The median time to achieve the target platelet count ≥90,000/µl (ENABLE 1) or ≥100,000/µl (ENABLE 2) was 2 weeks. The primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as the percentage of patients with no detectable HCV-RNA at 24 weeks after completion of the planned treatment period. 26 In both HCV studies, a significantly greater proportion of patients treated with eltrombopag (n=201, 21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 7). The improvement in the proportion of patients who achieved SVR was consistent across all subgroups in the randomisation strata (baseline platelet counts (<50,000 vs. >50,000), viral load (<800,000 IU/ml vs. ≥800,000 IU/ml) and genotype (2/3 vs. 1/4/6)). Table 7 Virologic response in HCV patients in ENABLE 1 and ENABLE 2 Pooled data ENABLE 1a ENABLE 2b Patients achieving target platelet counts and initiating antiviral therapy c 1,439/1,520 (95%) 680/715 (95%) 759/805 (94%) Eltrombopag Placebo Eltrombopag Placebo Eltrombopag Placebo Total number of patients entering antiviral treatment phase n=956 n=485 n=450 n=232 n=506 n=253 % patients achieving virologic response Overall SVR d 21 13 23 14 19 13 HCV RNA Genotype Genotype 2/3 35 25 35 24 34 25 Genotype 1/4/6e 15 8 18 10 13 7 Albumin levels f ≤ 35g/l 11 8 > 35g/l 25 16 MELD scoref ≥ 10 18 10 < 10 23 17 a Eltrombopag given in combination with peginterferon alfa-2a (180 μg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1200 mg daily in 2 divided doses orally) b Eltrombopag given in combination with peginterferon alfa-2b (1.5 μg/kg once weekly for 48 weeks for genotype 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1400 mg orally in 2 divided doses) c Target platelet count was 90,000/µl for ENABLE 1 and 100,000/µl for ENABLE 2. For ENABLE 1, 682 patients were randomised to the antiviral treatment phase; however 2 patients then withdrew consent prior to receiving antiviral therapy d p-value <0.05 for eltrombopag versus placebo e 64% patients participating in ENABLE 1 and ENABLE 2 were genotype 1 f Post-hoc analyses Other secondary findings of the studies included the following: significantly fewer patients treated with eltrombopag prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%, p=<0.0001). A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared to placebo (45% vs. 27%). Eltrombopag treatment delayed and reduced the number of peginterferon dose reductions. 27 Severe aplastic anaemia Eltrombopag was studied in a single-arm, single-centre open-label study in 43 patients with severe aplastic anaemia with refractory thrombocytopenia following at least one prior immunosuppressive therapy (IST) and who had a platelet count ≤30,000/µl. The majority of patients, 33 (77%), were considered to have ‘primary refractory disease’, defined as having no prior adequate response to IST in any lineage. The remaining 10 patients had insufficient platelet response to prior therapies. All 10 had received at least 2 prior IST regimens and 50% had received at least 3 prior IST regimens. Patients with diagnosis of Fanconi anaemia, infection not responding to appropriate therapy, PNH clone size in neutrophils of ≥50%, where excluded from participation. At baseline the median platelet count was 20,000/µl, haemoglobin was 8.4 g/dl, ANC was 0.58 x 109/l and absolute reticulocyte count was 24.3 x 109/l. Eighty-six percent of patients were RBC transfusion dependent, and 91% were platelet transfusion dependent. The majority of patients (84%) had received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. The primary endpoint was haematological response assessed after 12 weeks of eltrombopag treatment. Haematological response was defined as meeting one or more of the following criteria: 1) platelet count increases to 20,000/µl above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) haemoglobin increase by >1.5g/dl, or a reduction in ≥4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) absolute neutrophil count (ANC) increase of 100% or an ANC increase >0.5 x 109/l. The haematological response rate was 40% (17/43 patients; 95% CI 25, 56), the majority were unilineage responses (13/17, 76%) whilst there were 3 bilineage and 1 trilineage responses at week 12. Eltrombopag was discontinued after 16 weeks if no haematological response or transfusion independence was observed. Patients who responded continued therapy in an extension phase of the study. A total of 14 patients entered the extension phase of the trial. Nine of these patients achieved a multi-lineage response, 4 of the 9 remain on treatment and 5 tapered off treatment with eltrombopag and maintained the response (median follow up: 20.6 months, range: 5.7 to 22.5 months). The remaining 5 patients discontinued treatment, three due to relapse at the month 3 extension visit. During treatment with eltrombopag 59% (23/39) became platelet transfusion independent (28 days without platelet transfusion) and 27% (10/37) became RBC transfusion independent (56 days without RBC transfusion). The longest platelet transfusion-free period for non-responders was 27 days (median). The longest platelet transfusion-free period for responders was 287 days (median). The longest RBC transfusion-free period for non-responders was 29 days (median). The longest RBC transfusion-free period for responders was 266 days (median). Over 50% of responders who were transfusion-dependent at baseline, had >80% reduction in both platelet and RBC transfusion requirements compared to baseline. Preliminary results from a supportive study (Study ELT116826), an ongoing non-randomised, phase II, single-arm, open-label study in refractory SAA patients, showed consistent results. Data are limited to 21 out of the planned 60 patients with haematological responses reported by 52% of patients at 6 months. Multilineage responses were reported by 45% of patients. 28 5.2 Pharmacokinetic properties Pharmacokinetics The plasma eltrombopag concentration-time data collected in 88 patients with ITP in studies TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population PK analysis. Plasma eltrombopag AUC(0-) and Cmax estimates for ITP patients are presented (Table 8). Table 8 Geometric mean (95% confidence intervals) of steady-state plasma eltrombopag pharmacokinetic parameters in adults with ITP Eltrombopag dose, once daily N AUC(0-)a, g.h/ml Cmaxa, g/ml 30 mg 28 47 (39, 58) 3.78 (3.18, 4.49) 50 mg 34 108 (88, 134) 8.01 (6.73, 9.53) 75 mg 26 168 (143, 198) 12.7 (11.0, 14.5) a AUC(0-) and Cmax based on population PK post-hoc estimates. Plasma eltrombopag concentration-time data collected in 590 patients with HCV enrolled in phase III studies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patients with HCV enrolled in the phase II study TPL102357 and healthy adult patients in a population PK analysis. Plasma eltrombopag Cmax and AUC(0-) estimates for patients with HCV enrolled in the phase III studies are presented for each dose studied in Table 9. Table 9 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters in patients with chronic HCV Eltrombopag dose (once daily) N AUC(0-) (g.h/ml) Cmax (g/ml) 25 mg 330 118 (109, 128) 6.40 (5.97, 6.86) 50 mg 119 166 (143, 192) 9.08 (7.96, 10.35) 75 mg 45 301 (250, 363) 16.71 (14.26, 19.58) 100 mg 96 354 (304, 411) 19.19 (16.81, 21.91) Data presented as geometric mean (95% CI). AUC (0-) and Cmax based on population PK post-hoc estimates at the highest dose in the data for each patient. Absorption and bioavailability Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Administration of eltrombopag concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces eltrombopag exposure (see section 4.2). In a relative bioavailability study in adults, the eltrombopag powder for oral suspension delivered 22% higher plasma AUC(0-) than the film-coated tablet formulation. The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52%. 29 Distribution Eltrombopag is highly bound to human plasma proteins (>99.9%), predominantly to albumin. Eltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1. Biotransformation Eltrombopag is primarily metabolised through cleavage, oxidation and conjugation with glucuronic acid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64% of plasma radiocarbon AUC0-. Minor metabolites due to glucuronidation and oxidation were also detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidative metabolism of eltrombopag. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathway. Elimination Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is via faeces (59%) with 31% of the dose found in the urine as metabolites. Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for approximately 20% of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours. Pharmacokinetic interactions Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not anticipated due to limited contribution of individual UGT enzymes in the glucuronidation of eltrombopag. Approximately 21% of an eltrombopag dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag oxidation. Eltrombopag does not inhibit or induce CYP enzymes based on in vitro and in vivo data (see section 4.5). In vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter and an inhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1 and BCRP substrate rosuvastatin in a clinical drug interaction study (see section 4.5). In clinical studies with eltrombopag, a dose reduction of statins by 50% was recommended. Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc (see sections 4.2 and 4.5). In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter polypeptide, OATP1B1, but is an inhibitor of this transporter (IC50 value of 2.7 μM (1.2 μg/ml). In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor (IC50 value of 2.7 μM (1.2 μg/ml). 30 Special patient populations Renal impairment The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult patients with renal impairment. Following administration of a single 50 mg dose, the AUC0- of eltrombopag was 32% to 36% lower in patients with mild to moderate renal impairment, and 60% lower in patients with severe renal impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with renal impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound medicinal product were not measured. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or urine analysis (see section 4.2). The efficacy and safety of eltrombopag have not been established in patients with both moderate to severe renal impairment and hepatic impairment. Hepatic impairment The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult patients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0- of eltrombopag was 41% higher in patients with mild hepatic impairment and 80% to 93% higher in patients with moderate to severe hepatic impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound medicinal product were not measured. The influence of hepatic impairment on the pharmacokinetics of eltrombopag following repeat administration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and 714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver disease of other aetiology). Of the 714 patients, 642 were with mild hepatic impairment, 67 with moderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers, patients with mild hepatic impairment had approximately 111% (95% CI: 45% to 283%) higher plasma eltrombopag AUC(0-) values and patients with moderate hepatic impairment had approximately 183% (95% CI: 90% to 459%) higher plasma eltrombopag AUC(0-) values. Therefore, eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see sections 4.2 and 4.4). For patients with HCV initiate eltrombopag at a dose of 25 mg once daily (see section 4.2). Race The influence of Asian ethnicity (such as Japanese, Chinese, Taiwanese and Korean) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 Asians) and 88 patients with ITP (18 Asians). Based on estimates from the population pharmacokinetic analysis, Asian ITP patients had approximately 49% higher plasma eltrombopag AUC(0-) values as compared to non-Asian patients who were predominantly Caucasian (see section 4.2). The influence of Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean, and Thai) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 635 patients with HCV (145 Asians and 69 South Asians). Based on estimates from the population pharmacokinetic analysis, Asian patients had approximately 55% higher plasma eltrombopag AUC(0-) values as compared to patients of other races who were predominantly Caucasian (see section 4.2). 31 Gender The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). Based on estimates from the population pharmacokinetic analysis, female ITP patients had approximately 23% higher plasma eltrombopag AUC(0-) as compared to male patients, without adjustment for body weight differences. The influence of gender on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimate, female HCV patient had approximately 41% higher plasma eltrombopag AUC(0-) as compared to male patients. Age The influence of age on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 28 healthy subjects, 673 patients with HCV, and 41 patients with chronic liver disease of other aetiology ranging from 19 to 74 years old. There are no PK data on the use of eltrombopag in patients ≥75 years. Based on model estimate, elderly (≥65 years) patients had approximately 41% higher plasma eltrombopag AUC(0-) as compared to younger patients (see section 4.2). Paediatric population (aged 1 to 17 years) The pharmacokinetics of eltrombopag have been evaluated in 168 paediatric ITP patients dosed once daily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. The effects of race and sex on plasma eltrombopag CL/F estimates were consistent between paediatric and adult patients. Asian paediatric ITP patients had approximately 43% higher plasma eltrombopag AUC(0-) values as compared to non-Asian patients. Female paediatric ITP patients had approximately 25% higher plasma eltrombopag AUC(0-) values as compared to male patients. The pharmacokinetic parameters of eltrombopag in paediatric patients with ITP are shown in Table 10. Table 10 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters in paediatric patients with ITP (50 mg once daily dosing regimen) Age Cmax (µg/ml) AUC(0-) (µg.hr/ml) 12 to 17 years (n=62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n=68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n=38) 11.6 (10.4, 12.9) 162 (139, 187) Data presented as geometric mean (95%CI). AUC(0-) and Cmax based on population PK post-hoc estimates 32 5.3 Preclinical safety data Safety pharmacology and repeat-dose toxicity Eltrombopag does not stimulate platelet production in mice, rats or dogs because of unique TPO receptor specificity. Therefore, data from these animals do not fully model potential adverse effects related to the pharmacology of eltrombopag in humans, including the reproduction and carcinogenicity studies. Treatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥6 times the human clinical exposure in adult ITP patients at 75 mg/day and 3 times the human clinical exposure in adult HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after 6 weeks and rats after 28 weeks of dosing. At 4 times the human clinical exposure in ITP patients at 75 mg/day and 2 times the human exposure in HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. At non-tolerated doses in pre-weaning juvenile rats dosed from Days 4-32 (approximately equating to a 2-year-old human at the end of the dosing period), ocular opacities were observed (histology not performed) at 9 times the maximum human clinical exposure in paediatric ITP patients at 75 mg/day, based on AUC. However, cataracts were not observed in juvenile rats given tolerated doses at 5 times the human clinical exposure in paediatric ITP patients, based on AUC. Cataracts have not been observed in adult dogs after 52 weeks of dosing at 2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less severe at lower doses and were characterised by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 or 0.8 times the human clinical exposure based on AUC in adult or paediatric ITP patients at 75 mg/day and 0.6 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times the human clinical exposure in adult ITP patients and 3 and 2 times the human clinical exposure in paediatric ITP patients at 75 mg/day and 2 times and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Hepatocyte degeneration and/or necrosis, often accompanied by increased serum liver enzymes, was observed in mice, rats and dogs at doses that were associated with morbidity and mortality or were poorly tolerated. No hepatic effects were observed after chronic dosing in rats (28 weeks) and in dogs (52 weeks) at 4 or 2 times the human clinical exposure in adult ITP patients and 3 or 2 times the human clinical exposure in paediatric ITP patients at 75 mg/day and 2 times or equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC. At poorly tolerated doses in rats and dogs (>10 or 7 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and>4 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC), decreased reticulocyte counts and regenerative bone marrow erythroid hyperplasia (rats only) were observed in short-term studies. There were no effects of note on red cell mass or reticulocyte counts after dosing for up to 28 weeks in rats, 52 weeks in dogs and 2 years in mice or rats at maximally tolerated doses which were 2 to 4 times human clinical exposure in adult or paediatric ITP patients at 75 mg/day and ≤2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Endosteal hyperostosis was observed in a 28-week toxicity study in rats at a non-tolerated dose of 60 mg/kg/day (6 times or 4 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). There were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times or 2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. 33 Carcinogenicity and mutagenicity Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 or 2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times or 8 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 7 times the human clinical exposure in HCV patients at 100 mg/day, based on Cmax). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (<3-fold increase in mutation frequency). These in vitro and in vivo findings suggest that eltrombopag does not pose a genotoxic risk to humans. Reproductive toxicity Eltrombopag did not affect female fertility, early embryonic development or embryofoetal development in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure in adult or adolescent (12-17 years old) ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Also there was no effect on embryofoetal development in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.3 to 0.5 times the human clinical exposure in ITP patients at 75 mg/day and HCV patients at 100 mg/day, based on AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure in ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC) in rats, eltrombopag treatment was associated with embryo lethality (increased pre- and post-implantation loss), reduced foetal body weight and gravid uterine weight in the female fertility study and a low incidence of cervical ribs and reduced foetal body weight in the embryofoetal development study. Eltrombopag should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus (see section 4.6). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure in ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). In the pre- and post-natal development study in rats, there were no undesirable effects on pregnancy, parturition or lactation of F0 female rats at maternally non-toxic doses (10 and 20 mg/kg/day) and no effects on the growth, development, neurobehavioural or reproductive function of the offspring (F1). Eltrombopag was detected in the plasma of all F1 rat pups for the entire 22 hour sampling period following administration of medicinal product to the F0 dams, suggesting that rat pup exposure to eltrombopag was likely via lactation. Phototoxicity In vitro studies with eltrombopag suggest a potential phototoxicity risk; however, in rodents there was no evidence of cutaneous phototoxicity (10 or 7 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC) or ocular phototoxicity (4 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Furthermore, a clinical pharmacology study in 36 subjects showed no evidence that photosensitivity was increased following administration of eltrombopag 75 mg. This was measured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruled out since no specific preclinical study could be performed. Juvenile animal studies At non-tolerated doses in pre-weaning rats, ocular opacities were observed. At tolerated doses, no ocular opacities were observed (see above subsection ‘Safety pharmacology and repeat-dose toxicity’). In conclusion, taking into account the exposure margins based on AUC, a risk of eltrombopag-related cataracts in paediatric patients cannot be excluded. There are no findings in juvenile rats to suggest a greater risk of toxicity with eltrombopag treatment in paediatric vs. adult ITP patients. 34 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Revolade 12.5 mg film-coated tablets Tablet core Magnesium stearate Mannitol (E421) Microcrystalline cellulose Povidone Sodium starch glycolate Tablet coating Hypromellose (E464) Macrogol 400 (E1521) Polysorbate 80 (E433) Titanium dioxide (E171) Revolade 25 mg film-coated tablets Tablet core Magnesium stearate Mannitol (E421) Microcrystalline cellulose Povidone Sodium starch glycolate Tablet coating Hypromellose (E464) Macrogol 400 (E1521) Polysorbate 80 (E433) Titanium dioxide (E171) Revolade 50 mg film-coated tablets Tablet core Magnesium stearate Mannitol (E421) Microcrystalline cellulose Povidone Sodium starch glycolate Tablet coating Hypromellose (E464) Iron oxide red (E172) Iron oxide yellow (E172) Macrogol 400 (E1521) Titanium dioxide (E171) 35 Revolade 75 mg film-coated tablets Tablet core Magnesium stearate Mannitol (E421) Microcrystalline cellulose Povidone Sodium starch glycolate Tablet coating Hypromellose (E464) Iron oxide red (E172) Iron oxide black (E172) Macrogol 400 (E1521) Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Film-coated tablets Aluminum blisters (PA/Alu/PVC/Alu) in a carton containing 14 or 28 film-coated tablets and multipacks containing 84 (3 packs of 28) film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 36 8. MARKETING AUTHORISATION NUMBER(S) Revolade 12.5 mg film-coated tablets EU/1/10/612/010 EU/1/10/612/011 EU/1/10/612/012 Revolade 25 mg film-coated tablets EU/1/10/612/001 EU/1/10/612/002 EU/1/10/612/003 Revolade 50 mg film-coated tablets EU/1/10/612/004 EU/1/10/612/005 EU/1/10/612/006 Revolade 75 mg film-coated tablets EU/1/10/612/007 EU/1/10/612/008 EU/1/10/612/009 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 11 March 2010 Date of latest renewal: 15 January 2015 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. 37 1. NAME OF THE MEDICINAL PRODUCT Revolade 25 mg powder for oral suspension 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each sachet contains eltrombopag olamine equivalent to 25 mg of eltrombopag. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for oral suspension Reddish-brown to yellow powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Revolade is indicated for the treatment of patients aged 1 year and above with primary immune thrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1). Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1). Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation (see section 5.1). 4.2 Posology and method of administration Eltrombopag treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases or the management of chronic hepatitis C and its complications. Posology Eltrombopag dosing requirements must be individualised based on the patient’s platelet counts. The objective of treatment with eltrombopag should not be to normalise platelet counts. The powder for oral suspension may lead to higher eltrombopag exposure than the tablet formulation (see section 5.2). When switching between the tablet and powder for oral suspension formulations, platelet counts should be monitored weekly for 2 weeks. Immune (primary) thrombocytopenia The lowest dose of eltrombopag to achieve and maintain a platelet count ≥50,000/µl should be used. Dose adjustments are based upon the platelet count response. Eltrombopag must not be used to normalise platelet counts. In clinical studies, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag and decreased within 1 to 2 weeks after discontinuation. 38 Adults and paediatric population aged 6 to 17 years The recommended starting dose of eltrombopag is 50 mg once daily. For patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). Paediatric population aged 1 to 5 years The recommended starting dose of eltrombopag is 25 mg once daily. Monitoring and dose adjustment After initiating eltrombopag, the dose must be adjusted to achieve and maintain a platelet count ≥50,000/µl as necessary to reduce the risk for bleeding. A daily dose of 75 mg must not be exceeded. Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in Table 1. During therapy with eltrombopag full blood counts (FBCs), including platelet count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥50,000/µl for at least 4 weeks) has been achieved. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. Table 1 Dose adjustments of eltrombopag in ITP patients Platelet count Dose adjustment or response <50,000/µl following at least 2 weeks of therapy Increase daily dose by 25 mg to a maximum of 75 mg/day*. 50,000/µl to 150,000/µl Use lowest dose of eltrombopag and/or concomitant ITP treatment to maintain platelet counts that avoid or reduce bleeding. >150,000/µl to 250,000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments♦. >250,000/µl Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is ≤100,000/µl, reinitiate therapy at a daily dose reduced by 25 mg. * For patients taking 25 mg eltrombopag once every other day, increase dose to 25 mg once daily. ♦ For patients taking 25 mg eltrombopag once daily, consideration should be given to dosing at 12.5 mg once daily or alternatively a dose of 25 mg once every other day. Eltrombopag can be administered in addition to other ITP medicinal products. The dose regimen of concomitant ITP medicinal products should be modified, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag. It is necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient’s platelet response prior to considering another dose adjustment. The standard eltrombopag dose adjustment, either decrease or increase, would be 25 mg once daily. Discontinuation Treatment with eltrombopag should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of eltrombopag therapy at 75 mg once daily. Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician. In non-splenectomised patients this should include evaluation relative to splenectomy. The reoccurrence of thrombocytopenia is possible upon discontinuation of treatment (see section 4.4). 39 Chronic hepatitis C (HCV) associated thrombocytopenia When eltrombopag is given in combination with antivirals reference should be made to the full summary of product characteristics of the respective coadministered medicinal products for comprehensive details of relevant safety information or contraindications. In clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag. The aim of treatment with eltrombopag should be to achieve the minimum level of platelet counts needed to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviral therapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk of bleeding complications, normally around 50,000-75,000/µl. Platelet counts >75,000/µl should be avoided. The lowest dose of eltrombopag needed to achieve the targets should be used. Dose adjustments are based upon the platelet count response. Initial dose regimen Eltrombopag should be initiated at a dose of 25 mg once daily. No dosage adjustment is necessary for HCV patients of Asian ancestry or patients with mild hepatic impairment (see section 5.2). Monitoring and dose adjustment The dose of eltrombopag should be adjusted in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Platelet counts should be monitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose adjustments should be avoided (see Table 2). During antiviral therapy, the dose of eltrombopag should be adjusted as necessary to avoid dose reductions of peginterferon due to decreasing platelet counts that may put patients at risk of bleeding (see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved, normally around 50,000-75,000/µl. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by 25 mg should be considered if platelet counts exceed the required target. It is recommended to wait for 2 weeks to assess the effects of this and any subsequent dose adjustments. A dose of 100 mg eltrombopag once daily must not be exceeded. Table 2 Dose adjustments of eltrombopag in HCV patients during antiviral therapy Platelet count Dose adjustment or response <50,000/µl following at least 2 weeks of therapy Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥50,000/µl to ≤100,000/µl Use lowest dose of eltrombopag as necessary to avoid dose reductions of peginterferon. >100,000/µl to ≤150,000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments♦. >150,000/µl Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is ≤100,000/µl, reinitiate therapy at a daily dose reduced by 25 mg*. * For patients taking 25 mg eltrombopag once daily, consideration should be given to reinitiating dosing at 25 mg every other day. ♦ On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose reductions should be avoided. 40 Discontinuation If after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviral therapy is not achieved, eltrombopag should be discontinued. Eltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwise justified. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation. Severe aplastic anaemia Initial dose regimen Eltrombopag should be initiated at a dose of 50 mg once daily. For patients of Asian ancestry, eltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). The treatment should not be initiated when the patients has existing cytogenetic abnormalities of chromosome 7. Monitoring and dose adjustment Haematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag (see section 5.1). The dose of eltrombopag should be adjusted in 50 mg increments every 2 weeks as necessary to achieve the target platelet count ≥50,000/µl. For patients taking 25 mg once daily, the dose should be increased to 50 mg daily before increasing the dose amount by 50 mg. A dose of 150 mg daily must not be exceeded. Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dosage regimen of eltrombopag modified based on platelet counts as outlined in Table 3. Table 3 Dose adjustments of eltrombopag in patients with severe aplastic anaemia Platelet count Dose adjustment or response <50,000/µl following at least 2 weeks of therapy Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. 50,000/µl to 150,000/µl Use lowest dose of eltrombopag to maintain platelet counts. >150,000/µl to 250,000/µl Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. >250,000/µl Stop eltrombopag; for at least one week. Once the platelet count is ≤100,000/µl, reinitiate therapy at a daily dose reduced by 50 mg. Tapering for tri-lineage (white blood cells, red blood cells, and platelets) responders For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag may be reduced by 50%. If counts remain stable after 8 weeks at the reduced dose, then eltrombopag must be discontinued and blood counts monitored. If platelet counts drop to <30,000/µl, haemoglobin drops to <9 g/dl or absolute neutrophil count (ANC) to <0.5 x 109/l, eltrombopag may be reinitiated at the previous effective dose. Discontinuation If no haematological response has occurred after 16 weeks of therapy with eltrombopag, therapy should be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate (see sections 4.4 and 4.8). Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of eltrombopag (see section 4.8). 41 Special populations Renal impairment No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or performing urine analysis (see section 5.2). Hepatic impairment Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see section 4.4). If the use of eltrombopag is deemed necessary for ITP patients with hepatic impairment the starting dose must be 25 mg once daily. After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 3 weeks should be observed before increasing the dose. No dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepatic impairment (Child-Pugh score ≤6). Chronic HCV patients and severe aplastic anaemia patients with hepatic impairment should initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After initiating the dose of eltrombopag in patients with hepatic impairment an interval of 2 weeks should be observed before increasing the dose. There is an increased risk for adverse events, including hepatic decompensation and thromboembolic events, in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, either in preparation for invasive procedure or in HCV patients undergoing antiviral therapy (see sections 4.4 and 4.8). Elderly There are limited data on the use of eltrombopag in ITP patients aged 65 years and older and no clinical experience in ITP patients aged over 85 years. In the clinical studies of eltrombopag, overall no clinically significant differences in safety of eltrombopag were observed between patients aged at least 65 years and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see section 5.2). There are limited data on the use of eltrombopag in HCV and SAA patients aged over 75 years. Caution should be exercised in these patients (see section 4.4). Asian patients For patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), including those with hepatic impairment, eltrombopag should be initiated at a dose of 25 mg once daily (see section 5.2). Patient platelet count should continue to be monitored and the standard criteria for further dose modification followed. Paediatric population Revolade is not recommended for use in children under the age of one year with ITP due to insufficient data on safety and efficacy. The safety and efficacy of eltrombopag has not been established in children and adolescents (<18 years) with chronic HCV related thrombocytopenia or SAA. No data are available. 42 Method of administration (see section 6.6) Oral use. The suspension should be taken at least two hours before or four hours after any products such as antacids, dairy products (or other calcium containing food products), or mineral supplements containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc) (see sections 4.5 and 5.2). 4.3 Contraindications Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as defined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when treated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of treatment in terms of the proportion achieving sustained virological response (SVR) compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Treatment with eltrombopag in these patients should be initiated only by physicians experienced in the management of advanced HCV, and only when the risks of thrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered clinically indicated, close monitoring of these patients is required. Combination with direct-acting antiviral agents Safety and efficacy have not been established in combination with direct-acting antiviral agents approved for treatment of chronic hepatitis C infection. Risk of hepatotoxicity Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might be life-threatening (see section 4.8). Serum alanine aminotransferase (ALT), aspartate aminotrasferase (AST) and bilirubin should be measured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase (3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or >5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are:  progressive, or  persistent for ≥4 weeks, or  accompanied by increased direct bilirubin, or  accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. Caution is required when administering eltrombopag to patients with hepatic disease. In ITP and SAA patients a lower starting dose of eltrombopag should be used. Close monitoring is required when administering to patients with hepatic impairment (see section 4.2). 43 Hepatic decompensation (use with interferon) Hepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients with low albumin levels (≤35 g/l) or with MELD score ≥10 at baseline. Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) occurred more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or with a MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. In addition, the benefits of treatment in terms of the proportion achieving SVR compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. The respective interferon summary of product characteristics should be referenced for discontinuation criteria. Eltrombopag should be terminated if antiviral therapy is discontinued for hepatic decompensation. Thrombotic/thromboembolic complications In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n=1,439), 38 out of 955 patients (4%) treated with eltrombopag and 6 out of 484 patients (1%) in the placebo group experienced thromboembolic events (TEEs). Reported thrombotic/thromboembolic complications included both venous and arterial events. The majority of TEEs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus <1% for placebo). No specific temporal relationship between start of treatment and event of TEE were observed. Patients with low albumin levels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients should be closely monitored for signs and symptoms of TEE. The risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treated with 75 mg eltrombopag once daily for 2 weeks in preparation for invasive procedures. Six of 143 (4%) adult patients with CLD receiving eltrombopag experienced TEEs (all of the portal venous system) and 2 of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five of the 6 patients treated with eltrombopag experienced the thrombotic complication at a platelet count >200,000/µl and within 30 days of the last dose of eltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures. In eltrombopag clinical studies in ITP thromboembolic events were observed at low and normal platelet counts. Caution should be used when administering eltrombopag to patients with known risk factors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking. Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds the target levels (see section 4.2). The risk-benefit balance should be considered in patients at risk of TEEs of any aetiology. No case of TEE was identified from a clinical study in refractory SAA, however the risk of these events cannot be excluded in this patient population due to the limited number of exposed patients. As the highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient population. 44 Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis. When treatment is considered appropriate, caution is required when administering eltrombopag to patients with hepatic impairment (see sections 4.2 and 4.8). Bleeding following discontinuation of eltrombopag Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with eltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levels within 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may lead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following discontinuation of eltrombopag. In HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatal cases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. Following discontinuation of therapy, patients should be monitored for any signs or symptoms of gastrointestinal bleeding. Bone marrow reticulin formation and risk of bone marrow fibrosis Eltrombopag may increase the risk for development or progression of reticulin fibres within the bone marrow. The relevance of this finding, as with other thrombopoietin receptor (TPO-R) agonists, has not been established yet. Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, full blood count (FBC) with white blood cell count (WBC) differential should be performed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be examined for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued and a bone marrow biopsy considered, including staining for fibrosis. Progression of existing myelodysplastic syndrome (MDS) There is a theoretical concern that TPO-R agonists may stimulate the progression of existing haematological malignancies such as MDS. TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is predominantly expressed on the surface of cells of the myeloid lineage. For TPO-R agonists there is a concern that they may stimulate the progression of existing haematopoietic malignancies such as MDS. In clinical studies with a TPO-R agonist in patients with MDS, cases of transient increases in blast cell counts were observed and cases of MDS disease progression to acute myeloid leukaemia (AML) were reported. The diagnosis of ITP or SAA in adults and elderly patients should be confirmed by the exclusion of other clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be excluded. Consideration should be given to performing a bone marrow aspirate and biopsy over the course of the disease and treatment, particularly in patients over 60 years of age, those with systemic symptoms, or abnormal signs such as increased peripheral blast cells. 45 The effectiveness and safety of Revolade have not been established for the treatment of thrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS. Cytogenetic abnormalities and progression to MDS/AML in patients with SAA Cytogenetic abnormalities are known to occur in SAA patients. It is not known whether eltrombopag increases the risk of cytogenetic abnormalities in patients with SAA. In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was observed in 17.1% of patients [7/41 (where 4 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months. In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6. In clinical studies with eltrombopag in SAA, 4% of patients (5/133) were diagnosed with MDS. The median time to diagnosis was 3 months from the start of eltrombopag treatment. For SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bone marrow examination with aspirations for cytogenetics is recommended prior to initiation of eltrombopag, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate. Ocular changes Cataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). In controlled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1,439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the eltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, have been reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the eltrombopag group and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring of patients is recommended. QT/QTc prolongation A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically significant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical studies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of these QTc prolongation events is unknown. Loss of response to eltrombopag A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin. 46 Paediatric population The above warnings and precautions for ITP also apply to the paediatric population. Interference with laboratory tests Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum discolouration and interference with total bilirubin and creatinine testing have been reported in patients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testing using another method may help in determining the validity of the result. 4.5 Interaction with other medicinal products and other forms of interaction Effects of eltrombopag on other medicinal products HMG CoA reductase inhibitors Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103% (90% confidence interval [CI]: 82%, 126%) and AUC0- 55% (90% CI: 42%, 69%). Interactions are also expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. When co-administered with eltrombopag, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see section 5.2). OATP1B1 and BCRP substrates Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution (see section 5.2). Cytochrome P450 substrates In studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe substrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected when eltrombopag and CYP450 substrates are co-administered (see section 5.2). HCV protease inhibitors Dose adjustment is not required when eltrombopag is co-administered with either telaprevir or boceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours did not alter plasma telaprevir exposure. Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did not alter plasma boceprevir AUC(0-), but increased Cmax by 20%, and decreased Cmin by 32%. The clinical relevance of the decrease in Cmin has not been established, increased clinical and laboratory monitoring for HCV suppression is recommended. 47 Effects of other medicinal products on eltrombopag Ciclosporin A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg ciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the Cmax and the AUCinf of eltrombopag by 25% and 18%, respectively. The co-administration of 600 mg ciclosporin decreased the Cmax and the AUCinf of eltrombopag by 39% and 24%, respectively. Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient’s platelet count (see section 4.2). Platelet count should be monitored at least weekly for 2 to 3 weeks when eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increased based on these platelet counts. Polyvalent cations (chelation) Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma eltrombopag AUC0- by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62%, 76%). Eltrombopag should be taken at least two hours before or four hours after any products such as antacids, dairy products or mineral supplements containing polyvalent cations to avoid significant reduction in eltrombopag absorption due to chelation (see sections 4.2 and 5.2). Lopinavir/ritonavir Co-administration of eltrombopag with lopinavir/ritonavir may cause a decrease in the concentration of eltrombopag. A study in 40 healthy volunteers showed that the co-administration of a single 100 mg dose of eltrombopag with repeat dose lopinavir/ritonavir 400/100 mg twice daily resulted in a reduction in eltrombopag plasma AUCinf by 17% (90% CI: 6.6%, 26.6%). Therefore, caution should be used when co-administration of eltrombopag with lopinavir/ritonavir takes place. Platelet count should be closely monitored in order to ensure appropriate medical management of the dose of eltrombopag when lopinavir/ritonavir therapy is initiated or discontinued. CYP1A2 and CYP2C8 inhibitors and inducers Eltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and UGT1A3 (see section 5.2). Medicinal products that inhibit or induce a single enzyme are unlikely to significantly affect plasma eltrombopag concentrations, whereas medicinal products that inhibit or induce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease (e.g. rifampicin) eltrombopag concentrations. HCV protease inhibitors Results of a drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeat doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of eltrombopag 200 mg did not alter plasma eltrombopag exposure to a clinically significant extent. Medicinal products for treatment of ITP Medicinal products used in the treatment of ITP in combination with eltrombopag in clinical studies included corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. Platelet counts should be monitored when combining eltrombopag with other medicinal products for the treatment of ITP in order to avoid platelet counts outside of the recommended range (see section 4.2). 48 Food interaction The administration of eltrombopag tablet or powder for oral suspension formulations with a high- calcium meal (e.g. a meal that included dairy products) significantly reduced plasma eltrombopag AUC0-∞ and Cmax. In contrast, the administration of eltrombopag 2 hours before or 4 hours after a high- calcium meal or with low-calcium food [<50 mg calcium] did not alter plasma eltrombopag exposure to a clinically significant extent (see section 4.2). Administration of a single 50 mg dose of eltrombopag in tablet form with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag mean AUC0-∞ by 59% and mean Cmax by 65%. Administration of a single 25 mg dose of eltrombopag as powder for oral suspension with a high- calcium, moderate-fat and moderate-calorie meal reduced plasma eltrombopag mean AUC0-∞ by 75% and mean Cmax by 79%. This decrease of exposure was attenuated when a single 25 mg dose of eltrombopag powder for oral suspension was administered 2 hours before a high-calcium meal (mean AUC0-∞ was decreased by 20% and mean Cmax by 14%). Food low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no added calcium, magnesium or iron) fruit juice, unfortified soya milk and unfortified grain, did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see sections 4.2 and 4.5). 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Revolade is not recommended during pregnancy. Women of childbearing potential / Contraception in males and females Revolade is not recommended in women of childbearing potential not using contraception. Breast-feeding It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have shown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to continue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Fertility was not affected in male or female rats at exposures that were comparable to those in humans. However a risk for humans cannot be ruled out (see section 5.3). 4.7 Effects on ability to drive and use machines Eltrombopag has negligible influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of eltrombopag, including dizziness and lack of alertness, should be borne in mind when considering the patient’s ability to perform tasks that require judgement, motor and cognitive skills. 49 4.8 Undesirable effects Summary of the safety profile Immune thrombocytopenia in adult and paediatric patients The safety of Revolade was assessed using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completed open-label studies TRA108057, TRA105325 (EXTEND) and TRA112940. Patients received study medication for up to 8 years (in EXTEND). The most important serious adverse reactions were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included nausea, diarrhoea and increased alanine aminotransferase. The safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies. PETIT2 (TRA115450) was a 2-part, double-blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study. PETIT (TRA108062) was a 3-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea. Thrombocytopenia with HCV infection in adult patients ENABLE 1 (TPL103922 n=716) and ENABLE 2 (TPL108390 n=805) were randomised, double- blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=253). Patients are analysed according to the treatment received (total safety double-blind population, Revolade n=955 and placebo n=484). The most important serious adverse reactions identified were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included headache, anaemia, decreased appetite, cough, nausea, diarrhoea, hyperbilirubinaemia, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and oedema. Severe aplastic anaemia in adult patients The safety of eltrombopag in severe aplastic anaemia was assessed in a single-arm, open-label study (N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (16%) were treated for >1 year. The most important serious adverse reactions were febrile neutropenia and sepsis/infection. The most common adverse reactions occurring in at least 10% of patients included headache, dizziness, cough, oropharyngeal pain, nausea, diarrhoea, abdominal pain, transaminases increased, arthralgia, pain in extremity, fatigue and pyrexia. 50 List of adverse reactions The adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCV studies (N=1,520), the SAA studies (N=43) and post-marketing reports are listed below by MedDRA system organ class and by frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data). ITP study population System organ class Frequency Adverse reaction Infections and infestations Very common Nasopharyngitis♦, upper respiratory tract infection♦ Common Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, respiratory tract infection, gingivitis Uncommon Skin infection Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Rectosigmoid cancer Blood and lymphatic system disorders Common Anaemia, eosinophilia, leukocytosis, thrombocytopenia, haemoglobin decreased, white blood cell count decreased Uncommon Anisocytosis, haemolytic anaemia, myelocytosis, band neutrophil count increased, myelocyte present, platelet count increased, haemoglobin increased Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Common Hypokalaemia, decreased appetite, blood uric acid increased Uncommon Anorexia, gout, hypocalcaemia Psychiatric disorders Common Sleep disorder, depression Uncommon Apathy, mood altered, tearfulness Nervous system disorders Common Paraesthesia, hypoaesthesia, somnolence, migraine Uncommon Tremor, balance disorder, dysaesthesia, hemiparesis, migraine with aura, neuropathy peripheral, peripheral sensory neuropathy, speech disorder, toxic neuropathy, vascular headache Eye disorders Common Dry eye, vision blurred, eye pain, visual acuity reduced Uncommon Lenticular opacities, astigmatism, cataract cortical, lacrimation increased, retinal haemorrhage, retinal pigment epitheliopathy, visual impairment, visual acuity tests abnormal, blepharitis, keratoconjunctivitis sicca Ear and labyrinth disorders Common Ear pain, vertigo Cardiac disorders Uncommon Tachycardia, acute myocardial infarction, cardiovascular disorder, cyanosis, sinus tachycardia, electrocardiogram QT prolonged 51 Vascular disorders Common Deep vein thrombosis, haematoma, hot flush Uncommon Embolism, hot flush, thrombophlebitis superficial, flushing Respiratory, thoracic and mediastinal disorders Very common Cough♦ Common Oropharyngeal pain, rhinorrhoea♦ Uncommon Pulmonary embolism, pulmonary infarction, nasal discomfort, oropharyngeal blistering, sinus disorder, sleep apnoea syndrome Gastrointestinal disorders Very common Nausea, diarrhoea♦ Common Mouth ulceration, toothache♦, vomiting, abdominal pain*, mouth haemorrhage, flatulence * Very common in paediatric ITP Uncommon Dry mouth, glossodynia, abdominal tenderness, faeces discoloured, food poisoning, frequent bowel movements, haematemesis, oral discomfort Hepatobiliary disorders Very common Alanine aminotransferase increased† Common Aspartate aminotransferase increased†, hyperbilirubinaemia, hepatic function abnormal Uncommon Cholestasis, hepatic lesion, hepatitis, drug-induced liver injury Skin and subcutaneous tissue disorders Common Rash, alopecia, hyperhidrosis, pruritus generalised, petechiae Uncommon Urticaria, dermatosis, cold sweat, erythema, melanosis, pigmentation disorder, skin discolouration, skin exfoliation Musculoskeletal and connective tissue disorders Common Myalgia, muscle spasm, musculoskeletal pain, bone pain, back pain Uncommon Muscular weakness Renal and urinary disorders Common Proteinuria, blood creatinine increased, thrombotic microangiopathy with renal failure‡ Uncommon Renal failure, leukocyturia, lupus nephritis, nocturia, blood urea increased, urine protein/creatinine ratio increased Reproductive system and breast disorders Common Menorrhagia General disorders and administration site conditions Common Pyrexia*, chest pain, asthenia *Very common in paediatric ITP Uncommon Feeling hot, vessel puncture site haemorrhage, feeling jittery, inflammation of wound, malaise, sensation of foreign body Investigations Common Blood alkaline phosphatase increased Uncommon Blood albumin increased, protein total increased, blood albumin decreased, pH urine increased Injury, poisoning and procedural complications Uncommon Sunburn ♦ Additional adverse reactions observed in paediatric studies (aged 1to 17 years). † Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, although at a lower frequency. ‡ Grouped term with preferred terms acute kidney injury and renal failure HCV study population (in combination with anti-viral interferon and ribavirin therapy) System organ class Frequency Adverse reaction Infections and infestations Common Urinary tract infection, upper respiratory tract infection, bronchitis, nasopharyngitis, influenza, oral herpes Uncommon Gastroenteritis, pharyngitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Hepatic neoplasm malignant 52 Blood and lymphatic system disorders Very common Anaemia Common Lymphopenia Uncommon Haemolytic anaemia Metabolism and nutrition disorders Very common Decreased appetite Common Hyperglycaemia, abnormal loss of weight Psychiatric disorders Common Depression, anxiety, sleep disorder Uncommon Confusional state, agitation Nervous system disorders Very common Headache Common Dizziness, disturbance in attention, dysgeusia, hepatic encephalopathy, lethargy, memory impairment, paraesthesia Eye disorders Common Cataract, retinal exudates, dry eye, ocular icterus, retinal haemorrhage Ear and labyrinth disorders Common Vertigo Cardiac disorders Common Palpitations Respiratory, thoracic and mediastinal disorders Very common Cough Common Dyspnoea, oropharyngeal pain, dyspnoea exertional, productive cough Gastrointestinal disorders Very common Nausea, diarrhoea Common Vomiting, ascites, abdominal pain, abdominal pain upper, dyspepsia, dry mouth, constipation, abdominal distension, toothache, stomatitis, gastrooesophagal reflux disease, haemorrhoids, abdominal discomfort, varices oesophageal Uncomon Oesophageal varices haemorrhage, gastritis, aphthous stomatitis Hepatobiliary disorders Common Hyperbilirubinaemia, jaundice, drug-induced liver injury Uncommon Portal vein thrombosis, hepatic failure Skin and subcutaneous tissue disorders Very common Pruritus Common Rash, dry skin, eczema, rash pruritic, erythema, hyperhidrosis, pruritus generalised, alopecia Uncommon Skin lesion, skin discolouration, skin hyperpigmentation, night sweats Musculoskeletal and connective tissue disorder Very common Myalgia Common Arthralgia, muscle spasms, back pain, pain in extremity, musculoskeletal pain, bone pain Renal and urinary disorders Uncommon Thrombotic microangiopathy with acute renal failure†, dysuria General disorders and administration site conditions Very common Pyrexia, fatigue, influenza-like illness, asthenia, chills Common Irritability, pain, malaise, injection site reaction, non-cardiac chest pain, oedema, oedema peripheral Uncommon Injection site pruritus, injection site rash, chest discomfort Investigations Common Blood bilirubin increased, weight decreased, white blood cell count decreased, haemoglobin decreased, neutrophil count decreased, international normalised ratio increased, activated partial thromboplastin time prolonged, blood glucose increased, blood albumin decreased Uncommon Electrocardiogram QT prolonged † Grouped term with preferred terms oliguria, renal failure and renal impairment 53 SAA study population System organ class Frequency Adverse reaction Blood and lymphatic system disorders Common Neutropenia, splenic infarction Metabolism and nutrition disorders Common Iron overload, decreased appetite, hypoglycaemia, increased appetite Psychiatric disorders Common Anxiety, depression Nervous system disorders Very common Headache, dizziness Common Syncope Eye disorders Common Dry eye, cataract, ocular icterus, vision blurred, visual impairment, vitreous floaters Respiratory, thoracic and mediastinal disorders Very common Cough, oropharyngeal pain, rhinorrhoea Common Epistaxis Gastrointestinal disorders Very common Diarrhoea, nausea, gingival bleeding, abdominal pain Common Oral mucosal blistering, oral pain, vomiting, abdominal discomfort, constipation, abdominal distension, dysphagia, faeces discoloured, swollen tongue, gastrointestinal motility disorder, flatulence Hepatobiliary disorders Very common Transaminases increased Common Blood bilirubin increased (hyperbilirubinemia), jaundice Not known Drug-induced liver injury* * Cases of drug-induced liver injury have been reported in patients with ITP and HCV Skin and subcutaneous tissue disorders Common Petechiae, rash, pruritus, urticaria, skin lesion, rash macular Not known Skin discolouration, skin hyperpigmentation Musculosketal and connective tissue disorders Very common Arthralgia, pain in extremity, muscle spasms Common Back pain, myalgia, bone pain Renal and urinary disorders Common Chromaturia General disorders and administration site conditions Very common Fatigue, pyrexia, chills Common Asthenia, oedema peripheral, malaise Investigations Common Blood creatine phosphokinase increased Description of selected adverse reactions Thrombotic/thromboembolic events (TEEs) In 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving eltrombopag (n=446), 17 patients experienced a total of 19 TEEs, which included (in descending order of occurrence) deep vein thrombosis (n=6), pulmonary embolism (n=6), acute myocardial infarction (n=2), cerebral infarction (n=2), embolism (n=1) (see section 4.4). In a placebo-controlled study (n=288, Safety population), following 2 weeks’ treatment in preparation for invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag experienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo group experienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a platelet count >200,000/µl. No specific risk factors were identified in those patients who experienced a TEE with the exception of platelet counts ≥200,000/µl (see section 4.4). 54 In controlled studies in thrombocytopenic patients with HCV (n=1439), 38 out of 955 patients (4%) treated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus <1% for placebo) (see section 4.4). Patients with low albumin levels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. Hepatic decompensation (use with interferon) Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation (see section 4.4). Hepatotoxixity In the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and bilirubin were observed (see section 4.4). These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in adults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group experienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients (aged 1 to 17 years) with chronic ITP, ALT 3 x ULN was reported in 4.7% and 0% of the eltrombopag and placebo groups, respectively. In 2 controlled clinical studies in patients with HCV, ALT or AST 3 x ULN was reported in 34% and 38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag in combination with peginterferon / ribavirin therapy will experience indirect hyperbilirubinaemia. Overall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the eltrombopag and placebo groups, respectively. In the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULN with total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN occurred in 14% of patients. Thrombocytopenia following discontinuation of treatment In the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8% and 8% of the eltrombopag and placebo groups, respectively (see section 4.4). Increased bone marrow reticulin Across the programme, no patients had evidence of clinically relevant bone marrow abnormalities or clinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients, eltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4). 55 Cytogenetic abnormalities In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months. In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6. Haematologic malignancies In the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS following treatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and 1/62 (2%) patient has been diagnosed with MDS or AML in each study. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In case of an overdose, consideration should be given to oral administration of a metal cation-containing preparation, such as calcium, aluminium, or magnesium preparations to chelate eltrombopag and thus limit absorption. Platelet counts should be closely monitored. Treatment with eltrombopag should be reinitiated in accordance with dosing and administration recommendations (see section 4.2). In the clinical studies there was one report of overdose where the patient ingested 5000 mg of eltrombopag. Reported adverse reactions included mild rash, transient bradycardia, ALT and AST elevation, and fatigue. Liver enzymes measured between Days 2 and 18 after ingestion peaked at a 1.6-fold ULN in AST, a 3.9-fold ULN in ALT, and a 2.4-fold ULN in total bilirubin, The platelet counts were 672,000/µl on Day 18 after ingestion and the maximum platelet count was 929,000/µl. All events were resolved without sequelae following treatment. Because eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, haemodialysis would not be expected to be an effective method to enhance the elimination of eltrombopag. 56 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics. ATC code: B02BX 05. Mechanism of action TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates signalling cascades similar but not identical to that of endogenous thrombopoietin (TPO), inducing proliferation and differentiation from bone marrow progenitor cells. Clinical efficacy and safety Immune (primary) thrombocytopenia (ITP) studies Two phase III, randomised, double-blind, placebo-controlled studies RAISE (TRA102537) and TRA100773B and two open-label studies REPEAT (TRA108057) and EXTEND (TRA105325) evaluated the safety and efficacy of eltrombopag in adult patients with previously treated ITP. Overall, eltrombopag was administered to 277 ITP patients for at least 6 months and 202 patients for at least 1 year. Double-blind placebo-controlled studies RAISE: 197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and randomisation was stratified based upon splenectomy status, use of ITP medicinal products at baseline and baseline platelet count. The dose of eltrombopag was adjusted during the 6 month treatment period based on individual platelet counts. All patients initiated treatment with eltrombopag 50 mg. From Day 29 to the end of treatment, 15 to 28% of eltrombopag treated patients were maintained on ≤25 mg and 29 to 53% received 75 mg. In addition, patients could taper off concomitant ITP medicinal products and receive rescue treatments as dictated by local standard of care. More than half of all patients in each treatment group had ≥3 prior ITP therapies and 36% had a prior splenectomy. Median platelet counts at baseline were 16,000/l for both treatment groups and in the eltrombopag group were maintained above 50,000/µl at all on-therapy visits starting at Day 15; in contrast, median platelet counts in the placebo group remained <30,000/µl throughout the study. Platelet count response between 50,000-400,000/l in the absence of rescue treatment was achieved by significantly more patients in the eltrombopag treated group during the 6 month treatment period, p <0.001. Fifty-four percent of the eltrombopag-treated patients and 13% of placebo-treated patients achieved this level of response after 6 weeks of treatment. A similar platelet response was maintained throughout the study, with 52% and 16% of patients responding at the end of the 6-month treatment period. 57 Table 4 Secondary efficacy results from RAISE Eltrombopag N=135 Placebo N=62 Key secondary endpoints Number of cumulative weeks with platelet counts 50,000-400,000/µl, Mean (SD) 11.3 (9.46) 2.4 (5.95) Patients with ≥75% of assessments in the target range (50,000 to 400,000/l), n (%) p-value a 51 (38) 4 (7) <0.001 Patients with bleeding (WHO Grades 1-4) at any time during 6 months, n (%) p-value a 106 (79) 56 (93) 0.012 Patients with bleeding (WHO Grades 2-4) at any time during 6 months, n (%) p-value a 44 (33) 32 (53) 0.002 Requiring rescue therapy, n (%) p-value a 24 (18) 25 (40) 0.001 Patients receiving ITP therapy at baseline (n) 63 31 Patients who attempted to reduce or discontinue baseline therapy, n (%)b p-value a 37 (59) 10 (32) 0.016 a Logistic regression model adjusted for randomisation stratification variables b 21 out of 63 (33%) patients treated with eltrombopag who were taking an ITP medicinal product at baseline permanently discontinued all baseline ITP medicinal products. At baseline, more than 70% of ITP patients in each treatment group reported any bleeding (WHO Grades 1-4) and more than 20% reported clinically significant bleeding (WHO Grades 2-4), respectively. The proportion of eltrombopag-treated patients with any bleeding (Grades 1-4) and clinically significant bleeding (Grades 2-4) was reduced from baseline by approximately 50% from Day 15 to the end of treatment throughout the 6-month treatment period. TRA100773B: The primary efficacy endpoint was the proportion of responders, defined as ITP patients who had an increase in platelet counts to 50,000/l at Day 43 from a baseline of <30,000/l; patients who withdrew prematurely due to a platelet count 200,000/l were considered responders, those that discontinued for any other reason were considered non-responders irrespective of platelet count. A total of 114 patients with previously treated ITP were randomised 2:1 eltrombopag (n=76) to placebo (n=38). Table 5 Efficacy results from TRA100773B Eltrombopag N=74 Placebo N=38 Key primary endpoints Eligible for efficacy analysis, n 73 37 Patients with platelet count 50,000/l after up to 42 days of dosing (compared to a baseline count of <30,000/l), n (%) p-valuea 43 (59) 6 (16) <0.001 Key secondary endpoints Patients with a Day 43 bleeding assessment, n 51 30 Bleeding (WHO Grades 1-4) n (%) p-valuea 20 (39) 18 (60) 0.029 a Logistic regression model adjusted for randomisation stratification variables 58 In both RAISE and TRA100773B the response to eltrombopag relative to placebo was similar irrespective of ITP medicinal product use, splenectomy status and baseline platelet count (≤15,000/µl, >15,000/µl) at randomisation. In RAISE and TRA100773B studies, in the subgroup of ITP patients with baseline platelet count ≤15,000/μl the median platelet counts did not reach the target level (>50,000/l), although in both studies 43% of these patients treated with eltrombopag responded after 6 weeks of treatment. In addition, in the RAISE study, 42% of patients with baseline platelet count ≤15,000/μl treated with eltrombopag responded at the end of the 6 month treatment period. Forty-two to 60% of the eltrombopag-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of treatment. An open-label, repeat-dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks off treatment) showed that episodic use with multiple courses of eltrombopag has demonstrated no loss of response. Eltrombopag was administered to 302 ITP patients in the open-label extension study EXTEND (TRA105325), 218 patients completed 1 year, 180 completed 2 years, 107 completed 3 years, 75 completed 4 years, 34 completed 5 years and 18 completed 6 years. The median baseline platelet count was 19,000/l prior to eltrombopag administration. Median platelet counts at 1, 2, 3, 4, 5, 6 and 7 years on study were 85,000/l, 85,000/l, 105,000/l, 64,000/l, 75,000/l, 119,000/l and 76,000/l, respectively. Clinical studies comparing eltrombopag to other treatment options (e.g. splenectomy) have not been conducted. The long-term safety of eltrombopag should be considered prior to starting therapy. Paediatric population (aged 1 to 17 years) The safety and efficacy of eltrombopag in paediatric patients have been investigated two studies. TRA115450 (PETIT2): The primary endpoint was a sustained response, defined as the proportion of patients receiving eltrombopag, compared to placebo, achieving platelet counts ≥50,000/µl for at least 6 out of 8 weeks (in the absence of rescue therapy), between weeks 5 to 12 during the double-blind randomised period. Patients were diagnosed with chronic ITP for at least 1 year and were refractory or relapsed to at least one prior ITP therapy or unable to continue other ITP treatments for a medical reason and had platelet count <30,000/µl. Ninety-two patients were randomised by three age cohort strata (2:1) to eltrombopag (n=63) or placebo (n=29). The dose of eltrombopag could be adjusted based on individual platelet counts. Overall, a significantly greater proportion of eltrombopag patients (40%) compared with placebo patients (3%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9] p <0.001) which was similar across the three age cohorts (Table 6). Table 6 Sustained platelet response rates by age cohort in paediatric patients with chronic ITP Eltrombopag n/N (%) [95% CI] Placebo n/N (%) [95% CI] Cohort 1 (12 to 17 years) Cohort 2 (6 to 11 years) Cohort 3 (1 to 5 years) 9/23 (39%) [20%, 61%] 11/26 (42%) [23%, 63%] 5/14 (36%) [13%, 65%] 1/10 (10%) [0%, 45%] 0/13 (0%) [N/A] 0/6 (0%) [N/A] 59 Statistically fewer eltrombopag patients required rescue treatment during the randomised period compared to placebo patients (19% [12/63] vs. 24% [7/29], p=0.032). At baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported any bleeding (WHO Grades 1-4). At Week 12, the proportion of eltrombopag patients reporting any bleeding was decreased to half of baseline (36%). In comparison, at Week 12, 55% of placebo patients reported any bleeding. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the study and 53% (8/15) of patients were able to reduce (n=1) or discontinue (n=7) baseline ITP therapy, mainly corticosteroids, without needing rescue therapy. TRA108062 (PETIT): The primary endpoint was the proportion of patients achieving platelet counts ≥50,000/µl at least once between weeks 1 and 6 of the randomised period. Patients were diagnosed with ITP for at least 6 months and were refractory or relapsed to at least one prior ITP therapy with a platelet count <30,000/µl (n=67). During the randomised period of the study, patients were randomised by three age cohort strata (2:1) to eltrombopag (n=45) or placebo (n=22). The dose of eltrombopag could be adjusted based on individual platelet counts. Overall, a significantly greater proportion of eltrombopag patients (62%) compared with placebo patients (32%) met the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3] p=0.011). Sustained response was seen in 50% of the initial responders during 20 out of 24 weeks in the PETIT 2 study and 15 out of 24 weeks in the PETIT Study. Chronic hepatitis C associated thrombocytopenia studies The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV infection were evaluated in two randomised, double-blind, placebo-controlled studies. ENABLE 1 utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilised peginterferon alfa-2b plus ribavirin. Patients did not receive direct acting antiviral agents. In both studies, patients with a platelet count of <75,000/µl were enrolled and stratified by platelet count (<50,000/µl and ≥50,000/µl to <75,000/µl), screening HCV RNA (<800,000 IU/ml and ≥800,000 IU/ml), and HCV genotype (genotype 2/3, and genotype 1/4/6). Baseline disease characteristics were similar in both studies and were consistent with compensated cirrhotic HCV patient population. The majority of patients were HCV genotype 1 (64%) and had bridging fibrosis/cirrhosis. Thirty-one percent of patients had been treated with prior HCV therapies, primarily pegylated interferon plus ribavirin. The median baseline platelet count was 59,500/µl in both treatment groups: 0.8%, 28% and 72% of the patients recruited had platelet counts <20,000/µl, <50.000/µl and ≥50,000/µl respectively. The studies consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to ≥90,000/µl for ENABLE 1 and ≥100,000/µl for ENABLE 2. The median time to achieve the target platelet count ≥90,000/µl (ENABLE 1) or ≥100,000/µl (ENABLE 2) was 2 weeks. The primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as the percentage of patients with no detectable HCV-RNA at 24 weeks after completion of the planned treatment period. In both HCV studies, a significantly greater proportion of patients treated with eltrombopag (n=201, 21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 7). The improvement in the proportion of patients who achieved SVR was consistent across all subgroups in the randomisation strata (baseline platelet counts (<50,000 vs. >50,000), viral load (<800,000 IU/ml vs. ≥800,000 IU/ml) and genotype (2/3 vs. 1/4/6)). 60 Table 7 Virologic response in HCV patients in ENABLE 1 and ENABLE 2 Pooled data ENABLE 1a ENABLE 2b Patients achieving target platelet counts and initiating antiviral therapy c 1,439/1,520 (95%) 680/715 (95%) 759/805 (94%) Eltrombopag Placebo Eltrombopag Placebo Eltrombopag Placebo Total number of patients entering antiviral treatment phase n=956 n=485 n=450 n=232 n=506 n=253 % patients achieving virologic response Overall SVR d 21 13 23 14 19 13 HCV RNA Genotype Genotype 2/3 35 25 35 24 34 25 Genotype 1/4/6e 15 8 18 10 13 7 Albumin levels f ≤35g/l 11 8 >35g/l 25 16 MELD scoref ≥10 18 10 <10 23 17 a Eltrombopag given in combination with peginterferon alfa-2a (180 μg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1200 mg daily in 2 divided doses orally) b Eltrombopag given in combination with peginterferon alfa-2b (1.5 μg/kg once weekly for 48 weeks for genotype 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1400 mg orally in 2 divided doses) c Target platelet count was 90,000/µl for ENABLE 1 and 100,000/µl for ENABLE 2. For ENABLE 1, 682 patients were randomised to the antiviral treatment phase; however 2 patients then withdrew consent prior to receiving antiviral therapy. d p-value <0.05 for eltrombopag versus placebo e 64% patients participating in ENABLE 1 and ENABLE 2 were genotype 1 f Post-hoc analyses Other secondary findings of the studies included the following: significantly fewer patients treated with eltrombopag prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%, p=<0.0001). A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared to placebo (45% vs. 27%). Eltrombopag treatment delayed and reduced the number of peginterferon dose reductions. Severe aplastic anaemia Eltrombopag was studied in a single-arm, single-centre open-label study in 43 patients with severe aplastic anaemia with refractory thrombocytopenia following at least one prior immunosuppressive therapy (IST) and who had a platelet count ≤30,000/µl. The majority of patients, 33 (77%), were considered to have ‘primary refractory disease’, defined as having no prior adequate response to IST in any lineage. The remaining 10 patients had insufficient platelet response to prior therapies. All 10 had received at least 2 prior IST regimens and 50% had received at least 3 prior IST regimens. Patients with diagnosis of Fanconi anaemia, infection not responding to appropriate therapy, PNH clone size in neutrophils of ≥50%, where excluded from participation. 61 At baseline the median platelet count was 20,000/µl, haemoglobin was 8.4 g/dl, ANC was 0.58 x 109/l and absolute reticulocyte count was 24.3 x109/l. Eighty-six percent of patients were RBC transfusion dependent, and 91% were platelet transfusion dependent. The majority of patients (84%) had received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. The primary endpoint was haematological response assessed after 12 weeks of eltrombopag treatment. Haematological response was defined as meeting one or more of the following criteria: 1) platelet count increases to 20,000/µl above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) haemoglobin increase by >1.5g/dl, or a reduction in ≥4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) absolute neutrophil count (ANC) increase of 100% or an ANC increase >0.5 x 109/l. The haematological response rate was 40% (17/43 patients; 95 % CI 25, 56), the majority were unilineage responses (13/17, 76%) whilst there were 3 bilineage and 1 trilineage responses at week 12. Eltrombopag was discontinued after 16 weeks if no haematological response or transfusion independence was observed. Patients who responded continued therapy in an extension phase of the study. A total of 14 patients entered the extension phase of the trial. Nine of these patients achieved a multi-lineage response, 4 of the 9 remain on treatment and 5 tapered off treatment with eltrombopag and maintained the response (median follow up: 20.6 months, range: 5.7 to 22.5 months). The remaining 5 patients discontinued treatment, three due to relapse at the month 3 extension visit. During treatment with eltrombopag 59% (23/39) became platelet transfusion independent (28 days without platelet transfusion) and 27% (10/37) became RBC transfusion independent (56 days without RBC transfusion). The longest platelet transfusion-free period for non-responders was 27 days (median). The longest platelet transfusion-free period for responders was 287 days (median). The longest RBC transfusion-free period for non-responders was 29 days (median). The longest RBC transfusion-free period for responders was 266 days (median). Over 50% of responders who were transfusion-dependent at baseline, had >80% reduction in both platelet and RBC transfusion requirements compared to baseline. Preliminary results from a supportive study (Study ELT116826), an ongoing non-randomised, phase II, single-arm, open-label study in refractory SAA patients, showed consistent results. Data are limited to 21 out of the planned 60 patients with haematological responses reported by 52% of patients at 6 months. Multilineage responses were reported by 45% of patients. 5.2 Pharmacokinetic properties Pharmacokinetics The plasma eltrombopag concentration-time data collected in 88 patients with ITP in studies TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population PK analysis. Plasma eltrombopag AUC(0-) and Cmax estimates for ITP patients are presented (Table 8). Table 8 Geometric mean (95% confidence intervals) of steady-state plasma eltrombopag pharmacokinetic parameters in adults with ITP Eltrombopag dose, once daily N AUC(0-)a, g.h/ml Cmaxa, g/ml 30 mg 28 47 (39, 58) 3.78 (3.18, 4.49) 50 mg 34 108 (88, 134) 8.01 (6.73, 9.53) 75 mg 26 168 (143, 198) 12.7 (11.0, 14.5) a AUC(0-) and Cmax based on population PK post-hoc estimates. 62 Plasma eltrombopag concentration-time data collected in 590 patients with HCV enrolled in phase III studies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patients with HCV enrolled in the phase II study TPL102357 and healthy adult subjects in a population PK analysis. Plasma eltrombopag Cmax and AUC(0-) estimates for patients with HCV enrolled in the phase III studies are presented for each dose studied in Table 9. Table 9 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters in patients with chronic HCV Eltrombopag dose (once daily) N AUC(0-) (g.h/ml) Cmax (g/ml) 25 mg 330 118 (109, 128) 6.40 (5.97, 6.86) 50 mg 119 166 (143, 192) 9.08 (7.96, 10.35) 75 mg 45 301 (250, 363) 16.71 (14.26, 19.58) 100 mg 96 354 (304, 411) 19.19 (16.81, 21.91) Data presented as geometric mean (95% CI). AUC (0-) and Cmax based on population PK post-hoc estimates at the highest dose in the data for each patient. Absorption and bioavailability Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Administration of eltrombopag concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces eltrombopag exposure (see section 4.2). In a relative bioavailability study in adults, the eltrombopag powder for oral suspension delivered 22% higher plasma AUC(0-) than the film-coated tablet formulation. The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52%. Distribution Eltrombopag is highly bound to human plasma proteins (>99.9%), predominantly to albumin. Eltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1. Biotransformation Eltrombopag is primarily metabolised through cleavage, oxidation and conjugation with glucuronic acid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64% of plasma radiocarbon AUC0-. Minor metabolites due to glucuronidation and oxidation were also detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidative metabolism of eltrombopag. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathway. 63 Elimination Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is via faeces (59%) with 31% of the dose found in the urine as metabolites. Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for approximately 20% of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours. Pharmacokinetic interactions Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not anticipated due to limited contribution of individual UGT enzymes in the glucuronidation of eltrombopag. Approximately 21% of an eltrombopag dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag oxidation. Eltrombopag does not inhibit or induce CYP enzymes based on in vitro and in vivo data (see section 4.5). In vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter and an inhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1 and BCRP substrate rosuvastatin in a clinical drug interaction study (see section 4.5). In clinical studies with eltrombopag, a dose reduction of statins by 50% was recommended. Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc (see sections 4.2 and 4.5). In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter polypeptide, OATP1B1, but is an inhibitor of this transporter (IC50 value of 2.7 μM (1.2 μg/ml). In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor (IC50 value of 2.7 μM (1.2 μg/ml). Special patient populations Renal impairment The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult patients with renal impairment. Following administration of a single 50 mg dose, the AUC0- of eltrombopag was 32% to 36% lower in patients with mild to moderate renal impairment, and 60% lower in patients with severe renal impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with renal impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound medicinal product were not measured. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or urine analysis (see section 4.2). The efficacy and safety of eltrombopag have not been established in patients with both moderate to severe renal impairment and hepatic impairment. 64 Hepatic impairment The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult patients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0- of eltrombopag was 41% higher in patients with mild hepatic impairment and 80% to 93% higher in patients with moderate to severe hepatic impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound medicinal product were not measured. The influence of hepatic impairment on the pharmacokinetics of eltrombopag following repeat administration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and 714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver disease of other aetiology). Of the 714 patients, 642 were with mild hepatic impairment, 67 with moderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers, patients with mild hepatic impairment had approximately 111% (95% CI: 45% to 283%) higher plasma eltrombopag AUC(0-) values and patients with moderate hepatic impairment had approximately 183% (95% CI: 90% to 459%) higher plasma eltrombopag AUC(0-) values. Therefore, eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see sections 4.2 and 4.4). For patients with HCV initiate eltrombopag at a dose of 25 mg once daily (see section 4.2). Race The influence of Asian ethnicity (such as Japanese, Chinese, Taiwanese and Korean) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 Asians) and 88 patients with ITP (18 Asians). Based on estimates from the population pharmacokinetic analysis, Asian ITP patients had approximately 49% higher plasma eltrombopag AUC(0-) values as compared to non-Asian patients who were predominantly Caucasian (see section 4.2). The influence of Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean, and Thai) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 635 patients with HCV (145 Asians and 69 South Asians). Based on estimates from the population pharmacokinetic analysis, Asian patients had approximately 55% higher plasma eltrombopag AUC(0-) values as compared to patients of other races who were predominantly Caucasian (see section 4.2). Gender The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). Based on estimates from the population pharmacokinetic analysis, female ITP patients had approximately 23% higher plasma eltrombopag AUC(0-) as compared to male patients, without adjustment for body weight differences. The influence of gender on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimate, female HCV patient had approximately 41% higher plasma eltrombopag AUC(0-) as compared to male patients. 65 Age The influence of age on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 28 healthy subjects, 673 patients with HCV, and 41 patients with chronic liver disease of other aetiology ranging from 19 to 74 years old. There are no PK data on the use of eltrombopag in patients ≥75 years. Based on model estimate, elderly (≥65 years) patients had approximately 41% higher plasma eltrombopag AUC(0-) as compared to younger patients (see section 4.2). Paediatric Population (aged 1 to 17 years) The pharmacokinetics of eltrombopag have been evaluated in 168 paediatric ITP patients dosed once daily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. The effects of race and sex on plasma eltrombopag CL/F estimates were consistent between paediatric and adult patients. Asian paediatric ITP patients had approximately 43% higher plasma eltrombopag AUC(0-) values as compared to non-Asian patients. Female paediatric ITP patients had approximately 25% higher plasma eltrombopag AUC(0-) values as compared to male patients. The pharmacokinetic parameters of eltrombopag in paediatric patients with ITP are shown in Table 10. Table 10 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters in paediatric patients with ITP (50 mg once daily dosing regimen) Age Cmax (µg/ml) AUC(0-) (µg.hr/ml) 12 to 17 years (n=62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n=68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n=38) 11.6 (10.4, 12.9) 162 (139, 187) Data presented as geometric mean (95% CI). AUC(0-) and Cmax based on population PK post-hoc estimates 5.3 Preclinical safety data Safety pharmacology and repeat-dose toxicity Eltrombopag does not stimulate platelet production in mice, rats or dogs because of unique TPO receptor specificity. Therefore, data from these animals do not fully model potential adverse effects related to the pharmacology of eltrombopag in humans, including the reproduction and carcinogenicity studies. Treatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥6 times the human clinical exposure in adult ITP patients at 75 mg/day and 3 times the human clinical exposure in adult HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after 6 weeks and rats after 28 weeks of dosing. At 4 times the human clinical exposure in ITP patients at 75 mg/day and 2 times the human exposure in HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. At non-tolerated doses in pre-weaning juvenile rats dosed from days 4-32 (approximately equating to a 2-year-old human at the end of the dosing period), ocular opacities were observed (histology not performed) at 9 times the maximum human clinical exposure in paediatric ITP patients at 75 mg/day, based on AUC. However, cataracts were not observed in juvenile rats given tolerated doses at 5 times the human clinical exposure in paediatric ITP patients, based on AUC. Cataracts have not been observed in adult dogs after 52 weeks of dosing at 2 times the human clinical exposure in adult or paediatric ITP patients at 66 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less severe at lower doses and were characterised by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 or 0.8 times the human clinical exposure based on AUC in adult or paediatric ITP patients at 75 mg/day and 0.6 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times the human clinical exposure in adult ITP patients and 3 and 2 times the human clinical exposure in paediatric ITP patients at 75 mg/day and 2 times and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Hepatocyte degeneration and/or necrosis, often accompanied by increased serum liver enzymes, was observed in mice, rats and dogs at doses that were associated with morbidity and mortality or were poorly tolerated. No hepatic effects were observed after chronic dosing in rats (28 weeks) and in dogs (52 weeks) at 4 or 2 times the human clinical exposure in adult ITP and 3 or 2 times the human clinical exposure in paediatric ITP patients at 75 mg/day and 2 times and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC. At poorly tolerated doses in rats and dogs (>10 or 7 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and>4 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC), decreased reticulocyte counts and regenerative bone marrow erythroid hyperplasia (rats only) were observed in short-term studies. There were no effects of note on red cell mass or reticulocyte counts after dosing for up to 28 weeks in rats, 52 weeks in dogs and 2 years in mice or rats at maximally tolerated doses which were 2 to 4 times human clinical exposure in adult or paediatric ITP patients at 75 mg/day and ≤2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Endosteal hyperostosis was observed in a 28-week toxicity study in rats at a non-tolerated dose of 60 mg/kg/day (6 times or 4 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). There were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times or 2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC. Carcinogenicity and mutagenicity Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 or 2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times or 8 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 7 times the human clinical exposure in HCV patients at 100 mg/day, based on Cmax). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (<3-fold increase in mutation frequency). These in vitro and in vivo findings suggest that eltrombopag does not pose a genotoxic risk to humans. 67 Reproductive toxicity Eltrombopag did not affect female fertility, early embryonic development or embryofoetal development in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure in adult or adolescent (12-17 years) ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Also there was no effect on embryofoetal development in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.3 to 0.5 times the human clinical exposure in ITP patients at 75 mg/day and HCV patients at 100 mg/day, based on AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure in ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC) in rats, eltrombopag treatment was associated with embryo lethality (increased pre- and post- implantation loss), reduced foetal body weight and gravid uterine weight in the female fertility study and a low incidence of cervical ribs and reduced foetal body weight in the embryofoetal development study. Eltrombopag should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus (see section 4.6). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure in ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). In the pre- and post-natal development study in rats, there were no undesirable effects on pregnancy, parturition or lactation of F0 female rats at maternally non-toxic doses (10 and 20 mg/kg/day) and no effects on the growth, development, neurobehavioural or reproductive function of the offspring (F1). Eltrombopag was detected in the plasma of all F1 rat pups for the entire 22 hour sampling period following administration of medicinal product to the F0 dams, suggesting that rat pup exposure to eltrombopag was likely via lactation. Phototoxicity In vitro studies with eltrombopag suggest a potential phototoxicity risk; however, in rodents there was no evidence of cutaneous phototoxicity (10 or 7 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC) or ocular phototoxicity (4 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). Furthermore, a clinical pharmacology study in 36 subjects showed no evidence that photosensitivity was increased following administration of eltrombopag 75 mg. This was measured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruled out since no specific preclinical study could be performed. Juvenile animal studies At non-tolerated doses in pre-weaning rats, ocular opacities were observed. At tolerated doses, no ocular opacities were observed (see above subsection ‘Safety pharmacology and repeat-dose toxicity’). In conclusion, taking into account the exposure margins based on AUC, a risk of eltrombopag-related cataracts in paediatric patients cannot be excluded. There are no findings in juvenile rats to suggest a greater risk of toxicity with eltrombopag treatment in paediatric vs. adult ITP patients. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Mannitol (E421) Sucralose Xanthan gum 6.2 Incompatibilities Not applicable. 68 6.3 Shelf life 2 years. Following reconstitution, the medicinal product should be administered immediately but may be stored for a maximum period of 30 minutes. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Heat-sealed foil laminate sachets. The laminate material is comprised of polyester (PET) / orientated polyamide (OPA) / 9 µm aluminium foil (AL) / low density polyethylene heat seal layer (LDPE). The product contact material is the polyethylene heat seal layer. The sachets are co-packaged in a kit with a 40 ml HDPE mixing bottle, and 30 single-use 20 ml oral dosing syringes (polypropylene/silicon rubber) with 1 ml graduations. In addition, a screw cap (ethylene vinyl acetate / LDPE) with syringe- port capability is provided. Pack size of 30 sachets. 6.6 Special precautions for disposal Instructions for use Avoid direct contact with the medicine. Wash any exposed area immediately with soap and water. Preparation and administration of the powder for oral suspension:  Administer the oral suspension immediately after preparation. Discard suspension if not administered within 30 minutes after preparation.  Prepare the suspension with water only.  Add 20 ml of water and the contents of the prescribed number of sachets (depending on the recommended dose) to the provided mixing bottle and mix gently.  Give the entire contents of the bottle to the patient using one of the accompanying oral syringes.  IMPORTANT: Because some medicine will remain in the mixing bottle, complete the following steps.  Add 10 ml of water to the mixing bottle and mix gently.  Give the entire contents of the bottle to the patient using the same oral syringe. Cleaning of the mixing equipment:  Discard the used oral syringe.  Rinse the mixing bottle and lid, under running water. (The mixing bottle may become stained from the medicine. This is normal.)  Let all the equipment dry in the air.  Wash your hands with soap and water. Do not re-use the oral dosing syringe. A new single-use oral dosing syringe should be used to prepare each dose of Revolade for oral suspension. For more details on preparation and administration of the suspension, see Instructions for Use in the package leaflet. 69 Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 8. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/013 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 11 March 2010 Date of latest renewal: 15 January 2015 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. 70 ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 71 A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Revolade 12.5 mg, 25 mg, 50 mg and 75 mg film-coated tablets: Novartis Farmacéutica SA Ronda de Santa Maria 158 08210 Barberà del Vallès (Barcelona) Spain Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany Glaxo Wellcome S.A. Avenida de Extremadura 3 09400 Aranda de Duero Burgos Spain Revolade 25 mg powder for oral suspension: Lek d.d Verovskova Ulica 57 Ljubljana 1526 Slovenia Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription. (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. 72 D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 73 ANNEX III LABELLING AND PACKAGE LEAFLET 74 A. LABELLING 75 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF 12.5 mg – 14, 28, 84 (3 PACKS of 28) TABLETS 1. NAME OF THE MEDICINAL PRODUCT Revolade 12.5 mg film-coated tablets eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 film-coated tablets 28 film-coated tablets Multipack containing 84 (3 packs of 28) film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 76 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/010 (14 film-coated tablets) EU/1/10/612/011 (28 film-coated tablets) EU/1/10/612/012 84 film-coated tablets (3 packs of 28) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 12.5 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 77 PARTICULARS TO APPEAR ON INTERMEDIATE CARTON Multipacks of 84 (3 packs of 28 film-coated tablets) – without blue box – 12.5 mg film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT Revolade 12.5 mg film-coated tablets eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets. Component of a multipack, can’t be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 78 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/012 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 12.5 mg 79 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister 1. NAME OF THE MEDICINAL PRODUCT Revolade 12.5 mg film-coated tablets eltrombopag 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 80 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF 25 mg – 14, 28, 84 (3 PACKS of 28) TABLETS 1. NAME OF THE MEDICINAL PRODUCT Revolade 25 mg film-coated tablets eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 film-coated tablets 28 film-coated tablets Multipack containing 84 (3 packs of 28) film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 81 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/001 (14 film-coated tablets) EU/1/10/612/002 (28 film-coated tablets) EU/1/10/612/003 84 film-coated tablets (3 packs of 28) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 25 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 82 PARTICULARS TO APPEAR ON INTERMEDIATE CARTON Multipacks of 84 (3 packs of 28 film-coated tablets) – without blue box – 25 mg film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT Revolade 25 mg film-coated tablets eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets. Component of a multipack, can’t be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 83 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/003 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 25 mg 84 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister 1. NAME OF THE MEDICINAL PRODUCT Revolade 25 mg film-coated tablets eltrombopag 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 85 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF 50 mg – 14, 28, 84 (3 PACKS of 28) TABLETS 1. NAME OF THE MEDICINAL PRODUCT Revolade 50 mg film-coated tablets eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 film-coated tablets 28 film-coated tablets Multipack containing 84 (3 packs of 28) film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 86 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/004 (14 film-coated tablets) EU/1/10/612/005 (28 film-coated tablets) EU/1/10/612/006 84 film-coated tablets (3 packs of 28) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 50 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 87 PARTICULARS TO APPEAR ON INTERMEDIATE CARTON Multipacks of 84 (3 packs of 28 film-coated tablets) – without blue box – 50 mg film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT Revolade 50 mg film-coated tablets eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets. Component of a multipack, can’t be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 88 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/006 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 50 mg 89 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister 1. NAME OF THE MEDICINAL PRODUCT Revolade 50 mg film-coated tablets eltrombopag 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 90 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON OF 75 mg – 14, 28, 84 (3 PACKS of 28) TABLETS 1. NAME OF THE MEDICINAL PRODUCT Revolade 75 mg film-coated tablets eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 14 film-coated tablets 28 film-coated tablets Multipack containing 84 (3 packs of 28) film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 91 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/007 (14 film-coated tablets) EU/1/10/612/008 (28 film-coated tablets) EU/1/10/612/009 84 film-coated tablets (3 packs of 28) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 75 mg 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 92 PARTICULARS TO APPEAR ON INTERMEDIATE CARTON Multipacks of 84 (3 packs of 28 film-coated tablets) – without blue box –75 mg film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT Revolade 75 mg film-coated tablets eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 28 film-coated tablets. Component of a multipack, can’t be sold separately. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 93 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/009 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 75 mg 94 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Blister 1. NAME OF THE MEDICINAL PRODUCT Revolade 75 mg film-coated tablets eltrombopag 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 95 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton of 25 mg powder for oral suspension 1. NAME OF THE MEDICINAL PRODUCT Revolade 25 mg powder for oral suspension eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sachet contains eltrombopag olamine equivalent to 25 mg of eltrombopag. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 30 sachets and 1 mixing bottle + 30 single-use oral syringes 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Use within 30 minutes of reconstitution. 9. SPECIAL STORAGE CONDITIONS 96 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/013 (30 sachets of powder for oral suspension) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 25 mg sachets 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN: 97 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton of 25 mg powder for oral suspension – without blue box – 30 sachets 1. NAME OF THE MEDICINAL PRODUCT Revolade 25 mg powder for oral suspension eltrombopag 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sachet contains eltrombopag olamine equivalent to 25 mg of eltrombopag. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 30 sachets. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Use within 30 minutes of reconstitution. 9. SPECIAL STORAGE CONDITIONS 98 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/612/013 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE revolade 25 mg sachets 99 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SACHET 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Revolade 25 mg powder for oral suspension eltrombopag Oral use 2. NAME OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 100 B. PACKAGE LEAFLET 101 Package Leaflet: Information for the patient Revolade 12.5 mg film-coated tablets Revolade 25 mg film-coated tablets Revolade 50 mg film-coated tablets Revolade 75 mg film-coated tablets eltrombopag Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any of the side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4 What is in this leaflet: 1. What Revolade is and what it is used for 2. What you need to know before you take Revolade 3. How to take Revolade 4. Possible side effects 5. How to store Revolade 6. Contents of the pack and other information 1. What Revolade is and what it is used for Revolade contains eltrombopag, which belongs to a group of medicines called thrombopoietin receptor agonists. It is used to help increase the number of platelets in your blood. Platelets are blood cells that help to reduce or prevent bleeding.  Revolade is used to treat a bleeding disorder called immune (primary) thrombocytopenia (ITP) in patients aged 1 year and above who have already taken other medicines (corticosteroids or immunoglobulins), which have not worked. ITP is caused by a low blood platelet count (thrombocytopenia). People with ITP have an increased risk of bleeding. Symptoms patients with ITP may notice include petechiae (pinpoint- sized flat round red spots under the skin), bruising, nosebleeds, bleeding gums and not being able to control bleeding if they are cut or injured.  Revolade can also be used to treat low platelet count (thrombocytopenia) in adults with hepatitis C virus (HCV) infections, if they have had problems with side effects while on interferon treatment. Many people with hepatitis C have low platelet counts, not only as a result of the disease, but also due to some of the antiviral medicines that are used to treat it. Taking Revolade may make it easier for you to complete a full course of antiviral medicine (peginterferon and ribavirin).  Revolade may also be used to treat adult patients with low blood counts caused by severe aplastic anaemia (SAA). SAA is a disease in which the bone marrow is damaged, causing a deficiency of the red blood cells (anaemia), white blood cells (leukopenia) and platelets (thrombocytopenia). 102 2. What you need to know before you take Revolade Do not take Revolade  if you are allergic to eltrombopag or any of the other ingredients of this medicine (listed in section 6 under ‘What Revolade contains’).  Check with your doctor if you think this applies to you. Warnings and precautions Talk to your doctor before taking Revolade:  if you have liver problems. People who have low platelet counts as well as advanced chronic (long-term) liver disease are more at risk of side effects, including life-threatening liver damage and blood clots. If your doctor considers that the benefits of taking Revolade outweigh the risks, you will be closely monitored during treatment.  if you are at risk of blood clots in your veins or arteries, or you know that blood clots are common in your family. You may be at higher risk of blood clots: - as you get older - if you have had to stay in bed for a long time - if you have cancer - if you are taking the contraceptive birth control pill or hormone replacement therapy - if you have recently had surgery or received a physical injury - if you are very overweight (obese) - if you are a smoker - if you have advanced chronic liver disease  If any of these apply to you, tell your doctor before starting treatment. You should not take Revolade unless your doctor considers that the expected benefits outweigh the risk of blood clots.  if you have cataracts (the lens of the eye getting cloudy)  if you have another blood condition, such as myelodysplastic syndrome (MDS). Your doctor will carry out tests to check that you do not have this blood condition before you start Revolade. If you have MDS and take Revolade, your MDS may get worse.  Tell your doctor if any of these apply to you. Eye examinations Your doctor will recommend that you are checked for cataracts. If you do not have routine eye-tests your doctor should arrange regular testing. You may also be checked for the occurrence of any bleeding in or around your retina (the light-sensitive layer of cells at the back of the eye). You will need regular tests Before you start taking Revolade, your doctor will carry out blood tests to check your blood cells, including platelets. These tests will be repeated at intervals while you are taking it. Blood tests for liver function Revolade can cause blood test results that may be signs of liver damage - an increase of some liver enzymes, especially bilirubin and alanine / aspartate transaminases. If you are taking interferon-based treatments together with Revolade to treat low platelet count due to hepatitis C, some liver problems can get worse. You will have blood tests to check your liver function before you start taking Revolade and at intervals while you are taking it. You may need to stop taking Revolade if the amount of these substances increases too much, or if you get other signs of liver damage.  Read the information ‘Liver problems’ in section 4 of this leaflet. 103 Blood tests for platelet count If you stop taking Revolade, your blood platelet count is likely to become low again within several days. The platelet count will be monitored, and your doctor will discuss appropriate precautions with you. A very high blood platelet count may increase the risk of blood clotting. However blood clots can also form with normal or even low platelet counts. Your doctor will adjust your dose of Revolade to ensure that your platelet count does not become too high. Get medical help immediately if you have any of these signs of a blood clot:  swelling, pain or tenderness in one leg  sudden shortness of breath especially together with sharp pain in the chest or rapid breathing  abdominal (stomach) pain, enlarged abdomen, blood in your stools Tests to check your bone marrow In people who have problems with their bone marrow, medicines like Revolade could make the problems worse. Signs of bone marrow changes may show up as abnormal results in your blood tests. Your doctor may also carry out tests to directly check your bone marrow during treatment with Revolade. Checks for digestive bleeding If you are taking interferon-based treatments together with Revolade you will be monitored for any signs of bleeding in your stomach or intestine after you stop taking Revolade. Heart monitoring Your doctor may consider it necessary to monitor your heart during treatment with Revolade and carry out an electrocardiogram (ECG) test. Older people (65 years and above) There are limited data on the use of Revolade in patients aged 65 years and older. Care should be taken when using Revolade if you are aged 65 years or above. Children and adolescents Revolade is not recommended for children aged under 1 year who have ITP. It is also not recommended for people under 18 years with low platelet counts due to hepatitis C or severe aplastic anaemia. Other medicines and Revolade Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without prescription and vitamins. Some everyday medicines interact with Revolade – including prescription and non-prescription medicines and minerals. These include:  antacid medicines to treat indigestion, heartburn or stomach ulcers (see also ‘When to take it’ in section 3)  medicines called statins, to lower cholesterol  some medicines to treat HIV infection, such as lopinavir and/or ritonavir  ciclosporin used in the context of transplantations or immune diseases  minerals such as iron, calcium, magnesium, aluminium, selenium and zinc which may be found in vitamin and mineral supplements (see also ‘When to take it’ in section 3)  medicines such as methotrexate and topotecan, to treat cancer  Talk to your doctor if you take any of these. Some of them are not to be taken with Revolade, or the dose may need adjusting, or you may need to alter the timing of when you take them. Your doctor will review the medicines you are taking, and suggest suitable replacements if necessary. 104 If you are also taking medicines to prevent blood clots there is a greater risk of bleeding. Your doctor will discuss this with you. If you are taking corticosteroids, danazol, and/or azathioprine you may need to take a lower dose or to stop taking them while you are taking Revolade. Revolade with food and drink Do not take Revolade with dairy foods or drinks as the calcium in dairy products affects the absorption of the medicine. For more information, see ‘When to take it’ in section 3. Pregnancy and breast-feeding Don’t use Revolade if you are pregnant unless your doctor specifically recommends it. The effect of Revolade during pregnancy is not known.  Tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a baby.  Use a reliable method of contraception while you’re taking Revolade, to prevent pregnancy  If you do become pregnant during treatment with Revolade, tell your doctor. Don’t breast-feed while you are taking Revolade. It is not known whether Revolade passes into breast-milk.  If you are breast-feeding or planning to breast-feed, tell your doctor. Driving and using machines Revolade can make you dizzy and have other side effects that make you less alert.  Don’t drive or use machines unless you are sure you’re not affected. 3. How to take Revolade Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Do not change the dose or schedule for taking Revolade unless your doctor or pharmacist advises you to. While you are taking Revolade, you will be under the care of a doctor with specialist experience in treating your condition. How much to take For ITP Adults and children (6 to 17 years) – the usual starting dose for ITP is one 50 mg tablet of Revolade a day. If you are of Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to start at a lower dose of 25 mg. Children (1 to 5 years) — the usual starting dose for ITP is one 25 mg tablet of Revolade a day. For hepatitis C Adults - the usual starting dose for hepatitis C is one 25 mg tablet of Revolade a day. If you are of Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you will start on the same 25 mg dose. For SAA Adults - the usual starting dose for SAA is one 50 mg tablet of Revolade a day. If you are of Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to start at a lower dose of 25 mg. Revolade may take 1 to 2 weeks to work. Based on your response to Revolade your doctor may recommend that your daily dose is changed. 105 How to take the tablets Swallow the tablet whole, with some water. When to take it Make sure that –  in the 4 hours before you take Revolade  and the 2 hours after you take Revolade you don’t consume any of the following:  dairy foods such as cheese, butter, yoghurt or ice cream  milk or milk shakes, drinks containing milk, yoghurt or cream  antacids, a type of medicine for indigestion and heartburn  some mineral and vitamin supplements including iron, calcium, magnesium, aluminium, selenium and zinc If you do, the medicine will not be properly absorbed into your body. For more advice about suitable foods and drinks, talk to your doctor. If you take more Revolade than you should Contact a doctor or pharmacist immediately. If possible show them the pack, or this leaflet. Youwill be monitored for any signs or symptoms of side effects and given appropriate treatment immediately. If you forget to take Revolade Take the next dose at the usual time. Do not take more than one dose of Revolade in one day. If you stop taking Revolade Don’t stop taking Revolade without talking to your doctor. If your doctor advises you to stop treatment, your platelet count will then be checked each week for four weeks. See also ‘Bleeding or bruising after you stop treatment’ in section 4. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. NO dairy products, antacids or mineral supplements Take Revolade For 4 hours before you take Revolade... ... and for 2 hours after 106 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Symptoms needing attention: see a doctor People taking Revolade for either ITP or low blood platelet counts due to hepatitis C could develop signs of potentially serious side effects. It is important to tell a doctor if you develop these symptoms. Higher risk of blood clots Certain people may have a higher risk of blood clots, and medicines like Revolade could make this problem worse. The sudden blocking of a blood vessel by a blood clot is an uncommon side effect and may affect up to 1 in 100 people. Get medical help immediately if you develop signs and symptoms of a blood clot, such as:  swelling, pain, heat, redness, or tenderness in one leg  sudden shortness of breath, especially together with sharp pain in the chest or rapid breathing  abdominal (stomach) pain, enlarged abdomen, blood in your stools. Liver problems Revolade can cause changes that show up in blood tests, and may be signs of liver damage. Liver problems (increased enzymes showing up in blood tests) are common and may affect up to 1 in 10 people. Other liver problems (bile not flowing properly) are uncommon and may affect up to 1 in 100 people. If you have either of these signs of liver problems:  yellowing of the skin or the whites of the eyes (jaundice)  unusually dark-coloured urine  tell your doctor immediately. Bleeding or bruising after you stop treatment Within two weeks of stopping Revolade, your blood platelet count will usually drop back down to what it was before starting Revolade. The lower platelet count may increase the risk of bleeding or bruising. Your doctor will check your platelet count for at least 4 weeks after you stop taking Revolade.  Tell your doctor if you have any bleeding or bruising after stopping Revolade. Some people have bleeding in the digestive system after they stop taking peginterferon, ribavirin, and Revolade. Symptoms include:  black tarry stools (discoloured bowel movements are a uncommon side effect that may affect up to 1 in 100 people)  blood in your stools  vomiting blood or something that looks like coffee grounds  Tell your doctor immediately if you have any of these symptoms. The following side effects have been reported to be associated with treatment with Revolade in adult patients with ITP: Very common side effects These may affect more than 1 in 10 people:  common cold  feeling sick (nausea)  diarrhoea  cough  infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract infection) 107 Very common side effects that may show up in blood tests:  increased of liver enzymes (alanine aminotransferase (ALT)) Common side effects These may affect up to 1 in 10 people:  muscle pain, muscle spasm, muscle weakness  back pain  bone pain  heavy menstrual period  sore throat and discomfort when swallowing  eye problems including abnormal eye test, dry eye, eye pain and blurred vision  vomiting  flu (influenza)  cold sore  pneumonia  irritation and inflammation (swelling) of the sinuses  inflammation (swelling) and infection of the tonsils infection of the lungs, sinuses, tonsils, nose and throat  inflammation of the gum tissue  loss of appetite  feeling of tingling, prickling or numbness, commonly called “pins and needles”  feeling drowsy  ear pain  pain, swelling and tenderness in one of your legs (usually the calf) with warm skin in the affected area (signs of a blood clot in a deep vein)  localised swelling filled with blood from a break in a blood vessel (haematoma)  mouth problems including dry mouth, sore mouth, sensitive tongue, bleeding gums, mouth ulcers  runny nose  toothache  stomach pain and tenderness  liver problems  skin changes including excessive sweating, itching bumpy rash, red spots, changes in appearance of the skin  hair loss  foamy, frothy or bubbly-looking urine (signs of protein in urine)  generally feeling unwell, high temperature, feeling hot  chest pain  problems sleeping, depression  migraine  decreased vision  spinning sensation (vertigo)  digestive wind/gas Common side effects that may show up in blood test:  decreased number of red blood cells (anaemia)  decreased number of platelets (thrombocytopenia)  decreased number of white blood cells  decreased haemaglobin level  decreased number of eosinophils  increased number of white blood cells (leukocytosis)  increased levels of uric acid  decreased levels of potassium 108  increased levels of creatinine  increased levels of alkaline phosphatase  increase of liver enzymes (aspartate aminotransferase (AST))  increase in bilirubin (a substance produced by the liver)  increased levels of some proteins Uncommon side effects These may affect up to 1 in 100 people:  interruption of blood supply to part of the heart  sudden shortness of breath, especially when accompanied with sharp pain in the chest and /or rapid breathing, which could be signs of a blood clot in the lungs (see ‘Higher risk of blood clots’ earlier in section 4)  the loss of function of part of the lung caused by a blockage in the lung artery  including yellowing of the eyes and skin (see ‘Liver problems’ earlier in section 4)  liver injury due to medication  heart beating faster, irregular heartbeat, bluish discolouration of the skin  disturbances of heart rhythm (QT prolongation)  blood clot  painful swollen joints caused by uric acid (gout)  lack of interest, mood changes  problems with balance, speech and nerve function, shaking  eye problems including increased production of tears, cloudy lens in the eye (cataract), bleeding of the retina  problems with the nose, throat and sinuses, breathing problems when sleeping  digestive system problems including frequent bowel movements, food poisoning, blood in stool  rectal bleeding, blood in your stool, abdominal bloating, constipation  mouth problems, including dry or sore mouth, sensitive tongue, bleeding gums  sunburn  redness or swelling around, a woundbleeding around a catheter (if present) into the skinsensation of a foreign body  kidney problems including inflammation of the kidney, excessive urination at night, kidney failure, white cells in urine  cold sweat  infection of the skin  skin changes including change in colour, peeling, redness, itching and sweating Uncommon side effects that may show up in laboratory tests:  changes in the shape of red blood cells  increased number of platelets  decreased levels of calcium  decreased number of red blood cells (anaemia) cause by excessive destruction of red blood cells (haemolytic anaemia)  increased number of myelocytes  increased band neutrophils  increased blood urea  increased levels of blood albumin  increased levels of total protein  decreased levels of blood albumin  increased pH of urine  increased haemaglobin level 109 The following additional side effects have been reported to be associated with treatment with Revolade in children (aged 1 to 17 years) with ITP: If these side effects become severe, please tell your doctor, pharmacist or nurse. Very common side effects These may affect more than 1 in 10 children:  infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract infection)  diarrhoea  abdominal pain  cough  high temperature  feeling sick (nausea) Common side effects These may affect up to 1 in 10 children:  difficulty in sleeping (insomnia)  toothache  pain in the nose and throat  itchy, runny or blocked nose  sore throat, runny nose, nasal congestion and sneezing  mouth problems including dry mouth, sore mouth, sensitive tongue, bleeding gums, mouth ulcers The following side effects have been reported to be associated with treatment with Revolade in combination with peginterferon and ribavirin in patients with HCV: Very common side effects These may affect more than 1 in 10 people:  headache  decreased appetite  cough  feeling sick (nausea), diarrhoea  muscle pain, muscle weakness  itching  lack of energy  high temperature  unusual hair loss  feeling weak  flu-like illness  swelling in the hands or feet  chills Very common side effects that may show up in blood tests:  decreased number of red blood cells (anaemia) Common side effects These may affect up to 1 in 10 people:  infection of the urinary system  inflammation of the nasal passages, throat and mouth, flu-like symptoms, dry mouth, sore or inflamed mouth, toothache  weight loss  sleep disorders, abnormal drowsiness, depression, anxiety  dizziness, problems with attention and memory, change in mood  tingling or numbness of the hands or feet 110  fever, headache  eye problems, including cloudy lens in the eye (cataract), dry eye, small yellow deposits in the retina, yellowing of the whites of the eye  bleeding of the retina  spinning sensation (vertigo)  fast or irregular heartbeat (palpitations), shortness of breath  cough bringing up phlegm, runny nose, flu, cold sore, sore throat and discomfort when swallowing  digestive system problems, including being sick (vomiting), stomach pain, indigestion, constipation, swollen stomach, taste disturbances, inflammation of the stomach, piles (haemorrhoids), irritation of the gut  toothache  liver problems, including blood clot, tumour in the liver (see ‘Liver problems’ earlier in section 4)  skin changes, including rash, dry skin, eczema, redness of the skin, itching, excessive sweating, unusual skin growths  joint pain, back pain, bone pain, pain in the hands or feet, muscle spasms  irritability, generally feeling unwell, chest pain and discomfort  infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract infection)  depression, anxiety, sleep problems, nervousness Common side effects that may show up in blood tests:  increased blood sugar (glucose)  decreased number of white blood cells  decreased level of blood proteins  increased levels of blood bilirubin (a substance produced by the liver)  changes in the enzymes that control blood clotting Uncommon side effects These may affect up to 1 in 100 people:  painful urination  disturbances of heart rhythm (QT prolongation)  stomach flu (gastroenteritis)  skin changes including change in colour, peeling, redness, itching and sweating.  yellowing of the whites of the eyes or skin (jaundice)  swollen blood vessels and bleeding in the gullet (oesophagus)  rash, bruising at the injection site  decreased number of red blood cells (anaemia) caused by excessive destruction of red blood cells (haemolytic anaemia)  confusion, agitation  liver injury due to medication The following side effects have been reported to be associated with treatment with Revolade in patients with severe aplastic anaemia (SAA): If these side effects become severe, please tell your doctor, pharmacist or nurse. Very common side effects These may affect more than 1 in 10 people.  cough  headache  pain in the nose and throat  diarrhoea  nausea  joint pain (arthralgia) 111  pain in extremities (arms, legs, hands and feet)  dizziness  feeling very tired (fatigue)  fever  chills  itchy eyes  blisters in the mouth  abdominal pain  muscle spasms Very common side effects that may show up in the blood tests  abnormal changes to the cells in your bone marrow Common side effects These may affect up to 1 in 10 people.  anxiety  depression  feeling cold  feeling unwell  eye problems including blurred vision, cloudy lens in the eye (cataract), spots or deposits in eye (vitreous floaters), dry eye, itchy eye, yellowing of the whites of the eyes or skin  nose bleed  bleeding of the gums  digestive system problems including being sick (vomiting), change in appetite (increased or decreased), stomach pain/discomfort, swollen stomach, passing wind, change in stool colour  fainting  skin problems including small red or purple spots caused by bleeding into the skin (petechiae) rash, itching, skin lesion  back pain  muscle pain  bone pain  weakness (asthenia)  swelling of the lower limbs due to the accumulation of fluids  abnormal colored urine  interruption in blood supply to spleen (splenic infarction)  runny nose Common side effects that may show up in the blood tests  increase in enzymes due to muscle breakdown (creatine phosphokinase)  accumulation of iron in the body (iron overload)  decrease in blood sugar levels (hypoglycaemia)  increased levels of bilirubin (a substance produced by the liver)  increased levels of liver enzymes (aspartate aminotransferase (AST))  decreased levels of white blood cells Side effects with frequency not known Frequency cannot be estimated from the available data  skin discolouration  darkening of the skin  yellowing of the skin and eyes, tenderness around the liver 112 Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Revolade Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and the blister. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Revolade contains The active substance in Revolade is eltrombopag. 12.5 mg film-coated tablets Each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. 25 mg film-coated tablets Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. 50 mg film-coated tablets Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag. 75 mg film-coated tablets Each film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag. The other ingredients are: hypromellose, macrogol 400, magnesium stearate, mannitol (E421), microcrystalline cellulose, povidone, sodium starch glycolate, titanium dioxide (E171). Revolade 12.5 mg and 25 mg film-coated tablets also contain polysorbate 80 (E433). Revolade 50 mg film-coated tablets also contain iron oxide red (E172) and iron oxide yellow (E172). Revolade 75 mg film-coated tablets also contain iron oxide red (E172) and iron oxide black (E172). What Revolade looks like and contents of the pack Revolade 12.5 mg film-coated tablets are round, biconvex, white, debossed with ‘GS MZ1’ and ‘12.5’ on one side. Revolade 25 mg film-coated tablets are round, biconvex, white, debossed with ‘GS NX3’ and ‘25’ on one side. Revolade 50 mg film-coated tablets are round, biconvex, brown, debossed with ‘GS UFU’ and ‘50’ on one side. Revolade 75 mg film-coated tablets are round, biconvex, pink, debossed with ‘GS FFS’ and ‘75’ on one side. 113 They are supplied in aluminum blisters in a carton containing 14 or 28 film-coated tablets and multipacks containg 84 (3 packs of 28) film-coated tablets). Not all pack sizes may be available in your country. Marketing authorisation holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Novartis Farmacéutica SA Ronda de Santa Maria 158 08210 Barberà del Vallès (Barcelona) Spain Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany Glaxo Wellcome S.A. Avenida de Extremadura 3 09400 Aranda de Duero Burgos Spain For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA “Novartis Baltics” Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 26 37 82 555 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 114 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA “Novartis Baltics” Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu./ 115 Package Leaflet: Information for the patient Revolade 25 mg powder for oral suspension eltrombopag Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any of the side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4 What is in this leaflet: 1. What Revolade is and what it is used for 2. What you need to know before you take Revolade 3. How to take Revolade 4. Possible side effects 5. How to store Revolade 6. Contents of the pack and other information Instructions for use 1. What Revolade is and what it is used for Revolade contains eltrombopag, which belongs to a group of medicines called thrombopoietin receptor agonists. It is used to help increase the number of platelets in your blood. Platelets are blood cells that help to reduce or prevent bleeding.  Revolade is used to treat a bleeding disorder called immune (primary) thrombocytopenia (ITP) in patients aged 1 year and above who have already taken other medicines (corticosteroids or immunoglobulins), which have not worked. ITP is caused by a low blood platelet count (thrombocytopenia). People with ITP have an increased risk of bleeding. Symptoms patients with ITP may notice include petechiae (pinpoint- sized flat round red spots under the skin), bruising, nosebleeds, bleeding gums and not being able to control bleeding if they are cut or injured.  Revolade can also be used to treat low platelet count (thrombocytopenia) in adults with hepatitis C virus (HCV) infections, if they have had problems with side effects while on interferon treatment. Many people with hepatitis C have low platelet counts, not only as a result of the disease, but also due to some of the antiviral medicines that are used to treat it. Taking Revolade may make it easier for you to complete a full course of antiviral medicine (peginterferon and ribavirin).  Revolade may also be used to treat adult patients with low blood counts caused by severe aplastic anaemia (SAA). SAA is a disease in which the bone marrow is damaged, causing a deficiency of the red blood cells (anaemia), white blood cells (leukopenia) and platelets (thrombocytopenia). 116 2. What you need to know before you take Revolade Do not take Revolade  if you are allergic to eltrombopag or any of the other ingredients of this medicine (listed in section 6 under ‘What Revolade contains’).  Check with your doctor if you think this applies to you. Warnings and precautions Talk to your doctor before taking Revolade:  if you have liver problems. People who have low platelet counts as well as advanced chronic (long-term) liver disease are more at risk of side effects, including life-threatening liver damage and blood clots. If your doctor considers that the benefits of taking Revolade outweigh the risks, you will be closely monitored during treatment.  if you are at risk of blood clots in your veins or arteries, or you know that blood clots are common in your family. You may be at higher risk of blood clots: - as you get older - if you have had to stay in bed for a long time - if you have cancer - if you are taking the contraceptive birth control pill or hormone replacement therapy - if you have recently had surgery or received a physical injury - if you are very overweight (obese) - if you are a smoker - if you have advanced chronic liver disease  If any of these apply to you tell your doctor before starting treatment. You should not take Revolade unless your doctor considers that the expected benefits outweigh the risk of blood clots.  if you have cataracts (the lens of the eye getting cloudy)  if you have another blood condition, such as myelodysplastic syndrome (MDS). Your doctor will carry out tests to check that you do not have this blood condition before you start Revolade. If you have MDS and take Revolade, your MDS may get worse.  Tell your doctor if any of these apply to you. Eye examinations Your doctor will recommend that you are checked for cataracts. If you do not have routine eye-tests, your doctor should arrange regular testing. You may also be checked for the occurrence of any bleeding in or around your retina (the light-sensitive layer of cells at the back of the eye). You will need regular tests Before you start taking Revolade, your doctor will carry out blood tests to check your blood cells, including platelets. These tests will be repeated at intervals while you are taking it. Blood tests for liver function Revolade can cause blood test results that may be signs of liver damage - an increase of some liver enzymes, especially bilirubin and alanine / aspartate transaminases. If you are taking interferon-based treatments together with Revolade to treat low platelet count due to hepatitis C, some liver problems can get worse. You will have blood tests to check your liver function before you start taking Revolade and at intervals while you are taking it. You may need to stop taking Revolade if the amount of these substances increases too much, or if you get other signs of liver damage.  Read the information ‘Liver problems’ in section 4 of this leaflet. 117 Blood tests for platelet count If you stop taking Revolade, your blood platelet count is likely to become low again within several days. The platelet count will be monitored, and your doctor will discuss appropriate precautions with you. A very high blood platelet count may increase the risk of blood clotting. However blood clots can also form with normal or even low platelet counts. Your doctor will adjust your dose of Revolade to ensure that your platelet count does not become too high. Get medical help immediately if you have any of these signs of a blood clot:  swelling, pain or tenderness in one leg  sudden shortness of breath especially together with sharp pain in the chest or rapid breathing  abdominal (stomach) pain, enlarged abdomen, blood in your stools Tests to check your bone marrow In people who have problems with their bone marrow, medicines like Revolade could make the problems worse. Signs of bone marrow changes may show up as abnormal results in your blood tests. Your doctor may also carry out tests to directly check your bone marrow during treatment with Revolade. Checks for digestive bleeding If you are taking interferon-based treatments together with Revolade you will be monitored for any signs of bleeding in your stomach or intestine after you stop taking Revolade. Heart monitoring Your doctor may consider it necessary to monitor your heart during treatment with Revolade and carry out an electrocardiogram (ECG) test. Older people (65 years and above) There are limited data on the use of Revolade in patients aged 65 years and older. Care should be taken when using Revolade if you are aged 65 years or above. Children and adolescents Revolade is not recommended for children aged under 1 year who have ITP. It is also not recommended for people under 18 years with low platelet counts due to hepatitis C or severe aplastic anaemia. Other medicines and Revolade Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without prescription and vitamins. Some everyday medicines interact with Revolade – including prescription and non-prescription medicines and minerals. These include:  antacid medicines to treat indigestion, heartburn or stomach ulcers (see also ‘When to take it’ in section 3)  medicines called statins, to lower cholesterol  some medicines to treat HIV infection, such as lopinavir and/or ritonavir  ciclosporin used in the context of transplantations or immune diseases  minerals such as iron, calcium, magnesium, aluminium, selenium and zinc which may be found in vitamin and mineral supplements (see also ‘When to take it’ in section 3)  medicines such as methotrexate and topotecan, to treat cancer  Talk to your doctor if you take any of these. Some of them are not to be taken with Revolade, or the dose may need adjusting, or you may need to alter the timing of when you take them. Your doctor will review the medicines you are taking, and suggest suitable replacements if necessary. 118 If you are also taking medicines to prevent blood clots, there is a greater risk of bleeding. Your doctor will discuss this with you. If you are taking corticosteroids, danazol, and/or azathioprine you may need to take a lower dose or to stop taking them while you are taking Revolade. Revolade with food and drink Do not take Revolade with dairy foods or drinks as the calcium in dairy products affects the absorption of the medicine. For more information, see ‘When to take it’ in section 3. Pregnancy and breast-feeding Don’t use Revolade if you are pregnant unless your doctor specifically recommends it. The effect of Revolade during pregnancy is not known.  Tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a baby.  Use a reliable method of contraception while you’re taking Revolade, to prevent pregnancy  If you do become pregnant during treatment with Revolade, tell your doctor. Don’t breast-feed while you are taking Revolade. It is not known whether Revolade passes into breast-milk.  If you are breast-feeding or planning to breast-feed, tell your doctor. Driving and using machines Revolade can make you dizzy and have other side effects that make you less alert.  Don’t drive or use machines unless you are sure you’re not affected. 3. How to take Revolade Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Do not change the dose or schedule for taking Revolade unless your doctor or pharmacist advises you to. While you are taking Revolade, you will be under the care of a doctor with specialist experience in treating your condition. How much to take For ITP Adults and children (6 to 17 years) - the usual starting dose for ITP is two 25 mg sachets of Revolade a day. If you are of Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to start at a lower dose of 25 mg. Children (1 to 5 years) — the usual starting dose for ITP is one 25 mg sachet of Revolade a day. For hepatitis C Adults - the usual starting dose for hepatitis C is one 25 mg sachet of Revolade a day. If you are of Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you will start on the same 25 mg dose. For SAA Adults - the usual starting dose for SAA is two 25 mg sachets of Revolade a day. If you are of Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to start at a lower dose of 25 mg. Revolade may take 1 to 2 weeks to work. Based on your response to Revolade your doctor may recommend that your daily dose is changed. 119 How to give a dose of medicine The powder for oral suspension is in sachets, the contents of which will need to mixed before you can take the medicine. After section 6 of this leaflet there are Instructions For Use on how to mix and administer the medicine. If you have questions or do not understand the Instructions For Use, talk to your doctor, nurse or pharmacist. IMPORTANT — Use the medicine immediately after you have mixed the powder with water. If you do not use it within 30 minutes of mixing it, you will need to mix a new dose. Do not re-use the oral dosing syringe. A new single-use oral dosing syringe should be used to prepare each dose of Revolade for oral suspension. When to take it Make sure –  in the 4 hours before you take Revolade  and the 2 hours after you take Revolade you don’t consume any of the following:  dairy foods such as cheese, butter, yoghurt or ice cream  milk or milk shakes, drinks containing milk, yoghurt or cream  antacids, a type of medicine for indigestion and heartburn  some mineral and vitamin supplements including iron, calcium, magnesium, aluminium, selenium and zinc If you do, the medicine will not be properly absorbed into your body. For more advice about suitable foods and drinks, talk to your doctor. If you take more Revolade than you should Contact a doctor or pharmacist immediately. If possible show them the pack, or this leaflet. You will be monitored for any signs or symptoms of side effects and given appropriate treatment immediately. If you forget to take Revolade Take your next dose at the usual time. Do not take more than one dose of Revolade in one day. If you stop taking Revolade Don’t stop taking Revolade without talking to your doctor. If your doctor advises you to stop treatment, your platelet count will then be checked each week for four weeks. See also ‘Bleeding or bruising after you stop treatment’ in section 4. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. NO dairy products, antacids or mineral supplements Take Revolade For 4 hours before you take Revolade... ... and for 2 hours after 120 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Symptoms needing attention: see a doctor People taking Revolade for either ITP or low blood platelet counts due to hepatitis C could develop signs of potentially serious side effects. It is important to tell a doctor if you develop these symptoms. Higher risk of blood clots Certain people may have a higher risk of blood clots, and medicines like Revolade could make this problem worse. The sudden blocking of a blood vessel by a blood clot is an uncommon side effect and may affect up to 1 in 100 people. Get medical help immediately if you develop signs and symptoms of a blood clot, such as:  swelling, pain, heat, redness or tenderness in one leg  sudden shortness of breath, especially together with sharp pain in the chest or rapid breathing  abdominal (stomach) pain, enlarged abdomen, blood in your stools. Liver problems Revolade can cause changes that show up in blood tests, and may be signs of liver damage. Liver problems (increased enzymes showing up in blood tests) are common and may affect up to 1 in 10 people. Other liver problems (bile not flowing properly) are uncommon and may affect up to 1 in 100 people. If you have either of these signs of liver problems:  yellowing of the skin or the whites of the eyes (jaundice)  unusually dark-coloured urine  tell your doctor immediately. Bleeding or bruising after you stop treatment Within two weeks of stopping Revolade, your blood platelet count will usually drop back down to what it was before starting Revolade. The lower platelet count may increase the risk of bleeding or bruising. Your doctor will check your platelet count for at least 4 weeks after you stop taking Revolade.  Tell your doctor if you have any bleeding or bruising after stopping Revolade. Some people have bleeding in the digestive system after they stop taking peginterferon, ribavirin, and Revolade. Symptoms include: - black tarry stools (discoloured bowel movements are a uncommon side effect that may affect up to 1 in 100 people) - blood in your stools - vomiting blood or something that looks like coffee grounds  Tell your doctor immediately if you have any of these symptoms. The following side effects have been reported to be associated with treatment with Revolade in adult patients with ITP: Very common side effects These may affect more than 1 in 10 people:  common cold  feeling sick (nausea)  diarrhoea  cough  infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract infection) 121 Very common side effects that may show up in blood tests:  increased of liver enzymes (alanine aminotransferase (ALT)) Common side effects These may affect up to 1 in 10 people:  muscle pain, muscle spasm, muscle weakness  back pain  bone pain  heavy menstrual period  sore throat and discomfort when swallowing  eye problems including abnormal eye test, dry eye, eye pain and blurred vision  vomiting  flu (influenza)  cold sore  pneumonia  irritation and inflammation (swelling) of the sinuses  inflammation (swelling) and infection of the tonsils infection of the lungs, sinuses, tonsils, nose and throat  inflammation of the gum tissue  loss of appetite  feeling of tingling, prickling or numbness, commonly called “pins and needles”  feeling drowsy  ear pain  pain, swelling and tenderness in one of your legs (usually the calf) with warm skin in the affected area (signs of a blood clot in a deep vein)  localised swelling filled with blood from a break in a blood vessel (haematoma)  mouth problems including dry mouth, sore mouth, sensitive tongue, bleeding gums, mouth ulcers  runny nose  toothache  stomach pain and tenderness  liver problems  skin changes including excessive sweating, itching bumpy rash, red spots, changes in appearance of the skin  hair loss  foamy, frothy or bubbly-looking urine (signs of protein in urine)  generally feeling unwell, high temperature, feeling hot  chest pain  problems sleeping, depression  migraine  decreased vision  spinning sensation (vertigo)  digestive wind/gas Common side effects that may show up in blood test:  decreased number of red blood cells (anaemia)  decreased number of platelets (thrombocytopenia)  decreased number of white blood cells  decreased haemaglobin level  decreased number of eosinophils  increased number of white blood cells (leukocytosis)  increased levels of uric acid  decreased levels of potassium 122  increased levels of creatinine  increased levels of alkaline phosphatase  increase of liver enzymes (aspartate aminotransferase (AST))  increase in bilirubin (a substance produced by the liver)  increased levels of some proteins Uncommon side effects These may affect up to 1 in 100 people:  interruption of blood supply to part of the heart  sudden shortness of breath, especially when accompanied with sharp pain in the chest and /or rapid breathing, which could be signs of a blood clot in the lungs (see ‘Higher risk of blood clots’ earlier in section 4)  the loss of function of part of the lung caused by a blockage in the lung artery  including yellowing of the eyes and skin (see ‘Liver problems’ earlier in section 4)  liver injury due to medication  heart beating faster, irregular heartbeat, bluish discolouration of the skin  disturbances of heart rhythm (QT prolongation)  blood clot  painful swollen joints caused by uric acid (gout)  lack of interest, mood changes  problems with balance, speech and nerve function, shaking  eye problems including increased production of tears, cloudy lens in the eye (cataract), bleeding of the retina  problems with the nose, throat and sinuses, breathing problems when sleeping  digestive system problems including frequent bowel movements, food poisoning, blood in stool  rectal bleeding, blood in your stool, abdominal bloating, constipation  mouth problems, including dry or sore mouth, sensitive tongue, bleeding gums  sunburn  redness or swelling around, a woundbleeding around a catheter (if present) into the skinsensation of a foreign body  kidney problems including inflammation of the kidney, excessive urination at night, kidney failure, white cells in urine  cold sweat  infection of the skin  skin changes including change in colour, peeling, redness, itching and sweating Uncommon side effects that may show up in laboratory tests:  changes in the shape of red blood cells  increased number of platelets  decreased levels of calcium  decreased number of red blood cells (anaemia) cause by excessive destruction of red blood cells (haemolytic anaemia)  increased number of myelocytes  increased band neutrophils  increased blood urea  increased levels of blood albumin  increased levels of total protein  decreased levels of blood albumin  increased pH of urine  increased haemaglobin level 123 The following additional side effects have been reported to be associated with treatment with Revolade in children (aged 1 to 17 years) with ITP: If these side effects become severe, please tell your doctor, pharmacist or nurse. Very common side effects These may affect more than 1 in 10 children:  infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract infection)  diarrhoea  abdominal pain  cough  high temperature  feeling sick (nausea) Common side effects These may affect up to 1 in 10 children:  difficulty in sleeping (insomnia)  toothache  pain in the nose and throat  itchy, runny or blocked nose  sore throat, runny nose, nasal congestion and sneezing  mouth problems including dry mouth, sore mouth, sensitive tongue, bleeding gums, mouth ulcers The following side effects have been reported to be associated with treatment with Revolade in combination with peginterferon and ribavirin in patients with HCV: Very common side effects These may affect more than 1 in 10 people:  headache  decreased appetite  cough  feeling sick (nausea), diarrhoea  muscle pain, muscle weakness  itching  lack of energy  high temperature  unusual hair loss  feeling weak  flu-like illness  swelling in the hands or feet  chills Very common side effects that may show up in blood tests:  decreased number of red blood cells (anaemia) Common side effects These may affect up to 1 in 10 people:  infection of the urinary system  inflammation of the nasal passages, throat and mouth, flu-like symptoms, dry mouth, sore or inflamed mouth, toothache  weight loss  sleep disorders, abnormal drowsiness, depression, anxiety  dizziness, problems with attention and memory, change in mood  tingling or numbness of the hands or feet 124  fever, headache  eye problems, including cloudy lens in the eye (cataract), dry eye, small yellow deposits in the retina, yellowing of the whites of the eye  bleeding of the retina  spinning sensation (vertigo)  fast or irregular heartbeat (palpitations), shortness of breath  cough bringing up phlegm, runny nose, flu, cold sore, sore throat and discomfort when swallowing  digestive system problems, including being sick (vomiting), stomach pain, indigestion, constipation, swollen stomach, taste disturbances, inflammation of the stomach, piles (haemorrhoids), irritation of the gut  toothache  liver problems, including blood clot, tumour in the liver (see ‘Liver problems’ earlier in section 4)  skin changes, including rash, dry skin, eczema, redness of the skin, itching, excessive sweating, unusual skin growths  joint pain, back pain, bone pain, pain in the hands or feet, muscle spasms  irritability, generally feeling unwell, chest pain and discomfort  infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract infection)  depression, anxiety, sleep problems, nervousness Common side effects that may show up in blood tests:  increased blood sugar (glucose)  decreased number of white blood cells  decreased level of blood proteins  increased levels of blood bilirubin (a substance produced by the liver)  changes in the enzymes that control blood clotting Uncommon side effects These may affect up to 1 in 100 people:  painful urination  disturbances of heart rhythm (QT prolongation)  stomach flu (gastroenteritis)  skin changes including change in colour, peeling, redness, itching and sweating.  yellowing of the whites of the eyes or skin (jaundice)  swollen blood vessels and bleeding in the gullet (oesophagus)  rash, bruising at the injection site  decreased number of red blood cells (anaemia) caused by excessive destruction of red blood cells (haemolytic anaemia)  confusion, agitation  liver injury due to medication The following side effects have been reported to be associated with treatment with Revolade in patients with severe aplastic anaemia (SAA): If these side effects become severe, please tell your doctor, pharmacist or nurse. Very common side effects These may affect more than 1 in 10 people.  cough  headache  pain in the nose and throat  diarrhoea  nausea  joint pain (arthralgia) 125  pain in extremities (arms, legs, hands and feet)  dizziness  feeling very tired (fatigue)  fever  chills  itchy eyes  blisters in the mouth  abdominal pain  muscle spasms Very common side effects that may show up in the blood tests  abnormal changes to the cells in your bone marrow Common side effects These may affect up to 1 in 10 people.  anxiety  depression  feeling cold  feeling unwell  eye problems including blurred vision, cloudy lens in the eye (cataract), spots or deposits in eye (vitreous floaters), dry eye, itchy eye, yellowing of the whites of the eyes or skin  nose bleed  bleeding of the gums  digestive system problems including being sick (vomiting), change in appetite (increased or decreased), stomach pain/discomfort, swollen stomach, passing wind, change in stool colour  fainting  skin problems including small red or purple spots caused by bleeding into the skin (petechiae) rash, itching, skin lesion  back pain  muscle pain  bone pain  weakness (asthenia)  swelling of the lower limbs due to the accumulation of fluids  abnormal colored urine  interruption in blood supply to spleen (splenic infarction)  runny nose Common side effects that may show up in the blood tests  increase in enzymes due to muscle breakdown (creatine phosphokinase)  accumulation of iron in the body (iron overload)  decrease in blood sugar levels (hypoglycaemia)  increased levels of bilirubin (a substance produced by the liver)  increased levels of liver enzymes (aspartate aminotransferase (AST))  decreased levels of white blood cells Side effects with frequency not known Frequency cannot be estimated from the available data  skin discolouration  darkening of the skin  yellowing of the skin and eyes, tenderness around the liver 126 Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Revolade Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and the sachet. This medicine does not require any special storage conditions. Do not open the foil sachets until ready for use. After mixing, Revolade oral suspension should be administered immediately, but may be stored for no more than 30 minutes at room temperature. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Revolade contains 25 mg powder for oral suspension The active substance in Revolade is eltrombopag. Each sachet contains a powder for reconstitution that delivers 32 mg eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid. The other ingredients are: mannitol, sucralose and xanthan gum. What Revolade looks like and contents of the pack Revolade 25 mg powder for oral suspension is available in kits containing 30 sachets; each sachet contains a reddish-brown to yellow powder. Each pack contains 30 sachets, one 40 ml reusable mixing bottle with lid and cap, and 30 single-use oral dosing syringes. Marketing authorisation holder Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Ireland Manufacturer Lek d.d Verovskova Ulica 57 Ljubljana 1526 Slovenia Novartis Pharma GmbH Roonstraße 25 D-90429 Nuremberg Germany 127 For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Lietuva SIA “Novartis Baltics” Lietuvos filialas Tel: +370 5 269 16 50 България Novartis Bulgaria EOOD Тел: +359 2 489 98 28 Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11 Česká republika Novartis s.r.o. Tel: +420 225 775 111 Magyarország Novartis Hungária Kft. Tel.: +36 1 457 65 00 Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00 Malta Novartis Pharma Services Inc. Tel: +356 2122 2872 Deutschland Novartis Pharma GmbH Tel: +49 911 273 0 Nederland Novartis Pharma B.V. Tel: +31 26 37 82 555 Eesti SIA Novartis Baltics Eesti filiaal Tel: +372 66 30 810 Norge Novartis Norge AS Tlf: +47 23 05 20 00 Ελλάδα Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 Österreich Novartis Pharma GmbH Tel: +43 1 86 6570 España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00 Polska Novartis Poland Sp. z o.o. Tel.: +48 22 375 4888 France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600 Hrvatska Novartis Hrvatska d.o.o. Tel. +385 1 6274 220 România Novartis Pharma Services Romania SRL Tel: +40 21 31299 01 Ireland Novartis Ireland Limited Tel: +353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel: +421 2 5542 5439 Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1 Suomi/Finland Novartis Finland Oy Puh/Tel: +358 (0)10 6133 200 128 Κύπρος Novartis Pharma Services Inc. Τηλ: +357 22 690 690 Sverige Novartis Sverige AB Tel: +46 8 732 32 00 Latvija SIA “Novartis Baltics” Tel: +371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370 This leaflet was last revised in. Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu./ 129 INSTRUCTIONS FOR USE Revolade 25 mg powder for oral suspension (eltrombopag) Read and follow these instructions to prepare a dose of Revolade and give it to the child. If you have any questions, or if you damage or lose any of the supplies in your kit, ask your doctor, nurse or pharmacist for advice Before you start Read these messages first  Revolade powder must be mixed only with water at room temperature. Give the medicine to the child immediately after you have mixed the powder with water. If you don’t use the medicine within 30 minutes of mixing it, you will need to mix a new dose. Dispose of the unused mixture in your household waste; don’t pour it down the drain.  Try not to let the medicine touch your skin. If this happens, wash the area immediately with soap and water. If you get a skin reaction, or if you have any questions, contact the doctor.  If you spill any powder or liquid, clean it up with a damp cloth (see step 14 of the instructions).  Take care that the child does not play with the bottle, cap, lid or syringes — there is a risk of choking if the child puts them in their mouth. What you need Each Revolade powder for oral suspension kit contains: 30 sachets of powder 1 reusable mixing bottle with lid and cap (note — the mixing bottle may become stained) 30 single-use oral dosing syringes To prepare and give a dose of Revolade, you need:  The correct number of sachets your doctor has prescribed (supplied in the kit)  1 reusable mixing bottle with lid and cap (supplied in the kit)  1 single-use oral dosing syringe (supplied in the kit)  1 clean glass or cup filled with drinking water (not supplied)  scissors to cut sachet (not supplied) Cap Lid Plunger Syringe tip 130 Make sure that the bottle, cap and lid are dry before you use them. To prepare the dose 1. Make sure the lid is not on the mixing bottle. 2. Fill the syringe with 20 ml drinking water from the glass or cup. A new single-use oral dosing syringe should be used to prepare each dose of Revolade for oral suspension.  Start with the plunger pushed all the way into the syringe.  Put the tip of the syringe all the way into the water  Pull back on the plunger to the 20 ml mark on the syringe. 3. Empty water into open mixing bottle  Slowly pushing the plunger all the way into the syringe. 4. Take only the prescribed number of sachets for one dose out of the kit.  25 mg dose — 1 sachet  50 mg dose — 2 sachets  75 mg dose — 3 sachets 5. Add the powder from the prescribed number of sachets to the bottle.  Tap the top of each sachet to make sure the contents fall to the bottom  Cut off the top of each sachet with scissors  Empty all contents of each sachet into the mixing bottle  Make sure not to spill the powder outside the mixing bottle. 6. Screw the lid onto the mixing bottle. Make sure the cap is firmly pushed onto the lid, so it is closed. 7. Gently and slowly shake the mixing bottle backwards and forwards for at least 20 seconds to mix the water with the powder.  Don’t shake the bottle hard — that could make the medicine foam. To give a dose to a child 8. Make sure the plunger is pushed all the way into the syringe.  Pull cap off the lid of the mixing bottle  Insert the syringe tip into the hole in the bottle lid. 9. Fill the syringe with the medicine.  Turn the mixing bottle upside-down together with the syringe.  Pull back the plunger until all the medicine is in the syringe.  The medicine is a dark brown liquid.  Remove the syringe from the bottle. 131 10. Give the medicine to the child. Do this straight away when you have mixed the dose.  Place the tip of the syringe into the inside of the child’s cheek.  Slowly push the plunger all the way down so the medicine goes into the child’s mouth. Make sure the child has time to swallow. IMPORTANT: You have now given the child nearly all of their dose of medicine. But there will still be some left in the bottle, even though you may not be able to see it. Now you need to complete steps 11 to 13 to make sure the child receives all of the medicine. 11. Again fill the syringe, this time with 10 ml of drinking water.  Start with the plunger pushed all the way down into the syringe.  Put the tip of the syringe all the way into the water  Pull back on the plunger to the 10 ml mark on the syringe. 12. Empty the water into the mixing bottle.  Insert the tip of the syringe into the hole in the lid of the mixing bottle.  Slowly push the plunger all the way into the syringe.  Push the cap firmly back on to the lid of the mixing bottle. 13. Repeat steps 7 to 10 – gently shake the bottle to mix the rest of the medicine, then give all the rest of the liquid to the child. To clean up 14. If you have spilt any powder or mixed medicine, clean it up with a damp disposable cloth. You may choose to wear disposable gloves so your skin doesn’t get stained.  Dispose of the cloth and gloves used to clean up the spillage in your household waste. 15. Clean the mixing equipment.  Throw away the used oral dosing syringe. A new oral dosing syringe should be used to prepare each dose of Revolade for oral suspension.  Rinse the mixing bottle and lid under running water. (The mixing bottle may become stained from the medicine. This is normal.)  Let all the equipment dry in the air.  Wash your hands with soap and water. After you have used all 30 sachets in the kit, dispose of the bottle. Always start with a complete new kit for each 30 sachets. Keep Revolade powder for oral suspension, including the dosing kit, and all medicines out of the reach of children. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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infections, if they have had problems with side effects while on interferon treatment. many people with hepatitis c have low platelet counts, not only as a result of the disease, but also due to some of the antiviral medicines that are used to treat it. taking revolade may make it easier for you to complete a full course of antiviral medicine (peginterferon and ribavirin). revolade may also be used to treat adult patients with low blood counts caused by severe aplastic anaemia (saa). saa is a disease in which the bone marrow is damaged, causing a deficiency of the red blood cells (anaemia), white blood cells (leukopenia) and platelets (thrombocytopenia).', 'Entity_Recognition': [{'Text': 'revolade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 18, 'EndOffset': 29, 'Score': 0.641822338104248, 'Text': 'eltrombopag', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a group of medicines', 'Type': 'TREATMENT', 'BeginOffset': 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{'Title': '2. what you need to know before you take revolade', 'Section_Content': "do not take revolade if you are allergic to eltrombopag or any of the other ingredients of this medicine (listed in section 6 under 'what revolade contains'). check with your doctor if you think this applies to you. warnings and precautions talk to your doctor before taking revolade: if you have liver problems. people who have low platelet counts as well as advanced chronic (long-term) liver disease are more at risk of side effects, including life-threatening liver damage and blood clots. if your doctor considers that the benefits of taking revolade outweigh the risks, you will be closely monitored during treatment. if you are at risk of blood clots in your veins or arteries, or you know that blood clots are common in your family. you may be at higher risk of blood clots: - as you get older - if you have had to stay in bed for a long time - if you have cancer - if you are taking the contraceptive birth control pill or hormone replacement therapy - if you have recently had surgery or received a physical injury - if you are very overweight (obese) - if you are a smoker - if you have advanced chronic liver disease if any of these apply to you, tell your doctor before starting treatment. you should not take revolade unless your doctor considers that the expected benefits outweigh the risk of blood clots. if you have cataracts (the lens of the eye getting cloudy) if you have another blood condition, such as myelodysplastic syndrome (mds). your doctor will carry out tests to check that you do not have this blood condition before you start revolade. if you have mds and take revolade, your mds may get worse. tell your doctor if any of these apply to you. eye examinations your doctor will recommend that you are checked for cataracts. if you do not have routine eye-tests your doctor should arrange regular testing. you may also be checked for the occurrence of any bleeding in or around your retina (the light-sensitive layer of cells at the back of the eye). you will need regular tests before you start taking revolade, your doctor will carry out blood tests to check your blood cells, including platelets. these tests will be repeated at intervals while you are taking it. blood tests for liver function revolade can cause blood test results that may be signs of liver damage - an increase of some liver enzymes, especially bilirubin and alanine / aspartate transaminases. if you are taking interferon-based treatments together with revolade to treat low platelet count due to hepatitis c, some liver problems can get worse. you will have blood tests to check your liver function before you start taking revolade and at intervals while you are taking it. you may need to stop taking revolade if the amount of these substances increases too much, or if you get other signs of liver damage. read the information 'liver problems' in section 4 of this leaflet. blood tests for platelet count if you stop taking revolade, your blood platelet count is likely to become low again within several days. the platelet count will be monitored, and your doctor will discuss appropriate precautions with you. a very high blood platelet count may increase the risk of blood clotting. however blood clots can also form with normal or even low platelet counts. your doctor will adjust your dose of revolade to ensure that your platelet count does not become too high. get medical help immediately if you have any of these signs of a blood clot: swelling, pain or tenderness in one leg sudden shortness of breath especially together with sharp pain in the chest or rapid breathing abdominal (stomach) pain, enlarged abdomen, blood in your stools tests to check your bone marrow in people who have problems with their bone marrow, medicines like revolade could make the problems worse. signs of bone marrow changes may show up as abnormal results in your blood tests. your doctor may also carry out tests to directly check your bone marrow during treatment with revolade. checks for digestive bleeding if you are taking interferon-based treatments together with revolade you will be monitored for any signs of bleeding in your stomach or intestine after you stop taking revolade. heart monitoring your doctor may consider it necessary to monitor your heart during treatment with revolade and carry out an electrocardiogram (ecg) test. older people (65 years and above) there are limited data on the use of revolade in patients aged 65 years and older. care should be taken when using revolade if you are aged 65 years or above. children and adolescents revolade is not recommended for children aged under 1 year who have itp. it is also not recommended for people under 18 years with low platelet counts due to hepatitis c or severe aplastic anaemia. other medicines and revolade tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. this includes medicines obtained without prescription and vitamins. some everyday medicines interact with revolade including prescription and non-prescription medicines and minerals. these include: antacid medicines to treat indigestion, heartburn or stomach ulcers (see also 'when to take it' in section 3) medicines called statins, to lower cholesterol some medicines to treat hiv infection, such as lopinavir and/or ritonavir ciclosporin used in the context of transplantations or immune diseases minerals such as iron, calcium, magnesium, aluminium, selenium and zinc which may be found in vitamin and mineral supplements (see also 'when to take it' in section 3) medicines such as methotrexate and topotecan, to treat cancer talk to your doctor if you take any of these. some of them are not to be taken with revolade, or the dose may need adjusting, or you may need to alter the timing of when you take them. your doctor will review the medicines you are taking, and suggest suitable replacements if necessary. if you are also taking medicines to prevent blood clots there is a greater risk of bleeding. your doctor will discuss this with you. if you are taking corticosteroids, danazol, and/or azathioprine you may need to take a lower dose or to stop taking them while you are taking revolade. revolade with food and drink do not take revolade with dairy foods or drinks as the calcium in dairy products affects the absorption of the medicine. for more information, see 'when to take it' in section 3. pregnancy and breast-feeding don't use revolade if you are pregnant unless your doctor specifically recommends it. the effect of revolade during pregnancy is not known. tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a baby. use a reliable method of contraception while you're taking revolade, to prevent pregnancy if you do become pregnant during treatment with revolade, tell your doctor. don't breast-feed while you are taking revolade. it is not known whether revolade 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{'Title': '3. how to take revolade', 'Section_Content': "always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. do not change the dose or schedule for taking revolade unless your doctor or pharmacist advises you to. while you are taking revolade, you will be under the care of a doctor with specialist experience in treating your condition. how much to take for itp adults and children (6 to 17 years) the usual starting dose for itp is one 50 mg tablet of revolade a day. if you are of asian origin (chinese, japanese, taiwanese, thai or korean) you may need to start at a lower dose of 25 mg. children (1 to 5 years) — the usual starting dose for itp is one 25 mg tablet of revolade a day. for hepatitis c adults - the usual starting dose for hepatitis c is one 25 mg tablet of revolade a day. if you are of asian origin (chinese, japanese, taiwanese, thai or korean) you will start on the same 25 mg dose. for saa adults - the usual starting dose for saa is one 50 mg tablet of revolade a day. if you are of asian origin (chinese, japanese, taiwanese, thai or korean) you may need to start at a lower dose of 25 mg. revolade may take 1 to 2 weeks to work. based on your response to revolade your doctor may recommend that your daily dose is changed. how to take the tablets swallow the tablet whole, with some water. when to take it make sure that in the 4 hours before you take revolade and the 2 hours after you take revolade you don't consume any of the following: dairy foods such as cheese, butter, yoghurt or ice cream milk or milk shakes, drinks containing milk, yoghurt or cream antacids, a type of medicine for indigestion and heartburn some mineral and vitamin supplements including iron, calcium, magnesium, aluminium, selenium and zinc if you do, the medicine will not be properly absorbed into your body. for more advice about suitable foods and drinks, talk to your doctor. if you take more revolade than you 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supply to spleen (splenic infarction', 'Type': 'PROBLEM', 'BeginOffset': 11842, 'EndOffset': 11884}, {'Text': 'runny nose common side effects', 'Type': 'PROBLEM', 'BeginOffset': 11886, 'EndOffset': 11916}, {'Text': 'the blood tests', 'Type': 'TEST', 'BeginOffset': 11937, 'EndOffset': 11952}, {'Text': 'enzymes', 'Type': 'TEST', 'BeginOffset': 11965, 'EndOffset': 11972}, {'Id': 713, 'BeginOffset': 11980, 'EndOffset': 11996, 'Score': 0.6043890118598938, 'Text': 'muscle breakdown', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.759867250919342}]}, {'Text': 'creatine phosphokinase) accumulation of iron in the body', 'Type': 'PROBLEM', 'BeginOffset': 11998, 'EndOffset': 12054}, {'Id': 716, 'BeginOffset': 12056, 'EndOffset': 12069, 'Score': 0.8696306943893433, 'Text': 'iron overload', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4237353801727295}]}, {'Id': 717, 'BeginOffset': 12071, 'EndOffset': 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{'Title': '5. how to store revolade', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and the blister. this medicine does not require any special storage conditions. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what revolade contains the active substance in revolade is eltrombopag. 12.5 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. 25 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. 50 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag. 75 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag. the other ingredients are: hypromellose, macrogol 400, magnesium stearate, mannitol (e421), microcrystalline cellulose, povidone, sodium starch glycolate, titanium dioxide (e171). revolade 12.5 mg and 25 mg film-coated tablets also contain polysorbate 80 (e433). revolade 50 mg film-coated tablets also contain iron oxide red (e172) and iron oxide yellow (e172). revolade 75 mg film-coated tablets also contain iron oxide red (e172) and iron oxide black (e172). what revolade looks like and contents of the pack revolade 12.5 mg film-coated tablets are round, biconvex, white, debossed with 'gs mz1' and '12.5' on one side. revolade 25 mg film-coated tablets are round, biconvex, white, debossed with 'gs nx3' and '25' on one side. revolade 50 mg film-coated tablets are round, biconvex, brown, debossed with 'gs ufu' and '50' on one side. revolade 75 mg film-coated tablets are round, biconvex, pink, debossed with 'gs ffs' and '75' on one side. they are supplied in aluminum blisters in a carton containing 14 or 28 film-coated tablets and multipacks containg 84 (3 packs of 28) film-coated tablets). not all pack sizes may be available in your country.", 'Entity_Recognition': [{'Text': 'revolade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 59, 'EndOffset': 70, 'Score': 0.7694530487060547, 'Text': 'eltrombopag', 'Category': 'MEDICATION', 'Type': 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D88405464CAD9C406AE56D99F2ACED75

https://www.ema.europa.eu/documents/product-information/kovaltry-epar-product-information_en.pdf

Kovaltry

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 250 IU powder and solvent for solution for injection Kovaltry 500 IU powder and solvent for solution for injection Kovaltry 1000 IU powder and solvent for solution for injection Kovaltry 2000 IU powder and solvent for solution for injection Kovaltry 3000 IU powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Kovaltry 250 IU powder and solvent for solution for injection Kovaltry contains approximately 250 IU (100 IU / 1 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution. Kovaltry 500 IU powder and solvent for solution for injection Kovaltry contains approximately 500 IU (200 IU / 1 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution. Kovaltry 1000 IU powder and solvent for solution for injection Kovaltry contains approximately 1000 IU (400 IU / 1 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution. Kovaltry 2000 IU powder and solvent for solution for injection Kovaltry contains approximately 2000 IU (400 IU / 1 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution. Kovaltry 3000 IU powder and solvent for solution for injection Kovaltry contains approximately 3000 IU (600 IU / 1 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution. The potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of Kovaltry is approximately 4000 IU/mg protein. Octocog alfa (Full length recombinant human coagulation factor VIII (rDNA)) is a purified protein that has 2,332 amino acids. It is produced by recombinant DNA technology in baby hamster kidney cells (BHK) into which the human factor VIII gene has been introduced. Kovaltry is prepared without the addition of any human or animal derived protein in the cell culture process, purification or final formulation. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection Powder: solid, white to slightly yellow. Solvent: water for injections, a clear solution. 3 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). Kovaltry can be used for all age groups. 4.2 Posology and method of administration Treatment should be under the supervision of a physician experienced in the treatment of haemophilia. Treatment monitoring During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. Posology The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition. The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one mL of normal human plasma. On demand treatment The calculation of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2.5% of normal activity. The required dose is determined using the following formula: Required units = body weight (kg) x desired factor VIII rise (% or IU/dL) x reciprocal of observed recovery (i.e. 0.5 for recovery of 2.0%). The amount to be administered and the frequency of administration should always be targeted to the clinical effectiveness required in the individual case. In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given level (in % of normal) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery: 4 Table 1: Guide for dosing in bleeding episodes and surgery Degree of haemorrhage/ Type of surgical procedure Factor VIII level required (%) (IU/dL) Frequency of doses (hours)/ Duration of therapy (days) Haemorrhage Early haemarthrosis, muscle bleeding or oral bleeding 20 - 40 Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved. More extensive haemarthrosis, muscle bleeding or haematoma 30 - 60 Repeat infusion every 12 - 24 hours for 3 - 4 days or more until pain and acute disability are resolved. Life threatening haemorrhages 60 - 100 Repeat infusion every 8 to 24 hours until threat is resolved Surgery Minor surgery including tooth extraction 30 - 60 Every 24 hours, at least 1 day, until healing is achieved. Major surgery 80 - 100 (pre- and post- operative) Repeat infusion every 8 - 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dL). Prophylaxis For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses for adolescents (≥ 12 years age) and adult patients are 20 to 40 IU of Kovaltry per kg body weight two to three times per week. In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary. Paediatric population A safety and efficacy study has been performed in children of 012 years (see section 5.1); limited data are available for children below 1 year. The recommended prophylaxis doses are 20-50 IU/kg twice weekly, three times weekly or every other day according to individual requirements. For paediatric patients above the age of 12, the dose recommendations are the same as for adults. Method of administration Intravenous use. Kovaltry should be injected intravenously over 2 to 5 minutes depending on the total volume. The rate of administration should be determined by the patient’s comfort level (maximal rate of infusion: 2 mL/min). For instructions on reconstitution of the medicinal product before administration, see section 6.6 and the package leaflet. 4.3 Contraindications  Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Known allergic reactions to mouse or hamster proteins. 4.4 Special warnings and precautions for use Traceability In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. 5 Hypersensitivity Allergic type hypersensitivity reactions are possible with Kovaltry. If symptoms of hypersensitivity occur, patients should be advised to discontinue the use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. In case of shock, standard medical treatment for shock should be implemented. Inhibitors The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII , this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon. The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors. In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests (see section 4.2). If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors. Cardiovascular events In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk. Catheter-related complications If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered. It is strongly recommended that every time that Kovaltry is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product. Paediatric population The listed warnings and precautions apply both to adults and children. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’. 6 4.5 Interactions with other medicinal products and other forms of interaction No interactions of human coagulation factor VIII (rDNA) products with other medicinal products have been reported. 4.6 Fertility, pregnancy and lactation Pregnancy Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy is not available. Therefore, factor VIII should be used during pregnancy only if clearly indicated. Breast-feeding It is unknown whether Kovaltry is excreted in human milk. The excretion in animals has not been studied. Therefore, factor VIII should be used during breast-feeding only if clearly indicated. Fertility No animal fertility studies have been conducted with Kovaltry and its effect on human fertility has not been established in controlled clinical trials. Since Kovaltry is a replacement protein of endogenous factor VIII, no adverse effects on fertility are expected. 4.7 Effects on ability to drive or use machines If patients experience dizziness or other symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the reaction subsides. 4.8 Undesirable effects Summary of the safety profile Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed and may in some cases progress to severe anaphylaxis (including shock). Development of antibodies to mouse and hamster protein with related hypersensitivity reactions may occur. Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII (FVIII), including with Kovaltry. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. Tabulated list of adverse reactions The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) , rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 7 Table 2: Frequency of adverse drug reactions in clinical trials MedDRA System Organ Class Adverse reactions Frequency Blood and lymphatic system disorders Lymphadenopathy common FVIII inhibition very common (PUPs)* uncommon (PTPs)* Immune system disorders Hypersensitivity uncommon Psychiatric disorders Insomnia common Nervous system disorders Headache, dizziness common Dysgeusia uncommon Cardiac disorders Palpitation, sinus tachycardia common Vascular disorders Flushing uncommon Gastrointestinal disorders Abdominal pain, abdominal discomfort, dyspepsia common Skin and subcutaneous tissue disorders Pruritus, rash***, dermatitis allergic common Urticaria uncommon General disorders and administration site conditions Pyrexia, chest discomfort, injection site reactions ** common * Frequency is based on studies with all FVIII products which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients ** includes injection site extravasation, hematoma, infusion site pain, pruritus, swelling *** rash, rash erythematous, rash pruritic Description of selected adverse reactions The most frequently reported adverse reactions in PTPs were related to potential hypersensitivity reactions, including headache, pyrexia, pruritus, rash, and abdominal discomfort. Immunogenicity The immunogenicity of Kovaltry was evaluated in previously treated patients (PTPs). During clinical trials with Kovaltry in approximately 200 pediatric and adult patients diagnosed with severe hemophilia A (FVIII:C < 1%) with previous exposure to factor VIII concentrates ≥ 50 ED, one case of transient low titer inhibitor occurred in the ongoing LEOPOLD Kids Part A extension study. Paediatric population In completed clinical studies with 71 paediatric previously treated patients, the frequency, type and severity of adverse reactions in children were found to be similar to those in adults. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose No symptoms of overdose with recombinant human coagulation factor VIII have been reported. 8 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02. Mechanism of action The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and vWF) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to vWF in the patient’s circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies. Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies. Kovaltry does not contain von Willebrand factor. Pharmacodynamic effects The activated partial thromboplastin time (aPTT) is prolonged in people with haemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with rFVIII normalizes the aPTT similar to that achieved with plasma-derived factor VIII. Clinical efficacy and safety Control and Prevention of Bleeding Two multi-centre, open-label, cross-over, uncontrolled, randomised studies in previously treated adults/adolescents with severe haemophilia A (< 1%) and one multi-centre, open-label, uncontrolled study in previously treated children < 12 years with severe haemophilia A were conducted. A total of 204 subjects have been included in the clinical trial program, 153 subjects ≥ 12 years and 51 subjects < 12 years. 140 subjects were treated for at least 12 months, and 55 of these subjects for a median of 24 months. Paediatric population <12 years The paediatric trial enrolled 51 PTPs with severe haemophilia A, 26 subjects in the age group 6- 12 years and 25 subjects in the age group <6 years having accumulated a median number of 73 EDs (range: 37 to 103 EDs). Subjects were treated with 2 or 3 injections per week or up to every other day at a dose of 25 to 50 IU/kg. Consumption for prophylaxis and treatment of bleeds, annualised bleed rates and success rate for bleed treatment are presented in Table 3 9 Table 3: Consumption and overall success rates (patients treated with prophylaxis only) Younger children (0 <6 years) Older children (6 <12 years) Adolescents and adults 12-65 years Total Study 1 Study 2 2 x/week dosing Study 2 3 x/week dosing Study participants 25 26 62 28 31 172 Dose/prophylaxis injection, IU/kg BW median (min, max) 36 IU/kg (21; 58 IU/kg) 32 IU/kg (22; 50 IU/kg) 31 IU/kg (21; 43 IU/kg) 30 IU/kg (21; 34 IU/kg) 37 IU/kg (30; 42 IU/kg) 32 IU/kg (21; 58 IU/kg) ABR – all bleeds (median, Q1,Q3) 2.0 (0.0; 6.0) 0.9 (0.0; 5.8) 1.0 (0.0; 5.1) 4.0 (0.0; 8.0) 2.0 (0.0; 4.9) 2.0 (0.0; 6.1) Dose/injection for bleed treatment Median (min; max) 39 IU/kg (21;72 IU /kg) 32 IU/kg (22; 50 IU/kg) 29 IU/kg (13; 54 IU/kg) 28 IU/kg (19; 39 IU/kg) 31 IU/kg (21; 49 IU/kg) 31 IU/kg (13; 72 IU/kg) Success rate* 92.4% 86.7% 86.3% 95.0% 97.7% 91.4% ABR annualised bleed rate Q1 first quartile; Q3 third quartile BW: Body weight *Success rate defined as % of bleeds treated successfully with ≤ 2 infusions 5.2 Pharmacokinetic properties The pharmacokinetic (PK) profile of Kovaltry was evaluated in PTPs with severe haemophilia A following 50 IU/kg in 21 subjects ≥ 18 years, 5 subjects ≥ 12 years and < 18 years and 19 subjects < 12 years of age. A population PK model was developed based on all available factor VIII measurements (from dense PK sampling and all recovery samples) throughout the 3 clinical studies allowing calculation of PK parameters for subjects in the various studies. The table 4 below provides PK parameters based on the population PK model. 10 Table 4: PK parameters (geometric mean (%CV)) based on chromogenic assay. * PK parameter ≥ 18 years N=109 12-<18 years N=23 6-<12 years N=27 0-<6 years N=24 T1/2 (h) 14.8 (34) 13.3 (24) 14.1 (31) 13.3 (24) AUC (IU.h/dL)** 1,858 (38) 1,523 (27) 1,242 (35) 970 (25) CL (dL/h/kg) 0.03 (38) 0.03 (27) 0.04 (35) 0.05 (25) Vss (dL/kg) 0.56 (14) 0.61 (14) 0.77 (15) 0.92 (11) * Based on population PK estimates **AUC calculated for a dose of 50 IU/kg Repeated PK measurements after 6 to 12 months of prophylaxis treatment with Kovaltry did not indicate any relevant changes in PK characteristics after long-term treatment. In an international study involving 41 clinical laboratories, the performance of Kovaltry in FVIII:C assays was evaluated and compared to a marketed full length rFVIII product. Consistent results were determined for both products. The FVIII:C of Kovaltry can be measured in plasma with a one-stage coagulation assay as well as with a chromogenic assay using the routine methods of the laboratory. The analysis of all recorded incremental recoveries in previously treated patients demonstrated a median rise of > 2% (> 2 IU/dL) per IU/kg body weight for Kovaltry. This result is similar to the reported values for factor VIII derived from human plasma. There was no relevant change over the 6-12 months treatment period. Table 5: Phase III incremental recovery results Study participants N=115 Chromogenic assay results Median; (Q1; Q3) (IU/dL / IU/kg) 2.3 (1.8; 2.6) One-stage assay results Median; (Q1; Q3) (IU/dL / IU/kg) 2.2 (1.8; 2.4) 5.3 Preclinical safety data Non-clinical data reveal no special risk for humans based on safety pharmacology, in vitro genotoxicity, and short term repeat-dose toxicity studies. Repeat-dose toxicity studies longer than 5 days, reproductive toxicity studies, and carcinogenicity studies, have not been performed. Such studies are not considered meaningful due to the production of antibodies against the heterologous human protein in animals. Also factor VIII is an intrinsic protein and not known to cause any reproductive or carcinogenic effects. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder Sucrose Histidine Glycine (E 640) Sodium chloride Calcium chloride dihydrate (E 509) Polysorbate 80 (E 433) Acetic acid, glacial (for pH adjustment) (E 260) Solvent Water for injections 11 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Only the provided infusion sets should be used for reconstitution and injection because treatment failure can occur as a consequence of human recombinant coagulation factor VIII adsorption to the internal surfaces of some infusion equipment. 6.3 Shelf life 30 months The chemical and physical in-use stability after reconstitution has been demonstrated for 3 hours at room temperature. After reconstitution, from a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user. Do not refrigerate after reconstitution. 6.4 Special precautions for storage Store in a refrigerator (2 °C - 8 °C). Do not freeze. Keep the vial and the pre filled syringe in the outer carton in order to protect from light. Within its overall shelf life of 30 months the product when kept in its outer carton, may be stored up to 25 °C for a limited period of 12 months. In this case, the product expires at the end of this 12 month period or the expiry date on the product vial, whichever is earlier. The new expiry date must be noted on the outer carton. For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container and special equipment for use, administration or implantation Each single package of Kovaltry contains: • one vial with powder (10 mL clear glass type 1 vial with grey halogenobutyl rubber blend stopper and aluminium seal) • one pre-filled syringe with 2.5 mL (for 250 IU, 500 IU and 1000 IU) or 5 mL (for 2000 IU and 3000 IU) solvent (clear glass cylinder type 1 with grey bromobutyl rubber blend stopper) • syringe plunger rod • vial adapter • one venipuncture set Pack sizes  1 single pack.  1 multipack with 30 single packs.  Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Detailed instructions for preparation and administration are contained in the package leaflet provided with Kovaltry. The reconstituted medicinal product is a clear and colourless solution. 12 Kovaltry powder should only be reconstituted with the supplied solvent (2.5 mL or 5 mL water for injections) in the prefilled syringe and the vial adapter. For infusion, the product must be prepared under aseptic conditions. If any component of the package is opened or damaged, do not use this component. After reconstitution the solution is clear. Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration. Do not use Kovaltry if you notice visible particulate matter or turbidity. After reconstitution, the solution is drawn back into the syringe. Kovaltry should be reconstituted and administered with the components (vial adapter, prefilled syringe, venipuncture set) provided with each package. The reconstituted product must be filtered prior to administration to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter. The venipuncture set provided with the product must not be used for drawing blood because it contains an in line filter. For single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 8. MARKETING AUTHORISATION NUMBERS EU/1/15/1076/002 1 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/012 - 1 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/004 - 1 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/014 - 1 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/006 - 1 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/016 - 1 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/008 - 1 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/010 - 1 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/017 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/018 - 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/019 - 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/020 - 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/021 - 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/022 - 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/023 - 30 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) EU/1/15/1076/024 - 30 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 18 February 2016 Date of latest renewal: 13 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 14 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 15 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Bayer HealthCare LLC 800 Dwight Way Berkeley CA 94710 United States Name and address of the manufacturer responsible for batch release Bayer AG Kaiser-Wilhelm-Allee 51368 Leverkusen Germany B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 16  Obligation to conduct post-authorisation measures The MAH shall complete, within the stated timeframe, the below measures: Description Due date Post-authorisation Efficacy Study: In order to investigate the safety and efficacy of Kovaltry in previously untreated patients, the MAH should submit the results of the ongoing study “13400 - Leopold Kids Part B” 12/2022 Post-authorisation Efficacy Study: In order to investigate the safety and efficacy of long term treatment with Kovaltry, the MAH should submit the results of the ongoing study “13400 - Leopold Kids extension” 12/2022 17 ANNEX III LABELLING AND PACKAGE LEAFLET 18 A. LABELLING 19 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 250 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 250 IU (100 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 20 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/002 – 1 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/012 – 1 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 21 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 250 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 22 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 250 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 250 IU (100 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Multipack with 30 single packs, each containing: 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. 23 May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/017 – 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/018 – 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 250 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 24 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 25 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 250 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 250 IU (100 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Component of a multipack, can’t be sold separately. 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 26 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/017 – 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/018 – 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 27 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 250 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 28 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL WITH POWDER FOR SOLUTION FOR INJECTION 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Kovaltry 250 IU powder for solution for injection octocog alfa (recombinant human coagulation factor VIII) Intravenous use. 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 250 IU (octocog alfa) (100 IU/mL after reconstitution). 6. OTHER Bayer-Logo 29 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 500 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 500 IU (200 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 30 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/004 – 1 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/014 – 1 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 31 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 500 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 32 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 500 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 500 IU (200 IU / 1 mL)octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Multipack with 30 single packs, each containing: 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. 33 May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/019 – 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/020 – 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 500 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 34 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 35 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 500 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 500 IU (200 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Component of a multipack, can’t be sold separately. 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 36 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/019 – 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/020 – 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 37 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 500 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 38 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL WITH POWDER FOR SOLUTION FOR INJECTION 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Kovaltry 500 IU powder for solution for injection octocog alfa (recombinant human coagulation factor VIII) Intravenous use. 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 500 IU (octocog alfa) (200 IU/mL after reconstitution). 6. OTHER Bayer-Logo 39 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 1000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 1000 IU (400 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 40 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/006 – 1 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/016 – 1 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 41 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 1000 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 42 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 1000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 1000 IU (400 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Multipack with 30 single packs, each containing: 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. 43 May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/021 – 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/022 – 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 1000 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 44 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 45 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 1000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 1000 IU (400 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Component of a multipack, can’t be sold separately. 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 46 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/021 – 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) EU/1/15/1076/022 – 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 47 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 1000 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 48 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL WITH POWDER FOR SOLUTION FOR INJECTION 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Kovaltry 1000 IU powder for solution for injection octocog alfa (recombinant human coagulation factor VIII) Intravenous use. 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1000 IU (octocog alfa) (400 IU/mL after reconstitution). 6. OTHER Bayer-Logo 49 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 2000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 2000 IU (400 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 50 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/008 – 1 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 51 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 2000 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 52 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 2000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 2000 IU (400 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Multipack with 30 single packs, each containing: 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. 53 May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/023 – 30 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 2000 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 54 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 55 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 2000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 2000 IU (400 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Component of a multipack, can’t be sold separately. 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 56 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/023 – 30 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 57 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 2000 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 58 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL WITH POWDER FOR SOLUTION FOR INJECTION 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Kovaltry 2000 IU powder for solution for injection octocog alfa (recombinant human coagulation factor VIII) Intravenous use. 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2000 IU (octocog alfa) (400 IU/mL after reconstitution). 6. OTHER Bayer-Logo 59 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 3000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 3000 IU (600 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 60 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/010 – 1 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 61 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 3000 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 62 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 3000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 3000 IU (600 IU / 1 mL)octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Multipack with 30 single packs, each containing: 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. 63 May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/024 – 30 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 3000 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 64 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 65 PARTICULARS TO APPEAR ON THE OUTER PACKAGING INNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) 1. NAME OF THE MEDICINAL PRODUCT Kovaltry 3000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Kovaltry contains 3000 IU (600 IU / 1 mL) octocog alfa after reconstitution. 3. LIST OF EXCIPIENTS Sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS powder and solvent for solution for injection Component of a multipack, can’t be sold separately. 1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture set. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use. Single dose administration only. Read the package leaflet before use. For reconstitution read package leaflet before use. 66 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP EXP (End of the 12 month period, if stored up to 25 °C): ................ Do not use after this date. May be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused solution must be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Bayer AG 51368 Leverkusen Germany 12. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1076/024 – 30 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 67 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Kovaltry 3000 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 68 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL WITH POWDER FOR SOLUTION FOR INJECTION 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Kovaltry 3000 IU powder for solution for injection octocog alfa (recombinant human coagulation factor VIII) Intravenous use. 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 3000 IU (octocog alfa) (600 IU/mL after reconstitution). 6. OTHER Bayer-Logo 69 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED SYRINGE WITH WATER FOR INJECTIONS 1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF ADMINISTRATION water for injections 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2.5 mL [for reconstitution of strengths 250/500/1000 IU] 6. OTHER 70 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PRE-FILLED SYRINGE WITH WATER FOR INJECTIONS 1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF ADMINISTRATION water for injections 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 5 mL [for reconstitution of strengths 2000/3000 IU] 6. OTHER 71 B. PACKAGE LEAFLET 72 Package Leaflet: Information for the user Kovaltry 250 IU powder and solvent for solution for injection Kovaltry 500 IU powder and solvent for solution for injection Kovaltry 1000 IU powder and solvent for solution for injection Kovaltry 2000 IU powder and solvent for solution for injection Kovaltry 3000 IU powder and solvent for solution for injection octocog alfa (recombinant human coagulation factor VIII) Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Kovaltry is and what it is used for 2. What you need to know before you use Kovaltry 3. How to use Kovaltry 4. Possible side effects 5. How to store Kovaltry 6. Contents of the pack and other information 1. What Kovaltry is and what it is used for Kovaltry contains the active substance human recombinant coagulation factor VIII, also called octocog alfa. Kovaltry is prepared by recombinant technology without addition of any human- or animal derived components in the manufacturing process. Factor VIII is a protein naturally found in the blood that helps to clot it. Kovaltry is used to treat and prevent bleeding in adults, adolescents and children of all ages with haemophilia A (hereditary factor VIII deficiency). 2. What you need to know before you use Kovaltry Do not use Kovaltry if you are  allergic to octocog alfa or to any of the other ingredients of this medicine (listed in section 6).  allergic to mouse or hamster proteins. Warnings and precautions Talk to your doctor or pharmacist if you have:  tightness in the chest, dizziness (including when you get up from sitting or lying down), itchy nettle-rash, wheezing, feeling sick or faint. These may be signs of a rare severe sudden allergic reaction to Kovaltry. Stop administering the product immediately and seek medical advice if this occurs.  bleeding that is not being controlled with your usual dose of Kovaltry. The formation of inhibitors (antibodies) is a known complication that can occur during treatment with all Factor VIII medicines. These inhibitors, especially at high levels, stop the treatment working properly, patients receiving Kovaltry will be monitored carefully for the development of these 73 inhibitors. If your or your child’s bleeding is not being controlled with Kovaltry, tell your doctor immediately.  previously developed factor VIII inhibitors to a different product. If you switch factor VIII products, you may be at risk of your inhibitor coming back.  a confirmed heart disease or are at risk of heart disease.  to use a central venous access device for the administration of Kovaltry. You may be at risk of device related complications where the catheter is inserted including: - local infections - bacteria in the blood - a blood clot in the blood vessel. Children and adolescents The listed warnings and precautions apply to patients of all ages, adults and children. Other medicines and Kovaltry Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine. Kovaltry is not likely to affect the fertility in male or female patients, as the active substance is naturally occurring in the body. Driving and using machines If you experience dizziness or any other symptoms affecting your ability to concentrate and react, do not drive or use machines until the reaction subsides. Kovaltry contains sodium This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium- free’. 3. How to use Kovaltry Treatment with Kovaltry will be started by a doctor who is experienced in the care of patients with haemophilia A. Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. The number of factor VIII units is expressed in International Units (IU). Treatment of bleeding To treat a bleed, your doctor will calculate and adjust your dose and how often it should be given, depending on factors such as:  your weight  the severity of your haemophilia A  where the bleed is and how serious it is  whether you have inhibitors and how high their level is  the factor VIII level that is needed. Prevention of bleeding If you are using Kovaltry to prevent bleeding, your doctor will calculate the dose for you. This will usually be in the range of 20 to 40 IU of octocog alfa per kg of body weight, injected two or three times per week. However, in some cases, especially for younger patients, shorter dose intervals or higher doses may be necessary. 74 Laboratory tests Laboratory tests at suitable intervals help to ensure you always have adequate factor VIII levels. For major surgery in particular, your blood clotting must be closely monitored. Use in children and adolescents Kovaltry can be used in children of all ages. In children below the age of 12 higher doses or more frequent injections than prescribed for adults may be needed. Patients with inhibitors If you have been told by your doctor that you have developed factor VIII inhibitors you may need to use a larger dose of Kovaltry to control bleeding. If this dose does not control your bleeding your doctor may consider giving you another product. Speak to your doctor if you would like further information on this. Do not increase the dose of Kovaltry to control your bleeding without checking with your doctor. Duration of treatment Usually, Kovaltry treatment for haemophilia is needed life-long. How Kovaltry is given Kovaltry is injected into a vein over 2 to 5 minutes depending on the total volume and your comfort level and should be used within 3 hours after reconstitution. How Kovaltry is prepared for administration Use only the components (vial adapter, pre filled syringe containing solvent and venipuncture set) provided with each package of this medicine. Please contact your doctor if these components cannot be used. Do not use if any component of the package is opened or damaged. The reconstituted product must be filtered by using the vial adapter before administration to remove any possible particles in the solution. Do not use the venipuncture set provided for drawing blood because it contains an in-line filter. This medicine must not be mixed with other infusion solutions. Do not use solutions containing visible particles or that are cloudy. Follow the instructions for use given by your doctor and provided at the end of this leaflet. If you use more Kovaltry than you should Tell your doctor if this occurs. No cases of overdose have been reported. If you forget to use Kovaltry Administer your next dose immediately and continue at regular intervals as advised by your doctor. Do not use a double dose to make up for a forgotten dose. If you stop using Kovaltry Do not stop using this medicine without checking with your doctor. If you have any further questions on the use of this medicine, ask your doctor. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. 75 The most serious side effects are allergic reactions which may be severe allergic reaction. Stop injecting Kovaltry immediately and speak to your doctor at once if such reactions occur. The following symptoms could be an early warning of these reactions:  chest tightness/general feeling of being unwell  dizziness  feeling faint upon standing indicating a reduction in blood pressure  feeling sick (nausea) For children not previously treated with factor VIII medicines, inhibitor antibodies (see section 2) may form very commonly (more than 1 in 10 patients). For patients who have received previous treatment with factor VIII (more than 150 days of treatment) inhibitor antibodies (see section 2) may form uncommonly (less than 1 in 100 patients). If this happens your medicine may stop working properly and you may experience persistent bleeding. If this happens, please contact your doctor immediately. Other possible side effects: Common (may affect up to 1 in 10 users):  lymph nodes enlarged (swelling under the skin of the neck, armpit or groin)  heart palpitations (feeling your heart beating hard, rapidly, or irregularly)  rapid heartbeat  stomach pain or discomfort  indigestion  fever  local reactions where you injected the medicine (e.g. bleeding under the skin, intense itching, swelling, burning sensation, temporary redness)  headache  trouble sleeping  rash/itchy rash Uncommon (may affect up to 1 in 100 users):  dysgeusia (strange taste)  urticaria (itchy rash)  flushing (redness of the face) Reporting of side effects If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Kovaltry Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on labels and cartons. The expiry date refers to the last day of that month. Store in a refrigerator (2 °C – 8 °C). Do not freeze. Store this medicine in the original package in order to protect from light. This medicine may be stored at room temperature (up to 25 °C) for up to 12 months when you keep it in its outer carton. If you store it at room temperature it expires after 12 months or at the expiry date if this is earlier. The new expiry date must be noted on the outer carton when the medicine is removed from the refrigerator. 76 Do not refrigerate the solution after reconstitution. The reconstituted solution must be used within 3 hours. This product is for single use only. Any unused solution must be discarded. Do not use this medicine if you notice any particles in the solution or if the solution is cloudy. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Kovaltry contains The active substance is octocog alfa (human coagulation factor VIII). Each vial of Kovaltry contains nominally 250, 500, 1000, 2000 or 3000 IU octocog alfa. The other ingredients are sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. What Kovaltry looks like and contents of the pack Kovaltry is provided as a powder and solvent for solution for injection. The powder is dry and white to slightly yellow . The solvent is a clear liquid. Each single pack of Kovaltry contains  a glass vial with powder  a pre filled syringe with solvent  a separate plunger rod  a vial adapter  a venipuncture set (for injection into a vein). Kovaltry is available in pack sizes of:  1 single pack  1 multipack with 30 single packs Not all pack sizes may be marketed. Marketing Authorisation Holder Bayer AG 51368 Leverkusen Germany Manufacturer Bayer AG Kaiser-Wilhelm-Allee 51368 Leverkusen Germany 77 For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Bayer SA-NV Tél/Tel: +32-(0)2-535 63 11 Lietuva UAB Bayer Tel. +37 05 23 36 868 България Байер България ЕООД Tел.: +359-(0)2-424 72 80 Luxembourg/Luxemburg Bayer SA-NV Tél/Tel: +32-(0)2-535 63 11 Česká republika Bayer s.r.o. Tel: +420 266 101 111 Magyarország Bayer Hungária KFT Tel:+36 14 87-41 00 Danmark Bayer A/S Tlf: +45 45 23 50 00 Malta Alfred Gera and Sons Ltd. Tel: +35 621 44 62 05 Deutschland Bayer Vital GmbH Tel: +49 (0)214-30 513 48 Nederland Bayer B.V. Tel: +31-(0)297-28 06 66 Eesti Bayer OÜ Tel: +372 655 8565 Norge Bayer AS Tlf: +47 23 13 05 00 Ελλάδα Bayer Ελλάς ΑΒΕΕ Τηλ: +30-210-61 87 500 Österreich Bayer Austria Ges.m.b.H. Tel: +43-(0)1-711 46-0 España Bayer Hispania S.L. Tel: +34-93-495 65 00 Polska Bayer Sp. z o.o. Tel: +48 22 572 35 00 France Bayer HealthCare Tél (N° vert): +33-(0)800 87 54 54 Portugal Bayer Portugal, Lda. Tel: +351 21 416 42 00 Hrvatska Bayer d.o.o. Tel: +385-(0)1-6599 900 România SC Bayer SRL Tel: +40 21 529 59 00 Ireland Bayer Limited Tel: +353 1 216 3300 Slovenija Bayer d. o. o. Tel: +386 (0)1 58 14 400 Ísland Icepharma hf. Sími: +354 540 8000 Slovenská republika Bayer spol. s r.o. Tel. +421 2 59 21 31 11 Italia Bayer S.p.A. Tel: +39 02 397 81 Suomi/Finland Bayer Oy Puh/Tel: +358- 20 785 21 Κύπρος NOVAGEM Limited Tηλ: +357 22 48 38 58 Sverige Bayer AB Tel: +46 (0) 8 580 223 00 Latvija SIA Bayer Tel: +371 67 84 55 63 United Kingdom Bayer plc Tel: +44-(0)118 206 3000 This leaflet was last revised in Detailed information on this medicine is available on the website of the European Medicines Agency http://www.ema.europa.eu ------------------------------------------------------------------------------------------------------------------------- 78 Detailed instructions for reconstitution and administration of Kovaltry You will need alcohol swabs, gauze pads, plasters and tourniquet. These items are not included in the Kovaltry package. 1. Wash your hands thoroughly using soap and warm water. 2. Hold an unopened vial and also a syringe in your hands to warm it to a comfortable temperature (do not exceed 37 °C). 3. Remove the protective cap from the vial (A).Wipe the rubber stopper on the vial with an alcohol swab and allow the stopper to air dry before use. 4. Place the powder vial on a firm, non slip surface. Peel off the paper cover on the plastic housing of the vial adapter. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the powder vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this point. 5. Hold the pre filled syringe with solvent upright. Grasp the plunger rod as per the picture and attach the rod by turning it firmly clockwise into the threaded stopper (C). 6. Holding the syringe by the barrel, snap the syringe cap off the tip (D). Do not touch the syringe tip with your hand or any surface. Set the syringe aside for further use. 7. Now remove and discard the adapter housing (E). 8. Attach the pre filled syringe to the threaded vial adapter by turning clockwise (F). 9. Inject the solvent by slowly pushing down on the plunger rod (G). 10. Swirl vial gently until all the powder is dissolved (H). Do not shake vial. Be sure that the powder is completely dissolved. Look to check there are no particles or discoloration before you use the solution. Do not use solutions containing visible particles or that are cloudy. 79 11. Hold the vial on the end above the vial adapter and syringe (I). Fill the syringe by drawing the plunger out slowly and smoothly. Ensure that the full content of the vial is drawn into the syringe. Hold the syringe upright and push the plunger until no air is left in the syringe. 12. Apply a tourniquet to your arm. 13. Determine the point of injection and clean the skin with an alcohol swab. 14. Puncture the vein and secure the venipuncture set with a plaster. 15. Holding the vial adapter in place, remove the syringe from the vial adapter (the adapter should remain attached to the vial). Attach the syringe to the venipuncture set (J). Ensure that no blood enters the syringe. 16. Remove tourniquet. 17. Inject the solution into a vein over 2 to 5 minutes, keeping an eye on the position of the needle. The speed of injection should be based on your comfort, but should not be faster than 2 mL per minute. 18. If a further dose is needed, use a new syringe with the powder reconstituted as described above. 19. If no further dose is required, remove the venipuncture set and syringe. Hold a pad firmly over the injection site on your outstretched arm for about 2 minutes. Finally, apply a small pressure dressing to the injection site and consider if a plaster is necessary. 20. It is recommended that every time you use Kovaltry, you note down the name and the batch number of the product. 21. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist or physician how to throw away medicines you no longer use. These measures will help protect the environment SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to use kovaltry', 'Section_Content': 'treatment with kovaltry will be started by a doctor who is experienced in the care of patients with haemophilia a. always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. the number of factor viii units is expressed in international units (iu). treatment of bleeding to treat a bleed, your doctor will calculate and adjust your dose and how often it should be given, depending on factors such as: your weight the severity of your haemophilia a where the bleed is and how serious it is whether you have inhibitors and how high their level is the factor viii level that is needed. prevention of bleeding if you are using kovaltry to prevent bleeding, your doctor will calculate the dose for you. this will usually be in the range of 20 to 40 iu of octocog alfa per kg of body weight, injected two or three times per week. however, in some cases, especially for younger patients, shorter dose intervals or higher doses may be necessary. laboratory tests laboratory tests at suitable intervals help to ensure you always have adequate factor viii levels. for major surgery in particular, your blood clotting must be closely monitored. use in children and adolescents kovaltry can be used in children of all ages. in children below the age of 12 higher doses or more frequent injections than prescribed for adults may be needed. patients with inhibitors if you have been told by your doctor that you have developed factor viii inhibitors you may need to use a larger dose of kovaltry to control bleeding. if this dose does not control your bleeding your doctor may consider giving you another product. speak to your doctor if you would like further information on this. do not increase the dose of kovaltry to control your bleeding without checking with your doctor. duration of treatment usually, kovaltry treatment for haemophilia is needed life-long. how kovaltry is given kovaltry is injected into a vein over 2 to 5 minutes depending on the total volume and your comfort level and should be used within 3 hours after reconstitution. how kovaltry is prepared for administration use only the components (vial adapter, pre filled syringe containing solvent and venipuncture set) provided with each package of this medicine. please contact your doctor if these components cannot be used. do not use if any component of the package is opened or damaged. the reconstituted product must be filtered by using the vial adapter before administration to remove any possible particles in the solution. do not use the venipuncture set provided for drawing blood because it contains an in-line filter. this medicine must not be mixed with other infusion solutions. do not use solutions containing visible particles or that are cloudy. follow the instructions for use given by your doctor and provided at the end of this leaflet. if you use more kovaltry than you should tell your doctor if this occurs. no cases of overdose have been reported. if you forget to use kovaltry administer your next dose immediately and continue at regular intervals as advised by your doctor. do not use a double dose to make up for a forgotten dose. if you stop using kovaltry do not stop using this medicine without checking with your doctor. if you have any further questions on the use of this medicine, ask your doctor.', 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 15, 'EndOffset': 23, 'Score': 0.6045933365821838, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 100, 'EndOffset': 111, 'Score': 0.7080158591270447, 'Text': 'haemophilia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7179270386695862}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 126, 'EndOffset': 139}, {'Text': 'factor viii units', 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the most serious side effects are allergic reactions which may be severe allergic reaction. stop injecting kovaltry immediately and speak to your doctor at once if such reactions occur. the following symptoms could be an early warning of these reactions: chest tightness/general feeling of being unwell dizziness feeling faint upon standing indicating a reduction in blood pressure feeling sick (nausea) for children not previously treated with factor viii medicines, inhibitor antibodies (see section 2) may form very commonly (more than 1 in 10 patients). for patients who have received previous treatment with factor viii (more than 150 days of treatment) inhibitor antibodies (see section 2) may form uncommonly (less than 1 in 100 patients). if this happens your medicine may stop working properly and you may experience persistent bleeding. if this happens, please contact your doctor immediately. other possible side effects: common (may affect up to 1 in 10 users): lymph nodes enlarged (swelling under the skin of the neck, armpit or groin) heart palpitations (feeling your heart beating hard, rapidly, or irregularly) rapid heartbeat stomach pain or discomfort indigestion fever local reactions where you injected the medicine (e.g. bleeding under the skin, intense itching, swelling, burning sensation, temporary redness) headache trouble sleeping rash/itchy rash uncommon (may affect up to 1 in 100 users): dysgeusia (strange taste) urticaria (itchy rash) flushing (redness of the face) reporting of side effects if you get any side effects, talk to your doctor. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of this medicine.', 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1088, 'EndOffset': 1096, 'Score': 0.9776391386985779, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7670839428901672}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.8463728427886963, 'RelationshipScore': 0.7443068623542786, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 1066, 'EndOffset': 1077, 'Text': 'lymph nodes', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'DIRECTION', 'Score': 0.9492475390434265, 'RelationshipScore': 0.9999510049819946, 'RelationshipType': 'DIRECTION', 'Id': 2, 'BeginOffset': 1097, 'EndOffset': 1102, 'Text': 'under', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9081406593322754, 'RelationshipScore': 0.9914931654930115, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 3, 'BeginOffset': 1107, 'EndOffset': 1111, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9981426000595093, 'RelationshipScore': 0.9899141788482666, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 4, 'BeginOffset': 1119, 'EndOffset': 1123, 'Text': 'neck', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9922439455986023, 'RelationshipScore': 0.9942252039909363, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 5, 'BeginOffset': 1125, 'EndOffset': 1131, 'Text': 'armpit', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9957504272460938, 'RelationshipScore': 0.9965807795524597, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 6, 'BeginOffset': 1135, 'EndOffset': 1140, 'Text': 'groin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 3, 'BeginOffset': 1107, 'EndOffset': 1111, 'Score': 0.9081406593322754, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 4, 'BeginOffset': 1119, 'EndOffset': 1123, 'Score': 0.9981426000595093, 'Text': 'neck', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 5, 'BeginOffset': 1125, 'EndOffset': 1131, 'Score': 0.9922439455986023, 'Text': 'armpit', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'groin)', 'Type': 'PROBLEM', 'BeginOffset': 1135, 'EndOffset': 1141}, {'Id': 29, 'BeginOffset': 1142, 'EndOffset': 1160, 'Score': 0.5659563541412354, 'Text': 'heart palpitations', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8938663601875305}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9081406593322754, 'RelationshipScore': 0.5394372344017029, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 3, 'BeginOffset': 1107, 'EndOffset': 1111, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 30, 'BeginOffset': 1162, 'EndOffset': 1193, 'Score': 0.8345839977264404, 'Text': 'feeling your heart beating hard', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8970330357551575}]}, {'Text': 'irregularly) rapid heartbeat stomach pain', 'Type': 'PROBLEM', 'BeginOffset': 1207, 'EndOffset': 1248}, {'Text': 'discomfort indigestion', 'Type': 'PROBLEM', 'BeginOffset': 1252, 'EndOffset': 1274}, {'Text': 'fever local reactions', 'Type': 'PROBLEM', 'BeginOffset': 1275, 'EndOffset': 1296}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 1316, 'EndOffset': 1328}, {'Text': 'bleeding under the skin', 'Type': 'PROBLEM', 'BeginOffset': 1335, 'EndOffset': 1358}, {'Text': 'intense itching', 'Type': 'PROBLEM', 'BeginOffset': 1360, 'EndOffset': 1375}, {'Id': 39, 'BeginOffset': 1377, 'EndOffset': 1385, 'Score': 0.9987592697143555, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9914742708206177}]}, {'Text': 'burning sensation', 'Type': 'PROBLEM', 'BeginOffset': 1387, 'EndOffset': 1404}, {'Text': 'temporary redness)', 'Type': 'PROBLEM', 'BeginOffset': 1406, 'EndOffset': 1424}, {'Id': 43, 'BeginOffset': 1425, 'EndOffset': 1433, 'Score': 0.9978771209716797, 'Text': 'headache', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9921075701713562}]}, {'Text': 'trouble sleeping rash', 'Type': 'PROBLEM', 'BeginOffset': 1434, 'EndOffset': 1455}, {'Id': 46, 'BeginOffset': 1456, 'EndOffset': 1466, 'Score': 0.5048327445983887, 'Text': 'itchy rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9624521732330322}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1494, 'EndOffset': 1495}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 1499, 'EndOffset': 1502}, {'Text': 'dysgeusia (strange taste)', 'Type': 'PROBLEM', 'BeginOffset': 1511, 'EndOffset': 1536}, {'Text': 'urticaria (itchy rash)', 'Type': 'PROBLEM', 'BeginOffset': 1537, 'EndOffset': 1559}, {'Text': 'flushing (redness of the face', 'Type': 'PROBLEM', 'BeginOffset': 1560, 'EndOffset': 1589}, {'Id': 53, 'BeginOffset': 1604, 'EndOffset': 1616, 'Score': 0.8619434833526611, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8305978178977966}]}, {'Id': 54, 'BeginOffset': 1632, 'EndOffset': 1644, 'Score': 0.9279146194458008, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8299143314361572}]}, {'Id': 55, 'BeginOffset': 1694, 'EndOffset': 1706, 'Score': 0.9601562023162842, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7484397292137146}]}, {'Id': 56, 'BeginOffset': 1755, 'EndOffset': 1767, 'Score': 0.8744065761566162, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7487946152687073}]}, {'Id': 57, 'BeginOffset': 1821, 'EndOffset': 1832, 'Score': 0.3506644666194916, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.726527988910675}]}, {'Id': 58, 'BeginOffset': 1846, 'EndOffset': 1858, 'Score': 0.9246008992195129, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7989727258682251}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1915, 'EndOffset': 1928}]}

{'Title': '5. how to store kovaltry', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on labels and cartons. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not freeze. store this medicine in the original package in order to protect from light. this medicine may be stored at room temperature (up to 25 ) for up to 12 months when you keep it in its outer carton. if you store it at room temperature it expires after 12 months or at the expiry date if this is earlier. the new expiry date must be noted on the outer carton when the medicine is removed from the refrigerator. do not refrigerate the solution after reconstitution. the reconstituted solution must be used within 3 hours. this product is for single use only. any unused solution must be discarded. do not use this medicine if you notice any particles in the solution or if the solution is cloudy. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 226, 'EndOffset': 227}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 252, 'EndOffset': 265}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 377, 'EndOffset': 379}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 392, 'EndOffset': 394}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 493, 'EndOffset': 495}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 705, 'EndOffset': 731}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 752, 'EndOffset': 753}, {'Text': 'any unused solution', 'Type': 'TREATMENT', 'BeginOffset': 798, 'EndOffset': 817}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 848, 'EndOffset': 861}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 928, 'EndOffset': 934}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what kovaltry contains the active substance is octocog alfa (human coagulation factor viii). each vial of kovaltry contains nominally 250, 500, 1000, 2000 or 3000 iu octocog alfa. the other ingredients are sucrose, histidine, glycine (e 640), sodium chloride, calcium chloride dihydrate (e 509), polysorbate 80 (e 433), acetic acid glacial (e 260) and water for injections. what kovaltry looks like and contents of the pack kovaltry is provided as a powder and solvent for solution for injection. the powder is dry and white to slightly yellow . the solvent is a clear liquid. each single pack of kovaltry contains a glass vial with powder a pre filled syringe with solvent a separate plunger rod a vial adapter a venipuncture set (for injection into a vein). kovaltry is available in pack sizes of: 1 single pack 1 multipack with 30 single packs not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'octocog alfa', 'Type': 'TREATMENT', 'BeginOffset': 47, 'EndOffset': 59}, {'Id': 2, 'BeginOffset': 61, 'EndOffset': 90, 'Score': 0.5069359540939331, 'Text': 'human coagulation factor viii', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 106, 'EndOffset': 114, 'Score': 0.8263447284698486, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 134, 'EndOffset': 137}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 139, 'EndOffset': 142}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 144, 'EndOffset': 148}, {'Text': '2000', 'Type': 'NUMBER', 'BeginOffset': 150, 'EndOffset': 154}, {'Text': '3000', 'Type': 'NUMBER', 'BeginOffset': 158, 'EndOffset': 162}, {'Id': 5, 'BeginOffset': 166, 'EndOffset': 178, 'Score': 0.893954336643219, 'Text': 'octocog alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.5058310031890869, 'RelationshipScore': 0.9982574582099915, 'RelationshipType': 'STRENGTH', 'Id': 4, 'BeginOffset': 134, 'EndOffset': 165, 'Text': '250, 500, 1000, 2000 or 3000 iu', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 6, 'BeginOffset': 206, 'EndOffset': 213, 'Score': 0.7239546179771423, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'histidine, glycine (e', 'Type': 'TREATMENT', 'BeginOffset': 215, 'EndOffset': 236}, {'Id': 10, 'BeginOffset': 243, 'EndOffset': 258, 'Score': 0.9997001886367798, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 260, 'EndOffset': 286, 'Score': 0.9993336796760559, 'Text': 'calcium chloride dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 288, 'EndOffset': 293, 'Score': 0.5170265436172485, 'Text': 'e 509', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 296, 'EndOffset': 310, 'Score': 0.8174399733543396, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 312, 'EndOffset': 317, 'Score': 0.6266178488731384, 'Text': 'e 433', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 320, 'EndOffset': 339, 'Score': 0.99806147813797, 'Text': 'acetic acid glacial', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.35631537437438965, 'RelationshipScore': 0.9999990463256836, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 17, 'BeginOffset': 362, 'EndOffset': 372, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 16, 'BeginOffset': 341, 'EndOffset': 346, 'Score': 0.425204336643219, 'Text': 'e 260', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.35631537437438965, 'RelationshipScore': 0.837584912776947, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 17, 'BeginOffset': 362, 'EndOffset': 372, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 362, 'EndOffset': 372}, {'Text': 'the pack kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 415, 'EndOffset': 432}, {'Text': 'a powder and solvent for solution', 'Type': 'TREATMENT', 'BeginOffset': 448, 'EndOffset': 481}, {'Text': 'injection', 'Type': 'TREATMENT', 'BeginOffset': 486, 'EndOffset': 495}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 497, 'EndOffset': 507}, {'Text': 'white to slightly yellow', 'Type': 'PROBLEM', 'BeginOffset': 519, 'EndOffset': 543}, {'Text': 'kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 597, 'EndOffset': 605}, {'Text': 'a glass vial', 'Type': 'TREATMENT', 'BeginOffset': 615, 'EndOffset': 627}, {'Text': 'powder a pre filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 633, 'EndOffset': 660}, {'Text': 'solvent a separate plunger rod a vial adapter a venipuncture set', 'Type': 'TREATMENT', 'BeginOffset': 666, 'EndOffset': 730}, {'Id': 0, 'BeginOffset': 753, 'EndOffset': 757, 'Score': 0.6870084404945374, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 760, 'EndOffset': 768}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 800, 'EndOffset': 801}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 814, 'EndOffset': 815}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 831, 'EndOffset': 833}]}

4845D3160FDE0A0270C5AFDDFC80E5BE

https://www.ema.europa.eu/documents/product-information/ammonaps-epar-product-information_en.pdf

Ammonaps

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT AMMONAPS 500 mg tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 500 mg sodium phenylbutyrate. Each AMMONAPS tablet contains 62 mg of sodium. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablet. The tablets are off-white, oval and embossed with “UCY 500”. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications AMMONAPS is indicated as adjunctive therapy in the chronic management of urea cycle disorders, involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase or argininosuccinate synthetase. It is indicated in all patients with neonatal-onset presentation (complete enzyme deficiencies, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzyme deficiencies, presenting after the first month of life) who have a history of hyperammonaemic encephalopathy. 4.2 Posology and method of administration AMMONAPS treatment should be supervised by a physician experienced in the treatment of urea cycle disorders. The use of AMMONAPS tablets is indicated for adults and children who are able to swallow tablets. AMMONAPS is also available as granules for infants, children who are unable to swallow tablets and for patients with dysphagia. The daily dose should be individually adjusted according to the patient’s protein tolerance and the daily dietary protein intake needed to promote growth and development. The usual total daily dose of sodium phenylbutyrate in clinical experience is: • 450 - 600 mg/kg/day in children weighing less than 20 kg • 9.9 - 13.0 g/m2/day in children weighing more than 20 kg, adolescents and adults. The safety and efficacy of doses in excess of 20 g/day (40 tablets) have not been established. Therapeutic monitoring: Plasma levels of ammonia, arginine, essential amino acids (especially branched chain amino acids), carnitine and serum proteins should be maintained within normal limits. Plasma glutamine should be maintained at levels less than 1,000 µmol/l. Nutritional management: AMMONAPS must be combined with dietary protein restriction and, in some cases, essential amino acid and carnitine supplementation. 3 Citrulline or arginine supplementation is required for patients diagnosed with neonatal-onset form of carbamyl phosphate synthetase or ornithine transcarbamylase deficiency at a dose of 0.17 g/kg/day or 3.8 g/m2/day. Arginine supplementation is required for patients diagnosed with deficiency of argininosuccinate synthetase at a dose of 0.4 - 0.7 g/kg/day or 8.8 - 15.4 g/m2/day. If caloric supplementation is indicated, a protein-free product is recommended. The total daily dose of AMMONAPS should be divided into equal amounts and given with each meal (e.g. three times per day). The tablets should be taken with a large volume of water. 4.3 Contraindications − Pregnancy. − Breast-feeding. − Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use AMMONAPS tablets should not be used in patients with dysphagia due to the potential risk of oesophageal ulceration if tablets are not promptly delivered to the stomach. Each AMMONAPS tablet contains 62 mg (2.7 mmol) of sodium, corresponding to 2.5 g (108 mmol) of sodium per 20 g of sodium phenylbutyrate, which is the maximum daily dose. AMMONAPS should therefore be used with caution in patients with congestive heart failure or severe renal insufficiency, and in clinical conditions where there is sodium retention with oedema. Since the metabolism and excretion of sodium phenylbutyrate involves the liver and kidneys, AMMONAPS should be used with caution in patients with hepatic or renal insufficiency. Serum potassium should be monitored during therapy since renal excretion of phenylacetylglutamine may induce a urinary loss of potassium. Even on therapy, acute hyperammonaemic encephalopathy may occur in a number of patients. AMMONAPS is not recommended for the management of acute hyperammonaemia, which is a medical emergency. In children unable to swallow tablets, it is recommended to use AMMONAPS granules instead. 4.5 Interaction with other medicinal products and other forms of interaction Concurrent administration of probenecid may affect renal excretion of the conjugation product of sodium phenylbutyrate. There have been published reports of hyperammonaemia being induced by haloperidol and by valproate. Corticosteroids may cause the breakdown of body protein and thus increase plasma ammonia levels. More frequent monitoring of plasma ammonia levels is advised when these medications have to be used. 4.6 Fertility, pregnancy and lactation Pregnancy The safety of this medicinal product for use in human pregnancy has not been established. Evaluation of experimental animal studies has shown reproductive toxicity, i.e. effects on the development of the embryo or the foetus. Prenatal exposure of rat pups to phenylacetate (the active metabolite of 4 phenylbutyrate) produced lesions in cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number. The significance of these data in pregnant women is not known; therefore the use of AMMONAPS is contra-indicated during pregnancy (see section 4.3). Effective contraceptive measures must be taken by women of child-bearing potential. Lactation When high doses of phenylacetate (190 - 474 mg/kg) were given subcutaneously to rat pups, decreased proliferation and increased loss of neurons were observed, as well as a reduction in CNS myelin. Cerebral synapse maturation was retarded and the number of functioning nerve terminals in the cerebrum was reduced, which resulted in impaired brain growth. It has not been determined if phenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicated during lactation (see section 4.3). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects In clinical trials with AMMONAPS, 56 % of the patients experienced at least one adverse event and 78 % of these adverse events were considered as not related to AMMONAPS. Adverse reactions mainly involved the reproductive and gastrointestinal system. The adverse reactions are listed below, by system organ class and by frequency. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Blood and lymphatic system disorders Common: Anaemia, thrombocytopenia, leukopenia, leukocytosis, thrombocytosis Uncommon: Aplastic anaemia, ecchymosis Metabolism and nutrition disorders Common: Metabolic acidosis, alkalosis, decreased appetite Psychiatric disorders Common: Depression, irritability Nervous system disorders Common: Syncope, headache Cardiac disorders Common: Oedema Uncommon: Arrhythmia Gastrointestinal disorders Common: Abdominal pain, vomiting, nausea, constipation, dysgeusia Uncommon: Pancreatitis, peptic ulcer, rectal haemorrhage, gastritis Skin and subcutaneous tissue disorders Common: Rash, abnormal skin odour Renal and urinary disorders Common: Renal tubular acidosis 5 Reproductive system and breast disorders Very common: Amenorrhoea, irregular menstruation Investigations Common: Decreased blood potassium, albumin, total protein and phosphate. Increased blood alkaline phosphatase, transaminases, bilirubin, uric acid, chloride, phosphate and sodium. Increased weight. A probable case of toxic reaction to AMMONAPS (450 mg/kg/d) was reported in an 18-year old anorectic female patient who developed a metabolic encephalopathy associated with lactic acidosis, severe hypokalaemia, pancytopaenia, peripheral neuropathy, and pancreatitis. She recovered following dose reduction except for recurrent pancreatitis episodes that eventually prompted treatment discontinuation. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose One case of overdose occurred in a 5-month old infant with an accidental single dose of 10 g (1370 mg/kg). The patient developed diarrhoea, irritability and metabolic acidosis with hypokalaemia. The patient recovered within 48 hours after symptomatic treatment. These symptoms are consistent with the accumulation of phenylacetate, which showed dose-limiting neurotoxicity when administered intravenously at doses up to 400 mg/kg/day. Manifestations of neurotoxicity were predominantly somnolence, fatigue and light-headedness. Less frequent manifestations were confusion, headache, dysgeusia, hypacusis, disorientation, impaired memory and exacerbation of a pre-existing neuropathy. In the event of an overdose, discontinue the treatment and institute supportive measures. Haemodialysis or peritoneal dialysis may be beneficial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: various alimentary tract and metabolism products, ATC code: A16A X03. Sodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine which is then excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore provides an alternate vehicle for waste nitrogen excretion. Based on studies of phenylacetylglutamine excretion in patients with urea cycle disorders it is possible to estimate that, for each gram of sodium phenylbutyrate administered, between 0.12 and 0.15 g of phenylacetylglutamine nitrogen are produced. As a consequence, sodium phenylbutyrate reduces elevated plasma ammonia and glutamine levels in patients with urea cycle disorders. It is important that the diagnosis is made early and treatment is initiated immediately to improve the survival and the clinical outcome. Previously, neonatal-onset presentation of urea cycle disorders was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen- free analogues. With haemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in new-borns diagnosed after birth (but within the first month of life) increased to almost 80 % with most deaths occurring during an episode 6 of acute hyperammonaemic encephalopathy. Patients with neonatal-onset disease had a high incidence of mental retardation. In patients diagnosed during gestation and treated prior to any episode of hyperammonaemic encephalopathy, survival was 100 %, but even in these patients, many subsequently demonstrated cognitive impairment or other neurologic deficits. In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recovered from hyperammonaemic encephalopathy and were then treated chronically with dietary protein restriction and sodium phenylbutyrate, the survival rate was 98 %. The majority of the patients who were tested had an IQ in the average to low average/borderline mentally retarded range. Their cognitive performance remained relatively stable during phenylbutyrate therapy. Reversal of pre-existing neurologic impairment is not likely to occur with treatment, and neurologic deterioration may continue in some patients. AMMONAPS may be required life-long unless orthotopic liver transplantation is elected. 5.2 Pharmacokinetic properties Phenylbutyrate is known to be oxidised to phenylacetate which is enzymatically conjugated with glutamine to form phenylacetylglutamine in the liver and kidney. Phenylacetate is also hydrolysed by esterases in liver and blood. Plasma and urine concentrations of phenylbutyrate and its metabolites have been obtained from fasting normal adults who received a single dose of 5 g of sodium phenylbutyrate and from patients with urea cycle disorders, haemoglobinopathies and cirrhosis receiving single and repeated oral doses up to 20 g/day (uncontrolled studies). The disposition of phenylbutyrate and its metabolites has also been studied in cancer patients following intravenous infusion of sodium phenylbutyrate (up to 2 g/m²) or phenylacetate. Absorption Phenylbutyrate is rapidly absorbed under fasting conditions. After a single oral dose of 5 g of sodium phenylbutyrate, in the form of tablets, measurable plasma levels of phenylbutyrate are detected 15 minutes after dosing. The mean time to peak concentration is 1.35 hour and the mean peak concentration 218 µg/ml. The elimination half-life was estimated to be 0.8 hours. The effect of food on absorption is unknown. Distribution The volume of distribution of phenylbutyrate is 0.2 l/kg. Biotransformation After a single dose of 5 g of sodium phenylbutyrate, in the form of tablets, measurable plasma levels of phenylacetate and phenylacetylglutamine are detected 30 and 60 minutes respectively after dosing. The mean time to peak concentration is 3.74 and 3.43 hours, respectively, and the mean peak concentration is 48.5 and 68.5 µg/ml, respectively. The elimination half-life was estimated to be 1.2 and 2.4 hours, respectively. Studies with high intravenous doses of phenylacetate showed non linear pharmacokinetics characterised by saturable metabolism to phenylacetylglutamine. Repeated dosing with phenylacetate showed evidence of an induction of clearance. In the majority of patients with urea cycle disorders or haemoglobinopathies receiving various doses of phenylbutyrate (300 - 650 mg/kg/day up to 20 g/day) no plasma level of phenylacetate could be detected after overnight fasting. In patients with impaired hepatic function the conversion of phenylacetate to phenylacetylglutamine may be relatively slower. Three cirrhotic patients (out of 6) who received repeated oral administration of sodium phenylbutyrate (20 g/day in three doses) showed 7 sustained plasma levels of phenylacetate on the third day that were five times higher than those achieved after the first dose. In normal volunteers gender differences were found in the pharmacokinetic parameters of phenylbutyrate and phenylacetate (AUC and Cmax about 30 - 50 % greater in females), but not phenylacetylglutamine. This may be due to the lipophilicity of sodium phenylbutyrate and consequent differences in volume of distribution. Elimination Approximately 80 - 100 % of the medicinal product is excreted by the kidneys within 24 hours as the conjugated product, phenylacetylglutamine. 5.3 Preclinical safety data Sodium phenylbutyrate was negative in 2 mutagenicity tests, i.e. the Ames test and the micronucleus test. Results indicate that sodium phenylbutyrate did not induce any mutagenic effects in the Ames test with or without metabolic activation. Micronucleus test results indicate that sodium phenylbutyrate was considered not to have produced any clastogenic effect in rats treated at toxic or non-toxic dose levels (examined 24 and 48 hours after a single oral administration of 878 to 2800 mg/kg). Carcinogenicity and fertility studies have not been conducted with sodium phenylbutyrate. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline cellulose Magnesium stearate Colloidal anhydrous silica 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container HDPE bottles, with child resistant caps, containing 250 or 500 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 8 7. MARKETING AUTHORISATION HOLDER Immedica Pharma AB SE-113 29 Stockholm Sweden 8. MARKETING AUTHORISATION NUMBERS EU/1/99/120/001 (250 tablets) EU/1/99/120/002 (500 tablets) 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 08/12/1999 Date of latest renewal: 08/12/2009 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. 9 1. NAME OF THE MEDICINAL PRODUCT AMMONAPS 940 mg/g granules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each gram of granules contains 940 mg of sodium phenylbutyrate. One small spoon of AMMONAPS granules contains 149 mg of sodium. One medium sized spoon of AMMONAPS granules contains 408 mg of sodium. One large spoon of AMMONAPS granules contains 1200 mg of sodium. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Granules. The granules are off-white. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications AMMONAPS is indicated as adjunctive therapy in the chronic management of urea cycle disorders, involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase or argininosuccinate synthetase. It is indicated in all patients with neonatal-onset presentation (complete enzyme deficiencies, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzyme deficiencies, presenting after the first month of life) who have a history of hyperammonaemic encephalopathy. 4.2 Posology and method of administration AMMONAPS treatment should be supervised by a physician experienced in the treatment of urea cycle disorders. AMMONAPS granules should be administered orally (to infants and children unable to swallow tablets and to patients with dysphagia) or via gastrostomy or nasogastric tube. The daily dose should be individually adjusted according to the patient’s protein tolerance and the daily dietary protein intake needed to promote growth and development. The usual total daily dose of sodium phenylbutyrate in clinical experience is: • 450 - 600 mg/kg/day in neonates, infants and children weighing less than 20 kg • 9.9 - 13.0 g/m2/day in children weighing more than 20 kg, adolescents and adults. The safety and efficacy of doses in excess of 20 g/day have not been established. Therapeutic monitoring: Plasma levels of ammonia, arginine, essential amino acids (especially branched chain amino acids), carnitine and serum proteins should be maintained within normal limits. Plasma glutamine should be maintained at levels less than 1,000 µmol/l. Nutritional management: AMMONAPS must be combined with dietary protein restriction and, in some cases, essential amino acid and carnitine supplementation. 10 Citrulline or arginine supplementation is required for patients diagnosed with neonatal-onset form of carbamyl phosphate synthetase or ornithine transcarbamylase deficiency at a dose of 0.17 g/kg/day or 3.8 g/m2/day. Arginine supplementation is required for patients diagnosed with deficiency of argininosuccinate synthetase at a dose of 0.4 - 0.7 g/kg/day or 8.8 - 15.4 g/m2/day. If caloric supplementation is indicated, a protein-free product is recommended. The total daily dose should be divided into equal amounts and given with each meal or feeding (e.g. 4- 6 times per day in small children). When taken orally, the granules are to be mixed with solid foods (such as mashed potatoes or apple sauce) or liquid foods (such as water, apple juice, orange juice or protein-free infant formulas). Three dosing spoons are provided which dispense 1.2 g, 3.3 g or 9.7 g of sodium phenylbutyrate. Lightly shake the bottle before dispensing. 4.3 Contraindications − Pregnancy. − Breast-feeding. − Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use AMMONAPS granules contain 124 mg (5.4 mmol) of sodium per gram of sodium phenylbutyrate, corresponding to 2.5 g (108 mmol) of sodium per 20 g of sodium phenylbutyrate, which is the maximum daily dose. AMMONAPS should therefore be used with caution in patients with congestive heart failure or severe renal insufficiency, and in clinical conditions where there is sodium retention with oedema. Since the metabolism and excretion of sodium phenylbutyrate involves the liver and kidneys, AMMONAPS should be used with caution in patients with hepatic or renal insufficiency. Serum potassium should be monitored during therapy since renal excretion of phenylacetylglutamine may induce a urinary loss of potassium. Even on therapy, acute hyperammonaemic encephalopathy may occur in a number of patients. AMMONAPS is not recommended for the management of acute hyperammonaemia, which is a medical emergency. 4.5 Interaction with other medicinal products and other forms of interaction Concurrent administration of probenecid may affect renal excretion of the conjugation product of sodium phenylbutyrate. There have been published reports of hyperammonaemia being induced by haloperidol and by valproate. Corticosteroids may cause the breakdown of body protein and thus increase plasma ammonia levels. More frequent monitoring of plasma ammonia levels is advised when these medications have to be used. 4.6 Fertility, pregnancy and lactation Pregnancy The safety of this medicinal product for use in human pregnancy has not been established. Evaluation of experimental animal studies has shown reproductive toxicity, i.e. effects on the development of the 11 embryo or the foetus. Prenatal exposure of rat pups to phenylacetate (the active metabolite of phenylbutyrate) produced lesions in cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number. The significance of these data in pregnant women is not known; therefore the use of AMMONAPS is contra-indicated during pregnancy (see section 4.3). Effective contraceptive measures must be taken by women of child-bearing potential. Lactation When high doses of phenylacetate (190 - 474 mg/kg) were given subcutaneously to rat pups, decreased proliferation and increased loss of neurons were observed, as well as a reduction in CNS myelin. Cerebral synapse maturation was retarded and the number of functioning nerve terminals in the cerebrum was reduced, which resulted in impaired brain growth. It has not been determined if phenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicated during lactation (see section 4.3). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects In clinical trials with AMMONAPS, 56 % of the patients experienced at least one adverse event and 78 % of these adverse events were considered as not related to AMMONAPS. Adverse reactions mainly involved the reproductive and gastrointestinal system. The adverse reactions are listed below, by system organ class and by frequency. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Blood and lymphatic system disorders Common: Anaemia, thrombocytopenia, leukopenia, leukocytosis, thrombocytosis Uncommon: Aplastic anaemia, ecchymosis Metabolism and nutrition disorders Common: Metabolic acidosis, alkalosis, decreased appetite Psychiatric disorders Common: Depression, irritability Nervous system disorders Common: Syncope, headache Cardiac disorders Common: Oedema Uncommon: Arrhythmia Gastrointestinal disorders Common: Abdominal pain, vomiting, nausea, constipation, dysgeusia Uncommon: Pancreatitis, peptic ulcer, rectal haemorrhage, gastritis Skin and subcutaneous tissue disorders Common: Rash, abnormal skin odour Renal and urinary disorders Common: Renal tubular acidosis 12 Reproductive system and breast disorders Very common: Amenorrhoea, irregular menstruation Investigations Common: Decreased blood potassium, albumin, total protein and phosphate. Increased blood alkaline phosphatase, transaminases, bilirubin, uric acid, chloride, phosphate and sodium. Increased weight. A probable case of toxic reaction to AMMONAPS (450 mg/kg/d) was reported in an 18-year old anorectic female patient who developed a metabolic encephalopathy associated with lactic acidosis, severe hypokalaemia, pancytopaenia, peripheral neuropathy, and pancreatitis. She recovered following dose reduction except for recurrent pancreatitis episodes that eventually prompted treatment discontinuation. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose One case of overdose occurred in a 5-month old infant with an accidental single dose of 10 g (1370 mg/kg). The patient developed diarrhoea, irritability and metabolic acidosis with hypokalaemia. The patient recovered within 48 hours after symptomatic treatment. These symptoms are consistent with the accumulation of phenylacetate, which showed dose-limiting neurotoxicity when administered intravenously at doses up to 400 mg/kg/day. Manifestations of neurotoxicity were predominantly somnolence, fatigue and light-headedness. Less frequent manifestations were confusion, headache, dysgeusia, hypacusis, disorientation, impaired memory and exacerbation of a pre-existing neuropathy. In the event of an overdose, discontinue the treatment and institute supportive measures. Haemodialysis or peritoneal dialysis may be beneficial. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: various alimentary tract and metabolism products, ATC code: A16A X03. Sodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine which is then excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore provides an alternate vehicle for waste nitrogen excretion. Based on studies of phenylacetylglutamine excretion in patients with urea cycle disorders it is possible to estimate that, for each gram of sodium phenylbutyrate administered, between 0.12 and 0.15 g of phenylacetylglutamine nitrogen are produced. As a consequence, sodium phenylbutyrate reduces elevated plasma ammonia and glutamine levels in patients with urea cycle disorders. It is important that the diagnosis is made early and treatment is initiated immediately to improve the survival and the clinical outcome. Previously, neonatal-onset presentation of urea cycle disorders was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen- free analogues. With haemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in new-borns diagnosed after birth (but 13 within the first month of life) increased to almost 80 % with most deaths occurring during an episode of acute hyperammonaemic encephalopathy. Patients with neonatal-onset disease had a high incidence of mental retardation. In patients diagnosed during gestation and treated prior to any episode of hyperammonaemic encephalopathy, survival was 100 %, but even in these patients, many subsequently demonstrated cognitive impairment or other neurologic deficits. In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recovered from hyperammonaemic encephalopathy and were then treated chronically with dietary protein restriction and sodium phenylbutyrate, the survival rate was 98 %. The majority of the patients who were tested had an IQ in the average to low average/borderline mentally retarded range. Their cognitive performance remained relatively stable during phenylbutyrate therapy. Reversal of pre-existing neurologic impairment is not likely to occur with treatment, and neurologic deterioration may continue in some patients. AMMONAPS may be required life-long unless orthotopic liver transplantation is elected. 5.2 Pharmacokinetic properties Phenylbutyrate is known to be oxidised to phenylacetate which is enzymatically conjugated with glutamine to form phenylacetylglutamine in the liver and kidney. Phenylacetate is also hydrolysed by esterases in liver and blood. Plasma and urine concentrations of phenylbutyrate and its metabolites have been obtained from fasting normal adults who received a single dose of 5 g of sodium phenylbutyrate and from patients with urea cycle disorders, haemoglobinopathies and cirrhosis receiving single and repeated oral doses up to 20 g/day (uncontrolled studies). The disposition of phenylbutyrate and its metabolites has also been studied in cancer patients following intravenous infusion of sodium phenylbutyrate (up to 2 g/m²) or phenylacetate. Absorption Phenylbutyrate is rapidly absorbed under fasting conditions. After a single oral dose of 5 g of sodium phenylbutyrate, in the form of granules, measurable plasma levels of phenylbutyrate are detected 15 minutes after dosing. The mean time to peak concentration is 1 hour and the mean peak concentration 195 µg/ml. The elimination half-life was estimated to be 0.8 hours. The effect of food on absorption is unknown. Distribution The volume of distribution of phenylbutyrate is 0.2 l/kg. Biotransformation After a single dose of 5 g of sodium phenylbutyrate, in the form of granules, measurable plasma levels of phenylacetate and phenylacetylglutamine are detected 30 and 60 minutes respectively after dosing. The mean time to peak concentration is 3.55 and 3.23 hours, respectively, and the mean peak concentration is 45.3 and 62.8 µg/ml, respectively. The elimination half-life was estimated to be 1.3 and 2.4 hours, respectively. Studies with high intravenous doses of phenylacetate showed non linear pharmacokinetics characterised by saturable metabolism to phenylacetylglutamine. Repeated dosing with phenylacetate showed evidence of an induction of clearance. In the majority of patients with urea cycle disorders or haemoglobinopathies receiving various doses of phenylbutyrate (300 - 650 mg/kg/day up to 20 g/day) no plasma level of phenylacetate could be detected after overnight fasting. In patients with impaired hepatic function the conversion of phenylacetate to phenylacetylglutamine may be relatively slower. Three cirrhotic patients (out of 6) who received repeated oral administration of sodium phenylbutyrate (20 g/day in three doses) showed 14 sustained plasma levels of phenylacetate on the third day that were five times higher than those achieved after the first dose. In normal volunteers gender differences were found in the pharmacokinetic parameters of phenylbutyrate and phenylacetate (AUC and Cmax about 30 - 50 % greater in females), but not phenylacetylglutamine. This may be due to the lipophilicity of sodium phenylbutyrate and consequent differences in volume of distribution. Elimination Approximately 80 - 100 % of the medicinal product is excreted by the kidneys within 24 hours as the conjugated product, phenylacetylglutamine. 5.3 Preclinical safety data Sodium phenylbutyrate was negative in 2 mutagenicity tests, i.e. the Ames test and the micronucleus test. Results indicate that sodium phenylbutyrate did not induce any mutagenic effects in the Ames test with or without metabolic activation. Micronucleus test results indicate that sodium phenylbutyrate was considered not to have produced any clastogenic effect in rats treated at toxic or non-toxic dose levels (examined 24 and 48 hours after a single oral administration of 878 to 2800 mg/kg). Carcinogenicity and fertility studies have not been conducted with sodium phenylbutyrate. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Calcium stearate Colloidal anhydrous silica 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Do not store above 25oC 6.5 Nature and contents of container HDPE bottles, with child resistant caps, containing 266 g or 532 g of granules. Three measuring spoons of different measures are provided. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling It is recommended that a heaped measuring spoon is removed from the container and a flat surface, e.g. the blade of a knife, is drawn across the top of the measure. This will give the following doses: small measure 1.2 g, medium measure 3.3 g and large measure 9.7 g of sodium phenylbutyrate. 15 Where a patient requires administration by tube, it is possible to re-constitute AMMONAPS in water prior to use (solubility for sodium phenylbutyrate is up to 5 g in 10 ml water). Please note that the re- constituted granules will normally produce a milky white suspension. Where AMMONAPS granules need to be added to food, liquid or water, it is important that it is taken immediately after mixing. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Immedica Pharma AB SE-113 29 Stockholm Sweden 8. MARKETING AUTHORISATION NUMBERS EU/1/99/120/003 (266 g granules) EU/1/99/120/004 (532 g granules) 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: 08/12/1999 Date of latest renewal: 08/12/2009 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. 16 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 17 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release PATHEON France – BOURGOIN JALLIEU 40 boulevard de Champaret BOURGOIN JALLIEU 38300 France B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION Not applicable. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Not applicable. 18 ANNEX III LABELLING AND PACKAGE LEAFLET 19 A. LABELLING 20 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING OUTER CARTON AND BOTTLE LABEL FOR TABLETS 1. NAME OF THE MEDICINAL PRODUCT AMMONAPS 500 mg tablets sodium phenylbutyrate 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 500 mg of sodium phenylbutyrate. 3. LIST OF EXCIPIENTS Contains sodium, see package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 250 tablets 500 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30°C. 21 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Immedica Pharma AB SE-113 29 Stockholm Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/99/120/001 250 tablets EU/1/99/120/002 500 tablets 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Ammonaps 500 mg [outer packaging only] 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: {number} SN: {number} NN: {number} 22 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING OUTER CARTON AND BOTTLE LABEL FOR GRANULES 1. NAME OF THE MEDICINAL PRODUCT AMMONAPS 940 mg/g granules. sodium phenylbutyrate 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 g of granules contains 940 mg of sodium phenylbutyrate 3. LIST OF EXCIPIENTS Contains sodium, see package leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 266 g granules 532 g granules Three measuring spoons of different measures are provided. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 23 9. SPECIAL STORAGE CONDITIONS Do not store above 25°C. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Immedica Pharma AB SE-113 29 Stockholm Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/99/120/003 266 g granules EU/1/99/120/004 532 g granules 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE [Justification for not including Braille accepted] 17. UNIQUE IDENTIFIER – 2D BARCODE <2D barcode carrying the unique identifier included.> 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: {number} SN: {number} NN: {number} 24 B. PACKAGE LEAFLET 25 Package leaflet: Information for the user AMMONAPS 500 mg tablets Sodium phenylbutyrate Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What AMMONAPS is and what it is used for 2. What you need to know before you take AMMONAPS 3. How to take AMMONAPS 4. Possible side effects 5. How to store AMMONAPS 6. Contents of the pack and other information 1. What AMMONAPS is and what it is used for AMMONAPS is prescribed to patients with urea cycle disorders. Patients with these rare disorders have a deficiency of certain liver enzymes and are therefore unable to eliminate nitrogen waste. Nitrogen is a building block of proteins, because of this, there is a build up of nitrogen in the body after eating protein. Nitrogen waste, in the form of ammonia, is especially toxic for the brain and leads, in severe cases, to reduced levels of consciousness and to coma. AMMONAPS helps the body to eliminate nitrogen waste, reducing the amount of ammonia in your body. 2. What you need to know before you take AMMONAPS Do not take AMMONAPS - if you are pregnant. - if you are breast-feeding. - if you are allergic to sodium phenylbutyrate or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor before taking AMMONAPS - if you have difficulty swallowing. AMMONAPS tablets can get stuck in the oesophagus and cause ulcers. If you have difficulty swallowing it is recommended to use AMMONAPS granules instead. - if you suffer from heart failure, a decrease in your kidney function or other diseases, where the retention of the sodium salt contained in this medicine, may make your condition worse. - if you have decreased kidney or liver function, since AMMONAPS is eliminated from the body through the kidney and liver. - when given to small children, since they may not be able to swallow the tablets and may choke. It is recommended to use AMMONAPS granules instead. AMMONAPS must be combined with a diet reduced in proteins designed especially for you by the doctor and the dietician. You must follow this diet carefully. 26 AMMONAPS does not completely prevent the occurrence of an acute excess of ammonia in the blood and is not appropriate for treating such a condition, which is a medical emergency. If you require laboratory tests, it is important to remind your doctor that you are taking AMMONAPS, since sodium phenylbutyrate may influence certain laboratory test results. Other medicines and AMMONAPS Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. It is especially important to tell your doctor if you are taking medicines containing: - valproic acid (an antiepileptic drug), - haloperidol (used in certain psychotic disorders), - corticosteroids (cortisone-like medicines that are used to provide relief for inflamed areas of the body), - probenecid (for treatment of hyperuricemia associated with gout). These medicines may change the effect of AMMONAPS and you will need more frequent blood controls. If you are uncertain if your medicines contain these substances, you should check with your doctor or pharmacist. Pregnancy and breast-feeding Do not use AMMONAPS if you are pregnant, because this medicine can harm your unborn baby. If you are a woman who could get pregnant, you must use reliable contraception, during treatment with AMMONAPS. Do not use AMMONAPS if you are breast-feeding, because this medicine can pass into the breast- milk and harm your baby. Driving and using machines No studies on the effects on the ability to drive and use machines have been performed. AMMONAPS contains sodium Each AMMONAPS tablet contains 62 mg of sodium. To be taken into consideration by patients on a sodium controlled diet. 3. How to take AMMONAPS Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Dosage The daily dose of AMMONAPS will be calculated from your protein tolerance, diet and body weight or body surface. You will need regular blood tests to determine the correct daily dose. Your doctor will tell you how many tablets you should take. Method of administration You should take AMMONAPS by mouth in equally divided doses with each meal (for example three times per day).You should take AMMONAPS with a large volume of water. AMMONAPS must be taken with a special diet reduced in protein. AMMONAPS tablets should not be given to children who are not able to swallow tablets. It is recommended that AMMONAPS granules are used instead. 27 You will need to have treatment and to follow a diet throughout your life, unless you have a successful liver transplantation. If you take more AMMONAPS than you should Patients who have taken very high doses of AMMONAPS experienced: - sleepiness, tiredness, light-headedness and less frequently confusion, - headache, - changes in taste (taste disturbances), - decrease in hearing, - disorientation, - impaired memory, - worsening of existing neurological conditions. If you experience any of these symptoms, you should immediately contact your doctor or the nearest hospital emergency department for supportive treatment. If you forget to take AMMONAPS You should take a dose as soon as possible with your next meal. Make sure that there are at least 3 hours between two doses. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The frequency of possible side effects is listed below. Very common: Affects more than 1 user in 10 Common: Affects 1 to 10 users in 100 Uncommon: Affects 1 to 10 users in 1,000 Rare: Affects 1 to 10 users in 10,000 Very rare: Affects less than 1 user in 10,000 Not known: Frequency cannot be estimated from the available data Very common side effects: irregular menstrual periods and cessation of menstrual periods. If you are sexually active and your period stops altogether, do not assume that this is caused by AMMONAPS. If this occurs, please discuss it with your doctor, because the absence of your period may be caused by pregnancy (see Pregnancy and breast-feeding section above). Common side effects: changes in number of blood cells (red cells, white cells and platelets), reduced appetite, depression, irritability, headache, fainting, fluid retention (swelling), changes in taste (taste disturbances),pain in the abdomen, vomiting, nausea, constipation, skin odour, rash, abnormal kidney function, weight gain, altered laboratory test values. Uncommon side effects: deficiency in red blood cells due to bone marrow depression, bruising, altered heart rhythm, rectal bleeding, stomach irritation, stomach ulcer, inflammation of the pancreas. If persistent vomiting occurs, you should contact your doctor immediately. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 28 5. How to store AMMONAPS Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and the bottle label after “EXP”. The expiry date refers to the last day of that month. Do not store above 30°C. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What AMMONAPS contains - The active substance is sodium phenylbutyrate. Each tablet of AMMONAPS contains 500 mg of sodium phenylbutyrate. - The other ingredients are microcrystalline cellulose, magnesium stearate and colloidal anhydrous silica. What AMMONAPS looks like and contents of the pack AMMONAPS tablets are off-white, oval and embossed with “UCY 500”. The tablets are packaged in plastic bottles with child-resistant caps. Each bottle contains 250 or 500 tablets. Marketing Authorisation Holder Immedica Pharma AB SE-113 29 Stockholm Sweden Manufacturer PATHEON France – BOURGOIN JALLIEU 40 boulevard de Champaret BOURGOIN JALLIEU 38300 France This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. 29 Package leaflet: Information for the user AMMONAPS 940 mg/g granules Sodium phenylbutyrate Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What AMMONAPS is and what it is used for 2. What you need to know before you take AMMONAPS 3. How to take AMMONAPS 4. Possible side effects 5. How to store AMMONAPS 6. Contents of the pack and other information 1. What AMMONAPS is and what it is used for AMMONAPS is prescribed to patients with urea cycle disorders. Patients with these rare disorders have a deficiency of certain liver enzymes and are therefore unable to eliminate nitrogen waste. Nitrogen is a building block of proteins, because of this there is a build up of nitrogen in the body after eating protein. Nitrogen waste, in the form of ammonia, is especially toxic for the brain and leads, in severe cases, to reduced levels of consciousness and to coma. AMMONAPS helps the body to eliminate nitrogen waste, reducing the amount of ammonia in your body. 2. What you need to know before you take AMMONAPS Do not take AMMONAPS - if you are pregnant. - if you are breast-feeding. - if you are allergic to sodium phenylbutyrate or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor before taking AMMONAPS - if you suffer from heart failure, a decrease in your kidney function or other diseases where the retention of the sodium salt contained in this medicine may make your condition worse. - if you have decreased kidney or liver function, since AMMONAPS is eliminated from the body through the kidney and liver. AMMONAPS must be combined with a diet reduced in proteins, designed especially for you by the doctor and the dietician. You must follow this diet carefully. AMMONAPS does not completely prevent the occurrence of an acute excess of ammonia in the blood and is not appropriate for treating such a condition, which is a medical emergency. 30 If you require laboratory tests, it is important to remind your doctor that you are taking AMMONAPS, since sodium phenylbutyrate may influence certain laboratory test results. Other medicines and AMMONAPS Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. It is especially important to tell your doctor if you are taking medicines containing: - valproic acid (an antiepileptic drug), - haloperidol (used in certain psychotic disorders), - corticosteroids (cortisone-like medicines that are used to provide relief for inflamed areas of the body), - probenecid (for treatment of hyperuricemia associated with gout) These medicines may change the effect of AMMONAPS and you will need more frequent blood controls. If you are uncertain if your medicines contain these substances, you should check with your doctor or pharmacist. Pregnancy and breast-feeding Do not use AMMONAPS if you are pregnant, because this medicine can harm your unborn baby. If you are a woman who could get pregnant, you must use reliable contraception, during treatment with AMMONAPS. Do not use AMMONAPS if you are breast-feeding, because this medicine can pass into the breast- milk and harm your baby. Driving and using machines No studies on the effects on the ability to drive and use machines have been performed. AMMONAPS contains sodium One small white spoon of AMMONAPS granules contains 149 mg of sodium. One medium sized yellow spoon of AMMONAPS granules contains 408 mg of sodium. One large blue spoon of AMMONAPS granules contains 1200 mg of sodium. To be taken into consideration by patients on a sodium controlled diet. 3. How to take AMMONAPS Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Dosage The daily dose of AMMONAPS will be calculated from your protein tolerance, diet and body weight or body surface. You will need regular blood tests to determine the correct daily dose. Your doctor will tell you the amount of granules you should take. Method of administration You should take AMMONAPS in equally divided doses by mouth, through a gastrostomy (tube that goes through the abdomen to the stomach) or through a nasogastric tube (tube that goes through the nose to the stomach). AMMONAPS must be taken with a special diet reduced in protein. You should take AMMONAPS with each meal or feeding. In small children this can be 4 to 6 times per day. 31 To measure the dose: • Shake the bottle lightly before opening • Use the correct spoon to dispense the following amount of Ammonaps: 1.2 g = small white spoon, 3.3 g = medium sized yellow spoon and 9.7 g = large blue spoon • Take a heaped spoonful of granules out of the bottle • Pass a flat surface, e.g. the back of a knife blade, over the top of the spoon to remove the excess of granules • The granules left in the spoon are one spoonful • Take the correct number of spoonfuls granules from the bottle When taken by mouth Mix the measured dose with solid foods (such as mashed potatoes or apple sauce) or liquid foods (such as water, apple juice, orange juice or protein-free infant formulas) and take it immediately after mixing. Patients with a gastrostomy or nasogastric tube Mix the granules with water until there are no dry granules left (stirring the solution helps to dissolve the granules). When the granules are dissolved in water you get a milky white liquid. Take the solution immediately after mixing. You will need to have treatment and to follow a diet throughout your life, unless you have a successful liver transplantation. If you take more AMMONAPS than you should Patients who have taken very high doses of AMMONAPS experienced: - sleepiness, tiredness, light-headedness and less frequently confusion, - headache, - changes in taste (taste disturbances), - decrease in hearing, - disorientation, - impaired memory, - worsening of existing neurological conditions. If you experience any of these symptoms, you should immediately contact your doctor or the nearest hospital emergency department for supportive treatment. If you forget to take AMMONAPS You should take a dose as soon as possible with your next meal. Make sure that there are at least 3 hours between two doses. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The frequency of possible side effects is listed below. Very common: Affects more than 1 user in 10 Common: Affects 1 to 10 users in 100 Uncommon: Affects 1 to 10 users in 1,000 Rare: Affects 1 to 10 users in 10,000 Very rare: Affects less than 1 user in 10,000 Not known: Frequency cannot be estimated from the available data 32 Very common side effects: irregular menstrual periods and cessation of menstrual periods. If you are sexually active and your period stops altogether, do not assume that this is caused by AMMONAPS. If this occurs, please discuss it with your doctor, because the absence of your period may be caused by pregnancy (see Pregnancy and breast-feeding section above). Common side effects: changes in number of blood cells (red cells, white cells and platelets), reduced appetite, depression, irritability, headache, fainting, fluid retention (swelling), changes in taste (taste disturbances),pain in the abdomen, vomiting, nausea, constipation, skin odour, rash, abnormal kidney function, weight gain, altered laboratory test values. Uncommon side effects: deficiency in red blood cells due to bone marrow depression, bruising, altered heart rhythm, rectal bleeding, stomach irritation, stomach ulcer, inflammation of the pancreas. If persistent vomiting occurs, you should contact your doctor immediately. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store AMMONAPS Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and the bottle label after “EXP”. The expiry date refers to the last day of that month. Do not store above 25°C Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What AMMONAPS contains - The active substance is sodium phenylbutyrate. One gram of AMMONAPS granules contains 940 mg of sodium phenylbutyrate. - The other ingredients are calcium stearate and colloidal anhydrous silica. What AMMONAPS looks like and contents of the pack AMMONAPS granules are off-white. The granules are packaged in plastic bottles with child-resistant caps. Each bottle contains 266 g or 532 g of granules. Three spoons (one small white spoon, one medium sized yellow spoon and one large blue spoon) are included to measure your daily dose. Marketing Authorisation Holder Immedica Pharma AB SE-113 29 Stockholm Sweden Manufacturer PATHEON France – BOURGOIN JALLIEU 33 40 boulevard de Champaret BOURGOIN JALLIEU 38300 France This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to take ammonaps', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. dosage the daily dose of ammonaps will be calculated from your protein tolerance, diet and body weight or body surface. you will need regular blood tests to determine the correct daily dose. your doctor will tell you how many tablets you should take. method of administration you should take ammonaps by mouth in equally divided doses with each meal (for example three times per day).you should take ammonaps with a large volume of water. ammonaps must be taken with a special diet reduced in protein. ammonaps tablets should not be given to children who are not able to swallow tablets. it is recommended that ammonaps granules are used instead. you will need to have treatment and to follow a diet throughout your life, unless you have a successful liver transplantation. if you take more ammonaps than you should patients who have taken very high doses of ammonaps experienced: - sleepiness, tiredness, light-headedness and less frequently confusion, - headache, - changes in taste (taste disturbances), - decrease in hearing, - disorientation, - impaired memory, - worsening of existing neurological conditions. if you experience any of these symptoms, you should immediately contact your doctor or the nearest hospital emergency department for supportive treatment. if you forget to take ammonaps you should take a dose as soon as possible with your next meal. make sure that there are at least 3 hours between two doses. do not take a double dose to make up for a forgotten dose. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'ammonaps', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 'ammonaps', 'Type': 'TREATMENT', 'BeginOffset': 146, 'EndOffset': 154}, {'Text': 'your protein tolerance', 'Type': 'TREATMENT', 'BeginOffset': 179, 'EndOffset': 201}, {'Text': 'regular blood tests', 'Type': 'TEST', 'BeginOffset': 255, 'EndOffset': 274}, {'Text': 'method of administration', 'Type': 'TREATMENT', 'BeginOffset': 372, 'EndOffset': 396}, {'Text': 'ammonaps', 'Type': 'TREATMENT', 'BeginOffset': 413, 'EndOffset': 421}, {'Text': 'a large volume of water', 'Type': 'TREATMENT', 'BeginOffset': 535, 'EndOffset': 558}, {'Text': 'ammonaps', 'Type': 'TREATMENT', 'BeginOffset': 560, 'EndOffset': 568}, {'Text': 'ammonaps tablets', 'Type': 'TREATMENT', 'BeginOffset': 623, 'EndOffset': 639}, {'Id': 1, 'BeginOffset': 732, 'EndOffset': 749, 'Score': 0.30477893352508545, 'Text': 'ammonaps granules', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 790, 'EndOffset': 799}, {'Text': 'a successful liver transplantation', 'Type': 'TREATMENT', 'BeginOffset': 859, 'EndOffset': 893}, {'Id': 3, 'BeginOffset': 1004, 'EndOffset': 1014, 'Score': 0.8252826929092407, 'Text': 'sleepiness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8114113211631775}]}, {'Id': 4, 'BeginOffset': 1016, 'EndOffset': 1025, 'Score': 0.9968653321266174, 'Text': 'tiredness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.962749719619751}]}, {'Id': 5, 'BeginOffset': 1027, 'EndOffset': 1043, 'Score': 0.9980584979057312, 'Text': 'light-headedness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9608060121536255}]}, {'Text': 'less frequently confusion', 'Type': 'PROBLEM', 'BeginOffset': 1048, 'EndOffset': 1073}, {'Id': 7, 'BeginOffset': 1077, 'EndOffset': 1085, 'Score': 0.9982227683067322, 'Text': 'headache', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9598027467727661}]}, {'Text': 'changes in taste (taste disturbances', 'Type': 'PROBLEM', 'BeginOffset': 1089, 'EndOffset': 1125}, {'Id': 10, 'BeginOffset': 1130, 'EndOffset': 1149, 'Score': 0.438324511051178, 'Text': 'decrease in hearing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8179340362548828}]}, {'Id': 11, 'BeginOffset': 1153, 'EndOffset': 1167, 'Score': 0.9851855635643005, 'Text': 'disorientation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8502269983291626}]}, {'Id': 12, 'BeginOffset': 1171, 'EndOffset': 1186, 'Score': 0.9111800789833069, 'Text': 'impaired memory', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8394293189048767}]}, {'Text': 'worsening of existing neurological conditions', 'Type': 'PROBLEM', 'BeginOffset': 1190, 'EndOffset': 1235}, {'Text': 'these symptoms', 'Type': 'PROBLEM', 'BeginOffset': 1262, 'EndOffset': 1276}, {'Id': 14, 'BeginOffset': 1345, 'EndOffset': 1365, 'Score': 0.9714096188545227, 'Text': 'emergency department', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'ADDRESS', 'Traits': []}, {'Text': 'supportive treatment', 'Type': 'TREATMENT', 'BeginOffset': 1370, 'EndOffset': 1390}, {'Id': 2, 'BeginOffset': 1414, 'EndOffset': 1422, 'Score': 0.35826995968818665, 'Text': 'ammonaps', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 1521, 'EndOffset': 1522}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 1560, 'EndOffset': 1573}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1655, 'EndOffset': 1668}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the frequency of possible side effects is listed below. very common: affects more than 1 user in 10 common: affects 1 to 10 users in 100 uncommon: affects 1 to 10 users in 1,000 rare: affects 1 to 10 users in 10,000 very rare: affects less than 1 user in 10,000 not known: frequency cannot be estimated from the available data very common side effects: irregular menstrual periods and cessation of menstrual periods. if you are sexually active and your period stops altogether, do not assume that this is caused by ammonaps. if this occurs, please discuss it with your doctor, because the absence of your period may be caused by pregnancy (see pregnancy and breast-feeding section above). common side effects: changes in number of blood cells (red cells, white cells and platelets), reduced appetite, depression, irritability, headache, fainting, fluid retention (swelling), changes in taste (taste disturbances),pain in the abdomen, vomiting, nausea, constipation, skin odour, rash, abnormal kidney function, weight gain, altered laboratory test values. uncommon side effects: deficiency in red blood cells due to bone marrow depression, bruising, altered heart rhythm, rectal bleeding, stomach irritation, stomach ulcer, inflammation of the pancreas. if persistent vomiting occurs, you should contact your doctor immediately. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'ammonaps', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 9, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9633492231369019, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.64741051197052}]}, {'Id': 10, 'BeginOffset': 118, 'EndOffset': 130, 'Score': 0.8946520090103149, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6957399845123291}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 179, 'EndOffset': 180}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 189, 'EndOffset': 191}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 208, 'EndOffset': 209}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 213, 'EndOffset': 215}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 225, 'EndOffset': 228}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 247, 'EndOffset': 248}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 252, 'EndOffset': 254}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 264, 'EndOffset': 269}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 284, 'EndOffset': 285}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 289, 'EndOffset': 291}, {'Text': '10,000', 'Type': 'NUMBER', 'BeginOffset': 301, 'EndOffset': 307}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 337, 'EndOffset': 338}, {'Text': '10,000', 'Type': 'NUMBER', 'BeginOffset': 347, 'EndOffset': 353}, {'Id': 11, 'BeginOffset': 431, 'EndOffset': 443, 'Score': 0.7434471845626831, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.54529869556427}]}, {'Id': 12, 'BeginOffset': 445, 'EndOffset': 472, 'Score': 0.6346709132194519, 'Text': 'irregular menstrual periods', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7493974566459656}]}, {'Id': 13, 'BeginOffset': 490, 'EndOffset': 507, 'Score': 0.820941150188446, 'Text': 'menstrual periods', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8765824437141418}]}, {'Id': 14, 'BeginOffset': 520, 'EndOffset': 535, 'Score': 0.9621040225028992, 'Text': 'sexually active', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.900955080986023}]}, {'Text': 'pregnancy (see pregnancy', 'Type': 'PROBLEM', 'BeginOffset': 721, 'EndOffset': 745}, {'Text': 'breast-feeding section', 'Type': 'TREATMENT', 'BeginOffset': 750, 'EndOffset': 772}, {'Text': 'common side effects', 'Type': 'PROBLEM', 'BeginOffset': 781, 'EndOffset': 800}, {'Id': 18, 'BeginOffset': 802, 'EndOffset': 834, 'Score': 0.8516196608543396, 'Text': 'changes in number of blood cells', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 55, 'BeginOffset': 836, 'EndOffset': 845, 'Score': 0.44586771726608276, 'Text': 'red cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'white cells', 'Type': 'TEST', 'BeginOffset': 847, 'EndOffset': 858}, {'Text': 'platelets', 'Type': 'TEST', 'BeginOffset': 863, 'EndOffset': 872}, {'Text': 'reduced appetite', 'Type': 'PROBLEM', 'BeginOffset': 875, 'EndOffset': 891}, {'Id': 20, 'BeginOffset': 893, 'EndOffset': 903, 'Score': 0.9975147247314453, 'Text': 'depression', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8987703919410706}]}, {'Id': 21, 'BeginOffset': 905, 'EndOffset': 917, 'Score': 0.9991004467010498, 'Text': 'irritability', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.933651328086853}]}, {'Id': 22, 'BeginOffset': 919, 'EndOffset': 927, 'Score': 0.9995859265327454, 'Text': 'headache', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9704476594924927}]}, {'Id': 23, 'BeginOffset': 929, 'EndOffset': 937, 'Score': 0.9933411478996277, 'Text': 'fainting', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9618893265724182}]}, {'Id': 24, 'BeginOffset': 939, 'EndOffset': 954, 'Score': 0.9744051098823547, 'Text': 'fluid retention', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.951939582824707}]}, {'Id': 25, 'BeginOffset': 956, 'EndOffset': 964, 'Score': 0.9902564287185669, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.967388391494751}]}, {'Text': 'changes in taste (taste disturbances', 'Type': 'PROBLEM', 'BeginOffset': 967, 'EndOffset': 1003}, {'Text': 'pain in the abdomen', 'Type': 'PROBLEM', 'BeginOffset': 1005, 'EndOffset': 1024}, {'Id': 29, 'BeginOffset': 1026, 'EndOffset': 1034, 'Score': 0.9942197799682617, 'Text': 'vomiting', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9613228440284729}]}, {'Id': 30, 'BeginOffset': 1036, 'EndOffset': 1042, 'Score': 0.9995723366737366, 'Text': 'nausea', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9761106371879578}]}, {'Id': 31, 'BeginOffset': 1044, 'EndOffset': 1056, 'Score': 0.9996656179428101, 'Text': 'constipation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.97107994556427}]}, {'Id': 32, 'BeginOffset': 1058, 'EndOffset': 1068, 'Score': 0.9498388171195984, 'Text': 'skin odour', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9539608359336853}]}, {'Id': 33, 'BeginOffset': 1070, 'EndOffset': 1074, 'Score': 0.9990756511688232, 'Text': 'rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.975435197353363}]}, {'Id': 34, 'BeginOffset': 1076, 'EndOffset': 1100, 'Score': 0.9287369251251221, 'Text': 'abnormal kidney function', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9531803727149963}]}, {'Id': 2, 'BeginOffset': 1085, 'EndOffset': 1091, 'Score': 0.9906572103500366, 'Text': 'kidney', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 35, 'BeginOffset': 1102, 'EndOffset': 1113, 'Score': 0.9927088022232056, 'Text': 'weight gain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8796451091766357}]}, {'Id': 36, 'BeginOffset': 1115, 'EndOffset': 1145, 'Score': 0.40099814534187317, 'Text': 'altered laboratory test values', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'uncommon side effects', 'Type': 'PROBLEM', 'BeginOffset': 1147, 'EndOffset': 1168}, {'Text': 'deficiency in red blood cells', 'Type': 'PROBLEM', 'BeginOffset': 1170, 'EndOffset': 1199}, {'Id': 39, 'BeginOffset': 1207, 'EndOffset': 1229, 'Score': 0.5099768042564392, 'Text': 'bone marrow depression', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7425922155380249}]}, {'Id': 40, 'BeginOffset': 1231, 'EndOffset': 1239, 'Score': 0.9934784173965454, 'Text': 'bruising', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.830803394317627}]}, {'Id': 41, 'BeginOffset': 1241, 'EndOffset': 1261, 'Score': 0.9476794004440308, 'Text': 'altered heart rhythm', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4419301152229309}]}, {'Id': 4, 'BeginOffset': 1249, 'EndOffset': 1254, 'Score': 0.9525547027587891, 'Text': 'heart', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 42, 'BeginOffset': 1263, 'EndOffset': 1278, 'Score': 0.981869637966156, 'Text': 'rectal bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8163073062896729}]}, {'Id': 43, 'BeginOffset': 1280, 'EndOffset': 1298, 'Score': 0.9849900007247925, 'Text': 'stomach irritation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8467473983764648}]}, {'Id': 44, 'BeginOffset': 1300, 'EndOffset': 1313, 'Score': 0.9872223734855652, 'Text': 'stomach ulcer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6403799057006836}, {'Name': 'DIAGNOSIS', 'Score': 0.5116469860076904}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9853196144104004, 'RelationshipScore': 0.9128608703613281, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 7, 'BeginOffset': 1335, 'EndOffset': 1343, 'Text': 'pancreas', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'inflammation of the pancreas', 'Type': 'PROBLEM', 'BeginOffset': 1315, 'EndOffset': 1343}, {'Text': 'persistent vomiting', 'Type': 'PROBLEM', 'BeginOffset': 1348, 'EndOffset': 1367}, {'Id': 57, 'BeginOffset': 1407, 'EndOffset': 1418, 'Score': 0.9999963045120239, 'Text': 'immediately', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.9972067475318909, 'RelationshipScore': 0.7149173617362976, 'RelationshipType': 'OVERLAP', 'Id': 47, 'BeginOffset': 1359, 'EndOffset': 1367, 'Text': 'vomiting', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8583303689956665}]}]}, {'Id': 48, 'BeginOffset': 1433, 'EndOffset': 1445, 'Score': 0.9464550614356995, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8015707731246948}]}, {'Id': 49, 'BeginOffset': 1461, 'EndOffset': 1473, 'Score': 0.927300214767456, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7702286243438721}]}, {'Id': 50, 'BeginOffset': 1537, 'EndOffset': 1549, 'Score': 0.9565370678901672, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6589419841766357}]}, {'Id': 51, 'BeginOffset': 1598, 'EndOffset': 1610, 'Score': 0.8692007064819336, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7127127647399902}]}, {'Id': 52, 'BeginOffset': 1664, 'EndOffset': 1675, 'Score': 0.3957371413707733, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6254472732543945}]}, {'Id': 53, 'BeginOffset': 1689, 'EndOffset': 1701, 'Score': 0.8627779483795166, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7462045550346375}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1757, 'EndOffset': 1770}]}

{'Title': '5. how to store ammonaps', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and the bottle label after "exp". the expiry date refers to the last day of that month. do not store above 30. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what ammonaps contains - the active substance is sodium phenylbutyrate. each tablet of ammonaps contains 500 mg of sodium phenylbutyrate. - the other ingredients are microcrystalline cellulose, magnesium stearate and colloidal anhydrous silica. what ammonaps looks like and contents of the pack ammonaps tablets are off-white, oval and embossed with "ucy 500". the tablets are packaged in plastic bottles with child-resistant caps. each bottle contains 250 or 500 tablets.', 'Entity_Recognition': [{'Text': 'ammonaps', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 49, 'EndOffset': 70, 'Score': 0.9909177422523499, 'Text': 'sodium phenylbutyrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.2662223279476166, 'RelationshipScore': 0.9634901881217957, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 1, 'BeginOffset': 72, 'EndOffset': 83, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 2, 'BeginOffset': 87, 'EndOffset': 104, 'Score': 0.4561344087123871, 'Text': 'ammonaps contains', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.2662223279476166, 'RelationshipScore': 0.9998350143432617, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 1, 'BeginOffset': 72, 'EndOffset': 83, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 105, 'EndOffset': 108}, {'Id': 4, 'BeginOffset': 115, 'EndOffset': 136, 'Score': 0.9994053840637207, 'Text': 'sodium phenylbutyrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.2662223279476166, 'RelationshipScore': 0.9737232327461243, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 1, 'BeginOffset': 72, 'EndOffset': 83, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.879055917263031, 'RelationshipScore': 0.9881565570831299, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 105, 'EndOffset': 111, 'Text': '500 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 166, 'EndOffset': 192, 'Score': 0.9953896999359131, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 194, 'EndOffset': 212, 'Score': 0.9952231049537659, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 217, 'EndOffset': 243, 'Score': 0.9738145470619202, 'Text': 'colloidal anhydrous silica', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the pack ammonaps tablets', 'Type': 'TREATMENT', 'BeginOffset': 286, 'EndOffset': 311}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 355, 'EndOffset': 358}, {'Text': 'the tablets', 'Type': 'TREATMENT', 'BeginOffset': 361, 'EndOffset': 372}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 453, 'EndOffset': 456}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 460, 'EndOffset': 463}]}

04034542AB28557EFC1CC133B66770F7

https://www.ema.europa.eu/documents/product-information/apealea-epar-product-information_en.pdf

Apealea

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Apealea 60 mg powder for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One vial of powder contains 60 mg of paclitaxel. After reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar). Excipients with known effect Each vial contains 3.77 mg (0.164 mmol) sodium. After reconstitution, each mL of solution contains up to approximately 3.60 mg (0.157 mmol) sodium. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for solution for infusion. Greenish-yellow to yellow powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Apealea in combination with carboplatin is indicated for the treatment of adult patients with first relapse of platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer (see section 5.1). 4.2 Posology and method of administration Apealea should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents. It should not be interchanged with other paclitaxel formulations. Posology The recommended dose of Apealea is 250 mg/m2 body surface area (BSA) given as an intravenous infusion over 1 hour followed by carboplatin every three weeks for six cycles. The recommended dose of carboplatin is AUC = 5–6 mg/mL×min. Dose adjustments and delays during treatment Patients who experience neutropenia (neutrophil count < 1.5 × 109/L), febrile neutropenia or thrombocytopenia (platelet count < 100 × 109/L) during treatment should have the next treatment cycle delayed until neutrophil counts recover to ≥ 1.5 × 109/L and platelets recover to ≥ 100 × 109/L. For Apealea, dose reductions of initially 50 mg/m2 and additionally 25 mg/m2 should be considered for subsequent courses (see Table 1). In the case of febrile neutropenia or low platelet count (< 75 × 109/L), the dose of carboplatin should be reduced by 1 AUC unit in the treatment cycles following recovery. For appropriate use of carboplatin, the prescriber is advised to consult the prescribing information for carboplatin as well. 3 Dose reductions or/and delays should be considered as a result of any clinically significant adverse reaction as presented in Table 1. Table 1. Treatment delay and dose level reductions for adverse drug reactions Observationa Delay of next cycle Apealea/carboplatin Apealea dose for subsequent courses (mg/m2)b Haematological toxicityb neutrophil count < 1.5 × 109/L or platelet count < 100 × 109/L or febrile neutropenia Withhold treatment until recovery Standard dose: 250 Possible dose reductions: First dose level reduction: 200 Second dose level reduction: 175 Nervous system disorders grade ≥ 2 peripheral sensory neuropathy or grade ≥ 2 motor neuropathy Withhold treatment until recovery to < grade 2 Dose reduction: First dose level reduction: 200 Possible dose reduction: Second dose level reduction: 175 All other adverse reactions Any grade 4 toxicity Discontinue treatment Any grade 3 toxicity except nausea, vomiting and diarrhoea Withhold treatment until symptoms resolve to grade ≤ 1 Possible dose reductions: First dose level reduction: 200 Second dose level reduction: 175 a Grade of the adverse reaction is defined according to Common Terminology Criteria for Adverse Events (CTCAE). b The dose of carboplatin should be reduced by 1 AUC unit for treatment cycles following the occurrence of febrile neutropenia or low platelet count (< 75 × 109/L). Special populations Hepatic impairment Patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 × upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ 10 × ULN) may be treated with the same doses as patients with normal hepatic function. For patients with moderate to severe impairment (total bilirubin > 1.5 to ≤ 5 × ULN and AST ≤ 10 × ULN), a 20% reduction in dose is recommended. The reduced dose may be escalated to the dose for patients with normal hepatic function if the patient is tolerating the treatment for at least two cycles (see sections 4.4 and 5.2). For patients with total bilirubin > 5 × ULN or AST > 10 × ULN, there are insufficient data to permit dosage recommendations (see sections 4.4 and 5.2). Renal impairment Patients with mildly or moderately impaired renal function (glomerular filtration rate (GFR) 89−60 mL/min or GFR 59−30 mL/min, respectively) may be treated with Apealea without a dose modification. Patients with severe renal impairment (GFR < 30 mL/min) should not be treated with paclitaxel (see section 5.2). 4 Elderly No additional dosage reductions, other than those for all patients, are recommended for patients 65 years and older. Of the 391 patients with ovarian cancer in the randomised study who received Apealea in combination with carboplatin, 13% were between 65 and 74 years old. In this limited number of patients, anorexia, fatigue, myalgia, arthralgia, peripheral sensory neuropathy, and diarrhoea were observed more frequently compared to patients younger than 65 years. Limited data are available on use in patients ≥ 75 years (2% of the patients in the study). Non-Caucasian patients There are limited data of Apealea in non-Caucasian patients and current data is insufficient to recommend additional dose adjustments (see section 4.4). If neuropathy is observed, follow dose reduction recommendations in Table 1. Paediatric population There is no relevant use of paclitaxel in the paediatric population for the indications of epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer. The safety and efficacy of Apealea in children and adolescents aged 0−17 years has not been established. Method of administration Apealea is for intravenous use. After reconstitution of the powder, the solution for infusion is a clear, greenish-yellow solution. The solution should be administered by an intravenous infusion over approximately one hour (120−140 drops/min). Administration sets containing a 15 µm polyamide fluid filter should be used. It is important to flush the infusion set and catheter/cannula before and after the administration using the solution for reconstitution in order to avoid accidental administration into the surrounding tissue and to ensure administration of the complete dose. For instructions on reconstitution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4). Breast-feeding (see section 4.6). Baseline neutrophil count < 1.5 × 109/L. 4.4 Special warnings and precautions for use Haematology Paclitaxel causes myelosuppression (primarily neutropenia). Neutropenia is a dose-dependent and dose-limiting adverse reaction. Therefore, frequent complete blood cell counts should be performed during treatment with Apealea. In the pivotal study, about a third of the patients received granulocyte colony stimulating factor (GCSF) to treat neutropenia and clinicians should consider whether individual cases could benefit from GCSF. Patients should not be treated with subsequent cycles until neutrophils recover to ≥ 1.5 × 109/L and platelets recover to ≥ 100 × 109/L. Patients with low neutrophil count should be made aware of the increased risk of infections. The risk of myelosuppression is increased due to the combination use with carboplatin. Dose recommendations for Apealea as well as for carboplatin in the case of myelosuppression should be followed (see section 4.2). 5 Neuropathy Peripheral sensory neuropathy and peripheral neuropathy are very common adverse reactions. For CTCAE grade ≥ 2 sensory or motor neuropathy withhold treatment until resolution to < grade 2, followed by a dose reduction for all subsequent courses (see section 4.2). Hepatic impairment Patients with hepatic impairment have not been studied with Apealea but may be at increased risk of toxicity, particularly from myelosuppression. Administration in patients with hepatic impairment defined as total bilirubin > 1 to ≤ 5 × ULN and AST ≤ 10 × ULN (see section 4.2) should therefore be performed with caution and they should be closely monitored with regard to increased liver impairment and myelosuppression. Patients that have total bilirubin > 5 × ULN or AST > 10 × ULN should not be treated with paclitaxel. Gastrointestinal symptoms Gastrointestinal adverse reactions are very common. If patients experience nausea, vomiting and diarrhoea following the administration of Apealea, they may be treated with antiemetics and/or antidiarrhoeal agents. Premedication may be considered in patients who have previously experienced gastrointestinal symptoms when being treated with cytotoxic medicinal products. Infusion-associated reactions Local reactions at the infusion site are very common during Apealea infusions. The infusion site reactions observed include pain, phlebitis, discolouration, redness, oedema and rash. These reactions are more common on the first infusion and may be improved by slowing the rate of infusion. Patients who experience severe pain or other reactions to the infusion of Apealea are recommended to be considered for a central venous catheter. Care should be taken to avoid accidental administration into the surrounding tissue during intravenous administration. If any sign of extravasal injection occurs, take immediate action: terminate the infusion, aspirate fluid from the catheter/cannula before the needle is withdrawn, infuse the affected area with sterile saline or lactated or acetated Ringer’s solution and closely monitor the area. To avoid accidental administration into the surrounding tissue and to ensure intravenous delivery of the complete dose, flush the infusion set and catheter/cannula before as well as after the administration. Hypersensitivity Most hypersensitivity reactions related to Apealea are mild to moderate and mainly occur as skin and subcutaneous tissue disorders, general disorders and administration site conditions, but serious hypersensitivity reactions including anaphylactic shock have been reported. Minor symptoms such as flushing or skin reactions do not require interruption of therapy. Moderate cases may require premedication with corticosteroids, antihistamines and/or H2 antagonists for the following treatment cycles. Severe reactions, such as hypotension requiring treatment, dyspnoea requiring bronchodilators, angioedema or generalised urticaria require immediate discontinuation of paclitaxel and initiation of symptomatic treatment. Patients experiencing severe reactions should not be re-challenged with paclitaxel. Patients should be observed closely during treatment, particularly those patients who previously suffered hypersensitivity reactions with any taxane formulation. The true incidence, severity and time to onset of hypersensitivity reactions due to Apealea could not be established during clinical development due to the combination treatment with carboplatin. Delayed reactions related to paclitaxel occurring during or after infusion of carboplatin cannot be excluded. Alopecia Alopecia is a very common adverse reaction and occurs early in treatment. It can have a marked impact on the patients’ self-image and quality of life and patients should be counselled about the 6 likelihood of this adverse effect and on what measures might be available to mitigate it, for example the use of cold caps. In studies with Apealea, 45% of patients reported alopecia during therapy. Cardiotoxicity Heart failure has been observed in some patients receiving Apealea. In some of the cases, the patients had previously been exposed to cardiotoxic medicinal products such as doxorubicin or had underlying cardiac history. These patients should be vigilantly monitored by physicians for the occurrence of cardiac events. Patients 65 years and older There was no marked difference in overall tolerability between the 65–74 age group and younger patients. Limited data are available on use in patients ≥ 75 years. In view of this, and of the potential for frailty and co-morbidities, elderly patients should be carefully monitored. Race There are limited data on the use of Apealea in non-Caucasian patients. However, studies in breast cancer patients treated with paclitaxel-containing regimens indicate a possible increased risk of neuropathy in non-Caucasian patients (see section 4.2). Excipients When reconstituted, this medicinal product contains up to approximately 1.6 g sodium per dose (0.9 g/m2 BSA; 3.6 mg per mL), equivalent to 80% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 4.5 Interaction with other medicinal products and other forms of interaction No studies have been performed to evaluate drug-drug interactions between Apealea and other medicinal products. The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower paclitaxel exposures. Apealea contains a mixture of two retinoic acid derivatives as excipients. In vitro studies using human microsomes have shown these derivatives to have inhibitory activity on CYP2B6, CYP2C8, CYP2C9, and to a lesser extent on CYP2D6. In the absence of in vivo studies addressing inhibition of CYP2B6 and CYP2C9, the concomitant use of Apealea and substances metabolised primarily by these CYP enzymes should be exercised with caution. Apealea is indicated to be used in combination with carboplatin (see section 4.1). Apealea should be administered first, then carboplatin. Based on literature data, no clinically relevant pharmacokinetic interaction between paclitaxel and carboplatin is expected. Clinically relevant pharmacokinetic interaction has been observed between paclitaxel and cisplatin. When paclitaxel is given before cisplatin, the safety profile of solvent-based paclitaxel is consistent with that reported for single-agent use. When solvent-based paclitaxel was given after cisplatin, patients showed a more profound myelosuppression and an approximately 20% decrease in paclitaxel clearance. A similar effect can be anticipated for Apealea (paclitaxel micellar). Patients treated with 7 paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynaecological cancers. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/Contraception Women of childbearing potential must use effective contraception during treatment and for six months afterwards. Pregnancy There are very limited data on the use of paclitaxel in pregnant women. Paclitaxel is suspected to cause serious birth defects when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). Paclitaxel should not be used during pregnancy unless the clinical condition requires this treatment. Breast-feeding Paclitaxel is excreted in human milk. Because of potential serious adverse reactions in children being breastfed, Apealea is contraindicated during lactation. Breast-feeding must be discontinued for the duration of therapy. Fertility Studies in animals being treated with paclitaxel have shown decreased fertility (see section 5.3). 4.7 Effects on ability to drive and use machines Apealea has moderate influence on the ability to drive or use machines. Apealea may cause adverse reactions such as fatigue (very common) and dizziness (common) that may affect the ability to drive or use machinery. Patients should be advised not to drive or use machines if they feel tired or dizzy. 4.8 Undesirable effects Summary of the safety profile The most common clinically significant adverse reactions associated with the use of Apealea are neutropenia, gastrointestinal disorders, peripheral neuropathy, arthralgia/myalgia, and infusion site reactions. Approximately 86% of patients experienced adverse reactions. Tabulated list of adverse reactions The frequency of undesirable effects listed in Table 2 is defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 2 lists adverse reactions associated with the administration of Apealea in combination with carboplatin observed in a clinical study (N = 391) and adverse reactions from post-marketing experience. The latter ones may be attributed to paclitaxel regardless of the treatment regimen. 8 Table 2. Listing of adverse reactions System Organ Class Frequency Preferred term Infections and infestations Uncommon: Sepsis, abscess, pneumonia, influenza, respiratory tract infection viral, herpes simplex, infusion site cellulitis, tonsillitis, urinary tract infection, skin infection, cystitis Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Uncommon: Metastatic pain Blood and lymphatic system disorders Very common: Neutropeniaa Common: Febrile neutropeniaa, leukopeniaa, thrombocytopeniaa, granulocytopenia, anaemiaa Uncommon: Disseminated intravascular coagulationa, pancytopenia, haematotoxicity, coagulopathy Immune system disorders Common: Hypersensitivity Uncommon: Anaphylactic shock, drug hypersensitivity Metabolism and nutrition disorders Very common: Anorexia Uncommon: Hyponatraemia, hypokalaemia, hypomagnesaemia, dehydration, decreased appetite Psychiatric disorders Uncommon: Depression, insomnia, anxiety Nervous system disorders Very common: Peripheral sensory neuropathya,b, neuropathy peripherala,b Common: Hypoaesthesia, dizziness, paraesthesia, peripheral motor neuropathy, dysgeusia, headache Uncommon: Status epilepticus, coma, cerebrovascular accident, peripheral sensorimotor neuropathy, lethargy, hypotonia, neurotoxicity, polyneuropathy, polyneuropathy in malignant disease, burning sensation, somnolence, cognitive disorder, facial palsy, encephalopathy, hydrocephalus Eye disorders Uncommon: Vision blurred, eye irritation, ocular discomfort, lacrimation increased Ear and labyrinth disorders Uncommon: Vertigo, deafness, inner ear disorder, tinnitus Cardiac disorders Common: Angina pectoris, tachycardia Uncommon: Cardiac arrest, cardiac failure chronic, cyanosis, atrial fibrillation, sinus tachycardia, palpitations, sinus bradycardia Vascular disorders Common: Hypotension, flushing, phlebitis, vein pain, hyperaemia Uncommon: Circulatory collapse, venous thrombosis, vasculitis, thrombosis, hypertension, deep vein thrombosis, lymphoedema, phlebitis superficial, thrombophlebitis, blood pressure fluctuation, haemorrhage, angiopathy, hot flush, pallor 9 System Organ Class Frequency Preferred term Respiratory, thoracic and mediastinal disorders Common: Dyspnoea, nasal congestion Uncommon: Respiratory failure, epistaxis, cough, rhinorrhoea, oropharyngeal pain, pharyngeal disorder, asphyxia, bronchospasm, dysphonia, rhinitis allergic, allergic cough, oropharyngeal discomfort Gastrointestinal disorders Very common: Diarrhoeaa, nauseaa, vomitinga Common: Abdominal pain, constipation, abdominal pain upper, flatulence, dry mouth, stomatitis Uncommon: Abdominal distension, gastritis, abdominal discomfort, abdominal pain lower, dyspepsia, faecaloma, intestinal functional disorder, gingival bleeding, haematochezia, paraesthesia oral Hepatobiliary disorders Uncommon: Hepatitis, liver disorder Skin and subcutaneous tissue disorders Very common: Alopeciaa Common: Erythema, rash, pruritus, urticaria Uncommon: Angioedema, rash generalised, skin discolouration, hyperhidrosis, rash papular, dermatitis bullous, swelling face, pigmentation disorder, dry skin, cold sweat, livedo reticularis, nail disorder, pruritus allergic, skin disorder Not known: Palmar-plantar erythrodysesthesia syndromec Musculoskeletal and connective tissue disorders Very common: Arthralgiaa, myalgiaa Common: Back pain, bone pain, musculoskeletal pain, muscular weakness, pain in extremity Uncommon: Haemarthrosis, musculoskeletal discomfort, sensation of heaviness Renal and urinary disorders Uncommon: Azotaemia Reproductive system and breast disorders Uncommon: Vaginal haemorrhage, pelvic pain, breast pain General disorders and administration site conditions Very common: Astheniaa, fatiguea, infusion site reactiona,d Common: Oedema peripheral, pain, pyrexia, chest discomfort, hyperthermia, face oedema Uncommon: Death, multi-organ failure, oedema, administration site pain, catheter site haemorrhage, catheter site oedema, local swelling, generalised oedema, hernia, chest pain, influenza like illness, localised oedema, hypothermia, chills, feeling hot Investigations Uncommon: Alanine aminotransferase increased a See Description of selected adverse reactions. b Can persist beyond 6 months of paclitaxel discontinuation.c c As reported in the post-marketing surveillance of paclitaxel. d Includes the following preferred terms: infusion site pain, infusion site phlebitis, infusion site reaction, infusion site discolouration, infusion site erythema, infusion site extravasation, infusion site inflammation, infusion site oedema, infusion site paraesthesia, infusion site irritation, and infusion site rash. 10 Description of selected adverse reactions In the pivotal clinical study, patients were either treated with Apealea (paclitaxel micellar) at a dose of 250 mg/m2 in combination with carboplatin or with solvent-based paclitaxel at a dose of 175 mg/m2 in combination with carboplatin (N = 391 in each arm). Overall, there were higher rates of serious adverse events with paclitaxel micellar (41%) than with solvent-based paclitaxel (27%). In both groups, the majority of the serious adverse events were haematological toxicities. There were no differences in Eastern Cooperative Oncology Group (ECOG) performance score between the two study groups at any time during or after treatment (mainly score 0 or 1). Blood and lymphatic system disorders Almost all patients treated with Apealea had neutropenia of some grade, 79% of the patients had grade 3 or 4. Neutropenia as a serious adverse reaction occurred in 29% of the patients and febrile neutropenia occurred in 3% of the patients. Neutropenia resolved to ≥ 1.5 × 109/L before the next course of treatment. Almost all patients experienced anaemia, decreased platelet count and decreased white blood cell count of any grade during the treatment period (98%, 93% and 98%, respectively). Anaemia as serious adverse event occurred in 5% of the patients, thrombocytopenia and leukopenia in 3% and 6% of the patients, respectively. In comparison to the patients receiving solvent-based paclitaxel, there were more patients in the group receiving paclitaxel micellar who experienced haematological toxicities with grade 3 and 4. Neutropenia occurred in 79% and 66%, leukopenia in 53% and 34%, thrombocytopenia in 18% and 10%, and anaemia in 24% and 14% of the patients in the treatment arms receiving either paclitaxel micellar or solvent-based paclitaxel, respectively. Disseminated intravascular coagulation (DIC), often in association with sepsis or multi-organ failure, has been reported. Gastrointestinal disorders Nausea (38%), vomiting (22%) and diarrhoea (15%) were among the most commonly reported adverse reactions in the study. Nervous system disorders Peripheral neuropathies (including the preferred terms neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, and polyneuropathy in malignant disease) were reported in 29% of the patients and were mostly (98%) mild to moderate (CTCAE grade ≤ 2). The average time to onset was 53 days from the first dose. Peripheral sensory neuropathy represented the most common reaction and was reported in 16% of patients. Other associated reactions were reported in 10% of the patients and were mostly (98%) mild to moderate (CTCAE grade ≤ 2). Paraesthesia and hypoaesthesia were the most common ones. During the course of the pivotal study, 46% of the peripheral neuropathies as well as the majority (78%) of the associated reactions resolved. The dose-dependency of frequency and severity of neurotoxicity was not studied for Apealea, but has been observed for other paclitaxel formulations in other indications. Further, it has been demonstrated that peripheral neuropathies can persist beyond 6 months of paclitaxel discontinuation. Hypersensitivity reactions Most hypersensitivity reactions related to Apealea were mild to moderate (see section 4.4). The frequency of paclitaxel-related hypersensitivity reactions was similar in both groups (5% of the patients receiving paclitaxel micellar and 7% of the patients receiving solvent-based paclitaxel), whereas a higher frequency of carboplatin-related hypersensitivity reactions was observed in the group receiving paclitaxel micellar (12% vs 7%). As a result of the combined treatment, it is not possible to determine whether this observation is due to Apealea or to other factors, and delayed reactions related to paclitaxel cannot be excluded. 11 Skin and subcutaneous tissue disorders Alopecia was observed in 45% of patients and was abrupt in onset. Pronounced hair loss of ≥ 50% is expected for the majority of patients who experience alopecia. Musculoskeletal and connective tissue disorders Arthralgia occurred in 19% of patients and myalgia in 10%. General disorders and administration site conditions Asthenia and fatigue were very common and occurred in 23% and 11% of patients, respectively. Infusion site reactions, such as pain, phlebitis, and erythema, were seen in 12% of patients (see section 4.4). There were more reports of infusion site pain in the group receiving paclitaxel micellar as compared to the group treated with solvent-based paclitaxel (8% and 1%, respectively). Additional experience from clinical studies Apealea has been given as monotherapy in a total of 132 patients at doses ranging between 90 mg/m2 in a 3-week regimen to weekly doses of 250 mg/m2 for various indications. Based on the combined data from monotherapy studies, very common adverse reactions and those of special interest were the following: neutropenia (45%), fatigue (37%), leukopenia (33%), alopecia (30%), nausea (27%), infusion site reactiona (23%), peripheral sensory neuropathy (20%), diarrhoea (17%), asthenia (15%), pyrexia (12%), constipation (12%), arthralgia (12%), paraesthesia (11%), pain (11%), vomiting (9%), myalgia (9%), peripheral motor neuropathy (5%), neuropathy (5%), neuropathy peripheral (5%), thrombocytopenia (4%), febrile neutropenia (2%), sepsis (2%), tachycardia (2%), phlebitis (2%), thrombosis (2%). a Includes the following preferred terms: infusion site phlebitis, infusion site pain, injection site reaction, injection site inflammation, infusion site erythema, injection site extravasation, infusion site reaction, injection site oedema. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should be closely monitored. Treatment should be directed at the major anticipated toxicities, which are nausea, vomiting, diarrhoea, myelosuppression, peripheral sensory neuropathy and peripheral neuropathy. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, taxanes, ATC code: L01CD01 Mechanism of action Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. Stabilisation results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and 12 mitotic cellular functions. In addition, paclitaxel induces microtubule bundle formation throughout the cell cycle and induces microtubule aster formation during mitosis. Clinical efficacy and safety An open, randomised, multicentre study was conducted in 789 women with recurrent epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer to compare Apealea (paclitaxel micellar) in combination with carboplatin with solvent-based paclitaxel in combination with carboplatin. Patients were treated every three weeks for six cycles, either with Apealea 250 mg/m2 given as a 1-hour intravenous infusion (N = 391) or with solvent-based paclitaxel 175 mg/m2 given as a 3-hour infusion (N = 391). The paclitaxel infusion was followed by carboplatin after an interval of 30 minutes in both treatment arms. Patients were stratified based on relapse (first or second) and CA125 values. The proportions of patients treated at first or second relapse were then equal in both treatment groups (76% were treated at first relapse and 24% at second relapse). Patients who had pre-existing neuropathy of grade ≥ 2 or serious medical risk factors involving any of the major organ systems were not allowed to enter the study. The mean age was 56 years of age in both treatment groups (range 26–81). Most of the patients enrolled in the study had ECOG performance status of 0 or 1 (≥ 96%), in similar proportions between the treatment arms. Only a few patients had ECOG performance status of 2. In the clinical study, the proportion of patients receiving six treatment cycles was 81% in the group treated with paclitaxel micellar and 87% in the group receiving solvent-based paclitaxel. The corresponding median number of cycles (min;max) for the two groups were 6 (1;12) and 6 (1;9), respectively. Patients received premedication prior to infusion of solvent-based paclitaxel, paclitaxel micellar and carboplatin as summarised in Table 3 below. Premedication was not mandated prior to infusion of paclitaxel micellar. Table 3. Proportions of patients who received premedication prior to infusion of paclitaxel or carboplatin or overall (safety population) Apealea (N = 391) Paclitaxel (solvent-based) (N = 391) Type of premedication Overall Paclitaxel Carboplatin Overall Paclitaxel Carboplatin Corticosteroids 43% 6% 39% 99% 97% 15% Antihistamines 19% 4% 16% 85% 85% 9% H2 antagonists 5% 2% 2% 90% 90% 1% Antiemetics and antinauseants 87% 8% 81% 92% 38% 63% In the study, 35% of the patients in the paclitaxel micellar group and 30% of the patients in the solvent-based paclitaxel group, respectively, received GCSF to treat neutropenia. The median number of cycles with paclitaxel/carboplatin treatment for patients receiving GCSF was 6 in both groups. The median number of cycles with administration of GCSF was 3 (1;6) and the mean value 3.1, each in both groups. The principle measures of efficacy were progression-free survival (PFS) and overall survival (OS). PFS as the primary endpoint was evaluated by blinded assessment of computerised tomography images using Response Evaluation Criteria in Solid Tumours (RECIST) 1.0. 13 There was no statistically significant difference in PFS or OS between the two treatment arms. A non-inferiority analysis was conducted for PFS in the per-protocol (PP) population with pre-specified non-inferiority margin. The non-inferiority criterion was met for PFS with the upper bound limit of the one-sided 97.5% confidence interval (CI) for the associated hazard ratio being less than 1.2. The non-inferiority criterion was met for OS in the PP population with the upper bound limit of the one-sided 97.5% CI for the associated hazard ratio being less than 1.185 (Table 4; Figures 1 and 2). In the intention-to-treat (ITT) population (n = 789), the hazard ratios for PFS and OS were 0.85 (95% CI: 0.72;1.00) and 1.02 (95% CI: 0.85;1.22), respectively. Thereby, non-inferiority was shown in the ITT population for PFS, but not for OS. At the time of analysis of the OS data, death had occurred in 56% of the patients in the group treated with paclitaxel micellar compared to 60% in the group treated with solvent-based paclitaxel (ITT population). Table 4. Non-inferiority analyses on PFS and OS in a randomised trial in patients with recurrent epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer (PP population)a Apealea Q3W 250 mg/m2 + carboplatin (N = 311) Solvent-based paclitaxel Q3W 175 mg/m2 + carboplatin (N = 333) Progression free survival (independent review) Death or progression, n (%) 239 (77%) 270 (81%) Median time to death or disease progression [months] (95% CI) 10.3 (10.1;10.7) 10.1 (9.9;10.2) Hazard ratio (95% CI) 0.86 (0.72;1.03) Overall survival Number of deaths, n (%) 179 (58%) 206 (62%) Median time to death [months] (95% CI) 25.7 (22.9;28.1) 24.8 (21.7;27.1) Hazard ratio (95% CI) 0.95 (0.78;1.16) a Primary population in non-inferiority analysis was predefined as the PP population Figure 1. Kaplan-Meier curve of PFS (PP population) Pr ob ab ilit y of p ro gr es si on -fr ee s ur vi va l Months Apealea: solvent-based paclitaxel: Number at risk Patients Events Apealea: 311 239 solvent-based paclitaxel: 333 270 14 Figure 2. Kaplan-Meier curve of OS (PP population) Post-hoc subgroup analysis by relapse Additional subgroup analyses were conducted to investigate efficacy by relapse (first and second) in the PP and the ITT population. PFS and OS results in the PP population are summarised in Figures 3 and 4. Figure 3. Forest plot for PFS by relapse (PP population) Apealea Solvent-based paclitaxel Relapse n Events (%) Median months (95% CI) n Events (%) Median months (95% CI) non-inferiority margin (1.2) Hazard Ratio (95% CI) All 311 239 (77%) 10.3 (10.1;10.7) 333 270 (81%) 10.1 (9.9;10.2) 0.86 (0.72;1.03) First 240 180 (75%) 10.3 (10.2;11.3) 257 209 (81%) 10.1 (9.8;10.3) 0.82 (0.67;1.00) Second 71 59 (83%) 9.9 (8.6;10.6) 76 61 (80%) 10.1 (9.7;10.4) 1.01 (0.69;1.46) favours Apealea favours solvent-based paclitaxel Pr ob ab ilit y of s ur vi va l Months Apealea: solvent-based paclitaxel: Number at risk Patients Events Apealea: 311 179 solvent-based paclitaxel: 333 206 15 Figure 4. Forest plot for OS by relapse (PP population) Apealea Solvent-based paclitaxel Relapse n Events (%) Median months (95% CI) n Events (%) Median months (95% CI) non-inferiority margin (1.185) Hazard Ratio (95% CI) All 311 179 (58%) 25.7 (22.9;28.1) 333 206 (62%) 24.8 (21.7;27.1) 0.95 (0.78;1.16) First 240 139 (58%) 26.1 (23.0;28.4) 257 162 (63%) 23.6 (21.3;27.1) 0.92 (0.73;1.16) Second 71 40 (56%) 23.2 (18.3;28.9) 76 44 (58%) 24.8 (19.2;30.0) 1.07 (0.68;1.68) favours Apealea favours solvent-based paclitaxel In the ITT population, the hazard ratios for PFS in the subgroups of patients with first relapse and second relapse were 0.80 (95% CI: 0.66;0.97) and 1.04 (95% CI: 0.74;1.47), respectively. The hazard ratios for OS in patients with first and second relapse were 0.98 (95% CI: 0.79;1.21) and 1.18 (95% CI: 0.79;1.75), respectively. Thus, the results in the subgroup of patients with first relapse are consistent with the results in the overall population and in addition, there was an indication of PFS benefit for Apealea. For safety data comparing the results of combination treatment with Apealea (paclitaxel micellar)/carboplatin and solvent-based paclitaxel/carboplatin, see section 4.8. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Apealea in all subsets of the paediatric population in the treatment of ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumours) (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties When Apealea (paclitaxel micellar) is administered intravenously, its pharmacokinetic profile suggests that the formulation immediately releases paclitaxel into the blood. The pharmacokinetics of paclitaxel were studied in 22 patients with solid tumours after 1-hour infusions of Apealea (dose levels of 90 to 275 mg/m2). In addition, a study with a crossover design compared total and unbound paclitaxel concentrations in plasma after a 1-hour infusion of Apealea 260 mg/m2 with those after a 1-hour infusion of albumin-bound paclitaxel at the same dose. Total plasma levels of paclitaxel were similar after infusion of the two formulations. The plasma levels of unbound paclitaxel, i.e. the concentration that represents pharmacologically active paclitaxel in the body, were demonstrated to be bioequivalent (Cmax and AUC) after administration of albumin-bound paclitaxel and Apealea. Based on limited data, Cmax and AUC increased with dose after 1-hour infusions of Apealea in doses ranging from 150 to 275 mg/m2. Dose-linearity could not be ascertained since a large inter-individual variability was observed. Distribution Paclitaxel is distributed equally between plasma and blood as described in published in vitro data. The mean unbound fraction of paclitaxel (fu) varied between 5.2% and 4.3% over time after Apealea 16 infusion. This was in agreement with the mean fu after albumin-bound paclitaxel infusion which varied between 5.5% and 4.5% over time. Binding of paclitaxel to both albumin and α1-acid glycoprotein has been reported, but other binding proteins such as lipoproteins might be important. There are no reports of active substances able to displace protein-bound paclitaxel, nor is paclitaxel a likely candidate as a displacer of other active substances given its low molar concentrations in plasma. Based on the published literature, in vitro studies indicate that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine does not affect protein binding of paclitaxel. Paclitaxel has been shown in vitro to be a substrate for the influx transporter proteins OATP1B3 and OATP1A2. During and after infusion of Apealea, paclitaxel rapidly leaves the plasma compartment with a distribution half-life of about 0.6 hours. Thus, the distribution phase is essentially complete at 2 hours after the end of infusion. The tissue distribution is extensive, with a volume of distribution on the terminal elimination phase of about 155 L/m2 corresponding to about 280 L for an average patient with a body surface area of 1.8 m2. Thus, only about 1% of the paclitaxel in the body is located in plasma during the elimination phase. Biotransformation and elimination The terminal half-life of paclitaxel after Apealea infusion varied about 5-fold between the subjects, 5–23 hours. Likewise, total plasma clearance varied about 5-fold from 8 to 41 L/hour. The high interindividual variability in clearance is believed to be a consequence of variability in hepatic enzyme activity. The biotransformation and elimination of paclitaxel have been reported in published studies; paclitaxel is mainly eliminated by hepatic metabolism and biliary excretion. The main metabolite of paclitaxel is 6α-hydroxypaclitaxel. Other metabolites are 3’-p-hydroxypaclitaxel and 6α,3’-p-dihydroxypaclitaxel. The formation of these metabolites is catalysed by CYP2C8 and CYP3A4. No pharmacologically active metabolite has been found. In vitro and in vivo studies have demonstrated that paclitaxel is a substrate for the efflux protein P-glycoprotein. The major route of excretion of paclitaxel-derived material in humans is the faeces, where 6α-hydroxypaclitaxel constitutes the main material. Renal excretion accounts for a minor part, less than 15% of the dose. Special populations Hepatic impairment No clinical studies in patients with hepatic impairment have been undertaken with Apealea (see sections 4.2 and 4.4). A population pharmacokinetics study with albumin-bound paclitaxel demonstrated that patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 × ULN) have an elimination rate in the normal range. In contrast, patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN) and severe hepatic impairment (total bilirubin > 3 to ≤ 5 × ULN) had a 22% or a 26% reduction in paclitaxel elimination rate, respectively. Compared to patients with normal hepatic function, hepatically impaired patients with total bilirubin > 1.5 × ULN have an increase in mean paclitaxel AUC of approximately 20%. Hepatic impairment has no effect on mean paclitaxel Cmax. Pharmacokinetic data for patients with total bilirubin > 5 × ULN are not available. Renal impairment No clinical studies in patients with renal impairment have been undertaken with Apealea (see section 4.2 for dose recommendations). Since renal elimination is a minor pathway for paclitaxel, increased plasma levels are not expected in this patient group. A population pharmacokinetics study with albumin-bound paclitaxel demonstrated that patients with mild and moderate renal impairment (creatinine clearance ≥ 30 to < 90 mL/min) have an elimination rate similar to that of patients with normal renal function. Information is lacking for patients with severe renal impairment (GFR < 30 mL/min). 17 Effects of age, gender, race and body size No analysis of the effect of age, gender or body size on the elimination of Apealea has been undertaken. However, a population pharmacokinetics study of 168 patients (86 males and 82 females) treated with solvent-based paclitaxel has been reported. On average, the paclitaxel elimination rate was 20% higher in males compared to in females. With regard to age, the population model indicated an approximate 5% decline in paclitaxel elimination rate for each 10-year increase in age compared to the median age of 56 years of the study. This amounted to a 14% decline in an 86-year-old patient compared to one aged 56. Further it has been shown that the rate of paclitaxel elimination increased with increasing body size. The model indicated that a 0.2 m2 increase in BSA would lead to a 9% increase in the elimination rate. There is very little information available on whether the elimination of paclitaxel differs between races. 5.3 Preclinical safety data Mutagenesis, carcinogenesis, impairment of fertility In vitro studies using different cell systems have shown paclitaxel to be clastogenic inducing chromosomal aberrations, micronuclei and DNA damage. Chromosomal aberrations have also been detected in in vivo studies in mice and monkeys. Paclitaxel was devoid of mutagenic activity in the Ames test or the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT) gene mutation assay. The carcinogenic activity of paclitaxel has not been studied. However, paclitaxel is potentially carcinogenic based on its mechanism of action and demonstrated genotoxic activity. Paclitaxel at doses below the human therapeutic dose was associated with low fertility and foetal toxicity in rats. Repeat dose toxicity studies have shown non-reversible, toxic effects on male reproductive organs. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt Sodium hydroxide (for pH adjustment) 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial 3 years. After reconstitution Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C in lactated and acetated Ringer’s solution and for 4 hours at 2 °C to 8 °C in sodium chloride 9 mg/mL (0.9%) solution when protected from light. From a microbiological point of view, unless the method of opening and reconstituting precludes the risks of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. 18 6.4 Special precautions for storage Store in a refrigerator (2 °C – 8 °C). Keep the vial in the outer carton in order to protect from light. For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Clear type I glass vial with a silicon coated butyl rubber stopper, an aluminium overseal and a plastic flip-off cap containing powder equivalent to 60 mg of paclitaxel. Pack size: 1 vial. 6.6 Special precautions for disposal and other handling Administration precautions Paclitaxel is an antineoplastic medicinal product and as with other potentially toxic compounds, caution should be exercised in handling Apealea. The use of gloves, goggles and protective clothing is recommended. If the solution contacts the skin, the skin should be washed immediately and thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with water. Apealea should only be prepared and administered by personnel appropriately trained in the handling of cytotoxic agents. Pregnant and breast-feeding staff should not handle Apealea. The reconstituted product should not be diluted. Reconstitution of the medicinal product Apealea is supplied as a sterile powder for reconstitution before use. After reconstitution, the solution contains 1 mg/mL of paclitaxel formulated as micellar nanoparticles. The reconstituted solution for infusion is a clear, greenish-yellow solution. Protect from direct and/or bright light throughout the preparation process. The (reconstituted) product can only withstand short-term handling in absence of light protection. Only reconstitute Apealea using one of the following commercially available solutions for reconstitution: - sodium chloride 9 mg/mL (0.9%) solution suitable for infusion; - lactated Ringer’s solution suitable for infusion; - acetated Ringer’s solution suitable for infusion. The pH of lactated or acetated Ringer’s solution must be in the range of 5.0 to 7.5, and acceptable ion concentrations of calcium and magnesium are listed below (Table 5). Table 5. Acceptable ion concentrations for calcium and magnesium in lactated and acetated Ringer’s solutions suitable for reconstitution Ion Range (mmol/L) Ca2+ 1.0–3.5* Mg2+ 0.0–2.5* * Solutions containing both Ca2+ and Mg2+ should have a total (combined) concentration of Ca2+ and Mg2+ within the range of 1.0 to 3.5 mmol/L. Apealea should be reconstituted using either one of the three suitable solutions for reconstitution and according to the following steps: 19 a. Take the desired number of vials from the refrigerator. The powder should be greenish-yellow to yellow. In case of discolouration (orange), discard the vial. To reach room temperature, let the vials stand protected from light for approximately 15 to 20 minutes not above 25 °C. b. Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before and during injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of solution for reconstitution per vial. The solution should be injected during approximately one minute towards the inner wall of the vial and not directly onto the powder as this will result in foaming. c. Swirl the vial in an upright position for approximately 20 seconds. To keep the generation of foam to a minimum, do not shake the vial. d. Protect from light and allow the vial to stand for three to five minutes. e. Swirl the vial again in upright position for approximately 20 seconds, then gently invert it five times. Do not shake. f. Continue to swirl the vial until the powder is completely dissolved., Alternatively, the vial may be placed on a shaker and rotated for up to 20 minutes, while being protected from light (orbital shake pattern; 200–250 rpm). Steps c and to f should not be more than 30 minutes. g. The solution should be clear and greenish-yellow without visible particles or precipitates. If particles, precipitates, discolouration (orange) or opalescence are observed, the solution should be discarded. h. Inject the required amount of reconstituted Apealea into an empty, sterile ethylene-vinyl acetate (EVA) bag. Ensure that the solution is clear and place a light-protective bag over the EVA infusion bag. Compatibility with administration sets made of DEHP-free PVC (i.e. polyvinyl chloride without the plasticizer di-(2-ethylhexyl) phthalate) has been demonstrated. However, compatibility with DEHP-containing administration sets has not been demonstrated. Administration sets containing a 15 µm polyamide fluid filter should be used. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Oasmia Pharmaceutical AB Vallongatan 1 SE-752 28 Uppsala Sweden Tel +46 18 50 54 40 8. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1292/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 20 November 2018 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 20 ANNEX II A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 21 A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) responsible for batch release Oasmia Pharmaceutical AB Vallongatan 1 SE-752 28 Uppsala Sweden B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 22 ANNEX III LABELLING AND PACKAGE LEAFLET 23 A. LABELLING 24 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Apealea 60 mg powder for solution for infusion paclitaxel 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of powder contains 60 mg paclitaxel. After reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar). 3. LIST OF EXCIPIENTS Excipients: N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt, N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt, sodium hydroxide. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for solution for infusion 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravenous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic: handle with caution. Apealea should not be interchanged with other paclitaxel formulations. 25 8. EXPIRY DATE EXP After reconstitution: use immediately. 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Keep the vial in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Single-use vial 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Oasmia Pharmaceutical AB Vallongatan 1 752 28 Uppsala Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1292/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 26 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 27 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING VIAL LABEL 1. NAME OF THE MEDICINAL PRODUCT Apealea 60 mg powder for solution for infusion paclitaxel 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of powder contains 60 mg paclitaxel. After reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar). 3. LIST OF EXCIPIENTS Excipients: N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt, N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt, sodium hydroxide. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for solution for infusion 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravenous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic Apealea should not be interchanged with other paclitaxel formulations. 28 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Keep the vial in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Oasmia Pharmaceutical AB Uppsala, Sweden 12. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1292/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 29 B. PACKAGE LEAFLET 30 Package leaflet: Information for the user Apealea 60 mg powder for solution for infusion paclitaxel Read all of this leaflet carefully before you start using this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or nurse. • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Apealea is and what it is used for 2. What you need to know before you are given Apealea 3. How Apealea is given 4. Possible side effects 5. How to store Apealea 6. Contents of the pack and other information 1. What Apealea is and what it is used for Apealea is a cancer medicine containing the active substance paclitaxel, which belongs to a group of medicines called taxanes. Paclitaxel affects or stops growth of rapidly dividing cells, such as tumour cells. Apealea is used to treat the following cancers in adults, in combination with another medicine called carboplatin: • epithelial ovarian cancer – a cancer of the ovary, the organ that produces a woman’s egg cells • primary peritoneal cancer – a cancer of the cells lining the space between the wall of the belly and the internal organs • cancer of the fallopian tubes (the connection between the ovaries and the womb) It is used when other therapies have not worked. 2. What you need to know before you are given Apealea Do not use Apealea if you: • are allergic to paclitaxel or any of the other ingredients of this medicine (listed in section 6) • are breast-feeding • have a count of white blood cells called neutrophils below 1.5 × 109/L before start of the therapy Talk to your doctor or nurse, if you are not sure if any of the above applies to you. Warnings and precautions Talk to your doctor or nurse before you are given Apealea if you have: • reduced liver, kidney or heart function Apealea is not recommended for patients with severely reduced liver or kidney function. • previously had nausea, vomiting and diarrhoea during cancer treatment 31 Contact your doctor immediately, if during treatment you develop: • fever, pain, chills, weakness or other signs of infection • severe nausea, vomiting or diarrhoea • severe reactions at the site of infusion • an allergic reaction • numbness, tingling, pricking sensation, sensitivity to touch or muscle weakness You may need additional medicines if you develop any of these symptoms. Your doctor may wish to delay further treatment with Apealea or reduce the dose. Ask your doctor or nurse about hair loss and what can be done to avoid it. You will be observed closely during treatment: • regular blood tests to ensure it is safe for you to continue treatment • symptoms of allergic reaction during the infusion, such as: − reddening and swelling at the site of infusion − low blood pressure − breathing difficulties − puffing of the face Children and adolescents Apealea is not recommended for children and adolescents under 18 years, because it has not been studied in this age group. Other medicines and Apealea Tell your doctor if you are using, have recently used or might use any other medicines. In particular, tell your doctor or nurse before you are given Apealea if you are using: • ketoconazole, or other medicines to treat fungal infections • erythromycin, rifampicin: medicines to treat bacterial infections • fluoxetine: a medicine to treat depression • gemfibrozil: a medicine to lower blood fats • clopidogrel: a medicine that reduces the chances of getting blood clots • cimetidine: a medicine to reduce stomach acid • efavirenz, nevirapine, ritonavir, saquinavir, indinavir, nelfinavir: medicines to treat HIV infection • carbamazepine, phenytoin: medicines to treat epilepsy and certain pain conditions • cisplatin: a medicine to treat cancer Pregnancy and breast-feeding Tell your doctor before treatment if you are pregnant, think you may be pregnant or are breast-feeding. Apealea is not recommended during pregnancy, as paclitaxel may cause serious birth defects. Patients who can become pregnant should use effective contraception during treatment with Apealea and for six months afterwards. Stop breast-feeding while being treated, as paclitaxel passes into breast milk and may harm the child. Driving and using machines Apealea may cause side effects such as tiredness or dizziness that may reduce your ability to drive or use machines. Do not drive or use machines if you have these symptoms. 32 Apealea contains sodium After reconstitution, this medicine contains approximately up to 1.6 g sodium (component of cooking salt) per dose. This is equivalent to 80% of the recommended maximum daily dietary intake of sodium for an adult. 3. How Apealea is given Apealea is given to you by a doctor or nurse by a slow drip (infusion) into a vein. This will take about one hour. The dose is based on your body surface area (worked out from your height and weight) and blood test results. The usual dose is 250 mg/m2 body surface area given every three weeks for up to six treatments. If you have any further questions on the use of this medicine, ask your doctor or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor or nurse immediately if you have any of the following: • Very common (may affect more than 1 in 10 people): − nerve disorder in arms and legs which causes tingling, numbness or burning pain* • Common (may affect up to 1 in 10 people): − fever − muscle weakness, cramps or spasms − allergic reactions, such as breathing difficulties, fainting, swelling of the face, itching, feeling hot, chills, particularly during your infusion. Uncommonly these can lead to severe allergic shock. * Can persist beyond 6 months of paclitaxel discontinuation. Other side effects and their frequencies include: Very common (may affect more than 1 in 10 people): • low level of white blood cells called neutrophils • lack of appetite • diarrhoea, nausea, vomiting • hair loss • joint or muscle pain or discomfort • weakness, tiredness • reactions at the infusion site such as pain, inflammation, discolouration, redness, swelling, tingling, rash, bleeding Common (may affect up to 1 in 10 people): • low level of white blood cells called leukocytes and granulocytes • low level of blood platelets or red blood cells • reduced sense of touch or sensation • abnormal sensation such as tingling, burning, pricking or numbness of the skin or in the mouth • dizziness or feeling of spinning • taste disturbance • headache • rapid heartbeat • chest pain or discomfort • low blood pressure, flushing, vein inflammation, vein pain, increased blood flow to some parts of the body 33 • breathing difficulties, nasal congestion • abdominal pain, constipation, wind • dry mouth, inflammation of the inner lining of the mouth • skin reddening, rash, itching, nettle-rash • pain for instance in arms, legs, breast or at site of tumour • back pain, bone pain • swelling of ankles, feet, face or fingers Uncommon (may affect up to 1 in 100 people): • blood poisoning • pus in body tissue • lung inflammation, influenza, tonsil inflammation • herpes simplex (a viral infection), viral airways infections • urinary tract infection, inflammation of the bladder • skin infections, including infections at the infusion site • disturbed blood clotting mechanisms in the body • lack of white and red blood cells, and blood platelets • low blood levels of potassium, magnesium or sodium • excessive water loss (dehydration) • allergic reactions to other medicines, such as penicillin • depression, sleeplessness, anxiety • epileptic fit lasting longer than five minutes or more than one fit within five minutes • coma, feeling very sleepy, drowsy and/or being deeply unresponsive • low muscle tone, facial palsy • toxicity to the nervous system • cognitive disorder (difficulty thinking or processing thoughts, difficulty remembering) • brain damage, abnormal fluid accumulation within the brain • stroke • blurred vision, eye discomfort or irritation, watery eyes • deafness, inner ear disorder, ringing in the ears • blood vessel disorders, such as: − formation of blood clots − blood vessel inflammation − build-up of water in tissue because of blocked lymph vessel − hot flushes − bleeding • cardiac arrest, heart failure • blue tinged lips or skin • a heart rhythm disorder causing irregular rapid activity in the upper heart chambers • feeling your heartbeat (palpitations), slow heartbeat • blood circulation failure • high blood pressure, blood pressure changes, paleness • lung failure, narrowing of airways • severe lack of oxygen, arising from abnormal breathing • difficulty producing voice sounds • nosebleed, allergic inflammation inside the nose, runny nose • cough • mouth and throat pain or discomfort, throat disorder, bleeding gums • inflammation of the stomach lining, abdominal discomfort or bloating, lower abdominal pain • indigestion, disorder of bowel function, very hard stools, bloody stool • liver inflammation or disorder, raised liver enzyme in your blood • painful severe swelling of deep skin layers, mainly in the face • skin discolouration, pigmentation disorder • skin inflammation with blisters 34 • increased sweating, cold sweat • dry skin, nail disorder • bleeding into a joint • sensation of heaviness in the legs • multi-organ failure which can lead to death • tissue swelling caused by excess fluid • hernia • feeling hot • low body temperature • vaginal bleeding • abnormally high levels of nitrogen-containing compounds in the blood Frequency not known (cannot be estimated from the available data): • redness and swelling of the palms of your hands or soles of your feet which may cause your skin to peel Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Apealea Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the vial label and carton after EXP. The expiry date refers to the last day of that month. Unopened vials: Store in a refrigerator (2 °C – 8 °C). Keep the vial in the outer carton in order to protect from light. Once opened, Apealea is recommended to be used immediately. Any unused medicine or waste material should be disposed of in accordance with local requirements. Do not throw away any medicines via wastewater or household waste. These measures will help protect the environment. 6. Contents of the pack and other information What Apealea contains • The active substance is paclitaxel. One vial contains 60 mg of paclitaxel. After preparation, each millilitre of solution contains 1 mg of paclitaxel (micellar). • The other ingredients are: − N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt − N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt − sodium hydroxide (for pH adjustment) See section 2 “Apealea contains sodium”. 35 What Apealea looks like and contents of the pack Apealea is supplied as a greenish-yellow to yellow powder in a glass vial with a rubber stopper and aluminium seal. Each carton contains 1 glass vial with powder equivalent to 60 mg of paclitaxel. Marketing Authorisation Holder and Manufacturer Oasmia Pharmaceutical AB Vallongatan 1 SE-752 28 Uppsala Sweden Tel +46 18 50 54 40 e-mail: med-info@oasmia.com For any information about this medicine, please contact the Marketing Authorisation Holder. This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu. --------------------------------------------------------------------------------------------------------------------------- The following information is intended for healthcare professionals only: Administration precautions Paclitaxel is an antineoplastic medicinal product and as with other potentially toxic compounds, caution should be exercised in handling Apealea. The use of gloves, goggles and protective clothing is recommended. If the solution contacts the skin, the skin should be washed immediately and thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with water. Apealea should only be prepared and administered by personnel appropriately trained in the handling of cytotoxic agents. Pregnant and breast-feeding staff should not handle Apealea. The reconstituted product should not be diluted. Reconstitution of the medicinal product Apealea is supplied as a sterile powder for reconstitution before use. After reconstitution, the solution contains 1 mg/mL of paclitaxel formulated as micellar nanoparticles. The reconstituted solution for infusion is a clear, greenish-yellow solution. Protect from direct and/or bright light throughout the preparation process. The (reconstituted) product can only withstand short-term handling in absence of light protection. Only reconstitute Apealea using one of the following commercially available solutions for reconstitution: - sodium chloride 9 mg/mL (0.9%) solution suitable for infusion; - lactated Ringer’s solution suitable for infusion; - acetated Ringer’s solution suitable for infusion. The pH of lactated or acetated Ringer’s solution must be in the range of 5.0 to 7.5 and acceptable ion concentrations of calcium and magnesium are listed below (Table 1). 36 Table 1. Acceptable ion concentrations for calcium and magnesium in lactated and acetated Ringer’s solutions suitable for reconstitution Ion Range (mmol/L) Ca2+ 1.0–3.5* Mg2+ 0.0–2.5* * Solutions containing both Ca2+ and Mg2+ should have a total (combined) concentration of Ca2+ and Mg2+ within the range of 1.0 to 3.5 mmol/L. Apealea should be reconstituted using either one of the three suitable solutions for reconstitution and according to the following steps: 1. Take the desired number of vials from the refrigerator. The powder should be greenish-yellow to yellow. In case of discolouration (orange), discard the vial. To reach room temperature, let the vials stand protected from light for approximately 15 to 20 minutes not above 25 °C. 2. Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before and during injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of solution for reconstitution per vial. The solution should be injected during approximately one minute towards the inner wall of the vial and not directly onto the powder as this will result in foaming. 3. Swirl the vial in an upright position for approximately for 20 seconds. To keep the generation of foam to a minimum, do not shake the vial. 4. Protect from light and allow the vial to stand for three to five minutes. 5. Swirl the vial again in upright position for approximately 20 seconds, then gently invert it five times. Do not shake. 6. Continue to swirl the vial until the powder is completely dissolved. Alternatively, the vial may be placed on a shaker and rotated for up to 20 minutes, while being protected from light (orbital shake pattern; 200–250 rpm). Steps 3 to 6 should not be more than 30 minutes. 7. The solution should be clear and greenish-yellow without visible particles or precipitates. If particles, precipitates, discolouration (orange) or opalescence are observed, the solution should be discarded. 8. Inject the required amount of reconstituted Apealea into an empty, sterile ethylene-vinyl acetate (EVA) bag. Ensure that the solution is clear and place a light protective-bag over the EVA infusion bag. Shelf life after reconstitution Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C in lactated and acetated Ringer’s solution and for 4 hours at 2 °C to 8 °C in sodium chloride 9 mg/mL (0.9%) solution when protected from light. From a microbiological point of view, unless the method of opening and reconstituting precludes the risks of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Intravenous administration Compatibility with administration sets made of DEHP-free PVC (i.e. polyvinyl chloride without the plasticizer di-(2-ethylhexyl) phthalate) has been demonstrated. However, compatibility with DEHP-containing administration sets has not been demonstrated. Administration sets containing a 15 µm polyamide fluid filter should be used. It is important to flush the infusion set and catheter/cannula before and after the administration using the solution for reconstitution in order to avoid accidental administration into the surrounding tissue and to ensure administration of the complete dose. Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what apealea is and what it is used for', 'Section_Content': "apealea is a cancer medicine containing the active substance paclitaxel, which belongs to a group of medicines called taxanes. paclitaxel affects or stops growth of rapidly dividing cells, such as tumour cells. apealea is used to treat the following cancers in adults, in combination with another medicine called carboplatin: epithelial ovarian cancer a cancer of the ovary, the organ that produces a woman's egg cells primary peritoneal cancer a cancer of the cells lining the space between the wall of the belly and the internal organs cancer of the fallopian tubes (the connection between the ovaries and the womb) it is used when other therapies have not worked.", 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a cancer medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 28}, {'Text': 'the active substance paclitaxel', 'Type': 'TREATMENT', 'BeginOffset': 40, 'EndOffset': 71}, {'Text': 'taxanes', 'Type': 'TREATMENT', 'BeginOffset': 118, 'EndOffset': 125}, {'Text': 'paclitaxel affects', 'Type': 'PROBLEM', 'BeginOffset': 127, 'EndOffset': 145}, {'Text': 'rapidly dividing cells', 'Type': 'PROBLEM', 'BeginOffset': 165, 'EndOffset': 187}, {'Text': 'tumour cells', 'Type': 'PROBLEM', 'BeginOffset': 197, 'EndOffset': 209}, {'Id': 9, 'BeginOffset': 250, 'EndOffset': 257, 'Score': 0.8720345497131348, 'Text': 'cancers', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9108939170837402}]}, {'Id': 7, 'BeginOffset': 313, 'EndOffset': 324, 'Score': 0.9140863418579102, 'Text': 'carboplatin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 326, 'EndOffset': 351, 'Score': 0.4609653651714325, 'Text': 'epithelial ovarian cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9734088778495789}]}, {'Text': 'a cancer of the ovary', 'Type': 'PROBLEM', 'BeginOffset': 352, 'EndOffset': 373}, {'Text': "a woman's egg cells", 'Type': 'PROBLEM', 'BeginOffset': 399, 'EndOffset': 418}, {'Text': 'primary peritoneal cancer', 'Type': 'PROBLEM', 'BeginOffset': 419, 'EndOffset': 444}, {'Text': 'a cancer of the cells', 'Type': 'PROBLEM', 'BeginOffset': 445, 'EndOffset': 466}, {'Id': 1, 'BeginOffset': 496, 'EndOffset': 513, 'Score': 0.5167233347892761, 'Text': 'wall of the belly', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the internal organs cancer', 'Type': 'PROBLEM', 'BeginOffset': 518, 'EndOffset': 544}, {'Text': 'the fallopian tubes', 'Type': 'TREATMENT', 'BeginOffset': 548, 'EndOffset': 567}, {'Id': 4, 'BeginOffset': 596, 'EndOffset': 603, 'Score': 0.9413664937019348, 'Text': 'ovaries', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'other therapies', 'Type': 'TREATMENT', 'BeginOffset': 634, 'EndOffset': 649}]}

{'Title': '2. what you need to know before you are given apealea', 'Section_Content': 'do not use apealea if you: are allergic to paclitaxel or any of the other ingredients of this medicine (listed in section 6) are breast-feeding have a count of white blood cells called neutrophils below 1.5 × 109/l before start of the therapy talk to your doctor or nurse, if you are not sure if any of the above applies to you. warnings and precautions talk to your doctor or nurse before you are given apealea if you have: reduced liver, kidney or heart function apealea is not recommended for patients with severely reduced liver or kidney function. previously had nausea, vomiting and diarrhoea during cancer treatment 31 contact your doctor immediately, if during treatment you develop: fever, pain, chills, weakness or other signs of infection severe nausea, vomiting or diarrhoea severe reactions at the site of infusion an allergic reaction numbness, tingling, pricking sensation, sensitivity to touch or muscle weakness you may need additional medicines if you develop any of these symptoms. your doctor may wish to delay further treatment with apealea or reduce the dose. ask your doctor or nurse about hair loss and what can be done to avoid it. you will be observed closely during treatment: regular blood tests to ensure it is safe for you to continue treatment symptoms of allergic reaction during the infusion, such as: − reddening and swelling at the site of infusion − low blood pressure − breathing difficulties − puffing of the face children and adolescents apealea is not recommended for children and adolescents under 18 years, because it has not been studied in this age group. other medicines and apealea tell your doctor if you are using, have recently used or might use any other medicines. in particular, tell your doctor or nurse before you are given apealea if you are using: ketoconazole, or other medicines to treat fungal infections erythromycin, rifampicin: medicines to treat bacterial infections fluoxetine: a medicine to treat depression gemfibrozil: a medicine to lower blood fats clopidogrel: a medicine that reduces the chances of getting blood clots cimetidine: a medicine to reduce stomach acid efavirenz, nevirapine, ritonavir, saquinavir, indinavir, nelfinavir: medicines to treat hiv infection carbamazepine, phenytoin: medicines to treat epilepsy and certain pain conditions cisplatin: a medicine to treat cancer pregnancy and breast-feeding tell your doctor before treatment if you are pregnant, think you may be pregnant or are breast-feeding. apealea is not recommended during pregnancy, as paclitaxel may cause serious birth defects. patients who can become pregnant should use effective contraception during treatment with apealea and for six months afterwards. stop breast-feeding while being treated, as paclitaxel passes into breast milk and may harm the child. driving and using machines apealea may cause side effects such as tiredness or dizziness that may reduce your ability to drive or use machines. do not drive or use machines if you have these symptoms. apealea contains sodium after reconstitution, this medicine contains approximately up to 1.6 g sodium (component of cooking salt) per dose. this is equivalent to 80% of the recommended maximum daily dietary intake of sodium for an adult.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 31, 'EndOffset': 39}, {'Id': 8, 'BeginOffset': 43, 'EndOffset': 53, 'Score': 0.9988049268722534, 'Text': 'paclitaxel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5245382785797119}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 89, 'EndOffset': 102}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 122, 'EndOffset': 123}, {'Id': 49, 'BeginOffset': 160, 'EndOffset': 177, 'Score': 0.47810691595077515, 'Text': 'white blood cells', 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{'Title': '3. how apealea is given', 'Section_Content': 'apealea is given to you by a doctor or nurse by a slow drip (infusion) into a vein. this will take about one hour. the dose is based on your body surface area (worked out from your height and weight) and blood test results. the usual dose is 250 mg/m2 body surface area given every three weeks for up to six treatments. if you have any further questions on the use of this medicine, ask your doctor or nurse.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a slow drip (infusion', 'Type': 'TREATMENT', 'BeginOffset': 48, 'EndOffset': 69}, {'Id': 0, 'BeginOffset': 78, 'EndOffset': 82, 'Score': 0.8337357640266418, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your body surface area', 'Type': 'TREATMENT', 'BeginOffset': 136, 'EndOffset': 158}, {'Text': 'your height and weight', 'Type': 'TEST', 'BeginOffset': 176, 'EndOffset': 198}, {'Id': 6, 'BeginOffset': 204, 'EndOffset': 214, 'Score': 0.9880253672599792, 'Text': 'blood test', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 242, 'EndOffset': 245}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 368, 'EndOffset': 381}]}

{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor or nurse immediately if you have any of the following: very common (may affect more than 1 in 10 people): − nerve disorder in arms and legs which causes tingling, numbness or burning pain* common (may affect up to 1 in 10 people): − fever − muscle weakness, cramps or spasms − allergic reactions, such as breathing difficulties, fainting, swelling of the face, itching, feeling hot, chills, particularly during your infusion. uncommonly these can lead to severe allergic shock. * can persist beyond 6 months of paclitaxel discontinuation. other side effects and their frequencies include: very common (may affect more than 1 in 10 people): low level of white blood cells called neutrophils lack of appetite diarrhoea, nausea, vomiting hair loss joint or muscle pain or discomfort weakness, tiredness reactions at the infusion site such as pain, inflammation, discolouration, redness, swelling, tingling, rash, bleeding common (may affect up to 1 in 10 people): low level of white blood cells called leukocytes and granulocytes low level of blood platelets or red blood cells reduced sense of touch or sensation abnormal sensation such as tingling, burning, pricking or numbness of the skin or in the mouth dizziness or feeling of spinning taste disturbance headache rapid heartbeat chest pain or discomfort low blood pressure, flushing, vein inflammation, vein pain, increased blood flow to some parts of the body 33 breathing difficulties, nasal congestion abdominal pain, constipation, wind dry mouth, inflammation of the inner lining of the mouth skin reddening, rash, itching, nettle-rash pain for instance in arms, legs, breast or at site of tumour back pain, bone pain swelling of ankles, feet, face or fingers uncommon (may affect up to 1 in 100 people): blood poisoning pus in body tissue lung inflammation, influenza, tonsil inflammation herpes simplex (a viral infection), viral airways infections urinary tract infection, inflammation of the bladder skin infections, including infections at the infusion site disturbed blood clotting mechanisms in the body lack of white and red blood cells, and blood platelets low blood levels of potassium, magnesium or sodium excessive water loss (dehydration) allergic reactions to other medicines, such as penicillin depression, sleeplessness, anxiety epileptic fit lasting longer than five minutes or more than one fit within five minutes coma, feeling very sleepy, drowsy and/or being deeply unresponsive low muscle tone, facial palsy toxicity to the nervous system cognitive disorder (difficulty thinking or processing thoughts, difficulty remembering) brain damage, abnormal fluid accumulation within the brain stroke blurred vision, eye discomfort or irritation, watery eyes deafness, inner ear disorder, ringing in the ears blood vessel disorders, such as: − formation of blood clots − blood vessel inflammation − build-up of water in tissue because of blocked lymph vessel − hot flushes − bleeding cardiac arrest, heart failure blue tinged lips or skin a heart rhythm disorder causing irregular rapid activity in the upper heart chambers feeling your heartbeat (palpitations), slow heartbeat blood circulation failure high blood pressure, blood pressure changes, paleness lung failure, narrowing of airways severe lack of oxygen, arising from abnormal breathing difficulty producing voice sounds nosebleed, allergic inflammation inside the nose, runny nose cough mouth and throat pain or discomfort, throat disorder, bleeding gums inflammation of the stomach lining, abdominal discomfort or bloating, lower abdominal pain indigestion, disorder of bowel function, very hard stools, bloody stool liver inflammation or disorder, raised liver enzyme in your blood painful severe swelling of deep skin layers, mainly in the face skin discolouration, pigmentation disorder skin inflammation with blisters 34 increased sweating, cold sweat dry skin, nail disorder bleeding into a joint sensation of heaviness in the legs multi-organ failure which can lead to death tissue swelling caused by excess fluid hernia feeling hot low body temperature vaginal bleeding abnormally high levels of nitrogen-containing compounds in the blood frequency not known (cannot be estimated from the available data): redness and swelling of the palms of your hands or soles of your feet which may cause your skin to peel reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all 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0.6187651753425598}]}, {'Text': 'cough mouth', 'Type': 'PROBLEM', 'BeginOffset': 3523, 'EndOffset': 3534}, {'Id': 230, 'BeginOffset': 3539, 'EndOffset': 3550, 'Score': 0.6361968517303467, 'Text': 'throat pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9775794148445129}]}, {'Id': 231, 'BeginOffset': 3554, 'EndOffset': 3564, 'Score': 0.9969204664230347, 'Text': 'discomfort', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9870961904525757}]}, {'Id': 232, 'BeginOffset': 3566, 'EndOffset': 3581, 'Score': 0.9636312127113342, 'Text': 'throat disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9723941683769226}]}, {'Text': 'bleeding gums inflammation of the stomach lining', 'Type': 'PROBLEM', 'BeginOffset': 3583, 'EndOffset': 3631}, {'Id': 235, 'BeginOffset': 3633, 'EndOffset': 3653, 'Score': 0.8144292831420898, 'Text': 'abdominal discomfort', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9870883822441101}]}, {'Id': 236, 'BeginOffset': 3657, 'EndOffset': 3665, 'Score': 0.9961691498756409, 'Text': 'bloating', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9770718216896057}]}, {'Text': 'lower abdominal pain indigestion', 'Type': 'PROBLEM', 'BeginOffset': 3667, 'EndOffset': 3699}, {'Id': 239, 'BeginOffset': 3701, 'EndOffset': 3727, 'Score': 0.8598092198371887, 'Text': 'disorder of bowel function', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9614279866218567}]}, {'Id': 152, 'BeginOffset': 3713, 'EndOffset': 3718, 'Score': 0.9302407503128052, 'Text': 'bowel', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'very hard stools', 'Type': 'PROBLEM', 'BeginOffset': 3729, 'EndOffset': 3745}, {'Text': 'bloody stool liver inflammation', 'Type': 'PROBLEM', 'BeginOffset': 3747, 'EndOffset': 3778}, {'Id': 243, 'BeginOffset': 3782, 'EndOffset': 3790, 'Score': 0.9836265444755554, 'Text': 'disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.865816593170166}]}, {'Id': 244, 'BeginOffset': 3792, 'EndOffset': 3811, 'Score': 0.4584360718727112, 'Text': 'raised liver enzyme', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7402383089065552}]}, {'Id': 154, 'BeginOffset': 3799, 'EndOffset': 3804, 'Score': 0.8997893333435059, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your blood painful', 'Type': 'PROBLEM', 'BeginOffset': 3815, 'EndOffset': 3833}, {'Text': 'severe swelling', 'Type': 'PROBLEM', 'BeginOffset': 3834, 'EndOffset': 3849}, {'Text': 'deep skin layers', 'Type': 'PROBLEM', 'BeginOffset': 3853, 'EndOffset': 3869}, {'Id': 157, 'BeginOffset': 3885, 'EndOffset': 3889, 'Score': 0.9423086643218994, 'Text': 'face', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'skin discolouration', 'Type': 'PROBLEM', 'BeginOffset': 3890, 'EndOffset': 3909}, {'Id': 248, 'BeginOffset': 3911, 'EndOffset': 3932, 'Score': 0.773968517780304, 'Text': 'pigmentation disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.932033360004425}]}, {'Id': 249, 'BeginOffset': 3933, 'EndOffset': 3950, 'Score': 0.7760549783706665, 'Text': 'skin inflammation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8675609230995178}]}, {'Id': 250, 'BeginOffset': 3956, 'EndOffset': 3964, 'Score': 0.8632832765579224, 'Text': 'blisters', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8960714936256409}]}, {'Text': '34', 'Type': 'NUMBER', 'BeginOffset': 3965, 'EndOffset': 3967}, {'Text': 'increased sweating', 'Type': 'PROBLEM', 'BeginOffset': 3968, 'EndOffset': 3986}, {'Text': 'cold sweat dry skin', 'Type': 'PROBLEM', 'BeginOffset': 3988, 'EndOffset': 4007}, {'Text': 'nail disorder bleeding', 'Type': 'PROBLEM', 'BeginOffset': 4009, 'EndOffset': 4031}, {'Id': 257, 'BeginOffset': 4045, 'EndOffset': 4067, 'Score': 0.20634862780570984, 'Text': 'sensation of heaviness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8896256685256958}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9654280543327332, 'RelationshipScore': 0.8634321689605713, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 162, 'BeginOffset': 4039, 'EndOffset': 4044, 'Text': 'joint', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9696072936058044, 'RelationshipScore': 0.971541702747345, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 163, 'BeginOffset': 4075, 'EndOffset': 4079, 'Text': 'legs', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the legs multi-organ failure', 'Type': 'PROBLEM', 'BeginOffset': 4071, 'EndOffset': 4099}, {'Text': 'death tissue swelling', 'Type': 'PROBLEM', 'BeginOffset': 4118, 'EndOffset': 4139}, {'Text': 'excess fluid hernia', 'Type': 'PROBLEM', 'BeginOffset': 4150, 'EndOffset': 4169}, {'Id': 262, 'BeginOffset': 4170, 'EndOffset': 4202, 'Score': 0.7335290312767029, 'Text': 'feeling hot low body temperature', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7016527056694031}]}, {'Id': 263, 'BeginOffset': 4203, 'EndOffset': 4219, 'Score': 0.8339182734489441, 'Text': 'vaginal bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.889284074306488}]}, {'Id': 264, 'BeginOffset': 4220, 'EndOffset': 4275, 'Score': 0.3364778757095337, 'Text': 'abnormally high levels of nitrogen-containing compounds', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7386153340339661}]}, {'Id': 274, 'BeginOffset': 4356, 'EndOffset': 4363, 'Score': 0.9848102927207947, 'Text': 'redness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7707864046096802}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9853330254554749, 'RelationshipScore': 0.6601202487945557, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 268, 'BeginOffset': 4384, 'EndOffset': 4389, 'Text': 'palms', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9979859590530396, 'RelationshipScore': 0.9374656677246094, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 269, 'BeginOffset': 4398, 'EndOffset': 4403, 'Text': 'hands', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.8891689777374268, 'RelationshipScore': 0.7760419249534607, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 270, 'BeginOffset': 4407, 'EndOffset': 4412, 'Text': 'soles', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9956747889518738, 'RelationshipScore': 0.9136489033699036, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 271, 'BeginOffset': 4421, 'EndOffset': 4425, 'Text': 'feet', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'swelling of the palms', 'Type': 'PROBLEM', 'BeginOffset': 4368, 'EndOffset': 4389}, {'Id': 269, 'BeginOffset': 4398, 'EndOffset': 4403, 'Score': 0.9979859590530396, 'Text': 'hands', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 270, 'BeginOffset': 4407, 'EndOffset': 4412, 'Score': 0.8891689777374268, 'Text': 'soles', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 271, 'BeginOffset': 4421, 'EndOffset': 4425, 'Score': 0.9956747889518738, 'Text': 'feet', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your skin to peel', 'Type': 'PROBLEM', 'BeginOffset': 4442, 'EndOffset': 4459}, {'Id': 276, 'BeginOffset': 4473, 'EndOffset': 4485, 'Score': 0.9095777273178101, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8168026208877563}]}, {'Id': 277, 'BeginOffset': 4501, 'EndOffset': 4513, 'Score': 0.9156547784805298, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7791089415550232}]}, {'Id': 278, 'BeginOffset': 4584, 'EndOffset': 4596, 'Score': 0.952359676361084, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6574267745018005}]}, {'Id': 279, 'BeginOffset': 4645, 'EndOffset': 4657, 'Score': 0.8586530685424805, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7052484750747681}]}, {'Id': 280, 'BeginOffset': 4711, 'EndOffset': 4722, 'Score': 0.3791923522949219, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6152297258377075}]}, {'Id': 281, 'BeginOffset': 4736, 'EndOffset': 4748, 'Score': 0.8554664254188538, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7392748594284058}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 4804, 'EndOffset': 4817}]}

{'Title': '5. how to store apealea', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the vial label and carton after exp. the expiry date refers to the last day of that month. unopened vials: store in a refrigerator (2 8 ). keep the vial in the outer carton in order to protect from light. once opened, apealea is recommended to be used immediately. any unused medicine or waste material should be disposed of in accordance with local requirements. do not throw away any medicines via wastewater or household waste. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 259, 'EndOffset': 260}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 281, 'EndOffset': 297}, {'Text': 'waste material', 'Type': 'TREATMENT', 'BeginOffset': 413, 'EndOffset': 427}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what apealea contains the active substance is paclitaxel. one vial contains 60 mg of paclitaxel. after preparation, each millilitre of solution contains 1 mg of paclitaxel (micellar). the other ingredients are: − n-(all-trans-retinoyl)-l-cysteic acid methyl ester sodium salt − n-(13-cis-retinoyl)-l-cysteic acid methyl ester sodium salt − sodium hydroxide (for ph adjustment) see section 2 "apealea contains sodium". what apealea looks like and contents of the pack apealea is supplied as a greenish-yellow to yellow powder in a glass vial with a rubber stopper and aluminium seal. each carton contains 1 glass vial with powder equivalent to 60 mg of paclitaxel.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 46, 'EndOffset': 56, 'Score': 0.9991458654403687, 'Text': 'paclitaxel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8692106008529663, 'RelationshipScore': 0.9999945163726807, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 58, 'EndOffset': 66, 'Text': 'one vial', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.5139319896697998, 'RelationshipScore': 0.8014750480651855, 'RelationshipType': 'FORM', 'Id': 4, 'BeginOffset': 135, 'EndOffset': 143, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 76, 'EndOffset': 78}, {'Id': 3, 'BeginOffset': 85, 'EndOffset': 95, 'Score': 0.9992997646331787, 'Text': 'paclitaxel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8692106008529663, 'RelationshipScore': 0.9287548661231995, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 58, 'EndOffset': 66, 'Text': 'one vial', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9797617197036743, 'RelationshipScore': 0.9993281364440918, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 76, 'EndOffset': 81, 'Text': '60 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.5139319896697998, 'RelationshipScore': 0.991683840751648, 'RelationshipType': 'FORM', 'Id': 4, 'BeginOffset': 135, 'EndOffset': 143, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each millilitre of solution', 'Type': 'TREATMENT', 'BeginOffset': 116, 'EndOffset': 143}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 153, 'EndOffset': 154}, {'Text': 'paclitaxel (micellar)', 'Type': 'TREATMENT', 'BeginOffset': 161, 'EndOffset': 182}, {'Id': 8, 'BeginOffset': 213, 'EndOffset': 356, 'Score': 0.8054126501083374, 'Text': 'n-(all-trans-retinoyl)-l-cysteic acid methyl ester sodium salt − n-(13-cis-retinoyl)-l-cysteic acid methyl ester sodium salt − sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ph adjustment', 'Type': 'TREATMENT', 'BeginOffset': 362, 'EndOffset': 375}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 389, 'EndOffset': 390}, {'Text': 'the pack apealea', 'Type': 'TREATMENT', 'BeginOffset': 458, 'EndOffset': 474}, {'Text': 'a rubber stopper and aluminium seal', 'Type': 'TREATMENT', 'BeginOffset': 546, 'EndOffset': 581}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 604, 'EndOffset': 605}, {'Text': 'powder', 'Type': 'TREATMENT', 'BeginOffset': 622, 'EndOffset': 628}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 643, 'EndOffset': 645}, {'Id': 11, 'BeginOffset': 652, 'EndOffset': 662, 'Score': 0.9993017911911011, 'Text': 'paclitaxel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.47966888546943665, 'RelationshipScore': 0.566891074180603, 'RelationshipType': 'FORM', 'Id': 9, 'BeginOffset': 622, 'EndOffset': 628, 'Text': 'powder', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.978758692741394, 'RelationshipScore': 0.999961256980896, 'RelationshipType': 'DOSAGE', 'Id': 10, 'BeginOffset': 643, 'EndOffset': 648, 'Text': '60 mg', 'Category': 'MEDICATION', 'Traits': []}]}]}

5CB1F30065ADFE84951D65E10F9A2CCF

https://www.ema.europa.eu/documents/product-information/pylobactell-epar-product-information_en.pdf

Pylobactell

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Pylobactell, 100 mg, Soluble Tablet 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Active substance Quantity per tablet 13C-urea 100 mg For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Soluble tablet A white, biconvex tablet. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications This medicinal product is for diagnostic use only. For in vivo diagnosis of gastroduodenal Helicobacter pylori infection. 4.2 Posology and method of administration Pylobactell is not recommended for use in children below the age of 18 years due to insufficient data on efficacy. The Pylobactell tablet is for oral administration. Adults: The tablet is to be dissolved in water and taken 10 minutes after the start of the breath test procedure. The patient should fast for at least 4 hours before the test so that the test is taken on an empty stomach. If the patient has eaten a heavy meal then it will be necessary to fast for six hours prior to the test. It is important to follow the instructions for use described in Section 6.6 adequately, otherwise the validity of the test result will be questionable. 4.3 Contraindications The test must not be used in patients with documented or suspected gastric infection that might interfere with the urea breath test. Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use A positive urea breath test alone does not clinically confirm that eradication therapy is indicated. Alternative diagnosis with invasive endoscopic methods might be indicated in 3 order to examine the presence of any other complicating conditions, eg. gastric ulcer, autoimmune gastritis and malignancies. In individual cases of atrophic gastritis, the breath test result may have a false positive outcome and other tests may be required to confirm the presence of H.pylori. If a repeat test is required, it should not be carried out until the following day. For patients who do not tolerate the recommended test meal, an alternative test meal should be given. Care should be taken in patients where fasting may have medical implications. There are insufficient data on the diagnostic reliability of the Pylobactell test to recommend its use in patients with partial gastrectomy and in patients younger than 18 years. 4.5 Interaction with other medicinal products and other forms of interaction The validity of the test result may be affected if the patient is currently being treated with antibiotics or a proton-pump inhibitor or has completed a course of treatment with these drugs. The results may be affected in general by all treatments interfering with H.pylori status or urease activity. Suppression of H. pylori might give false negative results. Therefore, the test must not be used until four weeks without systemic antibacterial therapy and two weeks after last dose of acid antisecretory agents. This is especially important after eradication therapy. 4.6 Fertility, pregnancy and lactation The endogenous production of urea amounts to 25 - 35 g/day. It is therefore unlikely that the dose of 100 mg urea should cause any adverse effect on pregnancy and lactation. The Pylobactell test is not expected to be harmful during pregnancy or to the health of the foetus / newborn child. Pylobactell can be used during pregnancy and lactation. 4.7 Effects on ability to drive and use machines Not relevant. 4.8 Undesirable effects None known. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Overdose is unlikely to occur in the intended clinical circumstances. No case of overdose has been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 4 Pharmacotherapeutic group: Other diagnostic agents ATC code: V04C X. In the case of infection with H.pylori, orally ingested 13C-urea is metabolised by the enzyme urease which is present in H.pylori. H2N(13CO)NH2 + H2O → 2NH3 + 13CO2 The carbon dioxide which is liberated diffuses into the blood vessels and is transported as bicarbonate to the lungs where it is then liberated as 13CO2 in exhaled air. Infection with H.pylori will significantly change the 13C/12C - carbon isotope ratio. The proportion of 13CO2 in the breath samples may be determined by isotope-ratio-mass spectrometry (IRMS) or by another suitably-validated method carried out by any qualified laboratory, and stated as an absolute difference (excess) in the value between the pre-urea and post-urea breath samples (see Section 6.6). The cut off point for discriminating between H.pylori negative and positive patients is set to an excess value of 3.5, i.e. <3.5 is negative and 3.5 is positive. In comparison with biopsy based techniques for diagnosing H.pylori infection, using data from two therapeutic trials, Pylobactell achieved during different conditions (prestudy and follow-up visits) sensitivity estimates above 95 % with lower one-sided 95 % confidence limit ranging from 93 % to 98 %. The specificity estimates were all above 90 % with corresponding lower confidence limits ranging from 85 % to 90 %. 5.2 Pharmacokinetic properties Urea is rapidly absorbed from the gastro-intestinal tract and distributed into extracellular and intracellular fluids including lymph, bile, cerebrospinal fluid and blood. It is reported to cross the placenta and penetrate the eye. It is excreted unchanged in the urine. 5.3 Preclinical safety data There are no concerns in relation to the clinical use of the product. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Povidone (E1201) Microcrystalline Cellulose (E460i) Colloidal Anhydrous Silica Sodium Benzoate (E211) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. The dissolved tablet must be taken immediately. 5 6.4 Special precautions for storage Do not store above 25°C. 6.5 Nature and contents of container The Pylobactell 13C-urea breath test kit contains a sachet containing the Pylobactell tablet, six glass tubes with caps and bar code labels, three additional bar code labels, a 30 ml mixing and administration glass vial with cap, two straws, a package leaflet and an Analysis Request Form. A security label for re-sealing the kit is also provided. The Pylobactell breath test procedure includes the administering of a suitable test meal. This is not supplied within the box. The Pylobactell tablet container is a heat-sealed PET/aluminium foil/LDPE laminated sachet. 6.6 Special precautions for disposal and other handling The patient should fast for at least 4 hours before the test so that the test is taken on an empty stomach. If the patient has eaten a heavy meal then it will be necessary to fast for six hours prior to the test. It is recommended that the breath test is performed while the patient is in a seated position. Sampling instructions t = 0 minutes Note the time the patient drinks the test meal. t = 5 minutes Collect pre-urea breath samples. Three tubes of breath are to be taken by breathing normally through a straw held at the base of a small tube (white top). The patient must expire as the straw is slowly and completely withdrawn from the tube, which is then immediately capped. These breath samples are used to measure the natural level of 13C in the carbon dioxide of the breath. t = 10 minutes The Pylobactell tablet is placed in the 30 ml mixing vial and water added to the marked line. The bottle is capped and shaken well to dissolve the tablet. The entire contents must be swallowed immediately by the patient, the bottle is refilled with water to the line and the entire contents are again swallowed by the patient. t = 40 minutes Collect post-urea (red top) breath samples. Three tubes of breath are to be taken, which are used to measure the presence of excess levels of 13C, which will be present if the patient is H.pylori positive. On completion of the test retain one pre-urea sample (white top) and one post-urea sample (red top). Return two pre-urea and two post-urea samples to the box. Safely discard the 30 ml mixing vial. Complete the Analysis Request Form; attach one of three spare bar code labels to the area marked "AFFIX BAR CODE LABEL HERE". This bar code is the doctor's reference number used at the analysing laboratory as a patient identifier; the two spare bar code labels are for the doctor's use on the patient notes/files etc. After placing the four sample tubes and paperwork into the box, use the security label provided to seal the lid of the box, and send to a qualified laboratory for analysis. The optimal test meal recommended is 200 ml pure undiluted orange juice. 6 Analysis of breath samples and testing specification The accuracy and precision of the test depends heavily on the quality of the analysis and therefore only laboratories having appropriate certification are considered qualified to analyse the breath samples. Satisfactory specificity and sensitivity have been demonstrated in clinical studies where breath was analysed using isotope ratio mass spectrometry (IRMS). Breath samples collected during a test must remain in the original containers before analysis by IRMS. IRMS instruments may be of continuous flow or dual inlet configuration. A multi-position autosampler and bar code reader should be used to allow samples to be tracked throughout the analysis. IRMS source parameters and tuning must be optimised daily. Instruments must be linear over a wide range of CO2 concentrations, typically 1.0 - 6.0%. This should be checked routinely. Internal analytical precision must be less than + 0.3 ‰ 13C for 20 replicate analyses of the same reference gas sample and remain within 3SD’s of the mean for breath analyses. Transfer of the breath sample through the analytical system must be accomplished without isotope fractionation. The IRMS must possess a triple collector to allow the simultaneous detection of the ions at mass/charge ratio 44, 45 and 46 fluctuations in the oxygen isotope content. There must be provision for correction of instrumental drift during an analysis. Reference gases must be standardised against an appropriate international standard to allow inter-laboratory comparison of results. Alternatively, any other suitably-validated method may be used, carried out by any objectively qualified laboratory. Explanation of results:-  13C:- Difference in parts per thousand (‰) with respect to an accepted international standard. Excess 13C:- Difference between pre- and post-urea sample measurements. H. pylori status: -< 3.5 excess 13C = Negative > 3.5 excess 13C = Positive 7. MARKETING AUTHORISATION HOLDER Torbet Laboratories Ireland Limited 7 20 Holles Street Dublin 2 Ireland +44 (0)1953 607856 +44 (0)1953 713649 enquiries@torbetlaboratories.co.uk 8. MARKETING AUTHORISATION NUMBER EU/1/98/064/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 07 May 1998 Date of latest renewal: 07 May 2008 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ 8 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIRMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 9 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release Idifarma Desarrollo Farmaceutico S.L. Polígono Mocholí C/ Noáin, No.1 31110 Noáin Navarra, Spain B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Not applicable 10 ANNEX III LABELLING AND PACKAGE LEAFLET 11 A. LABELLING 12 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON/CARDBOARD BOX 1. NAME OF THE MEDICINAL PRODUCT Pylobactell, 100 mg, soluble tablet 13C-urea 2. STATEMENT OF ACTIVE SUBSTANCE(S) One tablet contains: 100 mg 13C-urea 3. LIST OF EXCIPIENTS Povidone (E1201), Microcrystalline Cellulose (E460i), Colloidal Anhydrous Silica, Sodium Benzoate (E211). 4. PHARMACEUTICAL FORM AND CONTENTS The kit contains: A sachet containing one Pylobactell 100 mg soluble tablet. Six glass tubes, with caps and bar code labels. 30 ml mixing and administration glass vial with cap. Two straws. Package Leaflet. Analysis Request Form. Security Label and three additional bar code labels. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Diagnostic test kit FOR ORAL ADMINISTRATION Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 8. EXPIRY DATE EXP: {MM/YYYY} 9. SPECIAL STORAGE CONDITIONS 13 Do not store above 25C 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Torbet Laboratories Ireland Ltd, 20 Holles Street, Dublin 2, Ireland. 12. MARKETING AUTHORISATION NUMBER(S) EU/1/98/064/001 13. BATCH NUMBER BN 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 16. INFORMATION IN BRAILLE Pylobactell 17. UNIQUE IDENTIFIER – 2D BARCODE Not applicable 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA Not applicable 14 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SACHET LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Pylobactell, 100 mg, soluble tablet 13C-urea Oral 2. METHOD OF ADMINISTRATION To be dissolved in water and taken orally. Read the package leaflet before use. 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER Batch 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT One tablet 6. OTHER Torbet Laboratories Ireland Limited, 20 Holles Street, Dublin 2, Ireland. EU/1/98/064/001 15 ADDITIONAL KIT ITEM: MIXING AND ADMINISTRATION VIAL LABEL Fill to line with water Dissolve tablet from sachet Shake well to dissolve When dissolved, drink entire contents Refill with water to line, shake bottle and drink Discard this bottle after use Do not return with kit ADDITIONAL KIT ITEM: SECURITY LABEL LABEL Seal lid of box before returning samples for analysis 16 B. PACKAGE LEAFLET 17 PACKAGE LEAFLET: INFORMATION FOR THE USER Pylobactell 100mg soluble tablet 13C-Urea Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What Pylobactell is and what it is used for 2. What you need to know before you use Pylobactell 3. How to use Pylobactell 4. Possible side effects 5. How to store Pylobactell 6. Contents of the pack and other information 1. WHAT PYLOBACTELL IS AND WHAT IT IS USED FOR Pylobactell is a breath test for determining the presence of the bacterium, Helicobacter pylori (H. pylori) in the gut (stomach and adjacent bowel) which may be the reason for your stomach (gastric) condition. Your doctor has recommended that you have a 13C-Urea breath test, for one of the following reasons: • Your doctor wants to confirm whether you are suffering from H. pylori infection to help diagnose your condition. • You have already been diagnosed with H. pylori and have been taking medication aimed to clear up the infection. Your doctor now wants to find out if the treatment has worked. This medicine is for diagnostic use only. How does the test work? All foods contain a substance called carbon 13 (13C), in varying amounts. This 13C can be detected in the carbon dioxide that you breathe out of your lungs. The actual amount of 13C in the breath will depend on the type of food that you have eaten. You will be asked to drink a "test meal". This will help keep the test 13C-urea solution in your stomach. Following the meal, 3 samples of your breath will be taken. These samples will be analysed to measure the normal amount of 13C in the carbon dioxide in your breath. You will then drink the Pylobactell 13C-urea solution. If H. pylori is present and active in your stomach, these bacteria will break down the 13C-urea and this is detected in the carbon dioxide in your breath. A further 3 samples of your breath will then be taken 30 minutes later. The amount of 13C in these samples will be compared to your normal level. If there is a significant increase in the amount of 13C, this will let your doctor know that active H. pylori is present. 18 2. WHAT YOU NEED TO KNOW BEFORE YOU USE PYLOBACTELL DO NOT use Pylobactell if you: - are allergic to 13C-urea or to any of the other ingredients of this medicine (listed in Section 6). - suffer from any medical condition that you think may affect, or be affected by, the test. Warnings and precautions Talk to your doctor, pharmacist or nurse before using Pylobactell if: • part of your stomach has been removed (partial gastrectomy) as the reliability of the test has not been proven in these patients • you have or suspect you have a gastric infection • you have long term stomach problems (atrophic gastritis) as the breath test may give the wrong result and other tests may be required to confirm the presence of H. pylori. • fasting (not taking food) may have medical implications for you • you are under 18 years. Other medicines and Pylobactell Please tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. Do not take the test if: • You have taken antibiotics or medication to treat Helicobacter pylori within the last 28 days • You have taken proton pump inhibitors in the last 14 days • You have taken H2 antagonists or antacids on the same day of the test. Do not stop taking medication without the advice of your doctor. Taking Pylobactell with food and drink You should fast for at least 4 hours before the test so that the test is taken on an empty stomach. If you have eaten a heavy meal it will be necessary to fast for six hours before the test. You can drink water during the fasting period. If fasting is a problem e.g. for diabetic patients, please tell your doctor, pharmacist or nurse. Pregnancy and breast-feeding Pylobactell can be used during pregnancy and breast-feeding. Driving and using machines This test should not affect your ability to drive or use machines. 3. HOW TO USE PYLOBACTELL Always use this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure. The test will take about 45 minutes. A supply of drinking water will be needed. It is recommended that the breath test is performed while you are in a seated position. You must not smoke before or during the test. The test procedure involves the following steps: (A brief form of these instructions is included on the back of the Analysis Request Form) 1. Fasting: You should fast for 4 hours before taking the test (See Section 2 Taking Pylobactell with food and drink) 19 2. Test Meal: Drink the recommended test meal. This is not included in this kit but may have been supplied separately. If no test meal has been supplied, the most suitable test meal is 200 ml of pure undiluted orange juice. If you cannot take the recommended test meal, an alternative test meal should be taken. Your doctor will advise you. 3. Wait 5 minutes 4. Pre-test Breath Samples (3 White Capped Tubes) i. Remove the cap from the tube ii. Breathe out through your mouth, using a straw, into the sample tube. iii. Gradually remove the straw from the tube as you breathe out. iv. Immediately replace the cap. v. Repeat with remaining white capped tubes. It is not necessary to blow hard into the tubes, just breathe normally and cap them quickly. Try to avoid getting saliva in the tubes. 5. Preparing the 13Carbon-urea solution Open the tablet sachet and empty the tablet into the mixer vial. Add water to the mark on the vial and replace the cap. Gently shake the vial to dissolve the tablet. Drink the solution. Note the time upon drinking. Fill the vial to the mark again with water and drink. 6. Wait 30 minutes from the time of drinking the Pylobactell 13C-urea solution. Do not smoke, eat or drink during this time. This is important for the proper functioning of the test. 7. Post-test Breath Samples (3 Red Capped Tubes) Using the red-capped, take samples of your breath as before (see step 4). 8. Analysis Request Form Fill out the analysis request form with patient details on the left hand side of the form and the doctor’s name and address on the right hand side. 9. Test is now complete Put your breath samples and the completed Analysis Request Form back into the carton and send to the address supplied by your doctor. Your doctor will tell you when the results of your test will be available and who to contact for these results. Dispose of the empty sachet, mixing vial and straws as normal waste, but keep this leaflet for reference. If a repeat test is required, it should not be carried out until the following day. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. POSSIBLE SIDE EFFECTS No side effects to Pylobactell have been reported. 13C and urea are harmless naturally occurring substances which are found in your body. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting 20 system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. HOW TO STORE PYLOBACTELL Keep out of the sight and reach of children. Do not store the kit above 25°C. The tablet must be taken when dissolved. Do not use Pylobactell after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month. 6. CONTENTS OF THE PACK AND OTHER INFORMATION What the Pylobactell tablet contains - The active substance is 13C-urea. Each tablet contains 100 mg of 13C-urea - The other ingredients are povidone (E1201), microcrystalline cellulose (E460i), colloidal anhydrous silica and sodium benzoate (E211). Each Pylobactell Breath Test kit contains: • 1 Sachet containing 1 tablet. • 6 glass tubes, 3 with white caps and 3 with red caps. • 30 ml glass mixing tube with cap. • 2 straws. • Package Leaflet • Analysis Request Form. • Security Label and 3 additional bar code labels. The contents of this kit are sufficient for a single test. If you need to repeat the test, a new kit will be required and it should not be carried out until the following day. Marketing Authorisation Holder Torbet Laboratories Ireland Limited, 20 Holles Street, Dublin 2, Ireland Tel. +44 (0)1953 607856 Fax. +44 (0)1953 713649 E-mail enquiries@torbetlaboratories.co.uk Manufacturer Idifarma Desarrollo Farmaceutico S.L., Polígono Mocholí, C/ Noáin, No.1, 31110 Noáin, Navarra, , Spain. For any information about this medicine, please contact the Marketing Authorisation Holder: This leaflet was last revised in Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 21 Analysis of breath samples and testing specification The accuracy and precision of the test depends heavily on the quality of the analysis and therefore only laboratories having appropriate certification are considered qualified to analyse the breath samples. Satisfactory specificity and sensitivity have been demonstrated in clinical studies where breath was analysed using isotope ratio mass spectrometry (IRMS). Breath samples collected during a test must remain in the original containers before analysis by IRMS. IRMS instruments may be of continuous flow or dual inlet configuration. A multi-position autosampler and bar code reader should be used to allow samples to be tracked throughout the analysis. IRMS source parameters and tuning must be optimised daily. Instruments must be linear over a wide range of CO2 concentrations, typically 1.0 - 6.0%. This should be checked routinely. Internal analytical precision must be less than + 0.3 ‰ 13C for 20 replicate analyses of the same reference gas sample and remain within 3SD’s of the mean for breath analyses. Transfer of the breath sample through the analytical system must be accomplished without isotope fractionation. The IRMS must possess a triple collector to allow the simultaneous detection of the ions at mass/charge ratio 44, 45 and 46 to allow for fluctuations in the oxygen isotope content. There must be provision for correction of instrumental drift during an analysis. Reference gases must be standardised against an appropriate international standard to allow inter- laboratory comparison of results. Alternatively, any other suitably-validated method may be used, carried out by any objectively qualified laboratory. Explanation of results:-  13C:- Difference in parts per thousand (‰) with respect to an accepted international standard Excess 13C:- Difference between pre- and post-urea sample measurements H. pylori status: - < 3.5 excess 13C = Negative > 3.5 excess 13C = Positive 22 ANALYSIS REQUEST FORM: Pylobactell [13Carbon] -UREA BREATH TEST (13C-UBT) for Helicobacter pylori ANALYSIS REQUEST FORM - Please complete in block capitals Please state clearly address for return of results: Centre: Patient Name: Date of Birth: Patient Reference: Date of Test: Referring Doctor: AFFIX BAR-CODE LABEL HERE PLEASE PLACE BAR-CODE LABEL ON PATIENT RECORDS, IF APPLICABLE M.A. Number: EU/1/98/064/001 Marketing Authorisation Holder: Torbet Laboratories Ireland Limited, 20 Holles Street, Dublin 2, Ireland MEDICATION RECORD TEST CHECK LIST Medical History - has the patient taken : Type &Date Mins Test Check List Time (i) antibiotics in the last 28 days? If so, please indicate type and when last taken t = 0 Note time patient drinks test meal (ii) proton pump inhibitors (PPIs) in the last 14 days? If so, please indicate type and when last taken. t = 5 Collect Pre-Urea samples (White Caps - 3 times) (iii) eradication therapy in the last 28 days? If so, please indicate when treatment ended t = 10 Patient to drink urea solution, then fill bottle to line again and drink. (iv) other medication (if applicable) t = 40 Collect Post-Urea samples (Red Caps - 3 times). (v) patient fasted for hours Please note that (i) - (iii) will affect result of test. Check Bar-code label and all details entered on Analysis Request Form. 1 x Pre/Post sample reserved in store. 2 x Pre/Post samples + this form for return to a qualified laboratory. Laboratory use only Date received: Analytical file reference: Laboratory code: Samples logged on by : Comments: SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you use pylobactell', 'Section_Content': 'do not use pylobactell if you: - are allergic to 13c-urea or to any of the other ingredients of this medicine (listed in section 6). - suffer from any medical condition that you think may affect, or be affected by, the test. warnings and precautions talk to your doctor, pharmacist or nurse before using pylobactell if: part of your stomach has been removed (partial gastrectomy) as the reliability of the test has not been proven in these patients you have or suspect you have a gastric infection you have long term stomach problems (atrophic gastritis) as the breath test may give the wrong result and other tests may be required to confirm the presence of h. pylori. fasting (not taking food) may have medical implications for you you are under 18 years. other medicines and pylobactell please tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. do not take the test if: you have taken antibiotics or medication to treat helicobacter pylori within the last 28 days you have taken proton pump inhibitors in the last 14 days you have taken h2 antagonists or antacids on the same day of the test. do not stop taking medication without the advice of your doctor. taking pylobactell with food and drink you should fast for at least 4 hours before the test so that the test is taken on an empty stomach. if you have eaten a heavy meal it will be necessary to fast for six hours before the test. you can drink water during the fasting period. if fasting is a problem e.g. for diabetic patients, please tell your doctor, pharmacist or nurse. pregnancy and breast-feeding pylobactell can be used during pregnancy and breast-feeding. driving and using machines this test should not affect your ability to drive or use machines.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 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[]}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 402, 'EndOffset': 410}, {'Text': 'a gastric infection', 'Type': 'PROBLEM', 'BeginOffset': 478, 'EndOffset': 497}, {'Text': 'long term stomach problems', 'Type': 'PROBLEM', 'BeginOffset': 507, 'EndOffset': 533}, {'Id': 11, 'BeginOffset': 535, 'EndOffset': 553, 'Score': 0.89921635389328, 'Text': 'atrophic gastritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8434075117111206}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9264009594917297, 'RelationshipScore': 0.8690347075462341, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 517, 'EndOffset': 524, 'Text': 'stomach', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the breath test', 'Type': 'TEST', 'BeginOffset': 558, 'EndOffset': 573}, {'Text': 'other tests', 'Type': 'TEST', 'BeginOffset': 604, 'EndOffset': 615}, {'Text': 'h. pylori', 'Type': 'PROBLEM', 'BeginOffset': 659, 'EndOffset': 668}, {'Text': '18', 'Type': 'NUMBER', 'BeginOffset': 748, 'EndOffset': 750}, {'Text': 'other medicines', 'Type': 'TREATMENT', 'BeginOffset': 758, 'EndOffset': 773}, {'Id': 4, 'BeginOffset': 778, 'EndOffset': 789, 'Score': 0.5089054703712463, 'Text': 'pylobactell', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'any other medicines', 'Type': 'TREATMENT', 'BeginOffset': 888, 'EndOffset': 907}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 919, 'EndOffset': 928}, {'Id': 19, 'BeginOffset': 1002, 'EndOffset': 1013, 'Score': 0.6712141036987305, 'Text': 'antibiotics', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'medication', 'Type': 'TREATMENT', 'BeginOffset': 1017, 'EndOffset': 1027}, {'Id': 12, 'BeginOffset': 1037, 'EndOffset': 1056, 'Score': 0.8685731887817383, 'Text': 'helicobacter pylori', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8579849600791931}]}, {'Id': 23, 'BeginOffset': 1068, 'EndOffset': 1080, 'Score': 0.9996623992919922, 'Text': 'last 28 days', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.8685731887817383, 'RelationshipScore': 0.7722228765487671, 'RelationshipType': 'OVERLAP', 'Id': 12, 'BeginOffset': 1037, 'EndOffset': 1056, 'Text': 'helicobacter pylori', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8579849600791931}]}]}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 1073, 'EndOffset': 1075}, {'Id': 20, 'BeginOffset': 1096, 'EndOffset': 1118, 'Score': 0.9536504745483398, 'Text': 'proton pump inhibitors', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 24, 'BeginOffset': 1126, 'EndOffset': 1138, 'Score': 0.9995330572128296, 'Text': 'last 14 days', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.9536504745483398, 'RelationshipScore': 0.8971474170684814, 'RelationshipType': 'OVERLAP', 'Id': 20, 'BeginOffset': 1096, 'EndOffset': 1118, 'Text': 'proton pump inhibitors', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 1131, 'EndOffset': 1133}, {'Id': 21, 'BeginOffset': 1154, 'EndOffset': 1180, 'Score': 0.5216602087020874, 'Text': 'h2 antagonists or antacids', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 25, 'BeginOffset': 1188, 'EndOffset': 1196, 'Score': 0.7497363686561584, 'Text': 'same day', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.5216602087020874, 'RelationshipScore': 0.8571357131004333, 'RelationshipType': 'OVERLAP', 'Id': 21, 'BeginOffset': 1154, 'EndOffset': 1180, 'Text': 'h2 antagonists or antacids', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1200, 'EndOffset': 1208}, {'Text': 'medication', 'Type': 'TREATMENT', 'BeginOffset': 1229, 'EndOffset': 1239}, {'Id': 8, 'BeginOffset': 1282, 'EndOffset': 1293, 'Score': 0.8689587712287903, 'Text': 'pylobactell', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 1343, 'EndOffset': 1344}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1358, 'EndOffset': 1366}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1375, 'EndOffset': 1383}, {'Id': 2, 'BeginOffset': 1405, 'EndOffset': 1412, 'Score': 0.8374875783920288, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1495, 'EndOffset': 1503}, {'Id': 13, 'BeginOffset': 1585, 'EndOffset': 1593, 'Score': 0.8031885623931885, 'Text': 'diabetic', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7500413060188293}]}, {'Id': 14, 'BeginOffset': 1650, 'EndOffset': 1659, 'Score': 0.9545457363128662, 'Text': 'pregnancy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9317742586135864}]}, {'Text': 'breast-feeding pylobactell', 'Type': 'TREATMENT', 'BeginOffset': 1664, 'EndOffset': 1690}, {'Id': 15, 'BeginOffset': 1710, 'EndOffset': 1719, 'Score': 0.9394713044166565, 'Text': 'pregnancy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9204466938972473}]}, {'Text': 'breast-feeding', 'Type': 'TREATMENT', 'BeginOffset': 1724, 'EndOffset': 1738}]}

{'Title': '3. how to use pylobactell', 'Section_Content': "always use this medicine exactly as your doctor, pharmacist or nurse has told you. check with your doctor, pharmacist or nurse if you are not sure. the test will take about 45 minutes. a supply of drinking water will be needed. it is recommended that the breath test is performed while you are in a seated position. you must not smoke before or during the test. the test procedure involves the following steps: (a brief form of these instructions is included on the back of the analysis request form) 1. fasting: you should fast for 4 hours before taking the test (see section 2 taking pylobactell with food and drink) 19 2. test meal: drink the recommended test meal. this is not included in this kit but may have been supplied separately. if no test meal has been supplied, the most suitable test meal is 200 ml of pure undiluted orange juice. if you cannot take the recommended test meal, an alternative test meal should be taken. your doctor will advise you. 3. wait 5 minutes 4. pre-test breath samples (3 white capped tubes) i. remove the cap from the tube ii. breathe out through your mouth, using a straw, into the sample tube. iii. gradually remove the straw from the tube as you breathe out. iv. immediately replace the cap. v. repeat with remaining white capped tubes. it is not necessary to blow hard into the tubes, just breathe normally and cap them quickly. try to avoid getting saliva in the tubes. 5. preparing the 13carbon-urea solution open the tablet sachet and empty the tablet into the mixer vial. add water to the mark on the vial and replace the cap. gently shake the vial to dissolve the tablet. drink the solution. note the time upon drinking. fill the vial to the mark again with water and drink. 6. wait 30 minutes from the time of drinking the pylobactell 13c-urea solution. do not smoke, eat or drink during this time. this is important for the proper functioning of the test. 7. post-test breath samples (3 red capped tubes) using the red-capped, take samples of your breath as before (see step 4). 8. analysis request form fill out the analysis request form with patient details on the left hand side of the form and the doctor's name and address on the right hand side. 9. test is now complete put your breath samples and the completed analysis request form back into the carton and send to the address supplied by your doctor. your doctor will tell you when the results of your test will be available and who to contact for these results. dispose of the empty sachet, mixing vial and straws as normal waste, but keep this leaflet for reference. if a repeat test is required, it should not be carried out until the following day. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.", 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 148, 'EndOffset': 156}, {'Text': '45', 'Type': 'NUMBER', 'BeginOffset': 173, 'EndOffset': 175}, {'Text': 'the breath test', 'Type': 'TEST', 'BeginOffset': 251, 'EndOffset': 266}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 352, 'EndOffset': 360}, {'Text': 'the test procedure', 'Type': 'TREATMENT', 'BeginOffset': 362, 'EndOffset': 380}, {'Text': '1.', 'Type': 'NUMBER', 'BeginOffset': 501, 'EndOffset': 503}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 533, 'EndOffset': 534}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 577, 'EndOffset': 578}, {'Text': '19', 'Type': 'NUMBER', 'BeginOffset': 619, 'EndOffset': 621}, {'Text': '2.', 'Type': 'NUMBER', 'BeginOffset': 622, 'EndOffset': 624}, {'Text': '200', 'Type': 'NUMBER', 'BeginOffset': 807, 'EndOffset': 810}, {'Text': 'test meal', 'Type': 'TREATMENT', 'BeginOffset': 881, 'EndOffset': 890}, {'Text': 'an alternative test meal', 'Type': 'TEST', 'BeginOffset': 892, 'EndOffset': 916}, {'Text': '3.', 'Type': 'NUMBER', 'BeginOffset': 963, 'EndOffset': 965}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 971, 'EndOffset': 972}, {'Text': '4.', 'Type': 'NUMBER', 'BeginOffset': 981, 'EndOffset': 983}, {'Text': 'pre-test breath samples', 'Type': 'TEST', 'BeginOffset': 984, 'EndOffset': 1007}, {'Text': '3 white capped tubes)', 'Type': 'TREATMENT', 'BeginOffset': 1009, 'EndOffset': 1030}, {'Text': 'the cap', 'Type': 'TREATMENT', 'BeginOffset': 1041, 'EndOffset': 1048}, {'Id': 0, 'BeginOffset': 1092, 'EndOffset': 1097, 'Score': 0.9099831581115723, 'Text': 'mouth', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a straw', 'Type': 'TREATMENT', 'BeginOffset': 1105, 'EndOffset': 1112}, {'Text': 'the sample tube', 'Type': 'TREATMENT', 'BeginOffset': 1119, 'EndOffset': 1134}, {'Text': 'the straw', 'Type': 'TREATMENT', 'BeginOffset': 1158, 'EndOffset': 1167}, {'Text': 'the tube', 'Type': 'TREATMENT', 'BeginOffset': 1173, 'EndOffset': 1181}, {'Text': 'iv', 'Type': 'TREATMENT', 'BeginOffset': 1202, 'EndOffset': 1204}, {'Text': 'the cap', 'Type': 'TREATMENT', 'BeginOffset': 1226, 'EndOffset': 1233}, {'Text': 'remaining white capped tubes', 'Type': 'TREATMENT', 'BeginOffset': 1250, 'EndOffset': 1278}, {'Id': 1, 'BeginOffset': 1322, 'EndOffset': 1327, 'Score': 0.44231852889060974, 'Text': 'tubes', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'saliva in the tubes', 'Type': 'TREATMENT', 'BeginOffset': 1394, 'EndOffset': 1413}, {'Text': '5.', 'Type': 'NUMBER', 'BeginOffset': 1415, 'EndOffset': 1417}, {'Text': 'the 13carbon-urea solution', 'Type': 'TREATMENT', 'BeginOffset': 1428, 'EndOffset': 1454}, {'Text': 'the tablet sachet', 'Type': 'TREATMENT', 'BeginOffset': 1460, 'EndOffset': 1477}, {'Text': 'the cap', 'Type': 'TREATMENT', 'BeginOffset': 1566, 'EndOffset': 1573}, {'Text': '6.', 'Type': 'NUMBER', 'BeginOffset': 1724, 'EndOffset': 1726}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 1732, 'EndOffset': 1734}, {'Text': 'the pylobactell 13c-urea solution', 'Type': 'TREATMENT', 'BeginOffset': 1769, 'EndOffset': 1802}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1897, 'EndOffset': 1905}, {'Text': '7.', 'Type': 'NUMBER', 'BeginOffset': 1907, 'EndOffset': 1909}, {'Text': 'post-test breath samples', 'Type': 'TEST', 'BeginOffset': 1910, 'EndOffset': 1934}, {'Text': '3 red capped tubes', 'Type': 'TREATMENT', 'BeginOffset': 1936, 'EndOffset': 1954}, {'Text': 'the red-capped', 'Type': 'TREATMENT', 'BeginOffset': 1962, 'EndOffset': 1976}, {'Text': 'your breath', 'Type': 'PROBLEM', 'BeginOffset': 1994, 'EndOffset': 2005}, {'Text': '4.', 'Type': 'NUMBER', 'BeginOffset': 2026, 'EndOffset': 2028}, {'Text': '8.', 'Type': 'NUMBER', 'BeginOffset': 2030, 'EndOffset': 2032}, {'Text': 'the analysis', 'Type': 'TEST', 'BeginOffset': 2064, 'EndOffset': 2076}, {'Id': 14, 'BeginOffset': 2123, 'EndOffset': 2127, 'Score': 0.922550618648529, 'Text': 'hand', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 16, 'BeginOffset': 2192, 'EndOffset': 2196, 'Score': 0.9333078265190125, 'Text': 'hand', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '9.', 'Type': 'NUMBER', 'BeginOffset': 2203, 'EndOffset': 2205}, {'Text': 'your breath samples', 'Type': 'TEST', 'BeginOffset': 2231, 'EndOffset': 2250}, {'Text': 'your test', 'Type': 'TEST', 'BeginOffset': 2407, 'EndOffset': 2416}, {'Text': 'the empty sachet', 'Type': 'TREATMENT', 'BeginOffset': 2484, 'EndOffset': 2500}, {'Text': 'mixing vial and straws', 'Type': 'TREATMENT', 'BeginOffset': 2502, 'EndOffset': 2524}, {'Text': 'a repeat test', 'Type': 'TEST', 'BeginOffset': 2582, 'EndOffset': 2595}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2711, 'EndOffset': 2724}]}

{'Title': '4. possible side effects', 'Section_Content': 'no side effects to pylobactell have been reported. 13c and urea are harmless naturally occurring substances which are found in your body. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting 20 system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'side effects to pylobactell', 'Type': 'PROBLEM', 'BeginOffset': 3, 'EndOffset': 30}, {'Id': 0, 'BeginOffset': 132, 'EndOffset': 136, 'Score': 0.4369065761566162, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 4, 'BeginOffset': 151, 'EndOffset': 163, 'Score': 0.9294357299804688, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6918842792510986}]}, {'Id': 5, 'BeginOffset': 179, 'EndOffset': 191, 'Score': 0.9097405076026917, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7081830501556396}]}, {'Id': 6, 'BeginOffset': 262, 'EndOffset': 274, 'Score': 0.9522606730461121, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6006610989570618}]}, {'Id': 7, 'BeginOffset': 323, 'EndOffset': 335, 'Score': 0.8625472187995911, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6883346438407898}]}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 372, 'EndOffset': 374}, {'Id': 8, 'BeginOffset': 392, 'EndOffset': 403, 'Score': 0.3820922374725342, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5346482992172241}, {'Name': 'DIAGNOSIS', 'Score': 0.44238629937171936}]}, {'Id': 9, 'BeginOffset': 417, 'EndOffset': 429, 'Score': 0.8633800745010376, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7070889472961426}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 485, 'EndOffset': 498}]}

{'Title': '5. how to store pylobactell', 'Section_Content': 'keep out of the sight and reach of children. do not store the kit above 25. the tablet must be taken when dissolved. do not use pylobactell after the expiry date which is stated on the carton after exp. the expiry date refers to the last day of that month.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the kit', 'Type': 'TEST', 'BeginOffset': 58, 'EndOffset': 65}, {'Text': '25.', 'Type': 'NUMBER', 'BeginOffset': 72, 'EndOffset': 75}, {'Text': 'the tablet', 'Type': 'TREATMENT', 'BeginOffset': 76, 'EndOffset': 86}, {'Id': 0, 'BeginOffset': 128, 'EndOffset': 139, 'Score': 0.8016964197158813, 'Text': 'pylobactell', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.7323630452156067}]}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what the pylobactell tablet contains - the active substance is 13c-urea. each tablet contains 100 mg of 13c-urea - the other ingredients are povidone (e1201), microcrystalline cellulose (e460i), colloidal anhydrous silica and sodium benzoate (e211). each pylobactell breath test kit contains: 1 sachet containing 1 tablet. 6 glass tubes, 3 with white caps and 3 with red caps. 30 ml glass mixing tube with cap. 2 straws. package leaflet analysis request form. security label and 3 additional bar code labels. the contents of this kit are sufficient for a single test. if you need to repeat the test, a new kit will be required and it should not be carried out until the following day.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the pylobactell tablet', 'Type': 'TEST', 'BeginOffset': 5, 'EndOffset': 27}, {'Id': 2, 'BeginOffset': 63, 'EndOffset': 71, 'Score': 0.47470834851264954, 'Text': '13c-urea', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.7301574349403381, 'RelationshipScore': 0.9998114705085754, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 78, 'EndOffset': 84, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 94, 'EndOffset': 97}, {'Id': 5, 'BeginOffset': 104, 'EndOffset': 136, 'Score': 0.706516444683075, 'Text': '13c-urea - the other ingredients', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9487869739532471, 'RelationshipScore': 0.9995668530464172, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 94, 'EndOffset': 100, 'Text': '100 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 6, 'BeginOffset': 141, 'EndOffset': 149, 'Score': 0.855804443359375, 'Text': 'povidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 159, 'EndOffset': 185, 'Score': 0.9978887438774109, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 187, 'EndOffset': 192, 'Score': 0.24539634585380554, 'Text': 'e460i', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'colloidal anhydrous silica and sodium benzoate', 'Type': 'TREATMENT', 'BeginOffset': 195, 'EndOffset': 241}, {'Text': 'each pylobactell breath test', 'Type': 'TEST', 'BeginOffset': 250, 'EndOffset': 278}, {'Text': '1 sachet containing', 'Type': 'TREATMENT', 'BeginOffset': 293, 'EndOffset': 312}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 313, 'EndOffset': 314}, {'Text': '6 glass tubes', 'Type': 'TREATMENT', 'BeginOffset': 323, 'EndOffset': 336}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 338, 'EndOffset': 339}, {'Text': 'white caps', 'Type': 'TREATMENT', 'BeginOffset': 345, 'EndOffset': 355}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 360, 'EndOffset': 361}, {'Id': 13, 'BeginOffset': 367, 'EndOffset': 375, 'Score': 0.48371946811676025, 'Text': 'red caps', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.7103658318519592, 'RelationshipScore': 0.932563066482544, 'RelationshipType': 'DOSAGE', 'Id': 11, 'BeginOffset': 293, 'EndOffset': 301, 'Text': '1 sachet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8168942928314209, 'RelationshipScore': 0.966148316860199, 'RelationshipType': 'DOSAGE', 'Id': 12, 'BeginOffset': 313, 'EndOffset': 321, 'Text': '1 tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 377, 'EndOffset': 379}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 411, 'EndOffset': 412}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 479, 'EndOffset': 480}, {'Text': 'a single test', 'Type': 'TEST', 'BeginOffset': 553, 'EndOffset': 566}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 590, 'EndOffset': 598}, {'Text': 'a new kit', 'Type': 'TREATMENT', 'BeginOffset': 600, 'EndOffset': 609}]}

A1DFAB9F4613067C3DFA5916453A4CC7

https://www.ema.europa.eu/documents/product-information/novoeight-epar-product-information_en.pdf

NovoEight

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT NovoEight 250 IU powder and solvent for solution for injection NovoEight 500 IU powder and solvent for solution for injection NovoEight 1000 IU powder and solvent for solution for injection NovoEight 1500 IU powder and solvent for solution for injection NovoEight 2000 IU powder and solvent for solution for injection NovoEight 3000 IU powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION NovoEight 250 IU powder and solvent for solution for injection. Each powder vial contains nominally 250 IU human coagulation factor VIII (rDNA), turoctocog alfa. After reconstitution NovoEight contains approximately 62.5 IU/ml of human coagulation factor VIII (rDNA), turoctocog alfa. NovoEight 500 IU powder and solvent for solution for injection. Each powder vial contains nominally 500 IU human coagulation factor VIII (rDNA), turoctocog alfa. After reconstitution NovoEight contains approximately 125 IU/ml of human coagulation factor VIII (rDNA), turoctocog alfa. NovoEight 1000 IU powder and solvent for solution for injection. Each powder vial contains nominally 1000 IU human coagulation factor VIII (rDNA), turoctocog alfa. After reconstitution NovoEight contains approximately 250 IU/ml of human coagulation factor VIII (rDNA), turoctocog alfa. NovoEight 1500 IU powder and solvent for solution for injection. Each powder vial contains nominally 1500 IU human coagulation factor VIII (rDNA), turoctocog alfa. After reconstitution NovoEight contains approximately 375 IU/ml of human coagulation factor VIII (rDNA), turoctocog alfa. NovoEight 2000 IU powder and solvent for solution for injection. Each powder vial contains nominally 2000 IU human coagulation factor VIII (rDNA), turoctocog alfa. After reconstitution NovoEight contains approximately 500 IU/ml of human coagulation factor VIII (rDNA), turoctocog alfa. NovoEight 3000 IU powder and solvent for solution for injection. Each powder vial contains nominally 3000 IU human coagulation factor VIII (rDNA), turoctocog alfa. After reconstitution NovoEight contains approximately 750 IU/ml of human coagulation factor VIII (rDNA), turoctocog alfa. The potency (IU) is determined using the European Pharmacopoeia (Ph. Eur) chromogenic assay. The specific activity of NovoEight is approximately 8,300 IU/mg protein. Turoctocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 1,445 amino acids with an approximate molecular mass of 166 kDA. It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells, and prepared without the addition of any human or animal derived protein in the cell culture process, purification or final formulation. 3 Turoctocog alfa is a B-domain truncated recombinant human coagulation factor VIII (B-domain consists of 21 amino acids of the wild type B-domain) without any other modifications in the amino acid sequence. Excipient with known effect The medicinal product contains 30.5 mg sodium per reconstituted vial. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. White or slightly yellow powder or friable mass. Clear and colourless solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). NovoEight can be used for all age groups. 4.2 Posology and method of administration Treatment should be under the supervision of a doctor experienced in the treatment of haemophilia. Treatment monitoring During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated injections. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In a single dose pharmacokinetic study in adult patients the maximum exposure (Cmax) and the total exposure (AUC) increased with increasing body mass index (BMI) indicating that dose adjustments may be required. An increase in dose may be required for underweight patients (BMI <18.5 kg/m2) and a decrease in dose may be required for obese patients (BMI ≥30 kg/m2), but there is insufficient data to recommend specific dose adjustments, see section 5.2. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. This is of importance particularly when changing the laboratory and/or reagents used in the assay. Posology The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and the patient’s clinical condition. 4 The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. The activity of factor VIII in plasma is expressed either as percentage (relative to normal level human plasma) or in International Units (relative to an International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml normal human plasma. On-demand treatment The calculation of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is determined using the following formula: Required units = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 (IU/kg per IU/dl). The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case. In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery: Table 1 Guide for dosing in bleeding episodes and surgery Degree of haemorrhage/Type of surgical procedure FVIII level required (%) (IU/dl) Frequency of doses (hours)/Duration of therapy (days) Haemorrhage Early haemarthrosis, muscle bleeding or oral bleeding 20–40 Repeat every 12 to 24 hours, at least 1 day, until the bleeding episode as indicated by pain is resolved or healing achieved More extensive haemarthrosis, muscle bleeding or haematoma 30–60 Repeat infusion every 12–24 hours for 3–4 days or more until pain and acute disability are resolved Life threatening haemorrhages 60–100 Repeat infusion every 8 to 24 hours until threat is resolved Surgery Minor surgery including tooth extraction 30–60 Every 24 hours, at least 1 day, until healing is achieved Major surgery 80–100 (pre- and postoperative) Repeat infusion every 8–24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dl) Prophylaxis For long term prophylaxis against bleeding in patients with severe haemophilia A. The usual recommended doses are 20–40 IU of factor VIII per kg body weight every second day or 20–50 IU of factor VIII per kg body weight 3 times weekly. In adults and adolesents (>12 years) a less frequent 5 regimen (40-60 IU/kg every third day or twice weekly) may be applicable. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary. Surgery There is limited experience of surgery in paediatric patients. Elderly There is no experience in patients >65 years. Paediatric population For long term prophylaxis against bleeding in patients below the age of 12, doses of 25–50 IU of factor VIII per kg body weight every second day or 25–60 IU of factor VIII per kg body weight 3 times weekly are recommended. For paediatric patients above the age of 12 the dose recommendations are the same as for adults. Method of administration Intravenous use. The recommended infusion rate for NovoEight is 1–2 ml/min. The rate should be determined by the patient’s comfort level. For instructions on reconstitution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Known allergic reaction to hamster proteins. 4.4 Special warnings and precautions for use Traceability In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Hypersensitivity Allergic type hypersensitivity reactions are possible with NovoEight. The product contains traces of hamster proteins, which in some patients may cause allergic reactions. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. In case of shock, standard medical treatment for shock should be implemented. Inhibitors The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon. The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors. In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observation and laboratory test. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate 6 dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors. Cardiovascular event In patients with existing cardiovascular risk factors, substitiution therapy with FVIII may increase the cardiovascular risk. Catheter-related complications If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered. It is strongly recommended that every time that NovoEight is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product. Paediatric population The listed warnings and precautions apply both to adults and children. Excipient related considerations The medicinal product contains 30.5 mg sodium per reconstituted vial, equivalent to 1.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 4.5 Interaction with other medicinal products and other forms of interaction No interactions of human coagulation factor VIII (rDNA) products with other medicinal products have been reported. 4.6 Fertility, pregnancy and lactation Animal reproduction studies have not been conducted with NovoEight. Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breastfeeding is not available. Therefore, factor VIII should be used during pregnancy and lactation only if clearly indicated. 4.7 Effects on ability to drive and use machines NovoEight has no influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock). Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed. Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with NovoEight. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre is contacted. Tabulated list of adverse reactions 7 The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 2 Frequency of adverse drug reactions in clinical trials System Organ Class Frequencya in PTPs Frequencya in PUPs Adverse reaction Blood and lymphatic system disorders Uncommonb Very commonb FVIII inhibition Psychiatric disorders Uncommon Insomnia Nervous system disorders Uncommon Headache, dizziness, burning sensation Cardiac disorders Uncommon Sinus tachycardia, acute myocardial infarction Vascular disorders Uncommon Hypertension, lymphoedema, hyperaemia Common Flushing, Thrombophlebitis superficial Skin and subcutaneous tissue disorders Common Rash, rash erythematous Uncommon Rash, lichenoid keratosis, skin burning sensation Musculoskeletal and connective tissue disorders Uncommon Musculoskeletal stiffness, arthropathy, pain in extremity, musculoskeletal pain Common Haemarthrosis, Muscle haemorrhage Respiratory, thoracic and mediastinal disorders Common Cough General disorders and administration site conditions Common Injection site reactionsc Common Pyrexia, catheter site erythema Uncommon Fatigue, feeling hot, oedema peripheral, pyrexia Investigations Common Hepatic enzymes increasedd Common Anti factor VIII antibody positive Uncommon Heart rate increased Gastrointestinal disorders Common Vomiting Injury, poisoning and procedural complications Common Incorrect dose administered Common Infusion related reaction Uncommon Contusion Product issues Common Thrombosis in device a Calculated based on total number of unique patients in all clinical trials (301), of which 242 were previously treated patients (PTPs) and 60 were previously untreated patients (PUPs). b Frequency is based on studies with all FVIII products which included patients with severe haemophilia A. c Injection site reactions include injection site erythema, injection site extravasation and injection site pruritus. d Hepatic enzymes increased include alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase and bilirubin. 8 Description of selected adverse reactions During all clinical studies with NovoEight in previously treated patients, a total of 35 adverse reactions were reported in 23 of 242 patients exposed to NovoEight. The most frequently reported adverse reactions were injection site reactions, incorrect dose administered and hepatic enzymes increased. Of the 35 adverse reactions, 2 were reported in 1 out of 31 patients below 6 years of age, none in patients from 6 to ≤12 years of age, 1 event in 1 out of 24 patients (12 to <18 years of age) and 32 were reported in 21 out of 155 adults (≥18 years). Paediatric population In clinical trials involving 63 previously treated paediatric patients between 0 and 12 years of age and 24 adolescents between 12 and 18 years of age with severe haemophilia A no difference in the safety profile of NovoEight was observed between paediatric patients and adults. In the trial with previously untreated patients, between 0 and 6 years of age, a total of 46 adverse reactions were reported in 33 of 60 patients exposed to NovoEight. The most frequently reported adverse reaction was Factor VIII inhibition, see section 4.4. High risk genetic mutations were identified in 92.3% of the overall and 93.8% of the high titre confirmed inhibitors. No other factors were significantly associated with inhibitor development. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose No symptoms of overdose with recombinant coagulation factor VIII have been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII, ATC code: B02BD02. Mechanism of action NovoEight contains turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B- domain. This glycoprotein has the same structure as human factor VIII when activated, and post- translational modifications that are similar to those of the plasma-derived molecule. The tyrosine sulphation site present at Tyr1680 (native full length), which is important for the binding to von Willebrand factor, has been found to be fully sulphated in the turoctocog alfa molecule. When infused into a haemophilia patient, factor VIII binds to endogenous von Willebrand Factor in the patient’s circulation. The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of bleeding tendencies. Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies. Clinical efficacy http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 Four multi-centre, open-labelled, non-controlled trials have been conducted to evaluate the safety and efficacy of NovoEight in the prevention and treatment of bleeds and during surgery in patients with severe haemophilia A (FVIII activity ≤1%). Three of these trials were performed in previously treated patients and the fourth in previously untreated patients. The trials included 298 exposed patients; 175 adolescents or adult patients without inhibitors from the age of 12 years (≥150 exposure days), 63 previously treated paediatric patients without inhibitors below 12 years of age (≥50 exposure days) and 60 previously untreated patients below 6 years of age. 188 out of 238 previously treated patients continued into the safety extension trial. Treatment with NovoEight was shown to be safe and had the intended haemostatic and preventive effect. Of the 3,293 reported bleeds observed in 298 of the patients, 2,902 (88.1%) of the bleeds were resolved with 1-2 infusions of NovoEight. Table 3 Consumption of NovoEight and haemostatic success rates in previously untreated patients (PUP) and previously treated patients (PTP) Younger children (0 – <6 years) PUP Younger children (0 – <6 years) PTP Older children (6 – <12 years) PTP Adolescents (12 – <18 years) PTP Adults (≥18 years) PTP Total Number of patients 60 31 32 24 151 298 Dose used for prevention per patient (IU/kg BW) Mean (SD) Min ; Max 45.2 (14.4) 4.5 ; 363.8 41.5 (8.1) 3.4 ; 196.3. 38.4 (9.4) 3.2 ; 62.5 28.5 (9.3) 17.4 ; 73.9 28.5 (8.3) 12.0 ; 97.4 32.8 (10.9) 3.2 ; 363.8 Dose used for treatment of bleed (IU/kg BW) Mean (SD) Min ; Max 43.6 (15.2) 11.9 ; 118.9 44.0 (12.6) 21.4 ; 193.8 40.4 (10.5) 24.0 ; 71.4 29.3 (10.3) 12.4 ; 76.8 35.0 (12.3) 6.4 ; 104.0 37.5 (13.4) 6.4 ; 193.8 Success ratea % 87.0% 92.2% 88.4% 85.1% 89.6% 88.9% BW: Body weight, SD: Standard deviation a Success is defined as either 'Excellent' or 'Good'. A total of 30 surgeries were performed in 25 patients of which 26 were major surgeries and 4 were minor. Haemostasis was successful in all surgeries and no treatment failures were reported. Data on Immune Tolerance Induction (ITI) has been collected in patients with haemophilia A who had developed inhibitors to factor VIII. During clinical trial in PUPs, 21 patients were treated with ITI and 18 (86%) patients completed ITI with a negative inhibitor test result. 5.2 Pharmacokinetic properties All pharmacokinetic (PK) studies with NovoEight were conducted after i.v. administration of 50 IU/kg NovoEight in previously treated patients with severe haemophilia A (FVIII ≤1%). The analysis of plasma samples was conducted using both the one-stage clotting assay and the chromogenic assay. The assay performance of NovoEight in FVIII:C assays was evaluated and compared to a marketed full length recombinant FVIII product. The study showed that comparable and consistent results were obtained for both products and that NovoEight can be reliably measured in plasma without the need of a separate NovoEight standard. The single dose pharmacokinetic parameters of NovoEight are listed in Table 4 for the one-stage clotting assay and in Table 5 for the chromogenic assay. 10 Table 4 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by age - one stage clotting assay - Mean (SD) Parameter 0 − <6 years 6 − <12 years ≥12 years n=14 n=14 n=33 Incremental recovery (IU/dl)/(IU/kg) 1.8 (0.7) 2.0 (0.4) 2.2 (0.4) AUC ((IU*h)/dl) 992 (411) 1109(374) 1526 (577) CL (ml/h/kg) 6.21 (3.66) 5.02 (1.68) 3.63 (1.09) t½ (h) 7.65 (1.84) 8.02 (1.89) 11.00 (4.65) Vss (ml/kg) 56.68 (26.43) 46.82 (10.63) 47.40 (9.21) Cmax (IU/dl) 100 (58) 107 (35) 123 (41) Mean residence time (h) 9.63 (2.50) 9.91 (2.57) 14.19 (5.08) Abbreviations: AUC = area under the factor VIII activity time profile; CL = clearance; t1/2 = terminal half-life; Vss = volume of distribution at steady-state; Cmax = maximum factor VIII activity. Table 5 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by age - chromogenic assay - Mean (SD) Parameter 0 − <6 years 6 − <12 years ≥12 years n=14 n=14 n=33 Incremental recovery (IU/dl)/(IU/kg) 2.2 (0.6) 2.5 (0.6) 2.9 (0.6) AUC ((IU*h)/dl) 1223 (436) 1437 (348) 1963 (773) CL (ml/h/kg) 4.59 (1.73) 3.70 (1.00) 2.86 (0.94) t½ (h) 9.99 (1.71) 9.42 (1.52) 11.22 (6.86) Vss (ml/kg) 55.46 (23.53) 41.23 (6.00) 38.18 (10.24) Cmax (IU/dl) 112 (31) 125 (27) 163 (50) Mean residence time (h) 12.06 (1.90) 11.61 (2.32) 14.54 (5.77) Abbreviations: AUC = area under the factor VIII activity time profile; CL = clearance; t1/2 = terminal half-life; Vss = volume of distribution at steady-state; Cmax = maximum factor VIII activity. The pharmacokinetic parameters were comparable between paediatric patients below 6 years of age and the paediatric patients from 6 to below 12 years of age. Some variation was observed in the pharmacokinetic parameters of NovoEight between paediatric and adult patients. The higher CL and the shorter t½ seen in paediatric patients compared to adult patients with haemophilia A may be due in part to the known higher plasma volume per kilogram body weight in younger patients. A single dose pharmacokinetic trial (50 IU/kg) was performed in 35 haemophilia patients (≥18 years of age) in different BMI categories. The maximum exposure (Cmax) and the total exposure (AUC) increase with increasing BMI indicating that dose adjustments may be required for underweight (BMI <18.5 kg/m2) and obese patients (BMI ≥30 kg/m2), see section 4.2. Table 6 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by BMI classesa – One-stage clotting assay - Mean (SD) PK parameter Underweight N=5 Normal weight N=7 Overweight N=8 Obese class I N=7 Obese class II/III N=7 Incremental recovery (IU/dl)/(IU/kg) 1.7 (0.2) 2.0 (0.2) 2.4 (0.4) 2.3 (0.3)b 2.6 (0.3) AUC ((IU*h)/dl) 1510 (360) 1920 (610) 1730 (610) 2030 (840) 2350 (590) CL (ml/h/kg) 3.91 (0.94) 3.20 (1.00) 3.63 (1.24) 3.37 (1.79) 2.51 (0.63) t½ (h) 11.3 (2.0) 11.7 (3.5) 9.4 (2.9) 11.2 (3.5) 11.1 (2.7) 11 Vss (ml/kg) 56.8 (5.4) 44.8 (6.5) 39.6 (6.0) 42.0 (9.0) 35.0 (4.6) Cmax (IU/dl) 100 (11) 121 (10) 144 (26) 140 (21) 161 (32) Mean residence time (h) 15.1 (3.0) 15.3 (4.8) 11.9 (3.7) 14.4 (4.6) 14.6 (3.7) a BMI groups: Underweight: BMI <18.5 kg/m2, Normal weight: BMI 18.5-24.9 kg/m2, Overweight: BMI 25-29.9 kg/m2, Obese class I: BMI 30-34.9 kg/m2, Obese class II/III: BMI ≥35 kg/m2. b Based on 6 patients only. Table 7 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by BMI classesa – Chromogenic assay - Mean (SD) PK parameter Underweight N=5 Normal weight N=7 Overweight N=9 Obese class I N=7 Obese class II/III N=7 Incremental recovery (IU/dl)/(IU/kg) 2.2 (0.4) 2.9 (0.3) 3.0 (0.5) 3.2 (0.5) 3.5 (0.5) AUC ((IU*h)/dl) 1860 (700) 2730 (860) 2310 (1020) 2780 (1210) 3050 (730) CL (ml/h/kg) 3.28 (0.87) 2.25 (0.73) 2.84 (1.09) 2.58 (1.56) 1.94 (0.52) t½ (h) 11.7 (2.4) 11.5 (3.6) 9.7 (3.4) 10.4 (3.2) 10.5 (2.5) Vss (ml/kg) 49.1 (10.4) 31.2 (4.5) 31.6 (5.8) 28.9 (5.1) 25.7 (4.0) Cmax (IU/dl) 138 (29) 185 (24) 194 (31) 200 (33) 227 (32) Mean residence time (h) 15.5 (3.2) 15.2 (4.9) 12.6 (4.8) 13.5 (4.6) 13.9 (3.7) a BMI groups: Underweight: BMI <18.5 kg/m2, Normal weight: BMI 18.5-24.9 kg/m2, Overweight: BMI 25-29.9 kg/m2, Obese class I: BMI 30-34.9 kg/m2, Obese class II/III: BMI ≥35 kg/m2. 5.3 Preclinical safety data Non-clinical data reveal no special concern for humans based on conventional studies of safety pharmacology and repeated dose toxicity. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder: Sodium chloride L-histidine Sucrose Polysorbate 80 L-methionine Calcium chloride dihydrate Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Solvent: Sodium chloride Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 12 Unopened vial 30 months when stored in a refrigerator (2°C – 8°C). During the shelf life, the product may be kept at: • room temperature (≤ 30°C) for a single period no longer than 9 months or • above room temperature (30°C up to 40°C) for a single period no longer than 3 months. Once the product has been taken out of the refrigerator, the product must not be returned to the refrigerator. Please record the beginning of storage and the storage temperature on the product carton. After reconstitution: Chemical and physical in-use stability have been demonstrated for: • 24 hours stored at 2°C – 8°C • 4 hours stored at 30°C, for product which has been kept for a single period no longer than 9 months at room temperature (≤30°C) • 4 hours stored up to 40°C, for product which has been kept for a single period no longer than 3 months at above room temperature (30°C up to 40°C). From a microbiological point of view, the medicinal product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than as stated above, unless reconstitution has taken place in controlled and validated aseptic conditions. Any unused reconstituted product stored at room temperature (≤30°C) or up to 40°C for more than 4 hours should be discarded. 6.4 Special precautions for storage Store in refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage at room temperature (≤30°C) or up to 40°C and storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Each pack of NovoEight 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU and 3000 IU powder and solvent for solution for injection contains: – 1 glass vial (type I) with powder and chlorobutyl rubber stopper – 1 sterile vial adapter for reconstitution – 1 pre-filled syringe of 4 ml solvent with backstop (polypropylene), a rubber plunger (bromobutyl) and a syringe cap with a stopper (bromobutyl) – 1 plunger rod (polypropylene). 6.6 Special precautions for disposal and other handling NovoEight is to be administered intravenously after reconstitution of the powder with the solvent supplied in the syringe. After reconstitution the solution appears as a clear or slightly opalescent solution. Do not use solutions that are cloudy or have deposits. 13 You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters. These devices are not included in the NovoEight package. Always use an aseptic technique. Reconstitution A) Take the vial, the vial adapter and the pre-filled syringe out of the carton. Leave the plunger rod untouched in the carton. Bring the vial and the pre-filled syringe to room temperature. You can do this by holding them in your hands until they feel as warm as your hands. Do not use any other way to heat the vial and pre-filled syringe. A B) Remove the plastic cap from the vial. If the plastic cap is loose or missing, do not use the vial. Wipe the rubber stopper on the vial with a sterile alcohol swab and allow it to air dry for a few seconds before use. B C) Remove the protective paper from the vial adapter. If the protective paper is not fully sealed or if it is broken, do not use the vial adapter. Do not take the vial adapter out of the protective cap with your fingers. C D) Turn over the protective cap and snap the vial adapter onto the vial. Once attached do not remove the vial adapter from the vial. D 14 E) Lightly squeeze the protective cap with your thumb and index finger as shown. Remove the protective cap from the vial adapter. E F) Grasp the plunger rod by the wide top and immediately connect the plunger rod to the syringe by turning it clockwise into the plunger inside the pre-filled syringe until resistance is felt. F G) Remove the syringe cap from the pre-filled syringe by bending it down until the perforation breaks. Do not touch the syringe tip under the syringe cap. G H) Screw the pre-filled syringe securely onto the vial adapter until resistance is felt. H I) Hold the pre-filled syringe slightly tilted with the vial pointing downwards. Push the plunger rod to inject all the solvent into the vial. I 15 J) Keep the plunger rod pressed down and swirl the vial gently until all the powder is dissolved. Do not shake the vial as this will cause foaming. J It is recommended to use NovoEight immediately after reconstitution. For storage conditions of the reconstituted medicinal product see section 6.3. If a larger dose is needed, repeat steps A to J with additional vials, vial adapters and pre-filled syringes. Administration of the reconstituted solution K) Keep the plunger rod pushed completely in. Turn the syringe with the vial upside down. Stop pushing the plunger rod and let it move back on its own while the reconstituted solution fills the syringe. Pull the plunger rod slightly downwards to draw the reconstituted solution into the syringe. In case you only need part of the entire vial, use the scale on the syringe to see how much reconstituted solution you withdraw, as instructed by your doctor or nurse. While holding the vial upside down, tap the syringe gently to let any air bubbles rise to the top. Push the plunger rod slowly until all air bubbles are gone. K L) Unscrew the vial adapter with the vial. NovoEight is now ready for injection. Locate a suitable site and slowly inject NovoEight into the vein over a period of 2-5 minutes. L 16 Disposal After injection, safely dispose of all unused NovoEight solution, the syringe with the infusion set, the vial with the vial adapter and other waste materials as instructed by your pharmacist. Do not throw it out with the ordinary household waste. 7. MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 8. MARKETING AUTHORISATION NUMBERS NovoEight 250 IU EU/1/13/888/001 NovoEight 500 IU EU/1/13/888/002 NovoEight 1000 IU EU/1/13/888/003 NovoEight 1500 IU EU/1/13/888/004 NovoEight 2000 IU EU/1/13/888/005 NovoEight 3000 IU EU/1/13/888/006 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 13 November 2013 Date of latest renewal: 30 July 2018 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.ema.europa.eu/ http://www.ema.europa.eu/ 17 ANNEX II A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 18 A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers of the biological active substance BioReliance Ltd Todd Campus, West of Scotland Science Park, Glasgow, G20 0XA United Kingdom Novo Nordisk US Bio Production Inc. 9 Technology Drive West Lebanon NH 03784 USA Name and address of the manufacturer responsible for batch release Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports (PSUR) The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 19 ANNEX III LABELLING AND PACKAGE LEAFLET 20 A. LABELLING 21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT NovoEight 250 IU powder and solvent for solution for injection turoctocog alfa (human coagulation factor VIII (rDNA)) 2. STATEMENT OF ACTIVE SUBSTANCE One ml of NovoEight contains approximately 62.5 IU of human coagulation factor VIII (rDNA), turoctocog alfa after reconstitution 3. LIST OF EXCIPIENTS Powder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride dihydrate, sodium hydroxide, hydrochloric acid Solvent: Sodium chloride, water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Intravenous use Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 22 Store in a refrigerator. Do not freeze During storage, the product may be kept at: • room temperature (≤ 30°C) for a single period no longer than 9 months or • above room temperature (30°C up to 40°C) for a single period no longer than 3 months Taken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ Store in the original package in order to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBERS EU/1/13/888/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE NovoEight 250 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: 23 NN: 24 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION NovoEight 250 IU powder for solution for injection turoctocog alfa Intravenous use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 250 IU 6. OTHER Novo Nordisk A/S 25 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT NovoEight 500 IU powder and solvent for solution for injection turoctocog alfa (human coagulation factor VIII (rDNA)) 2. STATEMENT OF ACTIVE SUBSTANCE One ml of NovoEight contains approximately 125 IU of human coagulation factor VIII (rDNA), turoctocog alfa after reconstitution 3. LIST OF EXCIPIENTS Powder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride dihydrate, sodium hydroxide, hydrochloric acid Solvent: Sodium chloride, water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Intravenous use Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 26 Store in a refrigerator. Do not freeze During storage, the product may be kept at: • room temperature (≤ 30°C) for a single period no longer than 9 months or • above room temperature (30°C up to 40°C) for a single period no longer than 3 months Taken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ Store in the original package in order to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBERS EU/1/13/888/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE NovoEight 500 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: 27 NN: 28 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION NovoEight 500 IU powder for solution for injection turoctocog alfa Intravenous use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 500 IU 6. OTHER Novo Nordisk A/S 29 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT NovoEight 1000 IU powder and solvent for solution for injection turoctocog alfa (human coagulation factor VIII (rDNA)) 2. STATEMENT OF ACTIVE SUBSTANCE One ml of NovoEight contains approximately 250 IU of human coagulation factor VIII (rDNA), turoctocog alfa after reconstitution 3. LIST OF EXCIPIENTS Powder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride dihydrate, sodium hydroxide, hydrochloric acid Solvent: Sodium chloride, water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Intravenous use Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 30 Store in a refrigerator. Do not freeze During storage, the product may be kept at: • room temperature (≤ 30°C) for a single period no longer than 9 months or • above room temperature (30°C up to 40°C) for a single period no longer than 3 months Taken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ Store in the original package in order to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBERS EU/1/13/888/003 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE NovoEight 1000 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: 31 NN: 32 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION NovoEight 1000 IU powder for solution for injection turoctocog alfa Intravenous use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1000 IU 6. OTHER Novo Nordisk A/S 33 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT NovoEight 1500 IU powder and solvent for solution for injection turoctocog alfa (human coagulation factor VIII (rDNA)) 2. STATEMENT OF ACTIVE SUBSTANCE One ml of NovoEight contains approximately 375 IU of human coagulation factor VIII (rDNA), turoctocog alfa after reconstitution 3. LIST OF EXCIPIENTS Powder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride dihydrate, sodium hydroxide, hydrochloric acid Solvent: Sodium chloride, water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Intravenous use Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 34 Store in a refrigerator. Do not freeze During storage, the product may be kept at: • room temperature (≤ 30°C) for a single period no longer than 9 months or • above room temperature (30°C up to 40°C) for a single period no longer than 3 months Taken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ Store in the original package in order to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBERS EU/1/13/888/004 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE NovoEight 1500 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: 35 SN: NN: 36 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION NovoEight 1500 IU powder for solution for injection turoctocog alfa Intravenous use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1500 IU 6. OTHER Novo Nordisk A/S 37 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT NovoEight 2000 IU powder and solvent for solution for injection turoctocog alfa (human coagulation factor VIII (rDNA)) 2. STATEMENT OF ACTIVE SUBSTANCE One ml of NovoEight contains approximately 500 IU of human coagulation factor VIII (rDNA), turoctocog alfa after reconstitution 3. LIST OF EXCIPIENTS Powder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride dihydrate, sodium hydroxide, hydrochloric acid Solvent: Sodium chloride, water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Intravenous use Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 38 Store in a refrigerator. Do not freeze During storage, the product may be kept at: • room temperature (≤ 30°C) for a single period no longer than 9 months or • above room temperature (30°C up to 40°C) for a single period no longer than 3 months Taken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ Store in the original package in order to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBERS EU/1/13/888/005 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE NovoEight 2000 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: 39 SN: NN: 40 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION NovoEight 2000 IU powder for solution for injection turoctocog alfa Intravenous use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2000 IU 6. OTHER Novo Nordisk A/S 41 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT NovoEight 3000 IU powder and solvent for solution for injection turoctocog alfa (human coagulation factor VIII (rDNA)) 2. STATEMENT OF ACTIVE SUBSTANCE One ml of NovoEight contains approximately 750 IU of human coagulation factor VIII (rDNA), turoctocog alfa after reconstitution 3. LIST OF EXCIPIENTS Powder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride dihydrate, sodium hydroxide, hydrochloric acid Solvent: Sodium chloride, water for injections 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection Pack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter 5. METHOD AND ROUTE OF ADMINISTRATION Intravenous use Read the package leaflet before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children 7. OTHER SPECIAL WARNINGS, IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 42 Store in a refrigerator. Do not freeze During storage, the product may be kept at: • room temperature (≤ 30°C) for a single period no longer than 9 months or • above room temperature (30°C up to 40°C) for a single period no longer than 3 months Taken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ Store in the original package in order to protect from light 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 12. MARKETING AUTHORISATION NUMBERS EU/1/13/888/006 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE NovoEight 3000 IU 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: 43 NN: 44 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION NovoEight 3000 IU powder for solution for injection turoctocog alfa Intravenous use 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 3000 IU 6. OTHER Novo Nordisk A/S 45 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Pre-filled syringe 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Solvent for NovoEight Sodium chloride 9 mg/ml 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 4 ml 6. OTHER Novo Nordisk A/S 46 B. PACKAGE LEAFLET 47 Package leaflet: Information for the user NovoEight 250 IU powder and solvent for solution for injection NovoEight 500 IU powder and solvent for solution for injection NovoEight 1000 IU powder and solvent for solution for injection NovoEight 1500 IU powder and solvent for solution for injection NovoEight 2000 IU powder and solvent for solution for injection NovoEight 3000 IU powder and solvent for solution for injection turoctocog alfa (human coagulation factor VIII (rDNA)) Read all of this leaflet carefully before you start using this medicine because it contains important information for you. – Keep this leaflet. You may need to read it again. – If you have any further questions, ask your doctor. – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. – If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What NovoEight is and what it is used for 2. What you need to know before you use NovoEight 3. How to use NovoEight 4. Possible side effects 5. How to store NovoEight 6. Contents of the pack and other information 1. What NovoEight is and what it is used for NovoEight contains the active substance turoctocog alfa, human coagulation factor VIII. Factor VIII is a protein naturally found in the blood that helps it to clot. NovoEight is used to treat and prevent bleeding episodes in patients with haemophilia A (inborn factor VIII deficiency) and can be used for all age groups. In patients with haemophilia A, factor VIII is missing or not working properly. NovoEight replaces this faulty or missing ‘factor VIII’ and helps blood to form clots at the site of bleeding. 2. What you need to know before you use NovoEight Do not use NovoEight: • if you are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6) • if you are allergic to hamster proteins. Do not use NovoEight if either of the above applies to you. If you are not sure, talk to your doctor before using this medicine. Warnings and precautions Talk to your doctor before using NovoEight. There is a rare chance that you may experience an anaphylactic reaction (a severe, sudden allergic reaction) to NovoEight. Early signs of allergic reactions are rash, hives, weals, generalised itching, 48 swelling of lips and tongue, difficulty in breathing, wheezing, tightness of the chest, general feeling of being unwell, and dizziness. If any of these symptoms occur, stop the injection immediately and contact your doctor. Talk to your doctor if you think that your bleed is not being controlled with the dose you receive, as there can be several reasons for this. Some people using this medicine can develop antibodies to factor VIII (also known as factor VIII inhibitors). Factor VIII inhibitors make NovoEight less effective in preventing or controlling bleeding. If this happens you may need a higher dose of NovoEight or a different medicine to control your bleed. Do not increase the total dose of NovoEight to control your bleed without talking to your doctor. You should tell your doctor if you have been previously treated with factor VIII products, especially if you developed inhibitors, since there might be a higher risk that it happens again. The formation of inhibitors (antibodies) is a known complication that can occur during treatment with all Factor VIII medicines. These inhibitors, especially at high levels, stop the treatment working properly and you or your child will be monitored carefully for the development of these inhibitors. If you or your child´s bleeding is not being controlled with NovoEight, tell your doctor immediately. Other medicines and NovoEight Tell your doctor if you are taking, have recently taken or might take any other medicines. Pregnancy and breastfeeding If you are pregnant or breastfeeding, think that you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Driving and using machines NovoEight has no influence on your ability to drive and use machines. NovoEight contains sodium This medicine contains 30.5 mg sodium (main component of cooking/table salt) per reconstituted vial. This is equivalent to 1.5% of the recommended maximum dietary intake of sodium for an adult. Talk to your doctor if you are on a controlled sodium diet. 3. How to use NovoEight Treatment with NovoEight will be started by a doctor who is experienced in the care of patients with haemophilia A. Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. Your doctor will calculate your dose for you. This will depend on your weight and what the medicine is being used for. Prevention of bleeding The usual dose of NovoEight is 20 to 50 international units (IU) per kg of body weight. The injection is given every 2 to 3 days. In some cases, especially in younger patients, more frequent injections or higher doses may be needed. Treatment of bleeding The dose of NovoEight is calculated depending on your body weight and the factor VIII levels to be achieved. The target factor VIII levels will depend on the severity and location of the bleeding. Use in children and adolescents NovoEight can be used in children of all ages. In children (below the age of 12) higher doses or more frequent injections may be needed. Adolescents (above the age of 12) can use the same dose as adults. 49 How NovoEight is given NovoEight is given as an injection into a vein. See ‘Instructions on how to use NovoEight’ for more information. If you use more NovoEight than you should If you use more NovoEight than you should, tell your doctor or go to a hospital straight away. If you forget to use NovoEight You should contact your doctor if you have missed a dose and do not know how to compensate for this. If you stop using NovoEight If you stop using NovoEight you may no longer be protected against bleeding or a current bleed may not stop. Do not stop using NovoEight without talking to your doctor. If you have any further questions on the use of this medicine, ask your doctor. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may occur with this medicine. If severe, sudden allergic reactions (anaphylactic reactions) occur (very rare), the injection must be stopped immediately. You must contact your doctor immediately if you have one of the following early symptoms: • difficulty in breathing, shortness of breath or wheezing • chest tightness • swelling of the lips and tongue • rash, hives, weals or generalised itching • feeling dizzy or loss of consciousness • low blood pressure (having pale and cold skin, fast heartbeat). Severe symptoms, including difficulty in swallowing or breathing and red or swollen face or hands, require prompt emergency treatment. If you have a severe allergic reaction, your doctor may change your medicine. For children not previously treated with Factor VIII medicines, inhibitor antibodies (see section 2) may form very commonly (more than 1 in 10 patients); however patients who have received previous treatment with Factor VIII (more than 150 days of treatment) the risk is uncommon (less than 1 in 100 patients). If this happens to you or your child´s medicines may stop working properly and you or your child may experience persistent bleeding. If this happens, you should contact your doctor immediately. Common side effects (may affect up to 1 in 10 people) • blood tests showing changes in the way the liver functions • reactions (redness and itching) around the site where you injected the medicine. Common side effects (may affect up to 1 in 10 people) in patients who have not previously treated with Factor VIII medicines • blushing of the skin • inflammation of vein • bleeding into joint spaces • bleeding in muscle tissue • cough 50 • redness around the site where you placed catheter • vomiting. Uncommon side effects (may affect up to 1 in 100 people) • feeling tired • headache • feeling dizzy • difficulty sleeping (insomnia) • fast heartbeat • increased blood pressure • rash • fever • feeling hot • stiffness of muscles • pain in muscles • pain in legs and arms • swelling of legs and feet • joint disease • bruising • heart attack. Side effects in children and adolescents The side effects observed in children and adolescents are the same as observed in adults. Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store NovoEight Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date, which is stated after ‘EXP’ on the carton and on the vial and the pre-filled syringe labels. The expiry date refers to the last day of that month. Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. Before the NovoEight powder is reconstituted it may be kept at: • room temperature (≤ 30°C) for a single period no longer than 9 months or • above room temperature (30°C up to 40°C) for a single period no longer than 3 months. Once the product has been taken out of the refrigerator, the product must not be returned to the refrigerator. Please record the beginning of storage and the storage temperature on the product carton. Once you have reconstituted NovoEight it should be used right away. If you cannot use the reconstituted NovoEight solution immediately, it should be used within: • 24 hours stored at 2°C – 8°C http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 51 • 4 hours stored at ≤ 30°C, for product which has been kept for a single period no longer than 9 months at room temperature (≤30°C) • 4 hours stored up to 40°C, for product which has been kept for a single period no longer than 3 months at above room temperature (30°C up to 40°C). Store the reconstituted product in the vial. If not used straight away the medicine may no longer be sterile and could cause infection. Do not store the solution without your doctor’s advice. The powder in the vial appears as a white or slightly yellow powder. Do not use the powder if the colour has changed. The reconstituted solution will be clear to slightly opalescent. Do not use this medicine if you notice that it is cloudy or contains visible particles. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What NovoEight contains – The active substance is turoctocog alfa (human coagulation factor VIII (rDNA)). Each vial of NovoEight contains nominally 250, 500, 1000, 1500, 2000 or 3000 IU turoctocog alfa. – The other ingredients are L-histidine, sucrose, polysorbate 80, sodium chloride, L-methionine, calcium chloride dihydrate, sodium hydroxide and hydrochloric acid. – The ingredients in the solvent are sodium chloride and water for injections. After reconstitution with the supplied solvent (sodium chloride 9 mg/ml (0.9%) solution for injection), the prepared solution for injection contains 62.5, 125, 250, 375, 500 or 750 IU turoctocog alfa per ml, respectively, (based on the strength of turoctocog alfa, i.e. 250, 500, 1000, 1500, 2000 or 3000 IU). What NovoEight looks like and contents of the pack NovoEight is a powder and solvent for solution for injection. Each pack of NovoEight contains a vial with white or slightly yellow powder, a 4 ml pre-filled syringe with a clear colourless solution, a plunger rod and a vial adapter. Marketing Authorisation Holder and Manufacturer Novo Nordisk A/S Novo Allé DK-2880 Bagsværd, Denmark This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. http://www.ema.europa.eu/ http://www.ema.europa.eu/ 52 Instructions on how to use NovoEight READ THESE INSTRUCTIONS CAREFULLY BEFORE USING NOVOEIGHT. NovoEight is supplied as a powder. Before injection (administration) it must be reconstituted with the solvent supplied in the syringe. The solvent is a sodium chloride 9 mg/ml (0.9%) solution. The reconstituted NovoEight must be injected into your vein (intravenous injection). The equipment in this package is designed to reconstitute and inject NovoEight. You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters. These devices are not included in the NovoEight package. Do not use the equipment without proper training from your doctor or nurse. Always wash your hands and ensure that the area around you is clean. When you prepare and inject medicine directly into the veins, it is important to use a clean and germ free (aseptic) technique. Improper technique can introduce germs that can infect the blood. Do not open the equipment until you are ready to use it. Do not use the equipment if it has been dropped, or if it is damaged. Use a new package instead. Do not use the equipment if it is expired. Use a new package instead. The expiry date is printed after ‘EXP’ on the outer carton, on the vial, on the vial adapter, and on the pre-filled syringe. Do not use the equipment if you suspect it is contaminated. Use a new package instead. Do not dispose of any of the items until after you have injected the reconstituted solution. The equipment is for single use only. Contents The package contains: • 1 vial with NovoEight powder • 1 vial adapter • 1 pre-filled syringe with solvent • 1 plunger rod (placed under the syringe) 53 Overview Vial with NovoEight powder Plastic cap Rubber stopper (under plastic cap) Protective cap Vial adapter Spike (under protective paper) Protective paper Syringe cap Syringe tip (under syringe cap) Pre-filled syringe with solvent Scale Plunger Thread Plunger rod Wide top end 1. Prepare the vial and the syringe • Take out the number of NovoEight packages you need. • Check the expiry date. • Check the name, strength and colour of the package, to make sure it contains the correct product. • Wash your hands and dry them properly using a clean towel or air dry. • Take the vial, the vial adapter and the pre-filled syringe out of the carton. Leave the plunger rod untouched in the carton. • Bring the vial and the pre-filled syringe to room temperature. You can do this by holding them in your hands until they feel as warm as your hands. • Do not use any other way to heat the A 54 vial and pre-filled syringe. • Remove the plastic cap from the vial. If the plastic cap is loose or missing, do not use the vial. • Wipe the rubber stopper with a sterile alcohol swab and allow it to air dry for a few seconds before use to ensure that it is as germ free as possible. • Do not touch the rubber stopper with your fingers as this can transfer germs. B 2. Attach the vial adapter • Remove the protective paper from the vial adapter. If the protective paper is not fully sealed or if it is broken, do not use the vial adapter. Do not take the vial adapter out of the protective cap with your fingers. If you touch the spike on the vial adapter, germs from your fingers can be transferred. C • Place the vial on a flat and solid surface. • Turn over the protective cap, and snap the vial adapter onto the vial. Once attached, do not remove the vial adapter from the vial. D • Lightly squeeze the protective cap with your thumb and index finger as shown. Remove the protective cap from the vial adapter. Do not lift the vial adapter from the vial when removing the protective cap. E 3. Attach the plunger rod and the syringe • Grasp the plunger rod by the wide top end and take it out of the carton. Do not touch the sides or the thread of the plunger rod. If you touch the sides or the thread, germs from your fingers can be transferred. • Immediately connect the plunger rod to the syringe by turning it clockwise F 55 into the plunger inside the pre-filled syringe until resistance is felt. • Remove the syringe cap from the pre- filled syringe by bending it down until the perforation breaks. • Do not touch the syringe tip under the syringe cap. If you touch the syringe tip, germs from your fingers can be transferred. If the syringe cap is loose or missing, do not use the pre-filled syringe. G • Screw the pre-filled syringe securely onto the vial adapter until resistance is felt. H 4. Reconstitute the powder with the solvent • Hold the pre-filled syringe slightly tilted with the vial pointing downwards. • Push the plunger rod to inject all the solvent into the vial. I • Keep the plunger rod pressed down and swirl the vial gently until all the powder is dissolved. Do not shake the vial as this will cause foaming. • Check the reconstituted solution. It must be clear to slightly opalescent (slightly unclear). If you notice visible particles or discolouration, do not use it. Use a new package instead. J NovoEight is recommended to be used immediately after it has been reconstituted. This is because if left, the medicine may no longer be sterile and could cause infections. If you cannot use the reconstituted NovoEight solution immediately, it should be used within 4 hours when stored at room temperature or up to 40°C and within 24 hours when stored at 2°C – 8°C. Store the reconstituted product in the vial. Do not freeze reconstituted NovoEight solution or store it in syringes. Do not store the solution without your doctor’s advice. Keep reconstituted NovoEight solution out of direct light. 56 If your dose requires more than one vial, repeat steps A to J with additional vials, vial adapters and pre-filled syringes until you have reached your required dose. • Keep the plunger rod pushed completely in. • Turn the syringe with the vial upside down. • Stop pushing the plunger rod and let it move back on its own while the reconstituted solution fills the syringe. • Pull the plunger rod slightly downwards to draw the reconstituted solution into the syringe. • In case you only need part of the entire vial, use the scale on the syringe to see how much reconstituted solution you withdraw, as instructed by your doctor or nurse. If, at any point, there is too much air in the syringe, inject the air back into the vial. • While holding the vial upside down, tap the syringe gently to let any air bubbles rise to the top. • Push the plunger rod slowly until all air bubbles are gone. K • Unscrew the vial adapter with the vial. • Do not touch the syringe tip. If you touch the syringe tip, germs from your fingers can be transferred. L 5. Inject the reconstituted solution NovoEight is now ready to be injected into your vein. • Inject the reconstituted solution as instructed by your doctor or nurse. • Inject slowly over 2 to 5 minutes. • Do not mix NovoEight with any other intravenous infusions or medicines. Injecting NovoEight via needleless connectors for intravenous (IV) catheters Caution: The pre-filled syringe is made of glass and is designed to be compatible with standard 57 luer-lock connections. Some needleless connectors with an internal spike are incompatible with the pre-filled syringe. This incompatibility may prevent administration of the medicine and/or result in damage to the needleless connector. Injecting the solution via a central venous access device (CVAD) such as a central venous catheter or a subcutaneous port: • Use a clean and germ free (aseptic) technique. Follow the instructions for proper use for your connector and CVAD in consultation with your doctor or nurse. • Injecting into a CVAD may require using a sterile 10 ml plastic syringe for withdrawal of the reconstituted solution. This should be done right after step J. • If the CVAD line needs to be flushed before or after NovoEight injection, use sodium chloride 9 mg/ml solution for injection. Disposal • After injection, safely dispose of all unused NovoEight solution, the syringe with the infusion set, the vial with the vial adapter and other waste materials as instructed by your pharmacist. Do not throw it out with the ordinary household waste. M Do not disassemble the equipment before disposal. Do not reuse the equipment. ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what novoeight is and what it is used for', 'Section_Content': "novoeight contains the active substance turoctocog alfa, human coagulation factor viii. factor viii is a protein naturally found in the blood that helps it to clot. novoeight is used to treat and prevent bleeding episodes in patients with haemophilia a (inborn factor viii deficiency) and can be used for all age groups. in patients with haemophilia a, factor viii is missing or not working properly. novoeight replaces this faulty or missing 'factor viii' and helps blood to form clots at the site of bleeding.", 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'novoeight', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 9}, {'Text': 'the active substance turoctocog alfa', 'Type': 'TREATMENT', 'BeginOffset': 19, 'EndOffset': 55}, {'Text': 'human coagulation factor viii', 'Type': 'TREATMENT', 'BeginOffset': 57, 'EndOffset': 86}, {'Text': 'factor viii', 'Type': 'PROBLEM', 'BeginOffset': 88, 'EndOffset': 99}, {'Text': 'a protein naturally', 'Type': 'PROBLEM', 'BeginOffset': 103, 'EndOffset': 122}, {'Text': 'the blood', 'Type': 'PROBLEM', 'BeginOffset': 132, 'EndOffset': 141}, {'Id': 0, 'BeginOffset': 159, 'EndOffset': 163, 'Score': 0.7891916036605835, 'Text': 'clot', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.47304147481918335}]}, {'Id': 1, 'BeginOffset': 165, 'EndOffset': 174, 'Score': 0.5823735594749451, 'Text': 'novoeight', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'bleeding episodes', 'Type': 'PROBLEM', 'BeginOffset': 204, 'EndOffset': 221}, {'Text': 'haemophilia a (inborn factor viii deficiency', 'Type': 'PROBLEM', 'BeginOffset': 239, 'EndOffset': 283}, {'Id': 5, 'BeginOffset': 338, 'EndOffset': 349, 'Score': 0.5161329507827759, 'Text': 'haemophilia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 353, 'EndOffset': 375, 'Score': 0.7121350765228271, 'Text': 'factor viii is missing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 401, 'EndOffset': 410, 'Score': 0.2092716246843338, 'Text': 'novoeight', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 481, 'EndOffset': 486, 'Score': 0.5697647929191589, 'Text': 'clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 502, 'EndOffset': 510, 'Score': 0.9601958394050598, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}]}

{'Title': '2. what you need to know before you use novoeight', 'Section_Content': 'do not use novoeight: if you are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6) if you are allergic to hamster proteins. do not use novoeight if either of the above applies to you. if you are not sure, talk to your doctor before using this medicine. warnings and precautions talk to your doctor before using novoeight. there is a rare chance that you may experience an anaphylactic reaction (a severe, sudden allergic reaction) to novoeight. early signs of allergic reactions are rash, hives, weals, generalised itching, 48 swelling of lips and tongue, difficulty in breathing, wheezing, tightness of the chest, general feeling of being unwell, and dizziness. if any of these symptoms occur, stop the injection immediately and contact your doctor. talk to your doctor if you think that your bleed is not being controlled with the dose you receive, as there can be several reasons for this. some people using this medicine can develop antibodies to factor viii (also known as factor viii inhibitors). factor viii inhibitors make novoeight less effective in preventing or controlling bleeding. if this happens you may need a higher dose of novoeight or a different medicine to control your bleed. do not increase the total dose of novoeight to control your bleed without talking to your doctor. you should tell your doctor if you have been previously treated with factor viii products, especially if you developed inhibitors, since there might be a higher risk that it happens again. the formation of inhibitors (antibodies) is a known complication that can occur during treatment with all factor viii medicines. these inhibitors, especially at high levels, stop the treatment working properly and you or your child will be monitored carefully for the development of these inhibitors. if you or your child´s bleeding is not being controlled with novoeight, tell your doctor immediately. other medicines and novoeight tell your doctor if you are taking, have recently taken or might take any other medicines. pregnancy and breastfeeding if you are pregnant or breastfeeding, think that you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. driving and using machines novoeight has no influence on your ability to drive and use machines. novoeight contains sodium this medicine contains 30.5 mg sodium (main component of cooking/table salt) per reconstituted vial. this is equivalent to 1.5% of the recommended maximum dietary intake of sodium for an adult. talk to your doctor if you are on a controlled sodium diet.', 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 33, 'EndOffset': 41}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 104, 'EndOffset': 117}, {'Text': '6', 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reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6178388595581055}]}, {'Id': 9, 'BeginOffset': 540, 'EndOffset': 544, 'Score': 0.9991183876991272, 'Text': 'rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9089606404304504}]}, {'Id': 10, 'BeginOffset': 546, 'EndOffset': 551, 'Score': 0.997627317905426, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8433966040611267}]}, {'Id': 11, 'BeginOffset': 553, 'EndOffset': 558, 'Score': 0.8641600608825684, 'Text': 'weals', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9092506170272827}]}, {'Id': 12, 'BeginOffset': 560, 'EndOffset': 579, 'Score': 0.42138323187828064, 'Text': 'generalised itching', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.963641345500946}]}, {'Text': '48 swelling of lips and tongue', 'Type': 'PROBLEM', 'BeginOffset': 581, 'EndOffset': 611}, {'Id': 14, 'BeginOffset': 613, 'EndOffset': 636, 'Score': 0.9751498699188232, 'Text': 'difficulty in breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9653730392456055}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9962557554244995, 'RelationshipScore': 0.7850874066352844, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 0, 'BeginOffset': 596, 'EndOffset': 600, 'Text': 'lips', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 15, 'BeginOffset': 638, 'EndOffset': 646, 'Score': 0.9987945556640625, 'Text': 'wheezing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9738582968711853}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9974320530891418, 'RelationshipScore': 0.9405819177627563, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 2, 'BeginOffset': 665, 'EndOffset': 670, 'Text': 'chest', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'tightness of the chest', 'Type': 'PROBLEM', 'BeginOffset': 648, 'EndOffset': 670}, {'Id': 17, 'BeginOffset': 680, 'EndOffset': 703, 'Score': 0.620624840259552, 'Text': 'feeling of being unwell', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9498584866523743}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9974320530891418, 'RelationshipScore': 0.7436643242835999, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 2, 'BeginOffset': 665, 'EndOffset': 670, 'Text': 'chest', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 18, 'BeginOffset': 709, 'EndOffset': 718, 'Score': 0.9976340532302856, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9462296962738037}]}, {'Text': 'these symptoms', 'Type': 'PROBLEM', 'BeginOffset': 730, 'EndOffset': 744}, {'Text': 'your bleed', 'Type': 'PROBLEM', 'BeginOffset': 846, 'EndOffset': 856}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 968, 'EndOffset': 981}, {'Text': 'factor viii', 'Type': 'TREATMENT', 'BeginOffset': 1008, 'EndOffset': 1019}, {'Id': 24, 'BeginOffset': 1035, 'EndOffset': 1057, 'Score': 0.4069144129753113, 'Text': 'factor viii inhibitors', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 25, 'BeginOffset': 1060, 'EndOffset': 1082, 'Score': 0.8191794157028198, 'Text': 'factor viii inhibitors', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'novoeight', 'Type': 'TREATMENT', 'BeginOffset': 1088, 'EndOffset': 1097}, {'Text': 'controlling bleeding', 'Type': 'PROBLEM', 'BeginOffset': 1130, 'EndOffset': 1150}, {'Text': 'a higher dose of novoeight', 'Type': 'TREATMENT', 'BeginOffset': 1181, 'EndOffset': 1207}, {'Text': 'a different medicine', 'Type': 'TREATMENT', 'BeginOffset': 1211, 'EndOffset': 1231}, {'Text': 'your bleed', 'Type': 'PROBLEM', 'BeginOffset': 1243, 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{'Title': '3. how to use novoeight', 'Section_Content': "treatment with novoeight will be started by a doctor who is experienced in the care of patients with haemophilia a. always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. your doctor will calculate your dose for you. this will depend on your weight and what the medicine is being used for. prevention of bleeding the usual dose of novoeight is 20 to 50 international units (iu) per kg of body weight. the injection is given every 2 to 3 days. in some cases, especially in younger patients, more frequent injections or higher doses may be needed. treatment of bleeding the dose of novoeight is calculated depending on your body weight and the factor viii levels to be achieved. the target factor viii levels will depend on the severity and location of the bleeding. use in children and adolescents novoeight can be used in children of all ages. in children (below the age of 12) higher doses or more frequent injections may be needed. adolescents (above the age of 12) can use the same dose as adults. how novoeight is given novoeight is given as an injection into a vein. see 'instructions on how to use novoeight' for more information. if you use more novoeight than you should if you use more novoeight than you should, tell your doctor or go to a hospital straight away. if you forget to use novoeight you should contact your doctor if you have missed a dose and do not know how to compensate for this. if you stop using novoeight if you stop using novoeight you may no longer be protected against bleeding or a current bleed may not stop. do not stop using novoeight without talking to your doctor. if you have any further questions on the use of this medicine, ask your doctor.", 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 9}, {'Text': 'novoeight', 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the following side effects may occur with this medicine. if severe, sudden allergic reactions (anaphylactic reactions) occur (very rare), the injection must be stopped immediately. you must contact your doctor immediately if you have one of the following early symptoms: difficulty in breathing, shortness of breath or wheezing chest tightness swelling of the lips and tongue rash, hives, weals or generalised itching feeling dizzy or loss of consciousness low blood pressure (having pale and cold skin, fast heartbeat). severe symptoms, including difficulty in swallowing or breathing and red or swollen face or hands, require prompt emergency treatment. if you have a severe allergic reaction, your doctor may change your medicine. for children not previously treated with factor viii medicines, inhibitor antibodies (see section 2) may form very commonly (more than 1 in 10 patients); however patients who have received previous treatment with factor viii (more than 150 days of treatment) the risk is uncommon (less than 1 in 100 patients). if this happens to you or your child´s medicines may stop working properly and you or your child may experience persistent bleeding. if this happens, you should contact your doctor immediately. common side effects (may affect up to 1 in 10 people) blood tests showing changes in the way the liver functions reactions (redness and itching) around the site where you injected the medicine. common side effects (may affect up to 1 in 10 people) in patients who have not previously treated with factor viii medicines blushing of the skin inflammation of vein bleeding into joint spaces bleeding in muscle tissue cough 50 redness around the site where you placed catheter vomiting. uncommon side effects (may affect up to 1 in 100 people) feeling tired headache feeling dizzy difficulty sleeping (insomnia) fast heartbeat increased blood pressure rash fever feeling hot stiffness of muscles pain in muscles pain in legs and arms swelling of legs and feet joint disease bruising heart attack. side effects in children and adolescents the side effects observed in children and adolescents are the same as observed in adults. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 19, 'BeginOffset': 44, 'EndOffset': 56, 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'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9991982579231262, 'RelationshipScore': 0.6660498380661011, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 452, 'EndOffset': 456, 'Text': 'lips', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'chest tightness swelling of the lips', 'Type': 'PROBLEM', 'BeginOffset': 420, 'EndOffset': 456}, {'Text': 'tongue rash', 'Type': 'PROBLEM', 'BeginOffset': 461, 'EndOffset': 472}, {'Id': 29, 'BeginOffset': 474, 'EndOffset': 479, 'Score': 0.9972769618034363, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9689964652061462}]}, {'Id': 30, 'BeginOffset': 481, 'EndOffset': 486, 'Score': 0.8949930667877197, 'Text': 'weals', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9535887837409973}]}, {'Text': 'generalised itching', 'Type': 'PROBLEM', 'BeginOffset': 490, 'EndOffset': 509}, {'Id': 33, 'BeginOffset': 510, 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[]}, {'Id': 47, 'BeginOffset': 1405, 'EndOffset': 1453, 'Score': 0.4297177791595459, 'Text': 'changes in the way the liver functions reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5681809782981873}]}, {'Id': 6, 'BeginOffset': 1428, 'EndOffset': 1433, 'Score': 0.9381654262542725, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 48, 'BeginOffset': 1455, 'EndOffset': 1462, 'Score': 0.9842891097068787, 'Text': 'redness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9098587036132812}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.4213845729827881, 'RelationshipScore': 0.9725016951560974, 'RelationshipType': 'DIRECTION', 'Id': 7, 'BeginOffset': 1476, 'EndOffset': 1482, 'Text': 'around', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 49, 'BeginOffset': 1467, 'EndOffset': 1474, 'Score': 0.9984993934631348, 'Text': 'itching', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9249996542930603}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.4213845729827881, 'RelationshipScore': 0.9998886585235596, 'RelationshipType': 'DIRECTION', 'Id': 7, 'BeginOffset': 1476, 'EndOffset': 1482, 'Text': 'around', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'common side effects', 'Type': 'PROBLEM', 'BeginOffset': 1525, 'EndOffset': 1544}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1563, 'EndOffset': 1564}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 1568, 'EndOffset': 1570}, {'Id': 80, 'BeginOffset': 1604, 'EndOffset': 1614, 'Score': 0.9999909400939941, 'Text': 'previously', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.8768852353096008, 'RelationshipScore': 0.6367756724357605, 'RelationshipType': 'OVERLAP', 'Id': 51, 'BeginOffset': 1628, 'EndOffset': 1658, 'Text': 'factor viii medicines blushing', 'Category': 'MEDICAL_CONDITION', 'Traits': []}]}, {'Id': 51, 'BeginOffset': 1628, 'EndOffset': 1658, 'Score': 0.8768852353096008, 'Text': 'factor viii medicines blushing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9883572459220886, 'RelationshipScore': 0.5096378922462463, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 8, 'BeginOffset': 1666, 'EndOffset': 1670, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the skin inflammation', 'Type': 'PROBLEM', 'BeginOffset': 1662, 'EndOffset': 1683}, {'Text': 'vein bleeding into joint spaces bleeding', 'Type': 'PROBLEM', 'BeginOffset': 1687, 'EndOffset': 1727}, {'Text': 'muscle tissue cough', 'Type': 'PROBLEM', 'BeginOffset': 1731, 'EndOffset': 1750}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 1751, 'EndOffset': 1753}, {'Id': 56, 'BeginOffset': 1754, 'EndOffset': 1761, 'Score': 0.9423660635948181, 'Text': 'redness', 'Category': 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'EndOffset': 1989}, {'Text': 'hot stiffness of muscles pain', 'Type': 'PROBLEM', 'BeginOffset': 1998, 'EndOffset': 2027}, {'Text': 'muscles pain in legs', 'Type': 'PROBLEM', 'BeginOffset': 2031, 'EndOffset': 2051}, {'Text': 'arms swelling of legs and feet joint disease bruising heart attack', 'Type': 'PROBLEM', 'BeginOffset': 2056, 'EndOffset': 2122}, {'Id': 87, 'BeginOffset': 2124, 'EndOffset': 2136, 'Score': 0.9040277004241943, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6759584546089172}]}, {'Id': 88, 'BeginOffset': 2169, 'EndOffset': 2181, 'Score': 0.6899211406707764, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6819000840187073}]}, {'Id': 89, 'BeginOffset': 2268, 'EndOffset': 2280, 'Score': 0.9460355639457703, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 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{'Title': '5. how to store novoeight', 'Section_Content': "keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date, which is stated after 'exp' on the carton and on the vial and the pre-filled syringe labels. the expiry date refers to the last day of that month. store in a refrigerator (2 8). do not freeze. keep the vial in the outer carton in order to protect from light. before the novoeight powder is reconstituted it may be kept at: room temperature (≤ 30) for a single period no longer than 9 months or above room temperature (30 up to 40) for a single period no longer than 3 months. once the product has been taken out of the refrigerator, the product must not be returned to the refrigerator. please record the beginning of storage and the storage temperature on the product carton. once you have reconstituted novoeight it should be used right away. if you cannot use the reconstituted novoeight solution immediately, it should be used within: 24 hours stored at 2 8 51 4 hours stored at ≤ 30, for product which has been kept for a single period no longer than 9 months at room temperature (≤30) 4 hours stored up to 40, for product which has been kept for a single period no longer than 3 months at above room temperature (30 up to 40). store the reconstituted product in the vial. if not used straight away the medicine may no longer be sterile and could cause infection. do not store the solution without your doctor's advice. the powder in the vial appears as a white or slightly yellow powder. do not use the powder if the colour has changed. the reconstituted solution will be clear to slightly opalescent. do not use this medicine if you notice that it is cloudy or contains visible particles. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.", 'Entity_Recognition': [{'Text': 'novoeight', 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A1B5CA77B539E285D47E3A64125A95D2

https://www.ema.europa.eu/documents/product-information/lartruvo-epar-product-information_en.pdf

Lartruvo

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Me dic ina l p rod uc t n o l on ge r a uth ori se d 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Lartruvo 10 mg/mL concentrate for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One mL of concentrate for solution for infusion contains 10 mg of olaratumab. Each 19 mL vial contains 190 mg of olaratumab. Each 50 mL vial contains 500 mg of olaratumab. Olaratumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology. Excipient with known effect Each 19mL vial contains approximately 22 mg (1 mmol) sodium. Each 50 mL vial contains approximately 57 mg (2.5 mmol) sodium. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion (sterile concentrate). The concentrate is clear to slightly opalescent and colourless to slightly yellow solution without visible particles. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Lartruvo is indicated in combination with doxorubicin for the treatment of adult patients with advanced soft tissue sarcoma who are not amenable to curative treatment with surgery or radiotherapy and who have not been previously treated with doxorubicin (see section 5.1). 4.2 Posology and method of administration Olaratumab therapy must be initiated and supervised by physicians experienced in oncology. Patients should be monitored during the infusion for signs and symptoms of infusion-related reactions (IRRs) in a setting with available resuscitation equipment (see section 4.4). Posology The recommended dose of olaratumab is 15 mg/kg administered by intravenous infusion on days 1 and 8 of each 3 week cycle until disease progression or unacceptable toxicity. Lartruvo is administered in combination with doxorubicin for up to 8 cycles of treatment, followed by Lartruvo monotherapy in Me dic ina l p rod uc t n o l on ge r a uth ori se d 3 patients whose disease has not progressed. Doxorubicin is given on day 1 of each cycle following the Lartruvo infusion. Premedication Premedication with an H1 antagonist (e.g., diphenhydramine) and dexamethasone (or equivalent medicinal products) should be given, intravenously, 30–60 minutes prior to the olaratumab doses on days 1 and 8 of cycle 1 in all patients. For subsequent cycles, premedication with an H1 antagonist (e.g., diphenhydramine) should be given intravenously 30–60 minutes prior to each dose of olaratumab. For patients who experience Grade 1 or 2 IRR, the infusion should be interrupted and paracetamol, H1 antagonist and dexamethasone (or equivalent medicinal products) administered as needed. For all subsequent infusions, premedication with the following (or equivalent medicinal products) diphenhydramine hydrochloride (intravenously), paracetamol, and dexamethasone, should be given. In the event that intravenous administration of an H1 antagonist is not possible, equivalent alternative premedication should be given (e.g. oral diphenhydramine hydrochloride at least 90 minutes prior to the infusion). Posology adjustments for olaratumab For dose adjustment recommendations related to doxorubicin, refer to the current doxorubicin prescribing information. Infusion-related reactions (IRRs) Recommendations for the management of olaratumab IRRs are provided in table 1. Table 1 – Management recommendations for infusion-related reactions (IRRs) Toxicity gradea Management recommendations (any occurrence) Grade 1-2 • Stop the infusion • Paracetamol, H1 antagonist and dexamethasone should be administered as needed (see premedication section) • Once the reaction has resolved, resume infusion at a 50 % decreased infusion rate.b • Monitor patient for worsening of condition. • For subsequent infusions, please see premedication section. Grade 3-4 • Immediately and permanently discontinue treatment with olaratumab (see section 4.4). a Grade per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03 b Once the infusion rate has been reduced for a Grade 1 or 2 infusion-related reaction, it is recommended that the lower infusion rate be utilized for all subsequent infusions. The infusion duration should not exceed 2 hours. Other non-haematology toxicities For serious Grade ≥ 3 non-haematologic toxicity deemed related to olaratumab, the dose of olaratumab should be withheld until toxicity is ≤ Grade 1 or has returned to pretreatment baseline. For subsequent infusions, the dose should be reduced to 12 mg/kg for serious Grade 3 toxicities and to 10 mg/kg for Grade 4 toxicities. If a Grade 3 toxicity recurs despite the dose reduction, the dose should be reduced further to 10 mg/kg. In case of recurrence of a Grade 4 toxicity, treatment with olaratumab should be permanently discontinued. Neutropenia Me dic ina l p rod uc t n o l on ge r a uth ori se d 4 If neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week occurs, administration of olaratumab should be temporarily discontinued until the absolute neutrophil count is 1,000 / µL or higher and then the dose of olaratumab should be resumed at the reduced dose of 12 mg/kg. If neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week recurs despite dose reduction, the dose should be reduced further to 10 mg/kg. Special populations Elderly (> 65 years) Data on very elderly patients (> 75 years) are very limited (see sections 4.8 and 5.1). No dose reductions other than those recommended for the general patient population are necessary. Renal impairment There have been no formal studies with olaratumab in patients with renal impairment. PopPK data suggest that no dose adjustments are required in patients with mild or moderate renal impairment. There are no data regarding olaratumab administration in patients with severe renal impairment (calculated creatinine clearance < 30 mL/min) (see section 5.2). Hepatic impairment There have been no formal studies with olaratumab in patients with hepatic impairment. PopPK data suggest that no dose adjustments are required in patients with mild hepatic impairment. There are very limited data regarding olaratumab administration in patients with moderate hepatic impairment. There are no data in patients with severe hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of olaratumab in children aged 0 to 18 years of age have not yet been established. No data are available. Method of administration After dilution in sodium chloride 9 mg/mL (0.9 %) solution for injection, olaratumab is administered as an intravenous infusion over approximately 60 minutes. In order to accommodate larger infusion volumes that may be needed for patients requiring higher doses, the duration of infusion should be increased such that the maximum infusion rate of 25 mg/minute is not exceeded. For instructions on dilution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Infusion-related reactions Infusion-related reactions (IRRs), including anaphylactic reactions, were reported in clinical trials with olaratumab. The majority of these reactions occurred during or following the first olaratumab infusion. Symptoms of IRRs included flushing, shortness of breath, bronchospasm, or fever/chills, and in some cases manifested as severe hypotension, anaphylactic shock, or fatal cardiac arrest. Severe IRRs such as anaphylactic reactions can occur despite the use of premedication. Patients should be monitored during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. For management and dose adjustments in patients who experience Grade 1 or 2 IRR during the infusion, see section 4.2. In patients who have experienced a previous Grade 1 or 2 IRR, premedication with diphenhydramine hydrochloride (intravenously), paracetamol, and dexamethasone is recommended. Olaratumab should be immediately and permanently discontinued in patients who experience Grade 3 or 4 IRR (see sections 4.2 and 4.8). Me dic ina l p rod uc t n o l on ge r a uth ori se d 5 Neutropenia Patients receiving olaratumab and doxorubicin are at risk of neutropenia (see section 4.8). Neutrophil count should be checked prior to Olaratumab dosing on Day 1 and Day 8 of each cycle. Neutrophil count should be monitored during the treatment with olaratumab and doxorubicin and supportive care should be administered such as antibiotics or G-CSF as per local guidelines. For dosage adjustments related to neutropenia, refer to section 4.2. Haemorrhagic events Patients receiving olaratumab and doxorubicin are at risk of haemorrhagic events (see section 4.8). Platelet counts should be checked prior to olaratumab dosing on Day 1 and Day 8 of each cycle. Coagulation parameters should be monitored in patients with conditions predisposing to bleeding, such as anticoagulant use. In a study of olaratumab in combination with liposomal doxorubicin, there was one case of fatal intracranial haemorrhage in a patient who had experienced a fall while on treatment. Anthracycline pre-treated patients The risk of cardiac toxicity rises with increasing cumulative doses of anthracyclines, including doxorubicin. There are no data for the combination of olaratumab and doxorubicin in anthracycline pre-treated patients, including pre-treatment with doxorubicin (see section 4.1). Sodium restricted diet This medicinal product contains 22 mg sodium per each 19 mL vial and 57 mg sodium per each 50 mL vial. To be taken into consideration by patients on a controlled sodium diet. Cardiac toxicity Doxorubicin can cause cardiotoxicity. The risk of toxicity rises with increasing cumulative doses and is higher in individuals with a history of cardiomyopathy, mediastinal irradiation or pre-existing cardiac disease. To minimise doxorubicin-related cardiotoxicity, the use of appropriate cardio- protective measures (LVEF measurement, such as ECHO or MUGA scan, ECG monitoring, and/or use of cardioprotective agents) should be considered and planned in all patients before the start and throughout the treatment. Please refer to doxorubicin SmPC for recommendation on cardiac monitoring. In the phase 2 trial, patients in both treatment groups that received 5 or more cycles of doxorubicin received dexrazoxane prior to each dose of doxorubicin from cycle 5 onwards to minimize the risk of doxorubicin-related cardiotoxicity (see sections 4.8 and 5.1). Hepatic impairment As doxorubicin is rapidly metabolised and predominantly eliminated by the biliary system, the toxicity of doxorubicin is enhanced in patients with hepatic impairment. Refer to doxorubicin SmPC for appropriate monitoring of hepatic function and doxorubicin dose adjustments in patients with impaired liver function. 4.5 Interaction with other medicinal products and other forms of interaction Olaratumab is a human monoclonal antibody. In a dedicated DDI study, no pharmacokinetic interactions were observed in patients between olaratumab and doxorubicin. No other formal DDI studies with olaratumab and medicinal products commonly used in cancer patients, including those with STS (e.g. antiemetics, analgesics, anti-diarrheal drugs, oral contraceptives, etc.), have been performed. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal Me dic ina l p rod uc t n o l on ge r a uth ori se d 6 products is not anticipated to affect the pharmacokinetics of olaratumab. Conversely, olaratumab is not anticipated to affect the pharmacokinetics of co-administered medicinal products. Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving olaratumab in combination with doxorubicin. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/contraception in females Women of childbearing potential should be advised to avoid becoming pregnant while on olaratumab and should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 3 months following the last dose of olaratumab. Pregnancy There are no or limited amount of data from the use of olaratumab in pregnant women. Reproductive and development toxicity study conducted with an anti-murine PDGFRα antibody in mice showed foetal malformations and skeletal alterations (see section 5.3). Based on its mechanism of action (see section 5.1), olaratumab has the potential to cause foetal harm. Olaratumab is not recommended during pregnancy and in women of childbearing potential not using contraception, unless the potential benefit justifies the potential risk to the foetus. Breast-feeding It is not known whether olaratumab is excreted in human milk. Human IgG is excreted in human milk, therefore breast-feeding is not recommended during treatment with olaratumab and for at least 3 months following the last dose. Fertility There are no data on the effect of olaratumab on human fertility. 4.7 Effects on ability to drive and use machines Olaratumab may have minor influence on the ability to drive and use machines. Due to frequent occurrence of fatigue, patients should be advised to use caution when driving or operating machinery. 4.8 Undesirable effects Summary of the safety profile Olaratumab-treated patients from Phase 2 study In the olaratumab plus doxorubicin arm, the most serious (Grade ≥3) adverse drug reactions (ADRs) observed were neutropenia (54.7 %) and musculoskeletal pain (7.8 %). The most frequently occurring ADRs were nausea, musculoskeletal pain, neutropenia and mucositis. The most frequent ADRs associated with permanent treatment discontinuation occurred in 3 (4.7 %) patients of which the most frequent were infusion-related reactions (3.1 %) and mucositis (1.6 %). Known toxicities reported for doxorubicin, observed in the combination of olaratumab and doxorubicin include fatigue, anaemia, thrombocytopenia and alopecia. Please refer to the doxorubicin SmPC for complete descriptions of all adverse events associated with doxorubicin treatment Me dic ina l p rod uc t n o l on ge r a uth ori se d 7 Tabulated list of adverse reactions ADRs which were reported in patients with soft tissue sarcoma treated with olaratumab in combination with doxorubicin in the Phase 2 study are listed below in Table 2 in MedDRA body system organ class, frequency and grade of severity. The following convention has been used for classification of frequency: Very common (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) Rare (≥ 1/10,000 to < 1/1,000) Very rare (< 1/10,000) Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Table 2: Adverse reactions in patients receiving olaratumab plus doxorubicin for soft tissue sarcoma during the Phase 2 portion of a Phase 1b/2 study System organ class Adverse Reactiona Frequency overall Grade 3/4 frequency Blood and lymphatic system disorders Neutropenia Very Common Very Common Lymphopenia Very Common Common Nervous system disorders Headache Very Common None reported Gastrointestinal disorders Diarrhoea Very Common Common Mucositis Very Common Common Nausea Very Common Common Vomiting Very Common None reported Musculoskeletal and connective tissue disorders Musculoskeletal Painb Very Common Common General disorders and administrative site conditions Infusion-related Reactionsc Very Common Common a Refer to NCI CTCAE Criteria (Version 4.03) for each Grade of toxicity b Musculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, muscle spasms, neck pain, and pain in extremity. c Infusion-related reactions includes anaphylactic reactions/anaphylactic shock. Description of selected ADRs Infusion-related reactions (IRRs) IRRs were reported in 12.5 % of patients and mainly present as chills, fever or dyspnoea. Severe IRRs, also including a fatal case (see section 4.4) were reported in 3.1 % of patients and mainly presented with shortness of breath, loss of consciousness and hypotension. All severe IRRs occurred during or immediately after the first administration of olaratumab. Neutropenia In the phase 2 trial, the incidence of neutropenia was 59.4 % (all Grades) and 54.7 % (Grade 3) in the olaratumab plus doxorubicin arm and 38.5 % (all Grades) and 33.8 % (Grade 3) in the doxorubicin alone arm. The rate of febrile neutropenia was 12.5 % in the olaratumab plus doxorubicin arm and 13.8 % in the doxorubicin alone arm. For dose adjustments, refer to section 4.2 Musculoskeletal pain In the phase 2 trial the incidence of Musculoskeletal pain was 64.1 % (all Grades) and 7.8 % (Grade 3) in the olaratumab plus doxorubicin arm and 24.6 % (all Grades) and 1.5 % (Grade 3) in the Me dic ina l p rod uc t n o l on ge r a uth ori se d 8 doxorubicin alone arm. In the majority of patients the pain was related to the patients’ underlying cancer or metastases or pre-existing or concomitant conditions. The majority of these events occurred in the first 4 cycles. The pain can last from few days to up to 200 days. In some patients there was a recurrence of pain .The pain did not worsen with time or during recurrence. Cardiac toxicity No clinically meaningful difference in doxorubicin-related cardiotoxicity was observed between the two treatment arms of the study. The rate of cardiac arrhythmias was similar in both arms (15.6 % in the Investigational Arm and 15.4 % in the Control Arm). The rate of treatment-emergent cardiac dysfunction was comparable between the two treatment arms (7.8 % in the Investigational Arm and 6.2 % in the Control Arm). Haemorrhagic events In the phase 2 trial, the frequency of haemorrhagic events considered related to any study drug was 3.1 % in either treatment arm. All of these events were Grade 1/2 and were confounded by multiple factors. Three Grade ≥3 events, including one fatal, have been reported across the clinical development programme of olaratumab (see section 4.4). Toxicity in the elderly There was a higher incidence of Grade ≥3 adverse reactions, adverse reactions leading to discontinuation and a higher rate of haematological toxicity in the elderly population compared to the overall study population (see section 4.2). The rates of discontinuation were comparable between treatment arms across all age groups. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose There is no experience with Lartruvo overdose in human clinical trials. Lartruvo has been administered in a Phase 1 study up to 20 mg/kg on days 1 and 8 of a 21 day cycle without reaching a maximum tolerated dose. In case of overdose, use supportive therapy. There is no known antidote to Lartruvo overdose. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC27 Mechanism of action Olaratumab is an antagonist of platelet derived growth factor receptor-α (PDGFR-α), expressed on tumour and stromal cells. Olaratumab is a targeted, recombinant, fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that specifically binds PDGFR-α, blocking PDGF AA, -BB, and -CC binding and receptor activation. As a result, in vitro olaratumab inhibits PDGFR-α pathway signalling in tumour and stromal cells. In addition, in vivo olaratumab has been shown to disrupt the PDGFR-α pathway in tumour cells and inhibit tumour growth. Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 Overall, a low incidence of both treatment emergent anti-drug antibodies and neutralising antibodies were detected in clinical trial samples. Clinical efficacy and safety The efficacy and safety of olaratumab was assessed in a Phase 1b/2, multi-centre study in anthracycline naïve patients with histologically or cytologically confirmed, advanced soft tissue sarcoma not amenable to receive surgery or radiotherapy with curative intent. Patients with gastrointestinal stromal tumours (GIST) or Kaposi sarcoma were not enrolled. The Phase 2 portion of the study was a randomised, open label study of olaratumab plus doxorubicin versus doxorubicin alone. A total of 133 patients were randomised, of whom 129 received at least one dose of study treatment (64 in the olaratumab plus doxorubicin arm and 65 in the doxorubicin arm). Patients were required to have histologically or cytologically confirmed, advanced soft tissue sarcoma and ECOG performance status of 0-2. Randomisation was stratified by PDGFR-α expression (positive versus negative), number of previous lines of treatment (0 versus 1 or more lines), histological tumour type (leiomyosarcoma, synovial sarcoma, and others) and ECOG performance status (0 or 1 versus 2). Patients were randomised in a 1:1 ratio to either olaratumab (15 mg/kg) on Day 1 and Day 8 plus doxorubicin (75 mg/m²) on Day 1 of each 21-day cycle for up to 8 cycles or doxorubicin (75 mg/m2) alone on Day 1 of each 21-day cycle, also for up to 8 cycles. Olaratumab and doxorubicin were administered by intravenous infusion. During Cycles 5 to 8 on both arms, dexrazoxane (dosed at a ratio of 10:1 to the administered dose of doxorubicin) could be administered on Day 1 of each cycle at the investigator’s discretion to reduce potential doxorubicin-related cardiotoxicity. All patients receiving more than 4 cycles of doxorubicin received dexrazoxane. Patients in the olaratumab plus doxorubicin arm could continue on olaratumab monotherapy until disease progression, unacceptable toxicity or any other reason for treatment discontinuation occurred. Demographics and baseline characteristics were quite similar between treatment arms in the phase 2 portion of the clinical trial. The median age was 58 years with 42 patients ≥ 65 years of age. 86.4 % of the patients were Caucasian. More than 25 different soft tissue sarcoma subtypes were represented in this trial, the most frequent being leiomyosarcoma (38.4 %), undifferentiated pleomorphic sarcoma (18.1 %) and liposarcoma (17.3 %). Other subtypes were infrequently represented. Patients had received 0-4 previous lines of therapy for treatment of advanced disease but had not previously received treatment with anthracyclines. The number of patients receiving post-study systemic therapy was similar between arms. Ten patients in the olaratumab plus doxorubicin arm and 5 patients in the doxorubicin arm received post-study radiotherapy only. 3 patients in the olaratumab plus doxorubicin arm and 1 patient in the doxorubicin arm had post-study surgery only. 2 patients in the olaratumab plus doxorubicin arm and none in the doxorubicin arm received both post-study radiotherapy and surgery. The median cumulative dose of doxorubicin was 487.6 mg/m2 in the olaratumab plus doxorubicin arm and 299.6 mg/m2 in the doxorubicin alone arm. The primary efficacy outcome measure was progression free survival (PFS) by investigator assessment. Key secondary efficacy outcome measures were overall survival (OS) and objective response rate (ORR) (see Table 3). The study met its primary endpoint (PFS). PFS according to a post-hoc, blinded, independent assessment was 8.2 months vs 4.4 months; HR = 0.670; p = 0.1208. A statistically significant improvement in OS was seen in the olaratumab plus doxorubicin arm in comparison to treatment with doxorubicin alone in the overall population. The main analysis was performed in the following two subgroups: Leiomyosarcoma (LMS) and non-LMS (other). Subgroups analysis of OS is shown in figure 2. Difference in objective response rate [complete response (CR) + partial response (PR)] according to investigator assessment was not statistically significant (18.2 % vs 11.9 % in patients randomised to olaratumab plus doxorubicin compared to patients randomized to doxorubicin respectively). Efficacy results are shown in Table 3 and Figures 1 and 2. Me dic ina l p rod uc t n o l on ge r a uth ori se d 10 Table 3. Summary of survival data – ITT population Lartruvo plus doxorubicin (n = 66) Doxorubicin alone (n = 67) Progression free survival, months* Median (95 % CI) 6.6 (4.1, 8.3) 4.1 (2.8, 5.4) Hazard ratio (95 % CI) 0.672 (0.442, 1.021) p-value 0.0615** Overall survival, months Median (95 % CI) 26.5 (20.9, 31.7) 14.7 (9.2, 17.1) Hazard ratio (95 % CI) 0.463 (0.301, 0.710) p-value 0.0003 Abbreviations: CI = confidence interval * By investigator assessment **Met phase 2 protocol defined significance level of 0.19 Figure 1. Kaplan-Meier curves of overall survival for Lartruvo plus doxorubicin versus doxorubicin alone Me dic ina l p rod uc t n o l on ge r a uth ori se d 11 Figure 2. Forest plot for subgroup analysis of overall survival (ITT population) Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with olaratumab in one or more subsets of the paediatric population in soft tissue sarcoma (see section 4.2 for information on paediatric use). This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary . 5.2 Pharmacokinetic properties Absorption Olaratumab is administered as an intravenous infusion only. Distribution The population pharmacokinetic (PopPK) model-based mean (CV %) volume of distribution of olaratumab at steady state (Vss) was 7.7 L (16 %). Elimination The PopPK model-based mean (CV %) clearance for olaratumab was 0.56 L/day (33 %). This corresponds to a mean terminal half-life of approximately 11 days. Special populations Age, sex, and race had no clinically meaningful effect on the PK of olaratumab based on a PopPK analysis. Clearance and volume of distribution had a positive correlation with body weight. Me dic ina l p rod uc t n o l on ge r a uth ori se d 12 Renal impairment No formal studies have been conducted to evaluate the effect of renal impairment on the PK of olaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of olaratumab were observed in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, n = 43), or moderate (CLcr 30-59 mL/min, n = 15) renal impairment compared to patients with normal renal function (CLcr ≥90 mL/min, n = 85). No data were available from patients with severe renal impairment (CLcr 15-29 mL/min). Hepatic impairment No formal studies have been conducted to evaluate the effect of hepatic impairment on the PK of olaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of olaratumab were observed in patients with mild (total bilirubin within upper limit of normal [ULN] and AST>ULN, or total bilirubin > 1.0-1.5 times ULN and any AST level, n = 16), or moderate (total bilirubin > 1.5-3.0 times ULN, n = 1) hepatic impairment compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN, n = 126). No data were available from patients with severe hepatic impairment (total bilirubin > 3.0 times ULN and any AST level). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on repeat dose toxicity studies in monkeys. No animal studies have been performed to test olaratumab for potential of carcinogenicity, genotoxicity, or fertility impairment. Administration of an anti-murine PDGFR- α surrogate antibody to pregnant mice during organogenesis at 50 and 150 mg/kg resulted in increased malformations (abnormal eyelid development) and skeletal alterations (frontal/parietal additional ossification site). The foetal effects in mice administered the surrogate antibody occurred at exposures less than the AUC exposure at the maximum recommended human dose of 15 mg/kg olaratumab. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Mannitol (E421) Glycine (E640) Sodium chloride L-Histidine monohydrochloride monohydrate L-Histidine Polysorbate 20 (E432) Water for injections 6.2 Incompatibilities The medicinal product should not be administered or mixed with dextrose containing solutions. 6.3 Shelf life Unopened vial 2 years. After dilution This product is preservative free. From a microbiological point of view the prepared dosing solution should be used immediately. If not used immediately, the dosing solution should be stored under refrigeration for up to 24 hours at 2 °C to 8 °C and up to an additional 8 hours at room temperature (up Me dic ina l p rod uc t n o l on ge r a uth ori se d 13 to 25 °C) assuming dilution has taken place in controlled and validated aseptic conditions. Storage times include the duration of infusion. 6.4 Special precautions for storage Store in a refrigerator (2° C - 8° C). Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 19 mL solution in a vial (Type I glass) with a chlorobutyl elastomeric stopper, an aluminium seal and a polypropylene cap. 50 mL solution in a vial (Type I glass) with a chlorobutyl elastomeric stopper, an aluminium seal and a polypropylene cap. Pack of 1 vial of 19 mL. Pack of 2 vials of 19 mL. Pack of 1 vial of 50 mL. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The infusion solution should be prepared using aseptic technique to ensure the sterility of the prepared solution. Each vial is intended for single use only. Do not shake the vial. The content of the vials should be inspected for particulate matter and discolouration (the concentrate for solution for infusion should be clear to slightly opalescent and colourless to slightly yellow without visible particles) prior to administration. If particulate matter or discolouration is identified, the vial must be discarded. The dose and volume of olaratumab needed should be calculated to prepare the infusion solution. Vials contain 190 mg or 500 mg as a 10 mg/mL solution of olaratumab. Only use sodium chloride 9 mg/mL (0.9 %) solution for injection as a diluent. In case of prefilled intravenous infusion container usage Based on the calculated volume of olaratumab, the corresponding volume of sodium chloride 9 mg/mL (0.9 %) solution for injection should be removed from the prefilled 250 mL intravenous container. The calculated volume of olaratumab should be aseptically transferred to the intravenous container. The final total volume in the container should be 250 mL. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. In case of empty intravenous infusion container usage The calculated volume of olaratumab should be aseptically transferred into an empty intravenous infusion container. A sufficient quantity of sodium chloride 9 mg/mL (0.9 %) solution for injection should be added to the container to make the total volume 250 mL. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. Administer via an infusion pump. A separate infusion line must be used and the line must be flushed with sodium chloride 9 mg/mL (0.9 %) solution for injection at the end of the infusion. Any unused portion of olaratumab left in a vial should be discarded, as the product contains no antimicrobial preservatives. Me dic ina l p rod uc t n o l on ge r a uth ori se d 14 Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V. Papendorpseweg 83 3528 BJ Utrecht The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1143/001-003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 9 November 2016 Date of latest renewal: 21 September 2017 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 15 ANNEX II A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION Me dic ina l p rod uc t n o l on ge r a uth ori se d 16 A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer(s) of the biological active substance(s) ImClone Systems LLC 33 ImClone Drive Branchburg New Jersey NJ 08876 UNITED STATES Name and address of the manufacturer(s) responsible for batch release Lilly S.A. Avda. de la Industria 30 Alcobendas 28108 Madrid SPAIN B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures Not applicable. Me dic ina l p rod uc t n o l on ge r a uth ori se d 17 E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: Description Due date In order to further confirm the efficacy and safety of olaratumab in the treatment of patients with advanced soft tissue sarcoma, the MAH should submit the clinical study report of the phase III study JGDJ comparing doxorubicin plus olaratumab versus doxorubicin in patients with advanced or metastatic STS (including exploratory biomarker data). 31 January 2020 Me dic ina l p rod uc t n o l on ge r a uth ori se d 18 ANNEX III LABELLING AND PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 19 A. LABELLING Me dic ina l p rod uc t n o l on ge r a uth ori se d 20 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON – 50 mL vial 1. NAME OF THE MEDICINAL PRODUCT Lartruvo 10 mg/mL concentrate for solution for infusion olaratumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One mL of concentrate contains 10 mg of olaratumab. One vial of 50 mL contains 500 mg olaratumab. 3. LIST OF EXCIPIENTS Excipients: mannitol, glycine, sodium chloride, L-histidine monohydrochloride monohydrate, L-histidine, polysorbate 20 and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion 500 mg/50 mL 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For intravenous use after dilution. For single use only. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake. 8. EXPIRY DATE EXP Me dic ina l p rod uc t n o l on ge r a uth ori se d 21 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V. Papendorpseweg 83, 3528 BJ Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1143/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: Me dic ina l p rod uc t n o l on ge r a uth ori se d 22 NN: Me dic ina l p rod uc t n o l on ge r a uth ori se d 23 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON – 19 mL vial 1. NAME OF THE MEDICINAL PRODUCT Lartruvo 10 mg/mL concentrate for solution for infusion olaratumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One mL of concentrate contains 10 mg of olaratumab. One vial of 19 mL contains 190 mg olaratumab. 3. LIST OF EXCIPIENTS Excipients: mannitol, glycine, sodium chloride, L-histidine monohydrochloride monohydrate, L-histidine, polysorbate 20 and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion 190 mg/19 mL 1 vial 2 vials 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For intravenous use after dilution. For single use only. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake. 8. EXPIRY DATE EXP Me dic ina l p rod uc t n o l on ge r a uth ori se d 24 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial in the outer carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V. Papendorpseweg 83, 3528 BJ Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1143/002 – 1 vial of 19 mL. EU/1/16/1143/003 – 2 vials of 19 mL. 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA Me dic ina l p rod uc t n o l on ge r a uth ori se d 25 PC: SN: NN: Me dic ina l p rod uc t n o l on ge r a uth ori se d 26 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING VIAL LABEL – 50 mL vial 1. NAME OF THE MEDICINAL PRODUCT Lartruvo 10 mg/mL sterile concentrate olaratumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One mL of concentrate contains 10 mg of olaratumab. One vial of 50 mL contains 500 mg olaratumab. 3. LIST OF EXCIPIENTS Excipients: mannitol, glycine, sodium chloride, L-histidine monohydrochloride monohydrate, L-histidine, polysorbate 20 and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion 500 mg/50 mL 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For IV use after dilution. For single use only. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake. 8. EXPIRY DATE EXP Me dic ina l p rod uc t n o l on ge r a uth ori se d 27 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial in the outer carton. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V. Papendorpseweg 83, 3528 BJ Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1143/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. Me dic ina l p rod uc t n o l on ge r a uth ori se d 28 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING VIAL LABEL – 19 mL vial 1. NAME OF THE MEDICINAL PRODUCT Lartruvo 10 mg/mL sterile concentrate olaratumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One mL of concentrate contains 10 mg of olaratumab. One vial of 19 mL contains 190 mg olaratumab. 3. LIST OF EXCIPIENTS Excipients: mannitol, glycine, sodium chloride, L-histidine monohydrochloride monohydrate, L-histidine, polysorbate 20 and water for injections. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion 190 mg/19 mL 1 vial 2 vials 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For IV use after dilution. For single use only. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake. 8. EXPIRY DATE EXP Me dic ina l p rod uc t n o l on ge r a uth ori se d 29 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial in the outer carton. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V. Papendorpseweg 83, 3528 BJ Utrecht The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1143/002 – 1 vial of 19 mL. EU/1/16/1143/003 – 2 vials of 19 mL. 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. Me dic ina l p rod uc t n o l on ge r a uth ori se d 30 B. PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 31 Package leaflet: Information for the user Lartruvo 10 mg/mL concentrate for solution for infusion olaratumab This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you are given this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor. - If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Lartruvo is and what it is used for 2. What you need to know before you are given Lartruvo 3. How you are given Lartruvo 4. Possible side effects 5. How to store Lartruvo 6. Contents of the pack and other information 1. What Lartruvo is and what it is used for Lartruvo contains the active substance olaratumab, which belongs to a group of medicines called monoclonal antibodies. Olaratumab recognises and attaches specifically to a protein known as platelet-derived growth factor receptor-α (PDGFR-α). PDGFR-α is found in large amounts on some cancer cells where it stimulates the cells to grow and divide. When olaratumab attaches to PDGFR-α it may prevent cancer cell growth and survival. Lartruvo is used in combination with another anti-cancer medicine called doxorubicin for the treatment of adults with advanced soft tissue sarcoma who have not been previously treated with doxorubicin. Soft tissue sarcoma is a cancer that starts in the soft tissues, such as the muscles, fat, cartilage and blood vessels. 2. What you need to know before you are given Lartruvo You must not be given Lartruvo - if you are allergic to olaratumab or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions You should tell your doctor about any of the following: - if you are receiving any treatment for heart disease or liver disease Talk to your doctor or nurse immediately if the following applies to you (or you are not sure): – Infusion-related reaction Infusion-related reactions may occur during treatment with Lartruvo. Such reactions may be allergic. Symptoms may include back pain, chest pain and/or tightness, chills, fever, flushing, difficulty in Me dic ina l p rod uc t n o l on ge r a uth ori se d 32 breathing and wheezing. In severe cases, you may experience very low blood pressure, feel faint, and experience breathing distress caused by narrowing of the airways, which could be life-threatening. Your doctor will give you other medicines before you receive Lartruvo to reduce the risk of infusion- related reactions. Your doctor or nurse will check for side effects during and after your infusion. If you have a severe infusion-related reaction, your doctor may recommend reducing the dose of Lartruvo or stop your treatment with Lartruvo. See section 4 for more details about infusion-related reactions which may occur during or after the infusion. – Bleeding Lartruvo and doxorubicin may decrease your platelet count. Platelets help your blood to clot and a low platelet count may increase the risk of bleeding. If you experience significant bleeding, symptoms may include extreme tiredness, weakness, dizziness or changes in the colour of your stools. Your doctor will check your platelet count prior to treatment with Lartruvo. – Reduction in the number of white blood cells Lartruvo and doxorubicin may decrease the number of white blood cells (including neutrophils). White blood cells are important for fighting infection. A low white blood cell count may increase your risk for infection. Your doctor will check your white blood cell counts prior to treatment with Lartruvo. Children and adolescents Lartruvo should not be given to patients under the age of 18 years because there is no information about how it works in this age group. Other medicines and Lartruvo Tell your doctor if you are taking, have recently taken or might take any other medicines. Pregnancy and breast-feeding Before starting treatment you must tell your doctor if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby. Avoid getting pregnant while receiving this medicine and for at least 3 months after the last dose of Lartruvo as this medicine may harm your unborn child. Talk to your doctor about the best contraception for you. It is not known whether olaratumab gets into breast milk and if the breast-fed infant is at risk of harm. Ask your doctor if you can breast-feed during or after treatment with Lartruvo. Driving and using machines It is not known if Lartruvo will affect your ability to drive. If you get any symptoms that affect your ability to concentrate and react, such as tiredness, do not drive or use machines until the effect goes away. Lartruvo contains sodium This medicine contains 22 mg sodium in each 19 mL vial and 57 mg sodium in each 50 mL vial. This should be taken into consideration if you are on a controlled sodium diet. 3. How you are given Lartruvo A doctor experienced in the use of anti-cancer medicines will supervise your Lartruvo therapy. Premedication You will be given medicines to reduce the risk of an infusion-related reaction before you receive Lartruvo. Me dic ina l p rod uc t n o l on ge r a uth ori se d 33 Dose and administration The recommended dose of Lartruvo is 15 mg per kilogram of your body weight on days 1 and 8 of each 3-week cycle. Lartruvo is given in combination with the medicine doxorubicin for up to 8 cycles and then it is given on its own. The number of infusions that you receive will depend on how well and for how long treatment with Lartruvo works and how well you feel. Your doctor will discuss this with you. This medicine is given as an infusion into a vein via a drip. The drip lasts about 60 minutes. Detailed instructions for your doctor or your nurse on how to prepare Lartruvo infusion are included at the end of this package leaflet (see ‘Handling instructions’). Dose adjustments During each infusion, your doctor or nurse will check for side effects. Your doctor may also give you a smaller dose or delay your dose of Lartruvo if you get serious side effects including a lowering of your white blood cell counts. If you have an infusion-related reaction during treatment, your doctor or nurse may slow down or stop your Lartruvo infusion. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Your doctor will discuss these with you and will explain the risks and benefits of your treatment. The following side effects have been reported: Infusion reactions Lartruvo has been associated with infusion reactions (see section 2 “Warnings and precautions”). Tell your doctor or nurse immediately if you feel unwell during infusion. Below is a list of some typical symptoms associated with infusion reactions: • Feeling faint • Fever • Chills • Flushing • Shortness of breath Other symptoms may occur as well (see section 2 “Warnings and precautions”). Your doctor may consider slowing the Lartruvo infusion or interrupting it to manage these symptoms. Very common (may affect more than 1 in 10 people): – nausea – pain in your muscles, joints or bones (musculoskeletal pain) – low white blood cell counts (including neutrophils and lymphocytes which may increase the risk of infection) – pain or sores in your mouth or throat (mucositis) – vomiting – diarrhoea – headache – infusion-related reactions Reporting of side effects If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 34 5. How to store Lartruvo Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the outer carton and vial label after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2 °C – 8 °C). Do not freeze or shake the vial. Keep the vial in the outer carton to protect from light. Infusion solution: After dilution and preparation, the medicine must be used immediately. If not used immediately, in-use storage times and conditions before use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 ºC and up to an additional 8 hours at room temperature (below 25 ºC). Do not freeze or shake the infusion solution. Do not administer the solution if you notice any particulate matter or discoloration. This medicine is for single use only. Do not store any unused portion of the infusion solution for reuse. Any unused medicine or waste material should be disposed of in accordance with local requirements. 6. Contents of the pack and other information What Lartruvo contains - The active substance is olaratumab. Each millilitre of the concentrate for solution for infusion contains 10 mg of olaratumab. Each 19 mL vial contains 190 mg of olaratumab. Each 50 mL vial contains 500 mg of olaratumab. - The other ingredients are mannitol, glycine, L-histidine monohydrochloride monohydrate, L-histidine, sodium chloride (see section 2 “Lartruvo contains sodium”), polysorbate 20 and water for injections. What Lartruvo looks like and contents of the pack Lartruvo concentrate for solution for infusion (sterile concentrate) is a clear to slightly opalescent and colourless to slightly yellow liquid supplied in a glass vial with an elastomeric stopper. It is available in packs of: - 1 vial of 19 mL - 2 vials of 19 mL - 1 vial of 50 mL Not all pack sizes may be marketed. Marketing Authorisation Holder Eli Lilly Nederland B.V. Papendorpseweg 83 3528 BJ Utrecht The Netherlands. Manufacturer Lilly S.A. Avda de la Industria, 30 28108 Alcobendas Madrid Spain Me dic ina l p rod uc t n o l on ge r a uth ori se d 35 For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Eli Lilly Benelux S.A./N.V. Tél/Tel: + 32-(0)2 548 84 84 Lietuva Eli Lilly Holdings Limited atstovybė Tel. +370 (5) 2649600 България ТП "Ели Лили Недерланд" Б.В. - България тел. + 359 2 491 41 40 Luxembourg/Luxemburg Eli Lilly Benelux S.A./N.V. Tél/Tel: + 32-(0)2 548 84 84 Česká republika ELI LILLY ČR, s.r.o. Tel: + 420 234 664 111 Magyarország Lilly Hungária Kft. Tel: + 36 1 328 5100 Danmark Eli Lilly Danmark A/S Tlf: +45 45 26 60 00 Malta Charles de Giorgio Ltd. Tel: + 356 25600 500 Deutschland Lilly Deutschland GmbH Tel. + 49-(0) 6172 273 2222 Nederland Eli Lilly Nederland B.V. Tel: + 31-(0) 30 60 25 800 Eesti Eli Lilly Holdings Limited Eesti filiaal Tel: +372 6 817 280 Norge Eli Lilly Norge A.S. Tlf: + 47 22 88 18 00 Ελλάδα ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε. Τηλ: +30 210 629 4600 Österreich Eli Lilly Ges.m.b.H. Tel: + 43-(0) 1 711 780 España Lilly S.A. Tel: + 34-91 663 50 00 Polska Eli Lilly Polska Sp. z o.o. Tel: +48 22 440 33 00 France Lilly France SAS Tél: +33-(0) 1 55 49 34 34 Portugal Lilly Portugal Produtos Farmacêuticos, Lda Tel: + 351-21-4126600 Hrvatska Eli Lilly Hrvatska d.o.o. Tel: +385 1 2350 999 România Eli Lilly România S.R.L. Tel: + 40 21 4023000 Ireland Eli Lilly and Company (Ireland) Limited Tel: + 353-(0) 1 661 4377 Slovenija Eli Lilly farmacevtska družba, d.o.o. Tel: +386 (0)1 580 00 10 Ísland Icepharma hf. Sími + 354 540 8000 Slovenská republika Eli Lilly Slovakia, s.r.o. Tel: + 421 220 663 111 Italia Eli Lilly Italia S.p.A. Tel: + 39- 055 42571 Suomi/Finland Oy Eli Lilly Finland Ab Puh/Tel: + 358-(0) 9 85 45 250 Κύπρος Phadisco Ltd Τηλ: +357 22 715000 Sverige Eli Lilly Sweden AB Tel: + 46-(0) 8 7378800 Latvija Eli Lilly Holdings Limited pārstāvniecība Latvijā Tel: +371 67364000 United Kingdom Eli Lilly and Company Limited Tel: + 44-(0) 1256 315000 This leaflet was last revised in < {month YYYY}>. This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine. The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary. Me dic ina l p rod uc t n o l on ge r a uth ori se d 36 Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 37 --------------------------------------------------------------------------------------------------------------------------- Handling instructions Lartruvo 10 mg/mL concentrate for solution for infusion olaratumab The following information is intended for healthcare professionals only Prepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution. Each vial is intended for single use only. Inspect the contents of the vials for particulate matter and discolouration. The concentrate for solution for infusion must be clear to slightly opalescent and colourless to slightly yellow prior to dilution. If particulate matter or discolouration is identified, the vial must be discarded. Vials contain 190 mg or 500 mg as a 10 mg/mL solution of olaratumab; calculate the dose and volume of olaratumab needed to prepare the infusion solution. Only use sodium chloride 9 mg/mL (0.9 %) solution for injection as a diluent. To administer using pre-filled intravenous infusion containers Based on the calculated volume of olaratumab, aseptically remove the corresponding volume of sodium chloride 9 mg/mL (0.9 %) solution for injection from the prefilled 250 mL intravenous container and transfer the olaratumab medicine into the container to bring the final volume in the container back to 250 mL. Gently invert the container to mix. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medicines. To administer using empty intravenous infusion containers Aseptically transfer the calculated volume of olaratumab into an empty intravenous infusion container. Add a sufficient quantity of sodium chloride 9 mg/mL (0.9 %) solution for injection to the container to make the total volume 250 mL. Gently invert the container to mix. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medicines. Administer via an infusion pump. A separate infusion line must be used and the line must be flushed with sodium chloride 9 mg/mL (0.9 %) solution for injection at the end of the infusion. Parenteral medicines should be inspected visually for particulate matter prior to administration. If particulate matter is identified, discard the infusion solution. Discard any unused portion of olaratumab left in a vial, as the product contains no antimicrobial preservatives. Any unused medicines or waste material should be disposed of in accordance with local requirements. Me dic ina l p rod uc t n o l on ge r a uth ori se d 38 Annex IV Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s) Me dic ina l p rod uc t n o l on ge r a uth ori se d 39 Scientific conclusions Taking into account the PRAC Assessment Report on the PSUR(s) for olaratumab, the scientific conclusions of CHMP are as follows: Based on cases of anaphylactic reaction and anaphylactic shock reported in the post-marketing setting, these adverse drug reactions should be specifically be mentioned under the category of infusion-related reactions in section 4.8 of the SmPC. The frequency of anaphylactic reactions/anaphylactic shock is already calculated as part of grade 3-4 infusion-related reactions in the table of Adverse Drug Reactions (ADRs) in the same section of the SmPC. The current wording of the Package leaflet is considered sufficient to communicate this risk. The CHMP agrees with the scientific conclusions made by the PRAC. Grounds for the variation to the terms of the marketing authorisation(s) On the basis of the scientific conclusions for olaratumab the CHMP is of the opinion that the benefit- risk balance of the medicinal product(s) containing olaratumab is unchanged subject to the proposed changes to the product information. The CHMP recommends that the terms of the marketing authorisation(s) should be varied. Me dic ina l p rod uc t n o l on ge r a uth ori se d SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION A. LABELLING B. PACKAGE LEAFLET Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)

{'Title': '1. what lartruvo is and what it is used for', 'Section_Content': 'lartruvo contains the active substance olaratumab, which belongs to a group of medicines called monoclonal antibodies. olaratumab recognises and attaches specifically to a protein known as platelet-derived growth factor receptor-α (pdgfr-α). pdgfr-α is found in large amounts on some cancer cells where it stimulates the cells to grow and divide. when olaratumab attaches to pdgfr-α it may prevent cancer cell growth and survival. lartruvo is used in combination with another anti-cancer medicine called doxorubicin for the treatment of adults with advanced soft tissue sarcoma who have not been previously treated with doxorubicin. soft tissue sarcoma is a cancer that starts in the soft tissues, such as the muscles, fat, cartilage and blood vessels.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 7, 'BeginOffset': 0, 'EndOffset': 8, 'Score': 0.6903592348098755, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 39, 'EndOffset': 49, 'Score': 0.9879558682441711, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.484682559967041}]}, {'Text': 'monoclonal antibodies', 'Type': 'TREATMENT', 'BeginOffset': 96, 'EndOffset': 117}, {'Text': 'olaratumab recognises', 'Type': 'PROBLEM', 'BeginOffset': 119, 'EndOffset': 140}, {'Text': 'a protein', 'Type': 'TEST', 'BeginOffset': 170, 'EndOffset': 179}, {'Id': 18, 'BeginOffset': 189, 'EndOffset': 228, 'Score': 0.36655837297439575, 'Text': 'platelet-derived growth factor receptor', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 19, 'BeginOffset': 232, 'EndOffset': 240, 'Score': 0.1843874305486679, 'Text': 'pdgfr-α)', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 20, 'BeginOffset': 242, 'EndOffset': 247, 'Score': 0.2565940022468567, 'Text': 'pdgfr', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'some cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 279, 'EndOffset': 296}, {'Id': 10, 'BeginOffset': 352, 'EndOffset': 362, 'Score': 0.8317338228225708, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'cancer cell growth', 'Type': 'PROBLEM', 'BeginOffset': 398, 'EndOffset': 416}, {'Id': 11, 'BeginOffset': 431, 'EndOffset': 439, 'Score': 0.5562602877616882, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'another anti-cancer medicine', 'Type': 'TREATMENT', 'BeginOffset': 468, 'EndOffset': 496}, {'Id': 12, 'BeginOffset': 504, 'EndOffset': 515, 'Score': 0.9988332390785217, 'Text': 'doxorubicin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'advanced soft tissue sarcoma', 'Type': 'PROBLEM', 'BeginOffset': 549, 'EndOffset': 577}, {'Id': 21, 'BeginOffset': 596, 'EndOffset': 606, 'Score': 0.9999992847442627, 'Text': 'previously', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_MEDICATION_NAME', 'Traits': [], 'Attributes': [{'Type': 'GENERIC_NAME', 'Score': 0.9986029267311096, 'RelationshipScore': 0.6663463115692139, 'RelationshipType': 'OVERLAP', 'Id': 13, 'BeginOffset': 620, 'EndOffset': 631, 'Text': 'doxorubicin', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 13, 'BeginOffset': 620, 'EndOffset': 631, 'Score': 0.9986029267311096, 'Text': 'doxorubicin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 633, 'EndOffset': 652, 'Score': 0.5068289637565613, 'Text': 'soft tissue sarcoma', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9104117751121521}]}, {'Text': 'a cancer', 'Type': 'PROBLEM', 'BeginOffset': 656, 'EndOffset': 664}, {'Id': 2, 'BeginOffset': 684, 'EndOffset': 696, 'Score': 0.9901099801063538, 'Text': 'soft tissues', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 3, 'BeginOffset': 710, 'EndOffset': 717, 'Score': 0.9265168905258179, 'Text': 'muscles', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 4, 'BeginOffset': 719, 'EndOffset': 722, 'Score': 0.4800533652305603, 'Text': 'fat', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 5, 'BeginOffset': 724, 'EndOffset': 733, 'Score': 0.9555637836456299, 'Text': 'cartilage', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 6, 'BeginOffset': 738, 'EndOffset': 751, 'Score': 0.9823331236839294, 'Text': 'blood vessels', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}]}

{'Title': '2. what you need to know before you are given lartruvo', 'Section_Content': 'you must not be given lartruvo - if you are allergic to olaratumab or any of the other ingredients of this medicine (listed in section 6). warnings and precautions you should tell your doctor about any of the following: - if you are receiving any treatment for heart disease or liver disease talk to your doctor or nurse immediately if the following applies to you (or you are not sure): infusion-related reaction infusion-related reactions may occur during treatment with lartruvo. such reactions may be allergic. symptoms may include back pain, chest pain and/or tightness, chills, fever, flushing, difficulty in 32 breathing and wheezing. in severe cases, you may experience very low blood pressure, feel faint, and experience breathing distress caused by narrowing of the airways, which could be life-threatening. your doctor will give you other medicines before you receive lartruvo to reduce the risk of infusion- related reactions. your doctor or nurse will check for side effects during and after your infusion. if you have a severe infusion-related reaction, your doctor may recommend reducing the dose of lartruvo or stop your treatment with lartruvo. see section 4 for more details about infusion-related reactions which may occur during or after the infusion. bleeding lartruvo and doxorubicin may decrease your platelet count. platelets help your blood to clot and a low platelet count may increase the risk of bleeding. if you experience significant bleeding, symptoms may include extreme tiredness, weakness, dizziness or changes in the colour of your stools. your doctor will check your platelet count prior to treatment with lartruvo. reduction in the number of white blood cells lartruvo and doxorubicin may decrease the number of white blood cells (including neutrophils). white blood cells are important for fighting infection. a low white blood cell count may increase your risk for infection. your doctor will check your white blood cell counts prior to treatment with lartruvo. children and adolescents lartruvo should not be given to patients under the age of 18 years because there is no information about how it works in this age group. other medicines and lartruvo tell your doctor if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding before starting treatment you must tell your doctor if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby. avoid getting pregnant while receiving this medicine and for at least 3 months after the last dose of lartruvo as this medicine may harm your unborn child. talk to your doctor about the best contraception for you. it is not known whether olaratumab gets into breast milk and if the breast-fed infant is at risk of harm. ask your doctor if you can breast-feed during or after treatment with lartruvo. driving and using machines it is not known if lartruvo will affect your ability to drive. if you get any symptoms that affect your ability to concentrate and react, such as tiredness, do not drive or use machines until the effect goes away. lartruvo contains sodium this medicine contains 22 mg sodium in each 19 ml vial and 57 mg sodium in each 50 ml vial. this should be taken into consideration if you are on a controlled sodium diet.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 22, 'EndOffset': 30, 'Score': 0.9644026756286621, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.45464766025543213}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 44, 'EndOffset': 52}, {'Id': 5, 'BeginOffset': 56, 'EndOffset': 66, 'Score': 0.9767333269119263, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 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{'Title': '3. how you are given lartruvo', 'Section_Content': "a doctor experienced in the use of anti-cancer medicines will supervise your lartruvo therapy. premedication you will be given medicines to reduce the risk of an infusion-related reaction before you receive lartruvo. dose and administration the recommended dose of lartruvo is 15 mg per kilogram of your body weight on days 1 and 8 of each 3-week cycle. lartruvo is given in combination with the medicine doxorubicin for up to 8 cycles and then it is given on its own. the number of infusions that you receive will depend on how well and for how long treatment with lartruvo works and how well you feel. your doctor will discuss this with you. this medicine is given as an infusion into a vein via a drip. the drip lasts about 60 minutes. detailed instructions for your doctor or your nurse on how to prepare lartruvo infusion are included at the end of this package leaflet (see 'handling instructions'). dose adjustments during each infusion, your doctor or nurse will check for side effects. your doctor may also give you a smaller dose or delay your dose of lartruvo if you get serious side effects including a lowering of your white blood cell counts. if you have an infusion-related reaction during treatment, your doctor or nurse may slow down or stop your lartruvo infusion.", 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'anti-cancer medicines', 'Type': 'TREATMENT', 'BeginOffset': 35, 'EndOffset': 56}, {'Text': 'your lartruvo therapy', 'Type': 'TREATMENT', 'BeginOffset': 72, 'EndOffset': 93}, {'Id': 20, 'BeginOffset': 95, 'EndOffset': 108, 'Score': 0.4059624671936035, 'Text': 'premedication', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 127, 'EndOffset': 136}, {'Id': 15, 'BeginOffset': 162, 'EndOffset': 187, 'Score': 0.397180438041687, 'Text': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. your doctor will discuss these with you and will explain the risks and benefits of your treatment. the following side effects have been reported: infusion reactions lartruvo has been associated with infusion reactions (see section 2 "warnings and precautions"). tell your doctor or nurse immediately if you feel unwell during infusion. below is a list of some typical symptoms associated with infusion reactions: feeling faint fever chills flushing shortness of breath other symptoms may occur as well (see section 2 "warnings and precautions"). your doctor may consider slowing the lartruvo infusion or interrupting it to manage these symptoms. very common (may affect more than 1 in 10 people): nausea pain in your muscles, joints or bones (musculoskeletal pain) low white blood cell counts (including neutrophils and lymphocytes which may increase the risk of infection) pain or sores in your mouth or throat (mucositis) vomiting diarrhoea headache infusion-related reactions reporting of side effects if you get any side effects, talk to your doctor. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 10, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.961088240146637, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6429709792137146}]}, {'Text': 'your treatment', 'Type': 'TREATMENT', 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'affect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 772, 'EndOffset': 773}, {'Id': 41, 'BeginOffset': 774, 'EndOffset': 786, 'Score': 0.5143553018569946, 'Text': 'in 10 people', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.9618617296218872, 'RelationshipScore': 0.5105944871902466, 'RelationshipType': 'OVERLAP', 'Id': 19, 'BeginOffset': 789, 'EndOffset': 795, 'Text': 'nausea', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8419660329818726}]}]}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 777, 'EndOffset': 779}, {'Text': 'nausea pain in your muscles', 'Type': 'PROBLEM', 'BeginOffset': 789, 'EndOffset': 816}, {'Text': 'joints or bones (musculoskeletal pain', 'Type': 'PROBLEM', 'BeginOffset': 818, 'EndOffset': 855}, {'Text': 'low white blood cell counts', 'Type': 'PROBLEM', 'BeginOffset': 857, 'EndOffset': 884}, {'Id': 38, 'BeginOffset': 896, 'EndOffset': 907, 'Score': 0.9645656943321228, 'Text': 'neutrophils', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 39, 'BeginOffset': 912, 'EndOffset': 923, 'Score': 0.8296375274658203, 'Text': 'lymphocytes', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'infection)', 'Type': 'PROBLEM', 'BeginOffset': 955, 'EndOffset': 965}, {'Id': 23, 'BeginOffset': 966, 'EndOffset': 970, 'Score': 0.99212646484375, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7961375713348389}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9955934882164001, 'RelationshipScore': 0.9825515747070312, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 4, 'BeginOffset': 988, 'EndOffset': 993, 'Text': 'mouth', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9981447458267212, 'RelationshipScore': 0.8702298998832703, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 5, 'BeginOffset': 997, 'EndOffset': 1003, 'Text': 'throat', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'sores in your mouth', 'Type': 'PROBLEM', 'BeginOffset': 974, 'EndOffset': 993}, {'Text': 'throat (mucositis)', 'Type': 'PROBLEM', 'BeginOffset': 997, 'EndOffset': 1015}, {'Text': 'vomiting diarrhoea headache infusion', 'Type': 'PROBLEM', 'BeginOffset': 1016, 'EndOffset': 1052}, {'Id': 30, 'BeginOffset': 1084, 'EndOffset': 1096, 'Score': 0.9214938282966614, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8361250162124634}]}, {'Id': 31, 'BeginOffset': 1112, 'EndOffset': 1124, 'Score': 0.9220611453056335, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8144997358322144}]}, {'Id': 32, 'BeginOffset': 1174, 'EndOffset': 1186, 'Score': 0.9557355046272278, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6710321307182312}]}, {'Id': 33, 'BeginOffset': 1235, 'EndOffset': 1247, 'Score': 0.8379074931144714, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6919504404067993}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.5005294680595398, 'RelationshipScore': 0.5842472314834595, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 6, 'BeginOffset': 1301, 'EndOffset': 1309, 'Text': 'appendix', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 6, 'BeginOffset': 1301, 'EndOffset': 1309, 'Score': 0.5005294680595398, 'Text': 'appendix', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 34, 'BeginOffset': 1326, 'EndOffset': 1338, 'Score': 0.7504786252975464, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.728080689907074}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1394, 'EndOffset': 1407}]}

{'Title': '5. how to store lartruvo', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer carton and vial label after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not freeze or shake the vial. keep the vial in the outer carton to protect from light. infusion solution: after dilution and preparation, the medicine must be used immediately. if not used immediately, in-use storage times and conditions before use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 ºc and up to an additional 8 hours at room temperature (below 25 ºc). do not freeze or shake the infusion solution. do not administer the solution if you notice any particulate matter or discoloration. this medicine is for single use only. do not store any unused portion of the infusion solution for reuse. any unused medicine or waste material should be disposed of in accordance with local requirements.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 247, 'EndOffset': 248}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 249, 'EndOffset': 250}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 304, 'EndOffset': 320}, {'Text': 'infusion solution', 'Type': 'TREATMENT', 'BeginOffset': 344, 'EndOffset': 361}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 395, 'EndOffset': 407}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 579, 'EndOffset': 581}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 591, 'EndOffset': 592}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 596, 'EndOffset': 597}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 625, 'EndOffset': 626}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 660, 'EndOffset': 662}, {'Text': 'the infusion solution', 'Type': 'TREATMENT', 'BeginOffset': 691, 'EndOffset': 712}, {'Text': 'the solution', 'Type': 'TREATMENT', 'BeginOffset': 732, 'EndOffset': 744}, {'Text': 'any particulate matter', 'Type': 'PROBLEM', 'BeginOffset': 759, 'EndOffset': 781}, {'Text': 'discoloration', 'Type': 'PROBLEM', 'BeginOffset': 785, 'EndOffset': 798}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 800, 'EndOffset': 813}, {'Text': 'the infusion solution', 'Type': 'TREATMENT', 'BeginOffset': 873, 'EndOffset': 894}, {'Text': 'waste material', 'Type': 'TREATMENT', 'BeginOffset': 929, 'EndOffset': 943}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what lartruvo contains - the active substance is olaratumab. each millilitre of the concentrate for solution for infusion contains 10 mg of olaratumab. each 19 ml vial contains 190 mg of olaratumab. each 50 ml vial contains 500 mg of olaratumab. - the other ingredients are mannitol, glycine, l-histidine monohydrochloride monohydrate, l-histidine, sodium chloride (see section 2 "lartruvo contains sodium"), polysorbate 20 and water for injections. what lartruvo looks like and contents of the pack lartruvo concentrate for solution for infusion (sterile concentrate) is a clear to slightly opalescent and colourless to slightly yellow liquid supplied in a glass vial with an elastomeric stopper. it is available in packs of: - 1 vial of 19 ml - 2 vials of 19 ml - 1 vial of 50 ml not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 13, 'Score': 0.3705810308456421, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 49, 'EndOffset': 59, 'Score': 0.9909273386001587, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5145581364631653, 'RelationshipScore': 0.99893718957901, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 2, 'BeginOffset': 113, 'EndOffset': 121, 'Text': 'infusion', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8160060048103333, 'RelationshipScore': 0.9796252250671387, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 157, 'EndOffset': 162, 'Text': '19 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 113, 'EndOffset': 121}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 131, 'EndOffset': 133}, {'Id': 4, 'BeginOffset': 140, 'EndOffset': 150, 'Score': 0.9934309124946594, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5145581364631653, 'RelationshipScore': 0.9923163652420044, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 2, 'BeginOffset': 113, 'EndOffset': 121, 'Text': 'infusion', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9643763303756714, 'RelationshipScore': 0.9999617338180542, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 131, 'EndOffset': 136, 'Text': '10 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8160060048103333, 'RelationshipScore': 0.9993178844451904, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 157, 'EndOffset': 162, 'Text': '19 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9667090177536011, 'RelationshipScore': 0.9492133259773254, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 204, 'EndOffset': 209, 'Text': '50 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '19', 'Type': 'NUMBER', 'BeginOffset': 157, 'EndOffset': 159}, {'Text': '190', 'Type': 'NUMBER', 'BeginOffset': 177, 'EndOffset': 180}, {'Id': 7, 'BeginOffset': 187, 'EndOffset': 197, 'Score': 0.9954624772071838, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8160060048103333, 'RelationshipScore': 0.9014355540275574, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 157, 'EndOffset': 162, 'Text': '19 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9884341359138489, 'RelationshipScore': 0.9999370574951172, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 177, 'EndOffset': 183, 'Text': '190 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9667090177536011, 'RelationshipScore': 0.9995555281639099, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 204, 'EndOffset': 209, 'Text': '50 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 204, 'EndOffset': 206}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 224, 'EndOffset': 227}, {'Id': 10, 'BeginOffset': 234, 'EndOffset': 244, 'Score': 0.9958981871604919, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9667090177536011, 'RelationshipScore': 0.8155466914176941, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 204, 'EndOffset': 209, 'Text': '50 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9837571978569031, 'RelationshipScore': 0.9999771118164062, 'RelationshipType': 'DOSAGE', 'Id': 9, 'BeginOffset': 224, 'EndOffset': 230, 'Text': '500 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 11, 'BeginOffset': 274, 'EndOffset': 282, 'Score': 0.9018888473510742, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 284, 'EndOffset': 291, 'Score': 0.9233996272087097, 'Text': 'glycine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 293, 'EndOffset': 334, 'Score': 0.8956173062324524, 'Text': 'l-histidine monohydrochloride monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 336, 'EndOffset': 347, 'Score': 0.9571364521980286, 'Text': 'l-histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 349, 'EndOffset': 364, 'Score': 0.9994927644729614, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 378, 'EndOffset': 379}, {'Id': 16, 'BeginOffset': 381, 'EndOffset': 389, 'Score': 0.5540238618850708, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 409, 'EndOffset': 420, 'Score': 0.3196868300437927, 'Text': 'polysorbate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.3692972660064697, 'RelationshipScore': 0.9998107552528381, 'RelationshipType': 'DOSAGE', 'Id': 18, 'BeginOffset': 421, 'EndOffset': 423, 'Text': '20', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.44503965973854065, 'RelationshipScore': 0.9999769926071167, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 19, 'BeginOffset': 438, 'EndOffset': 448, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 421, 'EndOffset': 423}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 438, 'EndOffset': 448}, {'Id': 20, 'BeginOffset': 455, 'EndOffset': 463, 'Score': 0.33027905225753784, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.44503965973854065, 'RelationshipScore': 0.8042891621589661, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 19, 'BeginOffset': 438, 'EndOffset': 448, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the pack lartruvo concentrate', 'Type': 'TREATMENT', 'BeginOffset': 491, 'EndOffset': 520}, {'Text': 'infusion (sterile concentrate', 'Type': 'TREATMENT', 'BeginOffset': 538, 'EndOffset': 567}, {'Text': 'slightly yellow liquid', 'Type': 'PROBLEM', 'BeginOffset': 621, 'EndOffset': 643}, {'Text': 'an elastomeric stopper', 'Type': 'TREATMENT', 'BeginOffset': 674, 'EndOffset': 696}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 729, 'EndOffset': 730}, {'Text': '19', 'Type': 'NUMBER', 'BeginOffset': 739, 'EndOffset': 741}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 747, 'EndOffset': 748}, {'Text': '19', 'Type': 'NUMBER', 'BeginOffset': 758, 'EndOffset': 760}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 766, 'EndOffset': 767}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 776, 'EndOffset': 778}]}

84076FDAE8517FC06F70D93160D601E0

https://www.ema.europa.eu/documents/product-information/solymbic-epar-product-information_en.pdf

Solymbic

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Me dic ina l p rod uc t n o l on ge r a uth ori se d 2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT SOLYMBIC 20 mg solution for injection in pre-filled syringe. SOLYMBIC 40 mg solution for injection in pre-filled syringe. SOLYMBIC 40 mg solution for injection in pre-filled pen. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION SOLYMBIC 20 mg solution for injection in pre-filled syringe Each single dose pre-filled syringe contains 20 mg of adalimumab in 0.4 mL (50 mg/mL) solution. SOLYMBIC 40 mg solution for injection in pre-filled syringe Each single dose pre-filled syringe contains 40 mg of adalimumab in 0.8 mL (50 mg/mL) solution. SOLYMBIC 40 mg solution for injection in pre-filled pen Each single dose pre-filled pen contains 40 mg of adalimumab in 0.8 mL (50 mg/mL) solution. Adalimumab is a recombinant human monoclonal antibody expressed in Chinese Hamster Ovary cells. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM SOLYMBIC 20 mg solution for injection in pre-filled syringe SOLYMBIC 40 mg solution for injection in pre-filled syringe Solution for injection. SOLYMBIC 40 mg solution for injection in pre-filled pen (SureClick) Solution for injection. Clear and colourless to slightly yellow solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Rheumatoid arthritis SOLYMBIC in combination with methotrexate, is indicated for: • the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs including methotrexate has been inadequate. • the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. SOLYMBIC can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Me dic ina l p rod uc t n o l on ge r a uth ori se d 3 SOLYMBIC reduces the rate of progression of joint damage as measured by x-ray and improves physical function, when given in combination with methotrexate. Juvenile idiopathic arthritis Enthesitis-related arthritis SOLYMBIC is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of age and older, who have had an inadequate response to, or who are intolerant of, conventional therapy (see section 5.1). Axial spondyloarthritis Ankylosing spondylitis (AS) SOLYMBIC is indicated for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy. Axial spondyloarthritis without radiographic evidence of AS SOLYMBIC is indicated for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated CRP and/or MRI, who have had an inadequate response to, or are intolerant to non-steroidal anti-inflammatory drugs. Psoriatic arthritis SOLYMBIC is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. SOLYMBIC reduces the rate of progression of peripheral joint damage as measured by x-ray in patients with polyarticular symmetrical subtypes of the disease (see section 5.1) and improves physical function. Psoriasis SOLYMBIC is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy. Paediatric plaque psoriasis SOLYMBIC is indicated for the treatment of severe chronic plaque psoriasis in children and adolescents from 4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapies. Hidradenitis suppurativa (HS) SOLYMBIC is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in adult patients with an inadequate response to conventional systemic HS therapy. Crohn’s disease SOLYMBIC is indicated for treatment of moderately to severely active Crohn’s disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. Paediatric Crohn's disease Me dic ina l p rod uc t n o l on ge r a uth ori se d 4 SOLYMBIC is indicated for the treatment of moderately to severely active Crohn's disease in paediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy including primary nutrition therapy, a corticosteroid, and an immunomodulator, or who are intolerant to or have contraindications for such therapies. Ulcerative colitis SOLYMBIC is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6- mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies. Uveitis SOLYMBIC is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients who have had an inadequate response to corticosteroids, in patients in need of corticosteroid-sparing, or in whom corticosteroid treatment is inappropriate. 4.2 Posology and method of administration SOLYMBIC treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which SOLYMBIC is indicated. Ophthalmologists are advised to consult with an appropriate specialist before initiation of treatment with SOLYMBIC (see section 4.4). Patients treated with SOLYMBIC should be given the special alert card. After proper training in injection technique, patients may self-inject with SOLYMBIC if their physician determines that it is appropriate and with medical follow-up as necessary. During treatment with SOLYMBIC, other concomitant therapies (e.g. corticosteroids and/or immunomodulatory agents) should be optimised. Posology Rheumatoid arthritis The recommended dose of SOLYMBIC for adult patients with rheumatoid arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection. Methotrexate should be continued during treatment with SOLYMBIC. Glucocorticoids, salicylates, non-steroidal anti-inflammatory drugs, or analgesics can be continued during treatment with SOLYMBIC. Regarding combination with disease-modifying anti-rheumatic drugs other than methotrexate see sections 4.4 and 5.1. In monotherapy, some patients who experience a decrease in their response may benefit from an increase in dose intensity to 40 mg adalimumab every week. Available adalimumab data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be reconsidered in a patient not responding within this time period. Dose interruption There may be a need for dose interruption, for instance before surgery or if a serious infection occurs. Re-introduction of SOLYMBIC after discontinuation for 70 days or longer should result in the same magnitudes of clinical response and similar safety profile as before dose interruption. Me dic ina l p rod uc t n o l on ge r a uth ori se d 5 Ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriatic arthritis The recommended dose of SOLYMBIC for patients with ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and for patients with psoriatic arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection. For all of the above indications, available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period. Psoriasis The recommended dose of SOLYMBIC for adult patients is an initial dose of 80 mg administered subcutaneously, followed by 40 mg subcutaneously given every other week starting one week after the initial dose. Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within this time period. Beyond 16 weeks, patients with inadequate response may benefit from an increase in dosing frequency to 40 mg every week. The benefits and risks of continued weekly therapy should be carefully reconsidered in a patient with an inadequate response after the increase in dosing frequency (see section 5.1). If adequate response is achieved with an increased dosing frequency, the dose may subsequently be reduced to 40 mg every other week. Hidradenitis suppurativa The recommended SOLYMBIC dose regimen for adult patients with hidradenitis suppurativa (HS) is 160 mg initially at day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later at day 15 (given as two 40 mg injections in one day). Two weeks later (day 29) continue with a dose of 40 mg every week. Antibiotics may be continued during treatment with SOLYMBIC if necessary. It is recommended that the patient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment with SOLYMBIC. Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement within this time period. Should treatment be interrupted, SOLYMBIC 40 mg every week may be re-introduced (see section 5.1). The benefit and risk of continued long-term treatment should be periodically evaluated (see section 5.1). Crohn’s disease The recommended SOLYMBIC induction dose regimen for adult patients with moderately to severely active Crohn’s disease is 80 mg at week 0 followed by 40 mg at week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at week 2, can be used with the awareness that the risk for adverse events is higher during induction. After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. Alternatively, if a patient has stopped SOLYMBIC and signs and symptoms of disease recur, SOLYMBIC may be re-administered. There is little experience from re-administration after more than 8 weeks since the previous dose. Me dic ina l p rod uc t n o l on ge r a uth ori se d 6 During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines. Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg SOLYMBIC every week. Some patients who have not responded by week 4 may benefit from continued maintenance therapy through week 12. Continued therapy should be carefully reconsidered in a patient not responding within this time period. Ulcerative colitis The recommended SOLYMBIC induction dose regimen for adult patients with moderate to severe ulcerative colitis is 160 mg at week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days) and 80 mg at week 2. After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines. Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg SOLYMBIC every week. Clinical response is usually achieved within 2-8 weeks of treatment. SOLYMBIC therapy should not be continued in patients failing to respond within this time period. Uveitis The recommended dose of SOLYMBIC for adult patients with uveitis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. There is limited experience in the initiation of treatment with adalimumab alone. Treatment with SOLYMBIC can be initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered in accordance with clinical practice starting two weeks after initiating treatment with SOLYMBIC. It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a yearly basis (see section 5.1). Elderly patients No dose adjustment is required. Impaired renal and/or hepatic function Adalimumab has not been studied in these patient populations. No dose recommendations can be made. Paediatric population SOLYMBIC is only available as 20 mg and 40 mg pre-filled syringe and 40 mg pre-filled pen. It is not possible to administer SOLYMBIC to paediatric patients that require less than a full 20 mg or 40 mg dose. If an alternate dose is required, other adalimumab products offering such an option should be used. Me dic ina l p rod uc t n o l on ge r a uth ori se d 7 Enthesitis-related arthritis The recommended dose of SOLYMBIC for patients with enthesitis-related arthritis 6 years of age and older is 24 mg/m² body surface area up to a maximum single dose of 40 mg adalimumab administered every other week via subcutaneous injection. The volume for injection is selected based on the patients' height and weight (table 1). Adalimumab has not been studied in patients with enthesitis-related arthritis aged less than 6 years. Table 1. SOLYMBIC dose in milligrams (mg) by height and weight of patients for enthesitis-related arthritis Height (cm) Total body weight (kg) 10 15 20 25 30 35 40 45 50 55 60 65 70 80 - - - - 90 - - - 20 20 20 100 - - - 20 20 20 - - 110 - - 20 20 20 - - - - - - 120 - 20 20 20 - - - - - - - - - 130 20 20 - - - - - - - - - - 140 20 20 - - - - - - - - - 40* 150 - - - - - - - - - 40* 40* 160 - - - - - - - 40* 40* 40* 40* 170 - - - - - 40* 40* 40* 40* 40* 180 - - - 40* 40* 40* 40* 40* 40* * Maximum single dose is 40 mg (0.8 mL) - Not applicable, SOLYMBIC is only available as 20 mg and 40 mg pre-filled syringe and 40 mg pre-filled pen Paediatric plaque psoriasis The recommended SOLYMBIC dose is 0.8 mg per kg body weight (up to a maximum of 40 mg per dose) administered subcutaneously weekly for the first two doses and every other week thereafter. Continued therapy beyond 16 weeks should be carefully considered in a patient not responding within this time period. If retreatment with SOLYMBIC is indicated, the above guidance on dose and treatment duration should be followed. The safety of adalimumab in paediatric patients with plaque psoriasis has been assessed for a mean of 13 months. Patients above 4 years of age but with a weight less than 23 kg or between 29 and 46 kg are not possible to dose with this product. There is no relevant use of adalimumab in children aged less than 4 years in this indication. Me dic ina l p rod uc t n o l on ge r a uth ori se d 8 The administered dose is selected based on the patients' weight (table 2). Table 2 SOLYMBIC dose in milligrams (mg) by weight for patients with paediatric psoriasis Body weight (kg) Paediatric psoriasis dose 13–16 - 17–22 - 23–28 20 mg 29–34 - 35–40 - 41–46 - 47+ 40 mg - Not applicable, SOLYMBIC is only available as 20 mg and 40 mg pre-filled syringe and 40 mg pre-filled pen. Paediatric Crohn's disease Paediatric Crohn's disease patients < 40 kg: The recommended SOLYMBIC induction dose regimen for paediatric subjects with severe Crohn's disease is 40 mg at week 0 followed by 20 mg at week 2. In case there is a need for a more rapid response to therapy, the regimen 80 mg at week 0 (dose can be administered as two injections in one day), 40 mg at week 2 can be used, with the awareness that the risk for adverse events may be higher with use of the higher induction dose. After induction treatment, the recommended dose is 20 mg every other week via subcutaneous injection. Some subjects who experience insufficient response may benefit from an increase in dosing frequency to 20 mg SOLYMBIC every week. Paediatric Crohn's disease patients ≥ 40 kg: The recommended SOLYMBIC induction dose regimen for paediatric subjects with severe Crohn's disease is 80 mg at week 0 followed by 40 mg at week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at week 2 can be used, with the awareness that the risk for adverse events may be higher with use of the higher induction dose. After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. Some subjects who experience insufficient response may benefit from an increase in dosing frequency to 40 mg SOLYMBIC every week. Continued therapy should be carefully considered in a subject not responding by week 12. There is no relevant use of adalimumab in children aged less than 6 years in this indication. Paediatric hidradenitis suppurativa The safety and efficacy of adalimumab in children aged 12-17 years have not yet been established for hidradenitis suppurativa. No data are available. There is no relevant use of adalimumab in children aged below 12 years in this indication. Paediatric ulcerative colitis The safety and efficacy of adalimumab in children aged 4-17 years have not yet been established. No data are available. There is no relevant use of adalimumab in children aged < 4 years in this indication. Me dic ina l p rod uc t n o l on ge r a uth ori se d 9 Psoriatic arthritis and axial spondyloarthritis including ankylosing spondylitis There is no relevant use of adalimumab in the paediatric population in the indications, ankylosing spondylitis and psoriatic arthritis. Paediatric uveitis The safety and efficacy of adalimumab in children aged 2-17 years have not yet been established. No data are available. Method of administration SOLYMBIC is administered by subcutaneous injection. Full instructions for use are provided in the package leaflet. A 40 mg pen, and a 20 mg and 40 mg pre-filled syringes are available for patients to administer a full 20 mg or 40 mg dose. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active tuberculosis or other severe infections such as sepsis, and opportunistic infections (see section 4.4). Moderate to severe heart failure (NYHA class III/IV) (see section 4.4). 4.4 Special warnings and precautions for use In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded. Infections Patients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function may increase the risk for developing infections. Patients must therefore be monitored closely for infections, including tuberculosis, before, during and after treatment with SOLYMBIC. Because the elimination of adalimumab may take up to four months, monitoring should be continued throughout this period. Treatment with SOLYMBIC should not be initiated in patients with active infections including chronic or localised infections until infections are controlled. In patients who have been exposed to tuberculosis and patients who have travelled in areas of high risk of tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with SOLYMBIC should be considered prior to initiating therapy (see Other opportunistic infections). Patients who develop a new infection while undergoing treatment with SOLYMBIC, should be monitored closely and undergo a complete diagnostic evaluation. Administration of SOLYMBIC should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. Physicians should exercise caution when considering the use of SOLYMBIC in patients with a history of recurring infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications. Me dic ina l p rod uc t n o l on ge r a uth ori se d 10 Serious infections Serious infections, including sepsis, due to bacterial, mycobacterial, invasive fungal, parasitic, viral, or other opportunistic infections such as listeriosis, legionellosis and pneumocystis have been reported in patients receiving adalimumab. Other serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicaemia. Hospitalisation or fatal outcomes associated with infections have been reported. Tuberculosis Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients receiving adalimumab. Reports included cases of pulmonary and extra-pulmonary (i.e. disseminated) tuberculosis. Before initiation of therapy with SOLYMBIC, all patients must be evaluated for both active or inactive (“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment of patient history of tuberculosis or possible previous exposure to people with active tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skin test and chest x-ray) should be performed in all patients (local recommendations may apply). It is recommended that the conduct and results of these tests are recorded in the patient alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised. If active tuberculosis is diagnosed, SOLYMBIC therapy must not be initiated (see section 4.3). In all situations described below, the benefit/risk balance of therapy should be very carefully considered. If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylaxis treatment before the initiation of SOLYMBIC, and in accordance with local recommendations. Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of SOLYMBIC in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab. Some patients who have been successfully treated for active tuberculosis have redeveloped tuberculosis while being treated with adalimumab. Patients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis infection (e.g. persistent cough, wasting/weight loss, low grade fever, listlessness) occur during or after therapy with SOLYMBIC. Other opportunistic infections Opportunistic infections, including invasive fungal infections have been observed in patients receiving adalimumab. These infections have not consistently been recognised in patients taking TNF- antagonists and this has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes. Me dic ina l p rod uc t n o l on ge r a uth ori se d 11 For patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats, cough, dyspnoea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant shock an invasive fungal infection should be suspected and administration of SOLYMBIC should be promptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the care of patients with invasive fungal infections. Hepatitis B reactivation Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including adalimumab, who are chronic carriers of this virus (i.e. surface antigen positive). Some cases have had a fatal outcome. Patients should be tested for HBV infection before initiating treatment with SOLYMBIC. For patients who test positive for hepatitis B infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Carriers of HBV who require treatment with SOLYMBIC should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data from treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, SOLYMBIC should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. Neurological events TNF-antagonists including adalimumab have been associated in rare instances with new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease including multiple sclerosis and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of SOLYMBIC in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of SOLYMBIC should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to the initiation of SOLYMBIC therapy and regularly during treatment to assess for pre-existing or developing central demyelinating disorders. Allergic reactions Serious allergic reactions associated with adalimumab were rare during clinical trials. Non-serious allergic reactions associated with adalimumab were uncommon during clinical trials. Reports of serious allergic reactions including anaphylaxis have been received following adalimumab administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of SOLYMBIC should be discontinued immediately and appropriate therapy initiated. Dry natural rubber The needle cover of the pre-filled syringe or pen is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. Immunosuppression In a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T-, B-, NK-cells, monocyte/macrophages, and neutrophils. Me dic ina l p rod uc t n o l on ge r a uth ori se d 12 Malignancies and lymphoproliferative disorders In the controlled portions of adalimumab clinical trials of TNF-antagonists, more cases of malignancies including lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare. In the post-marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing highly active, inflammatory disease, which complicates the risk estimation. With the current knowledge, a possible risk for the development of lymphomas, leukaemia, and other malignancies in patients treated with a TNF-antagonist cannot be excluded. Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), including adalimumab in the post-marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded. Rare post-marketing cases of hepatosplenic T-cell lymphoma have been identified in patients treated with adalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Some of these hepatosplenic T-cell lymphomas with adalimumab have occurred in young adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used for inflammatory bowel disease. The potential risk with the combination of azathioprine or 6-mercaptopurine and SOLYMBIC should be carefully considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with SOLYMBIC cannot be excluded (see section 4.8). No studies have been conducted that include patients with a history of malignancy or in whom treatment with adalimumab is continued following development of malignancy. Thus additional caution should be exercised in considering SOLYMBIC treatment of these patients (see section 4.8). All patients, and in particular patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of non- melanoma skin cancer prior to and during treatment with SOLYMBIC. Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab (see section 4.8). In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking. With current data it is not known if adalimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. Haematologic reactions Rare reports of pancytopenia including aplastic anaemia have been reported with TNF-antagonists. Adverse events of the haematologic system, including medically significant cytopenia (e.g. thrombocytopenia, leucopenia) have been reported with adalimumab. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias Me dic ina l p rod uc t n o l on ge r a uth ori se d 13 (e.g. persistent fever, bruising, bleeding, pallor) while on SOLYMBIC. Discontinuation of SOLYMBIC therapy should be considered in patients with confirmed significant haematologic abnormalities. Vaccinations Similar antibody responses to the standard 23-valent pneumococcal vaccine and the influenza trivalent virus vaccination were observed in a study in 226 adult subjects with rheumatoid arthritis who were treated with adalimumab or placebo. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab. It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating SOLYMBIC therapy. Patients on SOLYMBIC may receive concurrent vaccinations, except for live vaccines. Administration of live vaccines to infants exposed to SOLYMBIC in utero is not recommended for 5 months following the mother’s last SOLYMBIC injection during pregnancy. Congestive heart failure In a clinical trial with another TNF-antagonist worsening congestive heart failure and increased mortality due to congestive heart failure have been observed. Cases of worsening congestive heart failure have also been reported in patients receiving adalimumab. SOLYMBIC should be used with caution in patients with mild heart failure (NYHA class I/II). SOLYMBIC is contraindicated in moderate to severe heart failure (see section 4.3). Treatment with SOLYMBIC must be discontinued in patients who develop new or worsening symptoms of congestive heart failure. Autoimmune processes Treatment with SOLYMBIC may result in the formation of autoimmune antibodies. The impact of long-term treatment with SOLYMBIC on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with SOLYMBIC and is positive for antibodies against double-stranded DNA, further treatment with SOLYMBIC should not be given (see section 4.8). Concurrent administration of biologic DMARDS or TNF-antagonists Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF- antagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, the combination of SOLYMBIC and anakinra is not recommended (see section 4.5). Concomitant administration of SOLYMBIC with other biologic DMARDS (e.g. anakinra and abatacept) or other TNF-antagonists is not recommended based upon the possible increased risk for infections, including serious infections and other potential pharmacological interactions (see section 4.5). Surgery There is limited safety experience of surgical procedures in patients treated with adalimumab. The long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on SOLYMBIC should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving adalimumab. Me dic ina l p rod uc t n o l on ge r a uth ori se d 14 Small bowel obstruction Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture that may require surgical treatment. Available data suggest that adalimumab does not worsen or cause strictures. Elderly patients The frequency of serious infections among adalimumab-treated subjects over 65 years of age (3.7%) was higher than for those under 65 years of age (1.5%). Some of those had a fatal outcome. Particular attention regarding the risk for infection should be paid when treating the elderly. Paediatric population See Vaccinations above. 4.5 Interaction with other medicinal products and other forms of interaction Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant methotrexate. Antibody formation was lower when adalimumab was given together with methotrexate in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (see section 5.1). The combination of SOLYMBIC and anakinra is not recommended (see section 4.4 “Concurrent administration of biologic DMARDS or TNF-antagonists”). The combination of SOLYMBIC and abatacept is not recommended (see section 4.4 “Concurrent administration of biologic DMARDS or TNF-antagonists”). 4.6 Fertility, pregnancy and lactation Women of child bearing potential/Contraception in males and females Women of childbearing potential are strongly recommended to use adequate contraception to prevent pregnancy and continue its use for at least five months after the last SOLYMBIC treatment. Pregnancy For adalimumab, limited clinical data on exposed pregnancies are available. In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity of adalimumab are not available (see section 5.3). Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect normal immune responses in the newborn. Administration of SOLYMBIC is not recommended during pregnancy. Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumab during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother’s last adalimumab injection during pregnancy. Me dic ina l p rod uc t n o l on ge r a uth ori se d 15 Breast-feeding It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion. However, because human immunoglobulins are excreted in milk, women must not breast-feed for at least five months after the last SOLYMBIC treatment. Fertility Preclinical data on fertility effects of adalimumab are not available. 4.7 Effects on ability to drive and use machines SOLYMBIC may have a minor influence on the ability to drive and use machines. Vertigo and visual impairment may occur following administration of SOLYMBIC (see section 4.8). 4.8 Undesirable effects Summary of the safety profile Adalimumab was studied in 9,506 patients in pivotal controlled and open-label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long- standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis- related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlled period. The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking adalimumab and 5.4% for control treated patients. The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain. Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as SOLYMBIC affect the immune system and their use may affect the body’s defence against infection and cancer. Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV reactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been reported with use of adalimumab. Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome. Paediatric population Undesirable effects in paediatric patients In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients. Me dic ina l p rod uc t n o l on ge r a uth ori se d 16 Tabulated list of adverse reactions The following list of adverse reactions is based on experience from clinical trials and on post- marketing experience and are displayed by system organ class and frequency in table 3 below: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8. Table 3 Undesirable effects System Organ Class Frequency Adverse Reaction Infections and infestations* Very common Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral) Common Systemic infections (including sepsis, candidiasis and influenza), Intestinal infections (including gastroenteritis viral), Skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster), Ear infections, Oral infections (including herpes simplex, oral herpes and tooth infections), Reproductive tract infections (including vulvovaginal mycotic infection), Urinary tract infections (including pyelonephritis), Fungal infections, Joint infection Uncommon Neurological infections (including viral meningitis), Opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), Bacterial infections, Eye infections, Diverticulitis1) Neoplasms benign, malignant and unspecified (including cysts and polyps)* Common Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma), Benign neoplasm Uncommon Lymphoma**, Solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), Melanoma** Rare Leukaemia1) Not known Hepatosplenic T-cell lymphoma1), Merkel cell carcinoma (neuroendocrine carcinoma of the skin)1) Blood and the lymphatic system disorders* Very common Leucopaenia (including neutropaenia and agranulocytosis), Anaemia Common Leucocytosis, Thrombocytopaenia Uncommon Idiopathic thrombocytopaenic purpura Rare Pancytopaenia Immune system disorders* Common Hypersensitivity, Allergies (including seasonal allergy) Uncommon Sarcoidosis1), Vasculitis Me dic ina l p rod uc t n o l on ge r a uth ori se d 17 System Organ Class Frequency Adverse Reaction Rare Anaphylaxis1) Metabolism and nutrition disorders Very common Lipids increased Common Hypokalaemia, Uric acid increased, Blood sodium abnormal, Hypocalcaemia, Hyperglycaemia, Hypophosphataemia, Dehydration Psychiatric disorders Common Mood alterations (including depression), Anxiety, Insomnia Nervous system disorders* Very common Headache Common Paraesthesias (including hypoaesthesia), Migraine, Nerve root compression Uncommon Cerebrovascular accident1), Tremor, Neuropathy Rare Multiple sclerosis, Demyelinating disorders (e.g. optic neuritis, Guillain-Barré syndrome)1) Eye disorders Common Visual impairment, Conjunctivitis, Blepharitis, Eye swelling Uncommon Diplopia Ear and labyrinth disorders Common Vertigo Uncommon Deafness, Tinnitus Cardiac disorders* Common Tachycardia Uncommon Myocardial infarction1), Arrhythmia, Congestive heart failure Rare Cardiac arrest Vascular disorders Common Hypertension, Flushing, Haematoma Uncommon Aortic aneurysm, Vascular arterial occlusion, Thrombophlebitis Respiratory, thoracic and mediastinal disorders* Common Asthma, Dyspnoea, Cough Uncommon Pulmonary embolism1), Interstitial lung disease, Chronic obstructive pulmonary disease, Pneumonitis, Pleural effusion1) Rare Pulmonary fibrosis1) Gastrointestinal disorders Very common Abdominal pain, Nausea and vomiting Me dic ina l p rod uc t n o l on ge r a uth ori se d 18 System Organ Class Frequency Adverse Reaction Common GI haemorrhage, Dyspepsia, Gastroesophageal reflux disease, Sicca syndrome Uncommon Pancreatitis, Dysphagia, Face oedema Rare Intestinal perforation1) Hepato-biliary disorders* Very common Elevated liver enzymes Uncommon Cholecystitis and cholelithiasis, Hepatic steatosis, Bilirubin increased Rare Hepatitis, Reactivation of hepatitis B1), Autoimmune hepatitis1) Not known Liver failure1) Skin and subcutaneous tissue disorders Very common Rash (including exfoliative rash) Common Worsening or new onset of psoriasis (including palmoplantar pustular psoriasis)1), Urticaria, Bruising (including purpura), Dermatitis (including eczema), Onychoclasis, Hyperhidrosis, Alopecia1), Pruritus Uncommon Night sweats, Scar Rare Erythema multiforme1), Stevens-Johnson syndrome1), Angioedema1), Cutaneous vasculitis1) Not known Worsening of symptoms of dermatomyositis1) Musculoskeletal and connective tissue disorders Very common Musculoskeletal pain Common Muscle spasms (including blood creatine phosphokinase increased) Uncommon Rhabdomyolysis, Systemic lupus erythematosus Rare Lupus-like syndrome1) Renal and urinary disorders Common Renal impairment, Haematuria Uncommon Nocturia Reproductive system and breast disorders Uncommon Erectile dysfunction General disorders and administration site conditions* Very common Injection site reaction (including injection site erythema) Common Chest pain, Oedema, Pyrexia1) Uncommon Inflammation Investigations* Common Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), Autoantibody test positive (including double stranded DNA antibody), Blood lactate dehydrogenase increased Me dic ina l p rod uc t n o l on ge r a uth ori se d 19 System Organ Class Frequency Adverse Reaction Injury, poisoning and procedural complications Common Impaired healing * further information is found elsewhere in sections 4.3, 4.4 and 4.8 ** including open-label extension studies 1) including spontaneous reporting data Hidradenitis suppurativa The safety profile for patients with HS treated with adalimumab weekly was consistent with the known safety profile of adalimumab. Uveitis The safety profile for patients with uveitis treated with adalimumab every other week was consistent with the known safety profile of adalimumab. Description of selected adverse reactions Injection site reactions In the pivotal controlled trials in adults and children, 12.9% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product. Infections In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the adalimumab-treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on adalimumab after the infection resolved. The incidence of serious infections was 0.04 per patient year in adalimumab-treated patients and 0.03 per patient year in placebo and active control-treated patients. In controlled and open-label adult and paediatric studies with adalimumab, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g. disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. Malignancies and lymphoproliferative disorders No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient-years during adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with an exposure of 498.1 patient-years during an adalimumab trial in paediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient-years during an adalimumab trial in paediatric patients with chronic plaque psoriasis. During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and Me dic ina l p rod uc t n o l on ge r a uth ori se d 20 non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 adalimumab-treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for adalimumab and 3.8 months for control-treated patients). The rate (95% confidence interval) of non- melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. When combining controlled portions of these trials and ongoing and completed open-label extension studies of adalimumab, with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient-years. The observed rate of non- melanoma skin cancers is approximately 9.6 per 1,000 patient-years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient-years. In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively (see section 4.4). Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4). Autoantibodies Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies I−V. In these trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and active control-treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at week 24. Two patients out of 3,441 treated with adalimumab in all rheumatoid arthritis and psoriatic arthritis studies developed clinical signs suggestive of new onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. Hepato-biliary events In controlled phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.7% of adalimumab-treated patients and 1.6% of control-treated patients. In controlled phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥ 3 x ULN occurred in 6.1% of adalimumab-treated patients and 1.3% of control-treated patients. Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 2 to < 4 years. In controlled phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis with a control period ranging from 4 to 52 weeks. ALT elevations ≥ 3 x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of controlled-treated patients. In the phase 3 trial of adalimumab in patients with paediatric Crohn’s disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline. Me dic ina l p rod uc t n o l on ge r a uth ori se d 21 In controlled phase 3 trials of adalimumab in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab- treated patients and 1.8% of control-treated patients. No ALT elevations ≥ 3 X ULN occurred in the phase 3 trial of adalimumab in paediatric patients with plaque psoriasis. In controlled trials of adalimumab (initial doses of 160 mg at week 0 and 80 mg at week 2, followed by 40 mg every week starting at week 4), in patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of adalimumab-treated patients and 0.6% of control-treated patients. In controlled trials of adalimumab (initial doses of 80 mg at week 0 followed by 40 mg every other week starting at week 1) in patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in adalimumab-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients. Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have also been post- marketing reports of liver failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis in patients receiving adalimumab. Concurrent treatment with azathioprine/6-mercaptopurine In adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of adalimumab and azathioprine/6-mercaptopurine compared with adalimumab alone. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose No dose-limiting toxicity was observed during clinical trials. The highest dose level evaluated has been multiple intravenous doses of 10 mg/kg, which is approximately 15 times the recommended dose. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNFα) inhibitors. ATC code: L04AB04 SOLYMBIC is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu. Mechanism of action Adalimumab binds specifically to TNF and neutralises the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc http://www.ema.europa.eu/ 22 Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leucocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 0.1-0.2 nM). Pharmacodynamic effects After treatment with adalimumab, a rapid decrease in levels of acute phase reactants of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was observed, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage destruction were also decreased after adalimumab administration. Patients treated with adalimumab usually experienced improvement in haematological signs of chronic inflammation. A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis and hidradenitis suppurativa after treatment with adalimumab. In patients with Crohn’s disease, a reduction of the number of cells expressing inflammatory markers in the colon including a significant reduction of expression of TNFα was seen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab- treated patients. Clinical efficacy and safety Rheumatoid arthritis Adalimumab was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. The efficacy and safety of adalimumab were assessed in five randomised, double-blind and well-controlled studies. Some patients were treated for up to 120 months duration. RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old, had failed therapy with at least one disease-modifying, anti-rheumatic drug and had insufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks. RA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Doses of 20 or 40 mg of adalimumab were given by subcutaneous injection every other week with placebo on alternative weeks or every week for 26 weeks; placebo was given every week for the same duration. No other disease-modifying anti-rheumatic drugs were allowed. RA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg or have been intolerant to 10 mg of methotrexate every week. There were three groups in this study. The first received placebo injections every week for 52 weeks. The second received 20 mg of adalimumab every week for 52 weeks. The third group received 40 mg of adalimumab every other week with placebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab/MTX was administered every other week up to 10 years. RA study IV primarily assessed safety in 636 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old. Patients were permitted to be either disease-modifying, anti- rheumatic drug-naïve or to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. These therapies include methotrexate, leflunomide, hydroxychloroquine, sulfasalazine and/or gold salts. Patients were randomised to 40 mg of adalimumab or placebo every other week for 24 weeks. Me dic ina l p rod uc t n o l on ge r a uth ori se d 23 RA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active early rheumatoid arthritis (mean disease duration less than 9 months). This study evaluated the efficacy of adalimumab 40 mg every other week/methotrexate combination therapy, adalimumab 40 mg every other week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate of progression of joint damage in rheumatoid arthritis for 104 weeks. Upon completion of the first 104 weeks, 497 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week up to 10 years. The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was the percent of patients who achieved an ACR 20 response at week 24 or 26. The primary endpoint in RA study V was the percent of patients who achieved an ACR 50 response at week 52. RA studies III and V had an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by x-ray results). RA study III also had a primary endpoint of changes in quality of life. ACR response The percent of adalimumab-treated patients achieving ACR 20, 50 and 70 responses was consistent across RA studies I, II and III. The results for the 40 mg every other week dose are summarised in table 4. Table 4 ACR responses in placebo-controlled trials (percent of patients) Response RA study Ia** RA study IIa** RA study IIIa** Placebo/ MTXc n = 60 Adalimumabb / MTXc n = 63 Placebo n = 110 Adalimumabb n = 113 Placebo/ MTXc n = 200 Adalimumabb / MTXc n = 207 ACR 20 6 months 13.3% 65.1% 19.1% 46.0% 29.5% 63.3% 12 months NA NA NA NA 24.0% 58.9% ACR 50 6 months 6.7% 52.4% 8.2% 22.1% 9.5% 39.1% 12 months NA NA NA NA 9.5% 41.5% ACR 70 6 months 3.3% 23.8% 1.8% 12.4% 2.5% 20.8% 12 months NA NA NA NA 4.5% 23.2% a RA study I at 24 weeks, RA study II at 26 weeks, and RA study III at 24 and 52 weeks b 40 mg adalimumab administered every other week c MTX = methotrexate ** p < 0.01, adalimumab versus placebo In RA studies I-IV, all individual components of the ACR response criteria (number of tender and swollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ) scores and CRP (mg/dL) values) improved at 24 or 26 weeks compared to placebo. In RA study III, these improvements were maintained throughout 52 weeks. In the open-label extension for RA study III, most patients who were ACR responders maintained response when followed for up to 10 years. Of 207 patients who were randomised to adalimumab 40 mg every other week, 114 patients continued on adalimumab 40 mg every other week for 5 years. Among those, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses; and 41 patients (36%) had ACR 70 responses. Of 207 patients, 81 patients continued on adalimumab 40 mg every other week for 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56 patients (69.1%) had ACR 50 responses; and 43 patients (53.1%) had ACR 70 responses. In RA study IV, the ACR 20 response of patients treated with adalimumab plus standard of care was statistically significantly better than patients treated with placebo plus standard of care (p < 0.001). Me dic ina l p rod uc t n o l on ge r a uth ori se d 24 In RA studies I-IV, adalimumab-treated patients achieved statistically significant ACR 20 and 50 responses compared to placebo as early as one to two weeks after initiation of treatment. In RA study V with early rheumatoid arthritis patients who were methotrexate naïve, combination therapy with adalimumab and methotrexate led to faster and significantly greater ACR responses than methotrexate monotherapy and adalimumab monotherapy at week 52 and responses were sustained at week 104 (see table 5). Table 5 ACR responses in RA study V (percent of patients) Response MTX n = 257 Adalimumab n = 274 Adalimumab /MTX n = 268 p-valuea p-valueb p-valuec ACR 20 Week 52 62.6% 54.4% 72.8% 0.013 < 0.001 0.043 Week 104 56.0% 49.3% 69.4% 0.002 < 0.001 0.140 ACR 50 Week 52 45.9% 41.2% 61.6% < 0.001 < 0.001 0.317 Week 104 42.8% 36.9% 59.0% < 0.001 < 0.001 0.162 ACR 70 Week 52 27.2% 25.9% 45.5% < 0.001 < 0.001 0.656 Week 104 28.4% 28.1% 46.6% < 0.001 < 0.001 0.864 a p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test b p-value is from the pairwise comparison of adalimumab monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test c p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate monotherapy using the Mann-Whitney U test In the open-label extension for RA study V, ACR response rates were maintained when followed for up to 10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 170 patients continued on adalimumab 40 mg every other week for 10 years. Among those, 154 patients (90.6%) had ACR 20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients (60.0%) had ACR 70 responses. At week 52, 42.9% of patients who received adalimumab/methotrexate combination therapy achieved clinical remission (DAS28 < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy and 23.4% of patients receiving adalimumab monotherapy. Adalimumab/methotrexate combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and adalimumab monotherapy (p < 0.001) in achieving a low disease state in patients with recently diagnosed moderate to severe rheumatoid arthritis. The response for the two monotherapy arms was similar (p = 0.447). Radiographic response In RA study III, where adalimumab-treated patients had a mean duration of rheumatoid arthritis of approximately 11 years, structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (TSS) and its components, the erosion score and joint space narrowing score. Adalimumab/methotrexate patients demonstrated significantly less radiographic progression than patients receiving methotrexate alone at 6 and 12 months (see table 6). In the open-label extension of RA study III, the reduction in rate of progression of structural damage is maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with 40 mg adalimumab every other week were evaluated radiographically. Among those, 48 patients showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less. At 10 years, 79 of 207 patients originally treated with 40 mg adalimumab every other week were evaluated radiographically. Among those, 40 patients showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less. Me dic ina l p rod uc t n o l on ge r a uth ori se d 25 Table 6 Radiographic mean changes over 12 months in RA study III Placebo/ MTXa Adalimumab /MTX 40 mg every other week Placebo/MTX- adalimumab /MTX (95% confidence intervalb) p-value Total Sharp Score 2.7 0.1 2.6 (1.4, 3.8) < 0.001c Erosion score 1.6 0.0 1.6 (0.9, 2.2) < 0.001 JSNd score 1.0 0.1 0.9 (0.3, 1.4) 0.002 a methotrexate b 95% confidence intervals for the differences in change scores between methotrexate and adalimumab c Based on rank analysis d Joint Space Narrowing In RA study V, structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (see table 7). Table 7 Radiographic mean changes at week 52 in RA study V MTX n = 257 (95% confidence interval) Adalimumab n = 274 (95% confidence interval) Adalimumab /MTX n = 268 (95% confidence interval) p-valuea p-valueb p-valuec Total sharp score 5.7 (4.2-7.3) 3.0 (1.7-4.3) 1.3 (0.5-2.1) < 0.001 0.0020 < 0.001 Erosion score 3.7 (2.7-4.7) 1.7 (1.0-2.4) 0.8 (0.4-1.2) < 0.001 0.0082 < 0.001 JSN score 2.0 (1.2-2.8) 1.3 (0.5-2.1) 0.5 (0-1.0) < 0.001 0.0037 0.151 a p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test b p-value is from the pairwise comparison of adalimumab monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test c p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate monotherapy using the Mann-Whitney U test Following 52 weeks and 104 weeks of treatment, the percentage of patients without progression (change from baseline in modified Total Sharp Score ≤ 0.5) was significantly higher with adalimumab/methotrexate combination therapy (63.8% and 61.2% respectively) compared to methotrexate monotherapy (37.4% and 33.5% respectively, p < 0.001) and adalimumab monotherapy (50.7%, p < 0.002 and 44.5%, p < 0.001 respectively). In the open-label extension of RA study V, the mean change from baseline at year 10 in the modified Total Sharp Score was 10.8, 9.2 and 3.9 in patients originally randomised to methotrexate monotherapy, adalimumab monotherapy and adalimumab/methotrexate combination therapy, respectively. The corresponding proportions of patients with no radiographic progression were 31.3%, 23.7% and 36.7% respectively. Quality of life and physical function Health-related quality of life and physical function were assessed using the disability index of the Health Assessment Questionnaire (HAQ) in the four original adequate and well-controlled trials, which was a pre-specified primary endpoint at week 52 in RA study III. All doses/schedules of adalimumab in all four studies showed statistically significantly greater improvement in the disability index of the HAQ from baseline to month 6 compared to placebo and in RA study III the same was seen at week 52. Results from the Short Form Health Survey (SF 36) for all doses/schedules of Me dic ina l p rod uc t n o l on ge r a uth ori se d 26 adalimumab in all four studies support these findings, with statistically significant physical component summary (PCS) scores, as well as statistically significant pain and vitality domain scores for the 40 mg every other week dose. A statistically significant decrease in fatigue as measured by functional assessment of chronic illness therapy (FACIT) scores was seen in all three studies in which it was assessed (RA studies I, III, IV). In RA study III, most subjects who achieved improvement in physical function and continued treatment maintained improvement through week 520 (120 months) of open-label treatment. Improvement in quality of life was measured up to week 156 (36 months) and improvement was maintained through that time. In RA study V, the improvement in the HAQ disability index and the physical component of the SF 36 showed greater improvement (p < 0.001) for adalimumab/methotrexate combination therapy versus methotrexate monotherapy and adalimumab monotherapy at week 52, which was maintained through week 104. Among the 250 subjects who completed the open-label extension study, improvements in physical function were maintained through 10 years of treatment. Enthesitis-related arthritis The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind study in 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were randomised to receive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of 40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open- label (OL) period during which patients received 24 mg/m2 BSA of adalimumab up to a maximum of 40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint was the percent change from baseline to week 12 in the number of active joints with arthritis (swelling not due to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved with mean percent decrease of -62.6% (median percent change -88.9%) in patients in the adalimumab group compared to -11.6% (median percent change -50.0%) in patients in the placebo group. Improvement in number of active joints with arthritis was maintained during the OL period through week 156 for the 26 of 31 (84%) patients in the adalimumab group who remained in the study. Although not statistically significant, the majority of patients demonstrated clinical improvement in secondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen joint count (SJC), paediatric ACR 50 response, and paediatric ACR 70 response. Axial spondyloarthritis Ankylosing spondylitis (AS) Adalimumab 40 mg every other week was assessed in 393 patients in two randomised, 24 week double-blind, placebo-controlled studies in patients with active ankylosing spondylitis (mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in all groups) who have had an inadequate response to conventional therapy. Seventy-nine (20.1%) patients were treated concomitantly with disease-modifying anti-rheumatic drugs, and 37 (9.4%) patients with glucocorticoids. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks. Subjects (n = 215, 54.7%) who failed to achieve ASAS 20 at weeks 12, or 16 or 20 received early escape open-label adalimumab 40 mg every other week subcutaneously and were subsequently treated as non-responders in the double-blind statistical analyses. In the larger AS study I with 315 patients, results showed statistically significant improvement of the signs and symptoms of ankylosing spondylitis in patients treated with adalimumab compared to placebo. Significant response was first observed at week 2 and maintained through 24 weeks (table 8). Me dic ina l p rod uc t n o l on ge r a uth ori se d 27 Table 8 Efficacy responses in placebo-controlled AS study – study I reduction of signs and symptoms Response Placebo N = 107 Adalimumab N = 208 ASASa 20 Week 2 16% 42%*** Week 12 21% 58%*** Week 24 19% 51%*** ASAS 50 Week 2 3% 16%*** Week 12 10% 38%*** Week 24 11% 35%*** ASAS 70 Week 2 0% 7%** Week 12 5% 23%*** Week 24 8% 24%*** BASDAIb 50 Week 2 4% 20%*** Week 12 16% 45%*** Week 24 15% 42%*** ***, ** Statistically significant at p < 0.001, < 0.01 for all comparisons between adalimumab and placebo at weeks 2, 12 and 24 a Assessments in Ankylosing Spondylitis b Bath Ankylosing Spondylitis Disease Activity Index Adalimumab-treated patients had significantly greater improvement at week 12 which was maintained through week 24 in both the SF36 and Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL). Similar trends (not all statistically significant) were seen in the smaller randomised, double-blind, placebo controlled AS study II of 82 adult patients with active ankylosing spondylitis. Axial spondyloarthritis without radiographic evidence of AS Adalimumab 40 mg every other week was assessed in 185 patients in one randomised, 12 week double-blind, placebo-controlled study in patients with active non-radiographic axial spondyloarthritis (mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.4 for patients treated with adalimumab and 6.5 for those on placebo) who have had an inadequate response to or intolerance to ≥ 1 NSAIDs, or a contraindication for NSAIDs. Thirty-three (18%) of patients were treated concomitantly with disease-modifying anti-rheumatic drugs, and 146 (79%) patients with NSAIDs at baseline. The double-blind period was followed by an open-label period during which patients receive adalimumab 40 mg every other week subcutaneously for up to an additional 144 weeks. Week 12 results showed statistically significant improvement of the signs and symptoms of active non-radiographic axial spondyloarthritis in patients treated with adalimumab compared to placebo (table 9). Me dic ina l p rod uc t n o l on ge r a uth ori se d 28 Table 9 Efficacy response in placebo-controlled axial SpA study Double-Blind Response at week 12 Placebo N = 94 Adalimumab N = 91 ASASa 40 15% 36%*** ASAS 20 31% 52%** ASAS 5/6 6% 31%*** ASAS partial remission 5% 16%* BASDAIb 50 15% 35%** ASDASc,d,e -0.3 -1.0*** ASDAS Inactive Disease 4% 24%*** hs-CRPd,f,g -0.3 -4.7*** SPARCCh MRI Sacroiliac Jointsd,i -0.6 -3.2** SPARCC MRI Spined,j -0.2 -1.8** a Assessment of Spondyloarthritis International Society b Bath Ankylosing Spondylitis Disease Activity Index c Ankylosing Spondylitis Disease Activity Score d mean change from baseline e n = 91 placebo and n = 87 adalimumab f high sensitivity C-Reactive Protein (mg/L) g n = 73 placebo and n = 70 adalimumab h Spondyloarthritis Research Consortium of Canada i n = 84 placebo and adalimumab j n = 82 placebo and n = 85 adalimumab ***, **, * Statistically significant at p < 0.001, < 0.01, and < 0.05, respectively, for all comparisons between adalimumab and placebo In the open-label extension, improvement in the signs and symptoms was maintained with adalimumab therapy through week 156. Inhibition of inflammation Significant improvement of signs of inflammation as measured by hs-CRP and MRI of both Sacroiliac Joints and the Spine was maintained in adalimumab-treated patients through week 156 and week 104, respectively. Quality of life and physical function Health-related quality of life and physical function were assessed using the HAQ-S and the SF-36 questionnaires. Adalimumab showed statistically significantly greater improvement in the HAQ-S total score and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared to placebo. Improvement in health-related quality of life and physical function was maintained during the open-label extension through week 156. Psoriatic arthritis Adalimumab, 40 mg every other week, was studied in patients with moderately to severely active psoriatic arthritis in two placebo-controlled studies, PsA studies I and II. PsA study I with 24 week duration, treated 313 adult patients who had an inadequate response to non-steroidal anti-inflammatory drug therapy and of these, approximately 50% were taking methotrexate. PsA study II with 12-week duration, treated 100 patients who had an inadequate response to DMARD therapy. Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week (eow). There is insufficient evidence of the efficacy of adalimumab in patients with ankylosing spondylitis- like psoriatic arthropathy due to the small number of patients studied. Me dic ina l p rod uc t n o l on ge r a uth ori se d 29 Table 10 ACR response in placebo-controlled psoriatic arthritis studies (percent of patients) PsA study I PsA Study II PsA study II Response Placebo N = 162 Adalimumab N = 151 Placebo N = 49 Adalimumab N = 51 ACR 20 Week 12 14% 58%*** 16% 39%* Week 24 15% 57%*** N/A N/A ACR 50 Week 12 4% 36%*** 2% 25%*** Week 24 6% 39%*** N/A N/A ACR 70 Week 12 1% 20%*** 0% 14%* Week 24 1% 23%*** N/A N/A *** p < 0.001 for all comparisons between adalimumab and placebo * p < 0.05 for all comparisons between adalimumab and placebo N/A not applicable ACR responses in PsA study I were similar with and without concomitant methotrexate therapy. ACR responses were maintained in the open-label extension study for up to 136 weeks. Radiographic changes were assessed in the psoriatic arthritis studies. Radiographs of hands, wrists, and feet were obtained at baseline and week 24 during the double-blind period when patients were on adalimumab or placebo and at week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e. not identical to the TSS used for rheumatoid arthritis), was used. Adalimumab treatment reduced the rate of progression of peripheral joint damage compared with placebo treatment as measured by change from baseline in mTSS (mean ± SD) 0.8 ± 2.5 in the placebo group (at week 24) compared with 0.0 ± 1.9; (p < 0.001) in the adalimumab group (at week 48). In subjects treated with adalimumab with no radiographic progression from baseline to week 48 (n = 102), 84% continued to show no radiographic progression through 144 weeks of treatment. Adalimumab-treated patients demonstrated statistically significant improvement in physical function as assessed by HAQ and Short Form Health Survey (SF 36) compared to placebo at week 24. Improved physical function continued during the open-label extension up to week 136. Psoriasis The safety and efficacy of adalimumab were studied in adult patients with chronic plaque psoriasis (≥ 10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 or ≥ 10) who were candidates for systemic therapy or phototherapy in randomised, double-blind studies. 73% of patients enrolled in psoriasis studies I and II had received prior systemic therapy or phototherapy. The safety and efficacy of adalimumab were also studied in adult patients with moderate to severe chronic plaque psoriasis with concomitant hand and/or foot psoriasis who were candidates for systemic therapy in a randomised double-blind study (psoriasis study III). Psoriasis study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. After 16 weeks of therapy, patients who achieved at least a PASI 75 response (PASI score improvement of at least 75% relative to baseline), entered period B and received open-label 40 mg adalimumab every other week. Patients who maintained ≥ PASI 75 response at week 33 and were originally randomised to active therapy in period A, were re-randomised in period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups, the mean baseline PASI score was 18.9 and the baseline Physician’s Global Assessment (PGA) score ranged from “moderate” (53% of subjects included) to “severe” (41%) to “very severe” (6%). Me dic ina l p rod uc t n o l on ge r a uth ori se d 30 Psoriasis study II (CHAMPION) compared the efficacy and safety of adalimumab versus methotrexate and placebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg and thereafter dose increases up to week 12, with a maximum dose of 25 mg or an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data available comparing adalimumab and MTX beyond 16 weeks of therapy. Patients receiving MTX who achieved a ≥ PASI 50 response at week 8 and/or 12 did not receive further dose increases. Across all treatment groups, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from “mild” (< 1%) to “moderate” (48%) to “severe” (46%) to “very severe” (6%). Patients participating in all phase 2 and phase 3 psoriasis studies were eligible to enrol into an open- label extension trial, where adalimumab was given for at least an additional 108 weeks. In psoriasis studies I and II, a primary endpoint was the proportion of patients who achieved a PASI 75 response from baseline at week 16 (see tables 11 and 12). Table 11 Ps study I (REVEAL) - efficacy results at 16 weeks Placebo N = 398 n (%) Adalimumab 40 mg eow N = 814 n (%) ≥ PASI 75a 26 (6.5) 578 (70.9)b PASI 100 3 (0.8) 163 (20.0)b PGA: Clear/minimal 17 (4.3) 506 (62.2)b a Percent of patients achieving PASI75 response was calculated as centre-adjusted rate b p < 0.001, adalimumab versus placebo Table 12 Ps study II (CHAMPION) efficacy results at 16 weeks Placebo N = 53 n (%) MTX N = 110 n (%) Adalimumab 40 mg eow N = 108 n (%) ≥ PASI 75 10 (18.9) 39 (35.5) 86 (79.6) a, b PASI 100 1 (1.9) 8 (7.3) 18 (16.7) c, d PGA: Clear/minimal 6 (11.3) 33 (30.0) 79 (73.1) a, b a p < 0.001 adalimumab versus placebo b p < 0.001 adalimumab versus methotrexate c p < 0.01 adalimumab versus placebo d p < 0.05 adalimumab versus methotrexate In psoriasis study I, 28% of patients who were PASI 75 responders and were re-randomised to placebo at week 33 compared to 5% continuing on adalimumab, p < 0.001, experienced “loss of adequate response” (PASI score after week 33 and on or before week 52 that resulted in a < PASI 50 response relative to baseline with a minimum of a 6-point increase in PASI score relative to week 33). Of the patients who lost adequate response after re-randomisation to placebo who then enrolled into the open- label extension trial, 38% (25/66) and 55% (36/66) regained PASI 75 response after 12 and 24 weeks of retreatment, respectively. A total of 233 PASI 75 responders at week 16 and week 33 received continuous adalimumab therapy for 52 weeks in psoriasis study I, and continued adalimumab in the open-label extension trial. PASI 75 and PGA of clear or minimal response rates in these patients were 74.7% and 59.0%, respectively, after an additional 108 weeks of open-label therapy (total of 160 weeks). In an analysis in which all patients who dropped out of the study for adverse events or lack of efficacy, or who dose-escalated, were considered non-responders, PASI 75 and PGA of clear or minimal response rates in these patients were 69.6% and 55.7%, respectively, after an additional 108 weeks of open-label therapy (total of 160 weeks). Me dic ina l p rod uc t n o l on ge r a uth ori se d 31 A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open- label extension study. During the withdrawal period, symptoms of psoriasis returned over time with a median time to relapse (decline to PGA “moderate” or worse) of approximately 5 months. None of these patients experienced rebound during the withdrawal period. A total of 76.5% (218/285) of patients who entered the retreatment period had a response of PGA “clear” or “minimal” after 16 weeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1%[123/178] and 88.8% [95/107] for patients who relapsed and who did not relapse during the withdrawal period, respectively). A similar safety profile was observed during retreatment as before withdrawal. Significant improvements at week 16 from baseline compared to placebo (studies I and II) and MTX (study II) were demonstrated in the DLQI (Dermatology Life Quality Index). In study I, improvements in the physical and mental component summary scores of the SF-36 were also significant compared to placebo. In an open-label extension study, for patients who dose escalated from 40 mg every other week to 40 mg weekly due to a PASI response below 50%, 26.4% (92/349) and 37.8% (132/349) of patients achieved PASI 75 response at week 12 and 24, respectively. Psoriasis study III (REACH) compared the efficacy and safety of adalimumab versus placebo in 72 patients with moderate to severe chronic plaque psoriasis and hand and/or foot psoriasis. Patients received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 16 weeks. At week 16, a statistically significantly greater proportion of patients who received adalimumab achieved PGA of 'clear' or 'almost clear' for the hands and/or feet compared to patients who received placebo (30.6% versus 4.3%, respectively [P = 0.014]). Psoriasis study IV compared efficacy and safety of adalimumab versus placebo in 217 adult patients with moderate to severe nail psoriasis. Patients received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks. Nail psoriasis assessments included the Modified Nail Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) and the Nail Psoriasis Severity Index (NAPSI) (see table 13). Adalimumab demonstrated a treatment benefit in nail psoriasis patients with different extents of skin involvement (BSA ≥ 10% (60% of patients) and BSA < 10% and ≥ 5% (40% of patients)). Table 13 Ps study IV efficacy results at 16, 26 and 52 weeks Endpoint Week 16 Placebo-controlled Week 26 Placebo-controlled Week 52 Open-label Placebo N = 108 Adalimumab 40 mg eow N = 109 Placebo N = 108 Adalimumab 40 mg eow N = 109 Adalimumab 40 mg eow N = 80 ≥ mNAPSI 75 (%) 2.9 26.0a 3.4 46.6a 65.0 PGA-F clear/minimal and ≥ 2-grade improvement (%) 2.9 29.7a 6.9 48.9a 61.3 Percent change in total fingernail NAPSI (%) -7.8 -44.2 a -11.5 -56.2a -72.2 a p < 0.001, Adalimumab versus placebo Adalimumab treated patients showed statistically significant improvements at week 26 compared with placebo in the DLQI. Paediatric plaque psoriasis The efficacy of adalimumab was assessed in a randomised, double-blind, controlled study of 114 paediatric patients from 4 years of age with severe chronic plaque psoriasis (as defined by a PGA Me dic ina l p rod uc t n o l on ge r a uth ori se d 32 ≥ 4 or > 20% BSA involvement or > 10% BSA involvement with very thick lesions or PASI ≥ 20 or ≥ 10 with clinically relevant facial, genital, or hand/foot involvement) who were inadequately controlled with topical therapy and heliotherapy or phototherapy. Patients received adalimumab 0.8 mg/kg every other week (up to 40 mg), 0.4 mg/kg every other week (up to 20 mg), or methotrexate 0.1–0.4 mg/kg weekly (up to 25 mg). At week 16, more patients randomised to adalimumab 0.8 mg/kg had positive efficacy responses (e.g. PASI 75) than those randomised to 0.4 mg/kg every other week or MTX. Table 14 Paediatric plaque psoriasis efficacy results at 16 weeks MTXa N = 37 Adalimumab 0.8 mg/kg eow N = 38 PASI 75b 12 (32.4%) 22 (57.9%) PGA: Clear/minimalc 15 (40.5%) 23 (60.5%) a MTX = methotrexate b P = 0.027, adalimumab 0.8 mg/kg versus MTX c P = 0.083, adalimumab 0.8 mg/kg versus MTX Patients who achieved PASI 75 and PGA clear or minimal were withdrawn from treatment for up to 36 weeks and monitored for loss of disease control (i.e. a worsening of PGA by at least 2 grades). Patients were then retreated with adalimumab 0.8 mg/kg every other week for an additional 16 weeks and response rates observed during retreatment were similar to the previous double-blind period: PASI 75 response of 78.9% (15 of 19 subjects) and PGA clear or minimal of 52.6% (10 of 19 subjects). In the open-label period of the study, PASI 75 and PGA clear or minimal responses were maintained for up to an additional 52 weeks with no new safety findings. Hidradenitis suppurativa The safety and efficacy of adalimumab were assessed in randomised, double-blind, placebo-controlled studies and an open-label extension study in adult patients with moderate to severe hidradenitis suppurativa (HS) who were intolerant, had a contraindication or an inadequate response to at least a 3- month trial of systemic antibiotic therapy. The patients in HS-I and HS-II had Hurley Stage II or III disease with at least 3 abscesses or inflammatory nodules. Study HS-I (PIONEER I) evaluated 307 patients with 2 treatment periods. In Period A, patients received placebo or adalimumab at an initial dose of 160 mg at week 0, 80 mg at week 2, and 40 mg every week starting at week 4 to week 11. Concomitant antibiotic use was not allowed during the study. After 12 weeks of therapy, patients who had received adalimumab in Period A were re- randomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo from week 12 to week 35). Patients who had been randomised to placebo in Period A were assigned to receive adalimumab 40 mg every week in Period B. Study HS-II (PIONEER II) evaluated 326 patients with 2 treatment periods. In Period A, patients received placebo or adalimumab at an initial dose of 160 mg at week 0 and 80 mg at week 2 and 40 mg every week starting at week 4 to week 11. 19.3% of patients had continued baseline oral antibiotic therapy during the study. After 12 weeks of therapy, patients who had received adalimumab in Period A were re-randomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo from week 12 to week 35). Patients who had been randomised to placebo in Period A were assigned to receive placebo in Period B. Patients participating in Studies HS-I and HS-II were eligible to enrol into an open-label extension study in which adalimumab 40 mg was administered every week. Mean exposure in all adalimumab population was 762 days. Throughout all 3 studies patients used topical antiseptic wash daily. Clinical response Me dic ina l p rod uc t n o l on ge r a uth ori se d 33 Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas was assessed using Hidradenitis Suppurativa clinical response (HiSCR; at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to Baseline). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale in patients who entered the study with an initial baseline score of 3 or greater on a 11 point scale. At week 12, a significantly higher proportion of patients treated with adalimumab versus placebo achieved HiSCR. At week 12, a significantly higher proportion of patients in study HS-II experienced a clinically relevant decrease in HS-related skin pain (see table 15). Patients treated with adalimumab had significantly reduced risk of disease flare during the initial 12 weeks of treatment. Table 15 Efficacy results at 12 weeks, HS studies I and II HS study I HS study II Placebo Adalimumab 40 mg weekly Placebo Adalimumab 40 mg weekly Hidradenitis Suppurativa Clinical Response (HiSCR)a N = 154 40 (26.0%) N = 153 64 (41.8%) * N = 163 45 (27.6%) N = 163 96 (58.9%)*** ≥30% Reduction in Skin Painb N = 109 27 (24.8%) N = 122 34 (27.9%) N = 111 23 (20.7%) N = 105 48 (45.7%)*** *P < 0.05, ***P < 0.001, adalimumab versus placebo a Among all randomised patients b Among patients with baseline HS-related skin pain assessment ≥ 3, based on Numeric Rating Scale 0 – 10; 0 = no skin pain, 10 = skin pain as bad as you can imagine Treatment with adalimumab 40 mg every week significantly reduced the risk of worsening of abscesses and draining fistulas. Approximately twice the proportion of patients in the placebo group in the first 12 weeks of Studies HS-I and HS-II, compared with those in the adalimumab group experienced worsening of abscesses (23.0% versus 11.4%, respectively) and draining fistulas (30.0% versus 13.9%, respectively). Greater improvements at week 12 from baseline compared to placebo were demonstrated in skin- specific health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI; Studies HS-I and HS-II), patient global satisfaction with medication treatment as measured by the Treatment Satisfaction Questionnaire-medication (TSQM; Studies HS-I and HS-II), and physical health as measured by the physical component summary score of the SF-36 (study HS-I). In patients with at least a partial response to adalimumab 40 mg weekly at week 12, the HiSCR rate at week 36 was higher in patients who continued weekly adalimumab than in patients in whom dosing frequency was reduced to every other week, or in whom treatment was withdrawn (see table 16). Table 16 Proportion of patientsa achieving HiSCRb at weeks 24 and 36 after treatment reassignment from weekly adalimumab at week 12 Placebo (treatment withdrawal) N = 73 Adalimumab 40 mg every other week N = 70 Adalimumab 40 mg weekly N = 70 Week 24 24 (32.9%) 36 (51.4%) 40 (57.1%) Week 36 22 (30.1%) 28 (40.0%) 39 (55.7%) a Patients with at least a partial response to adalimumab 40 mg weekly after 12 weeks of treatment b Patients meeting protocol-specified criteria for loss of response or no improvement were required to discontinue from the studies and were counted as non-responders Me dic ina l p rod uc t n o l on ge r a uth ori se d 34 Among patients who were at least partial responders at week 12, and who received continuous weekly adalimumab therapy, the HiSCR rate at week 48 was 68.3% and at week 96 was 65.1%. Longer term treatment with adalimumab 40 mg weekly for 96 weeks identified no new safety findings. Among patients whose adalimumab treatment was withdrawn at week 12 in Studies HS-I and HS-II, the HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weekly returned to levels similar to that observed before withdrawal (56.0%). Crohn’s disease The safety and efficacy of adalimumab were assessed in over 1,500 patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomised, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted and 80% of patients continued to receive at least one of these medications. Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies, CD study I (CLASSIC I) and CD study II (GAIN). In CD study I, 299 TNF-antagonist naïve patients were randomised to one of four treatment groups; placebo at weeks 0 and 2, 160 mg adalimumab at week 0 and 80 mg at week 2, 80 mg at week 0 and 40 mg at week 2, and 40 mg at week 0 and 20 mg at week 2. In CD study II, 325 patients who had lost response or were intolerant to infliximab were randomised to receive either 160 mg adalimumab at week 0 and 80 mg at week 2 or placebo at weeks 0 and 2. The primary non-responders were excluded from the studies and therefore these patients were not further evaluated. Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD study III, 854 patients received open-label 80 mg at week 0 and 40 mg at week 2. At week 4 patients were randomised to 40 mg every other week, 40 mg every week, or placebo with a total study duration of 56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at week 4 were stratified and analysed separately from those not in clinical response at week 4. Corticosteroid taper was permitted after week 8. CD study I and CD study II induction of remission and response rates are presented in table 17 Table 17 Induction of clinical remission and response (percent of patients) CD study I: infliximab naïve patients CD study II: infliximab experienced patients Placebo N = 74 Adalimumab 80/40 mg N = 75 Adalimumab 160/80 mg N = 76 Placebo N = 166 Adalimumab 160/80 mg N = 159 Week 4 Clinical remission 12% 24% 36%* 7% 21%* Clinical response (CR-100) 24% 37% 49%** 25% 38%** All p-values are pairwise comparisons of proportions for adalimumab versus placebo * p < 0.001 ** p < 0.01 Similar remission rates were observed for the 160/80 mg and 80/40 mg induction regimens by week 8 and adverse events were more frequently noted in the 160/80 mg group. In CD study III, at week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. Of those in clinical response at week 4, 48% had been previously exposed to other TNF-antagonists. Maintenance of remission and response rates are presented in table 18. Clinical remission results remained relatively constant irrespective of previous TNF-antagonist exposure. Me dic ina l p rod uc t n o l on ge r a uth ori se d 35 Disease-related hospitalisations and surgeries were statistically significantly reduced with adalimumab compared with placebo at week 56. Table 18 Maintenance of clinical remission and response (percent of patients) Placebo 40 mg adalimumab every other week 40 mg adalimumab every week Week 26 N = 170 N = 172 N = 157 Clinical remission 17% 40%* 47%* Clinical response (CR-100) 27% 52%* 52%* Patients in steroid-free remission for > = 90 daysa 3% (2/66) 19% (11/58)** 15% (11/74)** Week 56 N = 170 N = 172 N = 157 Clinical remission 12% 36%* 41%* Clinical response (CR-100) 17% 41%* 48%* Patients in steroid-free remission for > = 90 daysa 5% (3/66) 29% (17/58)* 20% (15/74)** * p < 0.001 for adalimumab versus placebo pairwise comparisons of proportions ** p < 0.02 for adalimumab versus placebo pairwise comparisons of proportions a Of those receiving corticosteroids at baseline Among patients who were not in response at week 4, 43% of adalimumab maintenance patients responded by week 12 compared to 30% of placebo maintenance patients. These results suggest that some patients who have not responded by week 4 benefit from continued maintenance therapy through week 12. Therapy continued beyond 12 weeks did not result in significantly more responses (see section 4.2). 117/276 patients from CD study I and 272/777 patients from CD studies II and III were followed through at least 3 years of open-label adalimumab therapy. 88 and 189 patients, respectively, continued to be in clinical remission. Clinical response (CR-100) was maintained in 102 and 233 patients, respectively. Quality of life In CD study I and CD study II, statistically significant improvement in the disease-specific inflammatory bowel disease questionnaire (IBDQ) total score was achieved at week 4 in patients randomised to adalimumab 80/40 mg and 160/80 mg compared to placebo and was seen at weeks 26 and 56 in CD study III as well among the adalimumab treatment groups compared to the placebo group. Paediatric Crohn’s disease Adalimumab was assessed in a multicentre, randomised, double-blind clinical trial designed to evaluate the efficacy and safety of induction and maintenance treatment with doses dependent on body weight (< 40 kg or ≥ 40 kg) in 192 paediatric subjects between the ages of 6 and 17 (inclusive) years, with moderate to severe Crohn´s disease (CD) defined as Paediatric Crohn's Disease Activity Index (PCDAI) score > 30. Subjects had to have failed conventional therapy (including a corticosteroid and/or an immunomodulator) for CD. Subjects may also have previously lost response or been intolerant to infliximab. All subjects received open-label induction therapy at a dose based on their baseline body weight: 160 mg at week 0 and 80 mg at week 2 for subjects ≥ 40 kg, and 80 mg and 40 mg, respectively, for subjects < 40 kg. Me dic ina l p rod uc t n o l on ge r a uth ori se d 36 At week 4, subjects were randomised 1:1 based on their body weight at the time to either the low dose or standard dose maintenance regimens as shown in table 19. Table 19 Maintenance regimen Patient weight Low dose Standard dose < 40 kg 10 mg eow 20 mg eow ≥ 40 kg 20 mg eow 40 mg eow Efficacy results The primary endpoint of the study was clinical remission at week 26, defined as PCDAI score ≤ 10. Clinical remission and clinical response (defined as reduction in PCDAI score of at least 15 points from baseline) rates are presented in table 20. Rates of discontinuation of corticosteroids or immunomodulators are presented in table 21. Table 20 Paediatric CD study PCDAI clinical remission and response Standard dose 40/20 mg eow N = 93 Low dose 20/10 mg eow N = 95 P value* Week 26 Clinical remission 38.7% 28.4% 0.075 Clinical response 59.1% 48.4% 0.073 Week 52 Clinical remission 33.3% 23.2% 0.100 Clinical response 41.9% 28.4% 0.038 * p value for standard dose versus low dose comparison Table 21 Paediatric CD study discontinuation of corticosteroids or immunomodulators and fistula remission Standard dose 40/20 mg eow Low dose 20/10 mg eow P value1 Discontinued corticosteroids N = 33 N = 38 Week 26 84.8% 65.8% 0.066 Week 52 69.7% 60.5% 0.420 Discontinuation of Immunomodulators2 N = 60 N = 57 Week 52 30.0% 29.8% 0.983 Fistula remission3 N = 15 N = 21 Week 26 46.7% 38.1% 0.608 Week 52 40.0% 23.8% 0.303 1 p value for standard dose versus low dose comparison 2 Immunosuppressant therapy could only be discontinued at or after week 26 at the investigator's discretion if the subject met the clinical response criterion 3 defined as a closure of all fistulas that were draining at baseline for at least 2 consecutive post-baseline visits Statistically significant increases (improvement) from baseline to week 26 and 52 in body mass index and height velocity were observed for both treatment groups. Statistically and clinically significant improvements from baseline were also observed in both treatment groups for quality of life parameters (including IMPACT III). Me dic ina l p rod uc t n o l on ge r a uth ori se d 37 One hundred patients (n = 100) from the Paediatric CD Study continued in an open-label long-term extension study. After 5 years of adalimumab therapy, 74.0% (37/50) of the 50 patients remaining in the study continued to be in clinical remission, and 92.0% (46/50) of patients continued to be in clinical response per PCDAI. Ulcerative colitis The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopy subscore of 2 to 3) in randomised, double-blind, placebo-controlled studies. In study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at weeks 0 and 2, 160 mg adalimumab at week 0 followed by 80 mg at week 2, or 80 mg adalimumab at week 0 followed by 40 mg at week 2. After week 2, patients in both adalimumab arms received 40 mg every other week. Clinical remission (defined as Mayo score ≤ 2 with no subscore > 1) was assessed at week 8. In study UC-II, 248 patients received 160 mg of adalimumab at week 0, 80 mg at week 2 and 40 mg every other week thereafter, and 246 patients received placebo. Clinical results were assessed for induction of remission at week 8 and for maintenance of remission at week 52. Patients induced with 160/80 mg adalimumab achieved clinical remission versus placebo at week 8 in statistically significantly greater percentages in study UC-I (18% versus 9% respectively, p = 0.031) and study UC-II (17% versus 9% respectively, p = 0.019). In study UC-II, among those treated with adalimumab who were in remission at week 8, 21/41 (51%) were in remission at week 52. Results from the overall UC-II study population are shown in table 22. Table 22 Response, remission and mucosal healing in study UC-II (percent of patients) Placebo Adalimumab 40 mg eow Week 52 N = 246 N=248 N = 248 Clinical response 18% 30%* Clinical remission 9% 17%* Mucosal healing 15% 25%* Steroid-free remission for ≥ 90 daysa 6% (N = 140) 13%* (N = 150) Week 8 and 52 Sustained response 12% 24%** Sustained remission 4% 8%* Sustained mucosal healing 11% 19%* Clinical remission is Mayo score ≤ 2 with no subscore > 1; Clinical response is decrease from baseline in Mayo score ≥ 3 points and ≥ 30% plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1; * p < 0.05 for adalimumab versus placebo pairwise comparison of proportions ** p < 0.001 for adalimumab versus placebo pairwise comparison of proportions a Of those receiving corticosteroids at baseline Of those patients who had a response at week 8, 47% were in response, 29% were in remission, 41% had mucosal healing, and 20% were in steroid-free remission for ≥ 90 days at week 52. Approximately 40% of patients in study UC-II had failed prior anti-TNF treatment with infliximab. The efficacy of adalimumab in those patients was reduced compared to that in anti-TNF naïve patients. Among patients who had failed prior anti-TNF treatment, week 52 remission was achieved by 3% on placebo and 10% on adalimumab. Me dic ina l p rod uc t n o l on ge r a uth ori se d 38 Patients from studies UC-I and UC-II had the option to roll over into an open-label long-term extension study (UC III). Following 3 years of adalimumab therapy, 75% (301/402) continued to be in clinical remission per partial Mayo score. Hospitalisation rates During 52 weeks of studies UC-I and UC-II, lower rates of all-cause hospitalisations and UC-related hospitalisations were observed for the adalimumab-treated arm compared to the placebo arm. The number of all cause hospitalisations in the adalimumab treatment group was 0.18 per patient year versus 0.26 per patient year in the placebo group and the corresponding figures for UC-related hospitalisations were 0.12 per patient year versus 0.22 per patient year. Quality of life In study UC-II, treatment with adalimumab resulted in improvements in the Inflammatory Bowel Disease Questionnaire (IBDQ) score. Uveitis The safety and efficacy of adalimumab were assessed in adult patients with non-infectious intermediate, posterior, and panuveitis, excluding patients with isolated anterior uveitis, in two randomised, doublemasked, placebo-controlled studies (UV I and II). Patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. Concomitant stable doses of one non-biologic immunosuppressant were permitted. Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oral prednisone at a dose of 10 to 60 mg/day). All patients received a 2 week standardised dose of prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by week 15. Study UV II evaluated 226 patients with inactive uveitis requiring chronic corticosteroid treatment (oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequently underwent a mandatory taper schedule, with complete corticosteroid discontinuation by week 19. The primary efficacy endpoint in both studies was ‘time to treatment failure’. Treatment failure was defined by a multi-component outcome based on inflammatory chorioretinal and/or inflammatory retinal vascular lesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and best corrected visual acuity (BCVA). Clinical response Results from both studies demonstrated statistically significant reduction of the risk of treatment failure in patients treated with adalimumab versus patients receiving placebo (See table 23). Both studies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus placebo (see figure 1). Me dic ina l p rod uc t n o l on ge r a uth ori se d 39 Table 23 Time to treatment failure in studies UV I and UV II Analysis Treatment N Failure N (%) Median time to failure (months) HRa CI 95% for HRa P Value b Time to treatment failure at or after week 6 in study UV I Primary analysis (ITT) Placebo 107 84 (78.5) 3.0 -- -- -- Adalimumab 110 60 (54.5) 5.6 0.50 0.36, 0.70 < 0.001 Time to treatment failure at or after week 2 in study UV II Primary analysis (ITT) Placebo 111 61 (55.0) 8.3 -- -- -- Adalimumab 115 45 (39.1) NEc 0.57 0.39, 0.84 0.004 Note: Treatment failure at or after week 6 (study UV I), or at or after week 2 (study UV II), was counted as event. Drop outs due to reasons other than treatment failure were censored at the time of dropping out. a HR of adalimumab versus placebo from proportional hazards regression with treatment as factor. b 2-sided P value from log rank test. c NE = not estimable. Fewer than half of at-risk subjects had an event. Me dic ina l p rod uc t n o l on ge r a uth ori se d 40 Figure 1: Kaplan-Meier curves summarising time to treatment failure on or after week 6 (study UV I) or week 2 (study UV II) Note: P# = Placebo (number of events/number at risk); A# = Adalimumab (number of events/number at risk). In study UV I statistically significant differences in favour of adalimumab versus placebo were observed for each component of treatment failure. In study UV II, statistically significant differences were observed for visual acuity only, but the other components were numerically in favour of adalimumab. Of the 417 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 46 subjects were regarded ineligible (e.g. developed complications secondary to diabetic retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 371 remaining patients, 276 evaluable patients reached 78 weeks of open-label adalimumab treatment. Based on the observed data approach, 222 (80.4%) were in quiescence (no active inflammatory lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, and 184 (66.7%) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 letters deterioration) in 88.4% of the eyes at week 78. Among the patients who discontinued the study prior to week 78, 11% discontinued due to adverse events, and 5% due to insufficient response to adalimumab treatment. Me dic ina l p rod uc t n o l on ge r a uth ori se d 41 Quality of life Patient reported outcomes regarding vision-related functioning were measured in both clinical studies, using the NEI VFQ-25. Adalimumab was numerically favoured for the majority of subscores with statistically significant mean differences for general vision, ocular pain, near vision, mental health, and total score in study UV I, and for general vision and mental health in study UV II. vision related effects were not numerically in favour of adalimumab for colour vision in study UVI and for colour vision, peripheral vision and near vision in study UV II. Immunogenicity Anti-adalimumab antibodies may develop during adalimumab treatment. Formation of anti- adalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab. There is no apparent correlation between the presence of anti-adalimumab antibodies and the occurrence of adverse events. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of the studies with adalimumab in one or more subsets of the paediatric population in ulcerative colitis and non-infectious uveitis, see section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties Absorption and distribution After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab was slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to 15 mL/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of those in serum. Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoid arthritis (RA) patients the mean steady-state trough concentrations were approximately 5 μg/mL (without concomitant methotrexate) and 8 to 9 μg/mL (with concomitant methotrexate), respectively. The serum adalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week and every week. Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other week to patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (values measured at week 24) serum adalimumab concentrations were 8.8 ± 6.6 µg/mL for adalimumab without concomitant methotrexate and 11.8 ± 4.3 µg/mL with concomitant methotrexate. In adult patients with psoriasis, the mean steady-state trough concentration was 5 μg/mL during adalimumab 40 mg every other week monotherapy treatment. Following the administration of 0.8 mg/kg (up to a maximum of 40 mg) subcutaneously every other week to paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab trough concentration was approximately 7.4 ± 5.8 μg/mL (79% CV). In patients with hidradenitis suppurativa, a dose of 160 mg adalimumab on week 0 followed by 80 mg on week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg/mL at week 2 and week 4. The mean steady-state trough concentration at week 12 through week 36 were approximately 8 to 10 μg/mL during adalimumab 40 mg every week treatment. Me dic ina l p rod uc t n o l on ge r a uth ori se d 42 In patients with Crohn’s disease, the loading dose of 80 mg adalimumab on week 0 followed by 40 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 5.5 μg/mL during the induction period. A loading dose of 160 mg adalimumab on week 0 followed by 80 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/mL during the induction period. Mean steady-state trough levels of approximately 7 μg/mL were observed in Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab every other week. In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was 160/80 mg or 80/40 mg at weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. At week 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose (20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serum adalimumab trough concentrations achieved at week 4 were 15.7 ± 6.6 μg/mL for patients ≥ 40 kg (160/80 mg) and 10.6 ± 6.1 μg/mL for patients < 40 kg (80/40 mg). For patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough concentrations at week 52 were 9.5 ± 5.6 μg/mL for the standard dose group and 3.5 ± 2.2 μg/mL for the low dose group. The mean trough concentrations were maintained in patients who continued to receive adalimumab treatment every other week for 52 weeks. For patients who dose escalated from every other week to weekly regimen, the mean (±SD) serum concentrations of adalimumab at week 52 were 15.3 ± 11.4 μg/mL (40/20 mg, weekly) and 6.7 ± 3.5 μg/mL (20/10 mg, weekly). In patients with ulcerative colitis, a loading dose of 160 mg adalimumab on week 0 followed by 80 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/mL during the induction period. Mean steady-state trough levels of approximately 8 μg/mL were observed in ulcerative colitis patients who received a maintenance dose of 40 mg adalimumab every other week. In patients with uveitis, a loading dose of 80 mg adalimumab on week 0 followed by 40 mg adalimumab every other week starting at week 1, resulted in mean steady-state concentrations of approximately 8 to 10 μg/mL. Elimination Population pharmacokinetic analyses with data from over 1,300 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower in patients with measurable AAA. Hepatic or renal impairment Adalimumab has not been studied in patients with hepatic or renal impairment. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on studies of single dose toxicity, repeated dose toxicity, and genotoxicity. An embryo-foetal developmental toxicity/perinatal developmental study has been performed in Cynomolgus monkeys at 0, 30 and 100 mg/kg (9-17 monkeys/group) and has revealed no evidence of harm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard assessment of fertility and postnatal toxicity, were performed with adalimumab due to the lack of appropriate models for an antibody with limited cross-reactivity to rodent TNF and to the development of neutralising antibodies in rodents. Me dic ina l p rod uc t n o l on ge r a uth ori se d 43 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Glacial acetic acid Sucrose Polysorbate 80 Sodium hydroxide (for pH adjustment) Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). Do not freeze. Keep SOLYMBIC in the outer carton in order to protect from light. The pre-filled syringe or pre-filled pen may be stored at temperatures up to a maximum of 25°C for a period of up to 14 days. The pre-filled syringe or pre-filled pen must be protected from light, and discarded if not used within the 14-day period. 6.5 Nature and contents of container SOLYMBIC 20 mg solution for injection in pre-filled syringe 0.4 mL solution in pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber) and a stainless steel needle with a needle shield (thermoplastic elastomer). The needle cover of the pre-filled syringe is made from dry natural rubber (a derivative of latex) (see section 4.4). Packs size of one pre-filled syringe. SOLYMBIC 40 mg solution for injection in pre-filled syringe 0.8 mL solution in pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber) and a stainless steel needle with a needle shield (thermoplastic elastomer). The needle cover of the pre-filled syringe is made from dry natural rubber (a derivative of latex) (see section 4.4). Packs sizes of one, two, four and six pre-filled syringes. Not all pack sizes may be marketed. SOLYMBIC 40 mg solution for injection in pre-filled pen 0.8 mL solution for injection in pre-filled pen for patient use containing a pre-filled syringe (type I glass). The pen is a single use, disposable, handheld, mechanical injection device. The needle cover of the pre-filled pen is made from dry natural rubber (a derivative of latex) (see section 4.4). Packs sizes of one, two, four and six pre-filled pens. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Detailed instructions for use are provided in the package leaflet. Me dic ina l p rod uc t n o l on ge r a uth ori se d 44 Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) SOLYMBIC 20 mg solution for injection in pre-filled syringe EU/1/16/1163/001 – 1 pack SOLYMBIC 40 mg solution for injection in pre-filled syringe EU/1/16/1163/002 – 1 pack EU/1/16/1163/003 – 2 pack EU/1/16/1163/004 – 4 pack EU/1/16/1163/005 – 6 pack SOLYMBIC 40 mg solution for injection in pre-filled pen EU/1/16/1163/006 – 1 pack EU/1/16/1163/007 – 2 pack EU/1/16/1163/008 – 4 pack EU/1/16/1163/009 – 6 pack 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 22 March 2017 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu M ed ici na l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 45 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Me dic ina l p rod uc t n o l on ge r a uth ori se d 46 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Amgen Inc One Amgen Center Drive Thousand Oaks, California 91320 United States Name and address of the manufacturers responsible for batch release Amgen Europe B.V. Minervum 7061 4817 ZK Breda The Netherlands Amgen Technology Ireland UC Pottery Road Dun Laoghaire, Co Dublin Ireland Amgen NV Telecomlaan 5-7 1831 Diegem Belgium The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: • At the request of the European Medicines Agency; Me dic ina l p rod uc t n o l on ge r a uth ori se d 47 • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. • Additional risk minimisation measures Prior to launch of Solymbic in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority. The MAH shall ensure that in each Member State where Solymbic is marketed, all healthcare professionals who are expected to prescribe Solymbic have are provided with the following educational package: • Physician educational material • Patient information pack The physician educational material should contain: • The Summary of Product Characteristics • Guide for healthcare professionals • Patient alert card The Guide for healthcare professionals shall contain the following key elements: • Relevant information on the safety concerns of serious infections, sepsis, tuberculosis and opportunistic infections; congestive heart failure; demyelinating disorders; malignancies to be addressed by the additional risk minimisation measures (e.g. seriousness, severity, frequency, time to onset, reversibility of the AE as applicable). The patient alert card shall contain the following key messages: • A warning message for HCPs treating the patient at any time, including in conditions of emergency, that the patient is using Solymbic. • That Solymbic treatment may increase the potential risks of serious infections, sepsis, tuberculosis and opportunistic infections; congestive heart failure; demyelinating disorders; malignancies. • Signs or symptoms of the safety concern and when to seek attention from a HCP • Contact details of the prescriber The patient information pack should contain: • Patient information leaflet Me dic ina l p rod uc t n o l on ge r a uth ori se d 48 ANNEX III LABELLING AND PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 49 A. LABELLING Me dic ina l p rod uc t n o l on ge r a uth ori se d 50 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT SOLYMBIC 20 mg solution for injection in pre-filled syringe adalimumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled syringe contains 20 mg of adalimumab in 0.4 mL of solution. 3. LIST OF EXCIPIENTS Glacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 1 pre-filled syringe. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous use. Read the package leaflet before use. Single use only. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Contains latex, read the package leaflet before use. 8. EXPIRY DATE EXP Me dic ina l p rod uc t n o l on ge r a uth ori se d 51 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Do not shake. Store in the original carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061, NL-4817 ZK Breda, The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1163/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE SOLYMBIC 20 mg syringe 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN Me dic ina l p rod uc t n o l on ge r a uth ori se d 52 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION SOLYMBIC 20 mg injection adalimumab SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.4 mL 6. OTHER PARTICULARS TO APPEAR ON THE OUTER PACKAGING Me dic ina l p rod uc t n o l on ge r a uth ori se d 53 CARTON PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT SOLYMBIC 40 mg solution for injection in pre-filled syringe adalimumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled syringe contains 40 mg of adalimumab in 0.8 mL of solution. 3. LIST OF EXCIPIENTS Glacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 1 pre-filled syringe. 2 pre-filled syringes. 4 pre-filled syringes. 6 pre-filled syringes. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous use. Read the package leaflet before use. Single use only. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Contains latex, read the package leaflet before use. 8. EXPIRY DATE EXP Me dic ina l p rod uc t n o l on ge r a uth ori se d 54 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Do not shake. Store in the original carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061, NL-4817 ZK Breda, The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1163/002 1 pack EU/1/16/1163/003 2 pack EU/1/16/1163/004 4 pack EU/1/16/1163/005 6 pack 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE SOLYMBIC 40 mg syringe 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. Me dic ina l p rod uc t n o l on ge r a uth ori se d 55 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN Me dic ina l p rod uc t n o l on ge r a uth ori se d 56 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL PRE-FILLED SYRINGE 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION SOLYMBIC 40 mg injection adalimumab SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.8 mL 6. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 57 PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON PRE-FILLED PEN 1. NAME OF THE MEDICINAL PRODUCT SOLYMBIC 40 mg solution for injection in pre-filled pen adalimumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each pre-filled pen contains 40 mg of adalimumab in 0.8 mL of solution. 3. LIST OF EXCIPIENTS Glacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. 1 SureClick pre-filled pen. 2 SureClick pre-filled pens. 4 SureClick pre-filled pens. 6 SureClick pre-filled pens. 5. METHOD AND ROUTE(S) OF ADMINISTRATION For subcutaneous use. Read the package leaflet before use. Single use only. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Contains latex, read the package leaflet before use. 8. EXPIRY DATE EXP Me dic ina l p rod uc t n o l on ge r a uth ori se d 58 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Do not shake. Store in the original carton in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Amgen Europe B.V. Minervum 7061, NL-4817 ZK Breda, The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/16/1163/006 1 pack EU/1/16/1163/007 2 pack EU/1/16/1163/008 4 pack EU/1/16/1163/009 6 pack 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE SOLYMBIC 40 mg pen 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. Me dic ina l p rod uc t n o l on ge r a uth ori se d 59 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN Me dic ina l p rod uc t n o l on ge r a uth ori se d 60 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL PRE-FILLED PEN 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION SOLYMBIC 40 mg injection adalimumab SC 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.8 mL 6. OTHER Me dic ina l p rod uc t n o l on ge r a uth ori se d 61 B. PACKAGE LEAFLET Me dic ina l p rod uc t n o l on ge r a uth ori se d 62 Package leaflet: Information for the user SOLYMBIC 20 mg solution for injection in pre-filled syringe SOLYMBIC 40 mg solution for injection in pre-filled syringe adalimumab This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - Your doctor will also give you a Patient Alert Card, which contains important safety information that you need to be aware of before you are given SOLYMBIC and during treatment with SOLYMBIC. Keep this Patient Alert Card with you. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4). What is in this leaflet 1. What SOLYMBIC is and what it is used for 2. What you need to know before you use SOLYMBIC 3. How to use SOLYMBIC 4. Possible side effects 5. How to store SOLYMBIC 6. Contents of the pack and other information 1. What SOLYMBIC is and what it is used for SOLYMBIC contains the active substance adalimumab, a selective immuno suppressive agent. SOLYMBIC is intended for treatment of rheumatoid arthritis, enthesitis-related arthritis in children 6 to 17 years, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, paediatric psoriasis (patients weighing either 23 to 28 kg or 47 kg and greater), Crohn’s disease in adults and children, ulcerative colitis and non-infectious uveitis affecting the back of the eye. It is a medicine that decreases the inflammation process of these diseases. The active ingredient, adalimumab, is a human monoclonal antibody produced by cultured cells. Monoclonal antibodies are proteins that recognise and bind to other unique proteins. Adalimumab binds to a specific protein (tumour necrosis factor or TNFα), which is present at increased levels in inflammatory diseases such as rheumatoid arthritis, enthesitis-related arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and non-infectious uveitis affecting the back of the eye. Rheumatoid arthritis Rheumatoid arthritis is an inflammatory disease of the joints. SOLYMBIC is used to treat rheumatoid arthritis in adults. If you have moderate to severe active rheumatoid arthritis, you may first be given other disease-modifying medicines, such as methotrexate. Me dic ina l p rod uc t n o l on ge r a uth ori se d 63 If you do not respond well enough to these medicines, you will be given SOLYMBIC to treat your rheumatoid arthritis. SOLYMBIC can also be used to treat severe, active and progressive rheumatoid arthritis without previous methotrexate treatment. SOLYMBIC slows down the damage to the cartilage and bone of the joints caused by the disease and to improve physical function. Usually, SOLYMBIC is used with methotrexate. If your doctor determines that methotrexate is inappropriate, SOLYMBIC can be given alone. Enthesitis-related arthritis Enthesitis-related arthritis is an inflammatory disease of the joints. SOLYMBIC is used to treat enthesitis-related arthritis in children and adolescents aged 6 to 17 years. You may first be given other disease-modifying medicines, such as methotrexate. If you do not respond well enough to these medicines, you will be given SOLYMBIC to treat your enthesitis-related arthritis. Ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis Ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, are inflammatory diseases of the spine. SOLYMBIC is used to treat ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis in adults. If you have ankylosing spondylitis or axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, you will first be given other medicines. If you do not respond well enough to these medicines, you will be given SOLYMBIC to reduce the signs and symptoms of your disease. Psoriatic arthritis Psoriatic arthritis is an inflammation of the joints associated with psoriasis. SOLYMBIC is used to treat psoriatic arthritis in adults. SOLYMBIC slows down the damage to the cartilage and bone of the joints caused by the disease and to improve physical function. Plaque psoriasis in adults and children Plaque psoriasis is a skin condition that causes red, flaky, crusty patches of skin covered with silvery scales. Plaque psoriasis can also affect the nails, causing them to crumble, become thickened and lift away from the nail bed which can be painful. Psoriasis is believed to be caused by a problem with the body’s immune system that leads to an increased production of skin cells. SOLYMBIC is used to treat moderate to severe plaque psoriasis in adults. SOLYMBIC is also used to treat severe plaque psoriasis in children and adolescents weighing either 23 to 28 kg or 47 kg or greater for whom topical therapy and phototherapies have either not worked very well or are not suitable. Hidradenitis suppurativa Hidradenitis suppurativa (sometimes called acne inversa) is a chronic and often painful inflammatory skin disease. Symptoms may include tender nodules (lumps) and abscesses (boils) that may leak pus. Me dic ina l p rod uc t n o l on ge r a uth ori se d 64 It most commonly affects specific areas of the skin, such as under the breasts, the armpits, inner thighs, groin and buttocks. Scarring may also occur in affected areas. SOLYMBIC is used to treat hidradenitis suppurativa in adults. SOLYMBIC can reduce the number of nodules and abscesses you have, and the pain that is often associated with the disease. Crohn’s disease in adults and children Crohn’s disease is an inflammatory disease of the digestive tract. SOLYMBIC is used to treat Crohn’s disease in adults and children aged 6 to 17 years. If you have Crohn’s disease you will first be given other medicines. If you do not respond well enough to these medicines, you will be given SOLYMBIC to reduce the signs and symptoms of your Crohn’s disease. Ulcerative colitis Ulcerative colitis is an inflammatory disease of the bowel. SOLYMBIC is used to treat ulcerative colitis in adults. If you have ulcerative colitis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given SOLYMBIC to reduce the signs and symptoms of your disease. Non-infectious uveitis affecting the back of the eye Non-infectious uveitis is an inflammatory disease affecting certain parts of the eye. SOLYMBIC is used to treat adults with non-infectious uveitis with inflammation affecting the back of the eye. This inflammation leads to a decrease of vision and/or the presence of floaters in the eye (black dots or wispy lines that move across the field of vision). SOLYMBIC works by reducing this inflammation. 2. What you need to know before you use SOLYMBIC Do not use SOLYMBIC: - if you are allergic to adalimumab or any of the other ingredients of this medicine (listed in section 6). - if you have a severe infection, including active tuberculosis (see “Warnings and precautions”). It is important that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, feeling tired, dental problems. - if you have moderate or severe heart failure. It is important to tell your doctor if you have had or have a serious heart condition (see “Warnings and precautions”). Warnings and precautions Talk to your doctor or pharmacist before using SOLYMBIC: - If you experience allergic reactions with symptoms such as chest tightness, wheezing, dizziness, swelling or rash do not inject more SOLYMBIC and contact your doctor immediately since, in rare cases, these reactions can be life threatening. - If you have an infection, including long-term or localised infection (for example, leg ulcer) consult your doctor before starting SOLYMBIC. If you are unsure, please contact your doctor. - You might get infections more easily while you are receiving SOLYMBIC treatment. This risk may increase if your lung function is impaired. These infections may be serious and include tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other opportunistic infections and sepsis that may, in rare cases, be life-threatening. It is important to tell your Me dic ina l p rod uc t n o l on ge r a uth ori se d 65 doctor if you get symptoms such as fever, wounds, feeling tired or dental problems. Your doctor may recommend temporary discontinuation of SOLYMBIC. - As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor will check you for signs and symptoms of tuberculosis before starting SOLYMBIC. This will include a thorough medical evaluation including your medical history and appropriate screening tests (for example chest x-ray and a tuberculin test). The conduct and results of these tests should be recorded on your Patient Alert Card. It is very important that you tell your doctor if you have ever had tuberculosis, or if you have been in close contact with someone who has had tuberculosis. Tuberculosis can develop during therapy even if you have received preventative treatment for tuberculosis. If symptoms of tuberculosis (persistent cough, weight loss, listlessness, mild fever), or any other infection appear during or after therapy, tell your doctor immediately. - Advise your doctor if you reside or travel in regions where fungal infections such as histoplasmosis coccidioidomycosis or blastomycosis are endemic. - Advise your doctor if you have a history of recurrent infections or other conditions that increase the risk of infections. - Advise your doctor if you are a carrier of the hepatitis B virus (HBV), if you have active HBV or if you think you might be at risk of contracting HBV. Your doctor should test you for HBV. SOLYMBIC can cause reactivation of HBV in people who carry this virus. In some rare cases, especially if you are taking other medicines that suppress the immune system, reactivation of HBV can be life-threatening. - If you are over 65 years you may be more susceptible to infections while taking SOLYMBIC. You and your doctor should pay special attention to signs of infection while you are being treated with SOLYMBIC. It is important to tell your doctor if you get symptoms of infections, such as fever, wounds, feeling tired or dental problems. - If you are about to undergo surgery or dental procedures please inform your doctor that you are taking SOLYMBIC. Your doctor may recommend temporary discontinuation of SOLYMBIC. - If you have or develop demyelinating disease such as multiple sclerosis, your doctor will decide if you should receive or continue to receive SOLYMBIC. Tell your doctor immediately if you experience symptoms like changes in your vision, weakness in your arms or legs or numbness or tingling in any part of your body. - Certain vaccines may cause infections and should not be given while receiving SOLYMBIC. Please check with your doctor before you receive any vaccines. It is recommended that children, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating SOLYMBIC therapy. If you received SOLYMBIC while you were pregnant, your baby may be at higher risk for getting such an infection for up to approximately five months after the last dose you received during pregnancy. It is important that you tell your baby's doctors and other health care professionals about your SOLYMBIC use during your pregnancy so they can decide when your baby should receive any vaccine. - If you have mild heart failure and you are being treated with SOLYMBIC, your heart failure status must be closely monitored by your doctor. It is important to tell your doctor if you have had or have a serious heart condition. If you develop new or worsening symptoms of heart failure (e.g. shortness of breath, or swelling of your feet), you must contact your doctor immediately. - In some patients the body may fail to produce enough of the blood cells that help your body fight infections or help you to stop bleeding. If you develop a fever that does not go away, Me dic ina l p rod uc t n o l on ge r a uth ori se d 66 bruise or bleed very easily or look very pale, call your doctor right away. Your doctor may decide to stop treatment. - There have been very rare cases of certain kinds of cancer in children and adult patients taking adalimumab or other TNF blockers. People with more serious rheumatoid arthritis that have had the disease for a long time may have a higher than average risk of getting lymphoma (a type of cancer that affects the lymph system), and leukaemia (a type of cancer that affects the blood and bone marrow). If you take SOLYMBIC the risk of getting lymphoma, leukaemia, or other cancers may increase. On rare occasions, a specific and severe type of lymphoma has been observed in some patients taking adalimumab. Some of those patients were also treated with azathioprine or 6-mercaptopurine. Tell your doctor if you are taking azathioprine or 6-mercaptopurine with SOLYMBIC. In addition, cases of non-melanoma skin cancer have been observed in patients taking adalimumab. If new skin lesions appear during or after therapy or if existing lesions change appearance, tell your doctor. - There have been cases of cancers other than lymphoma in patients with a specific type of lung disease called Chronic Obstructive Pulmonary Disease (COPD) treated with another TNF blocker. If you have COPD, or are a heavy smoker, you should discuss with your doctor whether treatment with a TNF blocker is appropriate for you. The needle cover of the pre-filled syringe is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. In order to improve the traceability of this medicine, your doctor or pharmacist should record the tradename and the lot number of the product you have been given in your patient file. You may also wish to make a note of these details in case you are asked for this information in the future. Children and adolescents - Vaccinations: if possible children should be up to date with all vaccinations before using SOLYMBIC. - Do not use the 20 mg or 40 mg pre-filled syringe if doses other than 20 mg or 40 mg are recommended. Other medicines and SOLYMBIC Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. SOLYMBIC can be taken together with methotrexate or certain disease-modifying anti-rheumatic agents (sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), steroids or pain medications including non-steroidal anti-inflammatory drugs (NSAIDs). You should not take SOLYMBIC with medicines containing the active substance, anakinra or abatacept. If you have questions, please ask your doctor. Pregnancy and breast-feeding The effects of SOLYMBIC in pregnant women are not known and so the use of SOLYMBIC in pregnant women is not recommended. You are advised to avoid becoming pregnant and must use adequate contraception while using SOLYMBIC and for at least 5 months after the last SOLYMBIC treatment. If you become pregnant, you should consult your doctor. It is not known whether SOLYMBIC passes into breast milk. If you are a breast-feeding mother, you should stop breast-feeding during SOLYMBIC treatment and for at least 5 months after the last SOLYMBIC treatment. If you received SOLYMBIC during your Me dic ina l p rod uc t n o l on ge r a uth ori se d 67 pregnancy, your baby may have a higher risk for getting an infection. It is important that you tell your baby’s doctors and other health care professionals about your SOLYMBIC use during your pregnancy before the baby receives any vaccine (for more information see section on vaccination). If you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Driving and using machines SOLYMBIC may have a minor influence on your ability to drive, cycle or use machines. Room spinning sensation and vision disturbances may occur after taking SOLYMBIC. SOLYMBIC contains sodium This medicine contains less than 1 mmol of sodium (23 mg) per 0.8 mL dose, i.e. essentially ‘sodium- free’. 3. How to use SOLYMBIC Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis without radiographic evidence of ankylosing spondylitis SOLYMBIC is injected under the skin (subcutaneous use). The usual dose for adults with rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, and for patients with psoriatic arthritis is 40 mg given every other week as a single dose. In rheumatoid arthritis, methotrexate is continued while using SOLYMBIC. If your doctor determines that methotrexate is inappropriate, SOLYMBIC can be given alone. If you have rheumatoid arthritis and you do not receive methotrexate with your SOLYMBIC therapy, your doctor may decide to give 40 mg every week. Children with enthesitis-related arthritis The recommended dose of SOLYMBIC for patients with enthesitis-related arthritis, aged 6 to 17 years depends on the height and weight of the child. Your child’s doctor will tell you the correct dose to use. Adults with psoriasis The usual dose for adults with psoriasis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. You should continue to inject SOLYMBIC for as long as your doctor has told you. Depending on your response, your doctor may increase the dose frequency to 40 mg every week. Children or adolescents with plaque psoriasis The recommended dose of SOLYMBIC for patients aged 4 to 17 years with plaque psoriasis depends on the weight of your child. SOLYMBIC should only be used in patients weighing either 23 to 28 kg or 47 kg and greater. Your child’s doctor will tell you the correct dose to use. Adults with hidradenitis suppurativa Me dic ina l p rod uc t n o l on ge r a uth ori se d 68 The usual dose regimen for hidradenitis suppurativa is an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by an 80 mg dose (as two 40 mg injections on the same day) two weeks later. After two further weeks, continue with a dose of 40 mg every week. It is recommended that you use an antiseptic wash daily on the affected areas. Adults with Crohn’s disease The usual dose regimen for Crohn’s disease is 80 mg initially followed by 40 mg every other week two weeks later. If a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later, and thereafter as 40 mg every other week. Depending on your response, your doctor may increase the dose frequency to 40 mg every week. Children or adolescents with Crohn's disease Children or adolescents weighing less than 40 kg: The usual dose regimen is 40 mg initially followed by 20 mg two weeks later. If a faster response is required, your doctor may prescribe an initial dose of 80 mg (as two 40 mg injections in 1 day) followed by 40 mg two weeks later. Thereafter, the usual dose is 20 mg every other week. Depending on your response, your doctor may increase the dose frequency to 20 mg every week. Children or adolescents weighing 40 kg or more: The usual dose regimen is 80 mg initially followed by 40 mg two weeks later. If a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in 1 day or as two 40 mg injections per day for 2 consecutive days) followed by 80 mg two weeks later. Thereafter, the usual dose is 40 mg every other week. Depending on your response, your doctor may increase the dose frequency to 40 mg every week. Adults with ulcerative colitis The usual SOLYMBIC dose for adults with ulcerative colitis is 160 mg initially (dose can be administered as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days) followed by 80 mg two weeks later, then 40 mg every other week. Depending on your response, your doctor may increase the dose to 40 mg every week. Adults with non-infectious uveitis The usual dose for adults with non-infectious uveitis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. You should continue to inject SOLYMBIC for as long as your doctor has told you. In non-infectious uveitis, corticosteroids or other medicines that influence the immune system may be continued while using SOLYMBIC. SOLYMBIC can also be given alone. Method and route of administration SOLYMBIC is administered by injection under the skin (subcutaneous injection). If you use more SOLYMBIC than you should Me dic ina l p rod uc t n o l on ge r a uth ori se d 69 If you accidentally inject SOLYMBIC more frequently than told to by your doctor or pharmacist, you should call your doctor or pharmacist and tell him/her that you have taken more. Always take the outer carton of this medicine with you, even if it is empty. If you forget to use SOLYMBIC If you forget to give yourself an injection, you should inject it as soon as you remember. Then take your next dose as you would have on your originally scheduled day, had you not forgotten a dose. If you stop using SOLYMBIC The decision to stop using SOLYMBIC should be discussed with your doctor. Your symptoms may return upon discontinuation. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects are mild to moderate. However, some may be serious and require treatment. Side effects may occur at least up to 4 months after the last SOLYMBIC injection. Tell your doctor immediately if you notice any of the following: • severe rash, hives or other signs of allergic reaction; • swollen face, hands, feet; • trouble breathing, swallowing; • shortness of breath with exertion or upon lying down or swelling of the feet. Tell your doctor as soon as possible if you notice any of the following: • signs of infection such as fever, feeling sick, wounds, dental problems, burning on urination; • feeling weak or tired; • coughing; • tingling; • numbness; • double vision; • arm or leg weakness; • a bump or open sore that doesn't heal; • signs and symptoms suggestive of blood disorders such as persistent fever, bruising, bleeding, paleness. The symptoms described above can be signs of the below listed side effects, which have been observed with adalimumab: Very common side effects (may affect more than 1 in 10 people): • injection site reactions (including pain, swelling, redness or itching); • respiratory tract infections (including cold, runny nose, sinus infection, pneumonia); • headache; • abdominal pain; • nausea and vomiting; • rash; • musculoskeletal pain. Common side effects (may affect up to 1 in 10 people): • serious infections (including blood poisoning and influenza); • skin infections (including cellulitis and shingles); Me dic ina l p rod uc t n o l on ge r a uth ori se d 70 • ear infections; • oral infections (including tooth infections and cold sores); • reproductive tract infections; • urinary tract infection; • fungal infections; • joint infections; • benign tumours; • skin cancer; • allergic reactions (including seasonal allergy); • dehydration; • mood swings (including depression); • anxiety; • difficulty sleeping; • sensation disorders such as tingling, prickling or numbness; • migraine; • nerve root compression (including low back pain and leg pain); • vision disturbances; • eye inflammation; • inflammation of the eye lid and eye swelling; • vertigo; • sensation of heart beating rapidly; • high blood pressure; • flushing; • haematoma; • cough; • asthma; • shortness of breath; • gastrointestinal bleeding; • dyspepsia (indigestion, bloating, heart burn); • acid reflux disease; • sicca syndrome (including dry eyes and dry mouth); • itching; • itchy rash; • bruising; • inflammation of the skin (such as eczema); • breaking of finger nails and toe nails; • increased sweating; • hair loss; • new onset or worsening of psoriasis; • muscle spasms; • blood in urine; • kidney problems; • chest pain; • oedema; • fever; • reduction in blood platelets which increases risk of bleeding or bruising; • impaired healing. Uncommon side effects (may affect up to 1 in 100 people): • opportunistic infections (which include tuberculosis and other infections that occur when resistance to disease is lowered); • neurological infections (including viral meningitis); • eye infections; • bacterial infections; • diverticulitis (inflammation and infection of the large intestine); • cancer; Me dic ina l p rod uc t n o l on ge r a uth ori se d 71 • cancer that affects the lymph system; • melanoma; • immune disorders that could affect the lungs, skin and lymph nodes (most commonly presenting as sarcoidosis); • vasculitis (inflammation of blood vessels); • tremor; • neuropathy; • stroke; • double vision; • hearing loss, buzzing; • sensation of heart beating irregularly such as skipped beats; • heart problems that can cause shortness of breath or ankle swelling; • heart attack; • a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; • lung diseases causing shortness of breath (including inflammation); • pulmonary embolism (blockage in an artery of the lung); • pleural effusion (abnormal collection of fluid in the pleural space); • inflammation of the pancreas which causes severe pain in the abdomen and back; • difficulty in swallowing; • facial oedema; • gallbladder inflammation, gallbladder stones; • fatty liver; • night sweats; • scar; • abnormal muscle breakdown; • systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other organ systems); • sleep interruptions; • impotence; • inflammations. Rare side effects (may affect up to 1 in 1,000 people): • leukaemia (cancer affecting the blood and bone marrow); • severe allergic reaction with shock; • multiple sclerosis; • nerve disorders (such as eye nerve inflammation and Guillain-Barré syndrome that may cause muscle weakness, abnormal sensations, tingling in the arms and upper body); • heart stops pumping; • pulmonary fibrosis (scarring of the lung); • intestinal perforation; • hepatitis; • reactivation of hepatitis B; • autoimmune hepatitis (inflammation of the liver caused by the body's own immune system); • cutaneous vasculitis (inflammation of blood vessels in the skin); • Stevens-Johnson syndrome (early symptoms include malaise, fever, headache and rash); • facial oedema associated with allergic reactions; • erythema multiforme (inflammatory skin rash); • lupus-like syndrome. Not known (frequency cannot be estimated from available data): • hepatosplenic T-cell lymphoma (a rare blood cancer that is often fatal); • Merkel cell carcinoma (a type of skin cancer); • liver failure; • worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle weakness). Me dic ina l p rod uc t n o l on ge r a uth ori se d 72 Some side effects observed with adalimumab may not have symptoms and may only be discovered through blood tests. These include: Very common side effects (may affect more than 1 in 10 people): • low blood measurements for white blood cells; • low blood measurements for red blood cells; • increased lipids in the blood; • elevated liver enzymes. Common side effects (may affect up to 1 in 10 people): • high blood measurements for white blood cells; • low blood measurements for platelets; • increased uric acid in the blood; • abnormal blood measurements for sodium; • low blood measurements for calcium; • low blood measurements for phosphate; • high blood sugar; • high blood measurements for lactate dehydrogenase; • autoantibodies present in the blood. Rare side effects (may affect up to 1 in 1,000 people): • low blood measurements for white blood cells, red blood cells and platelet count. Not known (frequency cannot be estimated from available data): • liver failure. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store SOLYMBIC Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2C – 8C). Do not freeze. Store in the original carton in order to protect from light. A single SOLYMBIC pre-filled syringe may be stored at temperatures up to a maximum of 25°C for a period of up to 14 days. The pre-filled syringe must be protected from light, and discarded if not used within the 14-day period. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 73 6. Contents of the pack and other information What SOLYMBIC contains - The active substance is adalimumab. Each pre-filled syringe contains 20 mg of adalimumab in 0.4 mL of solution or 40 mg of adalimumab in 0.8 mL of solution. - The other ingredients are glacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. What SOLYMBIC looks like and contents of the pack SOLYMBIC is a clear and colourless to slightly yellow solution. Each pack contains 1 single-use 20 mg pre-filled syringe (with yellow plunger rod). Each pack contains 1, 2, 4 or 6 single-use 40 mg pre-filled syringes (with blue plunger rod). Marketing Authorisation Holder and Manufacturer Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda The Netherlands Marketing Authorisation Holder Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda The Netherlands Manufacturer Amgen Technology Ireland UC Pottery Road Dun Laoghaire Co Dublin Ireland Manufacturer Amgen NV Telecomlaan 5-7 1831 Diegem Belgium For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien s.a. Amgen n.v. Tel/Tél: +32 (0)2 7752711 Lietuva Amgen Switzerland AG Vilniaus filialas Tel: +370 5 219 7474 България Амджен България ЕООД Тел.: +359 (0)2 424 7440 Luxembourg/Luxemburg s.a. Amgen Belgique/Belgien Tel/Tél: +32 (0)2 7752711 Me dic ina l p rod uc t n o l on ge r a uth ori se d 74 Česká republika Amgen s.r.o. Tel: +420 221 773 500 Magyarország Amgen Kft. Tel.: +36 1 35 44 700 Danmark Amgen, filial af Amgen AB, Sverige Tlf: +45 39617500 Malta Amgen B.V. The Netherlands Tel: +31 (0)76 5732500 Deutschland AMGEN GmbH Tel.: +49 89 1490960 Nederland Amgen B.V. Tel: +31 (0)76 5732500 Eesti Amgen Switzerland AG Vilniaus filialas Tel: +372 586 09553 Norge Amgen AB Tel: +47 23308000 Ελλάδα Amgen Ελλάς Φαρμακευτικά Ε.Π.Ε. Τηλ.: +30 210 3447000 Österreich Amgen GmbH Tel: +43 (0)1 50 217 España Amgen S.A. Tel: +34 93 600 18 60 Polska Amgen Biotechnologia Sp. z o.o. Tel.: +48 22 581 3000 France Amgen S.A.S. Tél: +33 (0)9 69 363 363 Portugal Amgen Biofarmacêutica, Lda. Tel: +351 21 4220550 Hrvatska Amgen d.o.o. Tel: +385 (0)1 562 57 20 România Amgen România SRL Tel: +4021 527 3000 Ireland Amgen Limited United Kingdom Tel: +44 (0)1223 420305 Slovenija AMGEN zdravila d.o.o. Tel: +386 (0)1 585 1767 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Amgen Slovakia s.r.o. Tel: +421 2 321 114 49 Italia Amgen S.r.l. Tel: +39 02 6241121 Suomi/Finland Amgen AB, sivuliike Suomessa/Amgen AB, filial i Finland Puh/Tel: +358 (0)9 54900500 Kύπρος C.A. Papaellinas Ltd Τηλ.: +357 22741 741 Sverige Amgen AB Tel: +46 (0)8 6951100 Latvija Amgen Switzerland AG Rīgas filiāle Tel: +371 257 25888 United Kingdom Amgen Limited Tel: +44 (0)1223 420305 Me dic ina l p rod uc t n o l on ge r a uth ori se d 75 This leaflet was last revised in Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. --------------------------------------------------------------------------------------------------------------------------- Instructions for use: SOLYMBIC single use pre-filled syringe For subcutaneous use Guide to parts Before use After use Plunger rod Finger flange Label and expiration date Syringe barrel Medicine Needle cap on Used plunger rod Finger flange Label and expiration date Used syringe barrel Used needle Needle cap off Important: Needle is inside Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 76 Important Before you use a SOLYMBIC pre-filled syringe, read this important information: Using your SOLYMBIC pre-filled syringe ● It is important that you do not try to give the injection unless you or your caregiver has received training. ● Do not use a SOLYMBIC pre-filled syringe if it has been dropped on a hard surface. Part of the SOLYMBIC pre-filled syringe may be broken even if you cannot see the break. Use a new SOLYMBIC pre-filled syringe. ● The needle cover of the SOLYMBIC pre-filled syringe is made from dry natural rubber, which contains latex. Tell your healthcare provider if you are allergic to latex. Step 1: Prepare A. Remove the number of SOLYMBIC pre-filled syringes you need from the package. Grab the syringe barrel to remove the syringe from the tray. Place your finger or thumb on edge of tray to secure it while you remove the syringe. Grab Here Put the original package with any unused syringes back in the refrigerator. For safety reasons: ● Do not grasp the plunger rod. ● Do not grasp the needle cap. ● Do not remove the needle cap until you are ready to inject. ● Do not remove the finger flange. This is part of the syringe. For a more comfortable injection, leave the syringe at room temperature for 15 to 30 minutes before injecting. ● Do not put the syringe back in the refrigerator once it has reached room temperature. ● Do not try to warm the syringe by using a heat source such as hot water or microwave. ● Do not leave the syringe in direct sunlight. ● Do not shake the syringe. Important: Always hold the pre-filled syringe by the syringe barrel. Me dic ina l p rod uc t n o l on ge r a uth ori se d 77 B. Inspect the SOLYMBIC pre-filled syringe. Syringe barrel Label expiration date Plunger rod Needle cap on Medicine Finger flange Always hold the syringe by the syringe barrel. Make sure the medicine in the syringe is clear and colourless to slightly yellow. ● Do not use the syringe if: - The medicine is cloudy or discoloured or contains flakes, or particles. - Any part appears cracked or broken. - The needle cap is missing or not securely attached. - The expiration date printed on the label has passed. In all cases, use a new syringe. C. Gather all materials needed for your injection(s). Wash your hands thoroughly with soap and water. On a clean, well-lit work surface, place a new, pre-filled syringe. You will also need these additional items, as they are not included in the carton: ● Alcohol wipes ● Cotton ball or gauze pad ● Plaster ● Sharps disposal container Me dic ina l p rod uc t n o l on ge r a uth ori se d 78 D. Prepare and clean your injection site(s). Belly Thigh You can use: ● Your thigh ● Belly, except for a 2 inch (5 centimetres) area around your belly button Clean your injection site with an alcohol wipe. Let your skin dry. ● Do not touch this area again before injecting. ● If you want to use the same injection site, make sure it is not the same spot on the injection site you used for a previous injection. - Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. ● If you have psoriasis, you should avoid injecting directly into raised, thick, red, or scaly skin patch or lesion. Step 2: Get ready E. Pull the needle cap straight out and away from your body when you are ready to inject. It is normal to see a drop of liquid at the end of the needle. ● Do not twist or bend the needle cap. ● Do not put the needle cap back onto the syringe. ● Do not remove the needle cap from the syringe until you are ready to inject. Important: Throw the needle cap into the sharps disposal container provided. Me dic ina l p rod uc t n o l on ge r a uth ori se d 79 F. Pinch your injection site to create a firm surface. Pinch the skin firmly between your thumb and fingers, creating an area about 2 inch (5 centimetres) wide. Important: Keep the skin pinched while injecting. Step 3: Inject G. Hold the pinch. With the needle cap off, insert the syringe into your skin at 45 to 90 degrees. Do not place your finger on the plunger rod while inserting the needle. H. Using slow and constant pressure, push the plunger rod all the way down until it stops moving. I. When done, release your thumb, and gently lift the syringe off of your skin. Me dic ina l p rod uc t n o l on ge r a uth ori se d 80 Step 4: Finish J. Discard the used syringe and the needle cap. ● Do not reuse the used syringe. ● Do not use any medicine that is left in the used syringe. ● Put the used SOLYMBIC syringe in a sharps disposal container immediately after use. Do not throw away (dispose of) the syringe in your household waste. ● Talk with your doctor or pharmacist about proper disposal. There may be local guidelines for disposal. ● Do not recycle the syringe or sharps disposal container or throw them into the household waste. Important: Always keep the sharps disposal container out of the sight and reach of children. K. Examine the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply a plaster if needed. Me dic ina l p rod uc t n o l on ge r a uth ori se d 81 Package leaflet: Information for the user SOLYMBIC 40 mg solution for injection in a pre-filled pen adalimumab This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - Your doctor will also give you a Patient Alert Card, which contains important safety information that you need to be aware of before you are given SOLYMBIC and during treatment with SOLYMBIC. Keep this Patient Alert Card with you. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4). What is in this leaflet 1. What SOLYMBIC is and what it is used for 2. What you need to know before you use SOLYMBIC 3. How to use SOLYMBIC 4. Possible side effects 5. How to store SOLYMBIC 6. Contents of the pack and other information 1. What SOLYMBIC is and what it is used for SOLYMBIC contains the active substance adalimumab, a selective immuno suppressive agent. SOLYMBIC is intended for treatment of rheumatoid arthritis, enthesitis-related arthritis in children 6 to 17 years, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, paediatric psoriasis (patients weighing either 23 to 28 kg or 47 kg and greater), Crohn’s disease in adults and children, ulcerative colitis and non-infectious uveitis affecting the back of the eye. It is a medicine that decreases the inflammation process of these diseases. The active ingredient, adalimumab, is a human monoclonal antibody produced by cultured cells. Monoclonal antibodies are proteins that recognise and bind to other unique proteins. Adalimumab binds to a specific protein (tumour necrosis factor or TNFα), which is present at increased levels in inflammatory diseases such as rheumatoid arthritis, enthesitis-related arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and non-infectious uveitis affecting the back of the eye. Rheumatoid arthritis Rheumatoid arthritis is an inflammatory disease of the joints. SOLYMBIC is used to treat rheumatoid arthritis in adults. If you have moderate to severe active rheumatoid arthritis, you may first be given other disease-modifying medicines, such as methotrexate. Me dic ina l p rod uc t n o l on ge r a uth ori se d 82 If you do not respond well enough to these medicines, you will be given SOLYMBIC to treat your rheumatoid arthritis. SOLYMBIC can also be used to treat severe, active and progressive rheumatoid arthritis without previous methotrexate treatment. SOLYMBIC slows down the damage to the cartilage and bone of the joints caused by the disease and to improve physical function. Usually, SOLYMBIC is used with methotrexate. If your doctor determines that methotrexate is inappropriate, SOLYMBIC can be given alone. Enthesitis-related arthritis Enthesitis-related arthritis is an inflammatory disease of the joints. SOLYMBIC is used to treat enthesitis-related arthritis in children and adolescents aged 6 to 17 years. You may first be given other disease-modifying medicines, such as methotrexate. If you do not respond well enough to these medicines, you will be given SOLYMBIC to treat your enthesitis-related arthritis. Ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis Ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, are inflammatory diseases of the spine. SOLYMBIC is used to treat ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis in adults. If you have ankylosing spondylitis or axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, you will first be given other medicines. If you do not respond well enough to these medicines, you will be given SOLYMBIC to reduce the signs and symptoms of your disease. Psoriatic arthritis Psoriatic arthritis is an inflammation of the joints associated with psoriasis. SOLYMBIC is used to treat psoriatic arthritis in adults. SOLYMBIC slows down the damage to the cartilage and bone of the joints caused by the disease and to improve physical function. Plaque psoriasis in adults and children Plaque psoriasis is a skin condition that causes red, flaky, crusty patches of skin covered with silvery scales. Plaque psoriasis can also affect the nails, causing them to crumble, become thickened and lift away from the nail bed which can be painful. Psoriasis is believed to be caused by a problem with the body’s immune system that leads to an increased production of skin cells. SOLYMBIC is used to treat moderate to severe plaque psoriasis in adults. SOLYMBIC is also used to treat severe plaque psoriasis in children and adolescents weighing either 23 to 28 kg or 47 kg or greater for whom topical therapy and phototherapies have either not worked very well or are not suitable. Hidradenitis suppurativa Hidradenitis suppurativa (sometimes called acne inversa) is a chronic and often painful inflammatory skin disease. Symptoms may include tender nodules (lumps) and abscesses (boils) that may leak pus. Me dic ina l p rod uc t n o l on ge r a uth ori se d 83 It most commonly affects specific areas of the skin, such as under the breasts, the armpits, inner thighs, groin and buttocks. Scarring may also occur in affected areas. SOLYMBIC is used to treat hidradenitis suppurativa in adults. SOLYMBIC can reduce the number of nodules and abscesses you have, and the pain that is often associated with the disease. Crohn’s disease in adults and children Crohn’s disease is an inflammatory disease of the digestive tract. SOLYMBIC is used to treat Crohn’s disease in adults and children aged 6 to 17 years. If you have Crohn’s disease you will first be given other medicines. If you do not respond well enough to these medicines, you will be given SOLYMBIC to reduce the signs and symptoms of your Crohn’s disease. Ulcerative colitis Ulcerative colitis is an inflammatory disease of the bowel. SOLYMBIC is used to treat ulcerative colitis in adults. If you have ulcerative colitis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given SOLYMBIC to reduce the signs and symptoms of your disease. Non-infectious uveitis affecting the back of the eye Non-infectious uveitis is an inflammatory disease affecting certain parts of the eye. SOLYMBIC is used to treat adults with non-infectious uveitis with inflammation affecting the back of the eye. This inflammation leads to a decrease of vision and/or the presence of floaters in the eye (black dots or wispy lines that move across the field of vision). SOLYMBIC works by reducing this inflammation. 2. What you need to know before you use SOLYMBIC Do not use SOLYMBIC: - if you are allergic to adalimumab or any of the other ingredients of this medicine (listed in section 6). - if you have a severe infection, including active tuberculosis (see “Warnings and precautions”). It is important that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, feeling tired, dental problems. - if you have moderate or severe heart failure. It is important to tell your doctor if you have had or have a serious heart condition (see “Warnings and precautions”). Warnings and precautions Talk to your doctor or pharmacist before using SOLYMBIC: - If you experience allergic reactions with symptoms such as chest tightness, wheezing, dizziness, swelling or rash do not inject more SOLYMBIC and contact your doctor immediately since, in rare cases, these reactions can be life threatening. - If you have an infection, including long-term or localised infection (for example, leg ulcer) consult your doctor before starting SOLYMBIC. If you are unsure, please contact your doctor. - You might get infections more easily while you are receiving SOLYMBIC treatment. This risk may increase if your lung function is impaired. These infections may be serious and include tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other opportunistic infections and sepsis that may, in rare cases, be life-threatening. It is important to tell your Me dic ina l p rod uc t n o l on ge r a uth ori se d 84 doctor if you get symptoms such as fever, wounds, feeling tired or dental problems. Your doctor may recommend temporary discontinuation of SOLYMBIC. - As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor will check you for signs and symptoms of tuberculosis before starting SOLYMBIC. This will include a thorough medical evaluation including your medical history and appropriate screening tests (for example chest x-ray and a tuberculin test). The conduct and results of these tests should be recorded on your Patient Alert Card. It is very important that you tell your doctor if you have ever had tuberculosis, or if you have been in close contact with someone who has had tuberculosis. Tuberculosis can develop during therapy even if you have received preventative treatment for tuberculosis. If symptoms of tuberculosis (persistent cough, weight loss, listlessness, mild fever), or any other infection appear during or after therapy, tell your doctor immediately. - Advise your doctor if you reside or travel in regions where fungal infections such as histoplasmosis coccidioidomycosis or blastomycosis are endemic. - Advise your doctor if you have a history of recurrent infections or other conditions that increase the risk of infections. - Advise your doctor if you are a carrier of the hepatitis B virus (HBV), if you have active HBV or if you think you might be at risk of contracting HBV. Your doctor should test you for HBV. SOLYMBIC can cause reactivation of HBV in people who carry this virus. In some rare cases, especially if you are taking other medicines that suppress the immune system, reactivation of HBV can be life-threatening. - If you are over 65 years you may be more susceptible to infections while taking SOLYMBIC. You and your doctor should pay special attention to signs of infection while you are being treated with SOLYMBIC. It is important to tell your doctor if you get symptoms of infections, such as fever, wounds, feeling tired or dental problems. - If you are about to undergo surgery or dental procedures please inform your doctor that you are taking SOLYMBIC. Your doctor may recommend temporary discontinuation of SOLYMBIC. - If you have or develop demyelinating disease such as multiple sclerosis, your doctor will decide if you should receive or continue to receive SOLYMBIC. Tell your doctor immediately if you experience symptoms like changes in your vision, weakness in your arms or legs or numbness or tingling in any part of your body. - Certain vaccines may cause infections and should not be given while receiving SOLYMBIC. Please check with your doctor before you receive any vaccines. It is recommended that children, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating SOLYMBIC therapy. If you received SOLYMBIC while you were pregnant, your baby may be at higher risk for getting such an infection for up to approximately five months after the last dose you received during pregnancy. It is important that you tell your baby's doctors and other health care professionals about your SOLYMBIC use during your pregnancy so they can decide when your baby should receive any vaccine. - If you have mild heart failure and you are being treated with SOLYMBIC, your heart failure status must be closely monitored by your doctor. It is important to tell your doctor if you have had or have a serious heart condition. If you develop new or worsening symptoms of heart failure (e.g. shortness of breath, or swelling of your feet), you must contact your doctor immediately. - In some patients the body may fail to produce enough of the blood cells that help your body fight infections or help you to stop bleeding. If you develop a fever that does not go away, Me dic ina l p rod uc t n o l on ge r a uth ori se d 85 bruise or bleed very easily or look very pale, call your doctor right away. Your doctor may decide to stop treatment. - There have been very rare cases of certain kinds of cancer in children and adult patients taking adalimumab or other TNF blockers. People with more serious rheumatoid arthritis that have had the disease for a long time may have a higher than average risk of getting lymphoma (a type of cancer that affects the lymph system), and leukaemia (a type of cancer that affects the blood and bone marrow). If you take SOLYMBIC the risk of getting lymphoma, leukaemia, or other cancers may increase. On rare occasions, a specific and severe type of lymphoma has been observed in some patients taking adalimumab. Some of those patients were also treated with azathioprine or 6-mercaptopurine. Tell your doctor if you are taking azathioprine or 6- mercaptopurine with SOLYMBIC. In addition, cases of non-melanoma skin cancer have been observed in patients taking adalimumab. If new skin lesions appear during or after therapy or if existing lesions change appearance, tell your doctor. - There have been cases of cancers other than lymphoma in patients with a specific type of lung disease called Chronic Obstructive Pulmonary Disease (COPD) treated with another TNF blocker. If you have COPD, or are a heavy smoker, you should discuss with your doctor whether treatment with a TNF blocker is appropriate for you. The needle cover of the pre-filled pen is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. In order to improve the traceability of this medicine, your doctor or pharmacist should record the tradename and the lot number of the product you have been given in your patient file. You may also wish to make a note of these details in case you are asked for this information in the future. Children and adolescents - Vaccinations: if possible children should be up to date with all vaccinations before using SOLYMBIC. - Do not use the 40 mg pre-filled pen if doses other than 40 mg are recommended. Other medicines and SOLYMBIC Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. SOLYMBIC can be taken together with methotrexate or certain disease-modifying anti-rheumatic agents (sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), steroids or pain medications including non-steroidal anti-inflammatory drugs (NSAIDs). You should not take SOLYMBIC with medicines containing the active substance, anakinra or abatacept. If you have questions, please ask your doctor. Pregnancy and breast-feeding The effects of SOLYMBIC in pregnant women are not known and so the use of SOLYMBIC in pregnant women is not recommended. You are advised to avoid becoming pregnant and must use adequate contraception while using SOLYMBIC and for at least 5 months after the last SOLYMBIC treatment. If you become pregnant, you should consult your doctor. It is not known whether SOLYMBIC passes into breast milk. If you are a breast-feeding mother, you should stop breast-feeding during SOLYMBIC treatment and for at least 5 months after the last SOLYMBIC treatment. If you received SOLYMBIC during your Me dic ina l p rod uc t n o l on ge r a uth ori se d 86 pregnancy, your baby may have a higher risk for getting an infection. It is important that you tell your baby’s doctors and other health care professionals about your SOLYMBIC use during your pregnancy before the baby receives any vaccine (for more information see section on vaccination). If you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Driving and using machines SOLYMBIC may have a minor influence on your ability to drive, cycle or use machines. Room spinning sensation and vision disturbances may occur after taking SOLYMBIC. SOLYMBIC contains sodium This medicine contains less than 1 mmol of sodium (23 mg) per 0.8 mL dose, i.e. essentially ‘sodium- free’. 3. How to use SOLYMBIC Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis without radiographic evidence of ankylosing spondylitis SOLYMBIC is injected under the skin (subcutaneous use). The usual dose for adults with rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, and for patients with psoriatic arthritis is 40 mg given every other week as a single dose. In rheumatoid arthritis, methotrexate is continued while using SOLYMBIC. If your doctor determines that methotrexate is inappropriate, SOLYMBIC can be given alone. If you have rheumatoid arthritis and you do not receive methotrexate with your SOLYMBIC therapy, your doctor may decide to give 40 mg every week. Children with enthesitis-related arthritis The recommended dose of SOLYMBIC for patients with enthesitis-related arthritis, aged 6 to 17 years depends on the height and weight of the child. Your child’s doctor will tell you the correct dose to use. Adults with psoriasis The usual dose for adults with psoriasis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. You should continue to inject SOLYMBIC for as long as your doctor has told you. Depending on your response, your doctor may increase the dose frequency to 40 mg every week. Children or adolescents with plaque psoriasis The recommended dose of SOLYMBIC for patients aged 4 to 17 years with plaque psoriasis depends on the weight of your child. SOLYMBIC should only be used in patients weighing either 23 to 28 kg or 47 kg and greater. Your child’s doctor will tell you the correct dose to use. Adults with hidradenitis suppurativa Me dic ina l p rod uc t n o l on ge r a uth ori se d 87 The usual dose regimen for hidradenitis suppurativa is an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by an 80 mg dose (as two 40 mg injections on the same day) two weeks later. After two further weeks, continue with a dose of 40 mg every week. It is recommended that you use an antiseptic wash daily on the affected areas. Adults with Crohn’s disease The usual dose regimen for Crohn’s disease is 80 mg initially followed by 40 mg every other week two weeks later. If a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later, and thereafter as 40 mg every other week. Depending on your response, your doctor may increase the dose frequency to 40 mg every week. Children or adolescents with Crohn's disease Children or adolescents weighing less than 40 kg: The usual dose regimen is 40 mg initially followed by 20 mg two weeks later. If a faster response is required, your doctor may prescribe an initial dose of 80 mg (as two 40 mg injections in 1 day) followed by 40 mg two weeks later. Thereafter, the usual dose is 20 mg every other week. Depending on your response, your doctor may increase the dose frequency to 20 mg every week. Do not use the 40 mg pre-filled pen for the 20 mg dose in children or adolescent weighing less than 40 kg with Crohn’s disease. The 20 mg solution for injection in pre-filled syringe can be used for the 20 mg dose. Children or adolescents weighing 40 kg or more: The usual dose regimen is 80 mg initially followed by 40 mg two weeks later. If a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in 1 day or as two 40 mg injections per day for 2 consecutive days) followed by 80 mg two weeks later. Thereafter, the usual dose is 40 mg every other week. Depending on your response, your doctor may increase the dose frequency to 40 mg every week. Adults with ulcerative colitis The usual SOLYMBIC dose for adults with ulcerative colitis is 160 mg initially (dose can be administered as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days) followed by 80 mg two weeks later, then 40 mg every other week. Depending on your response, your doctor may increase the dose to 40 mg every week. Adults with non-infectious uveitis The usual dose for adults with non-infectious uveitis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. You should continue to inject SOLYMBIC for as long as your doctor has told you. In non-infectious uveitis, corticosteroids or other medicines that influence the immune system may be continued while using SOLYMBIC. SOLYMBIC can also be given alone. Method and route of administration SOLYMBIC is administered by injection under the skin (subcutaneous injection). Me dic ina l p rod uc t n o l on ge r a uth ori se d 88 If you use more SOLYMBIC than you should If you accidentally inject SOLYMBIC more frequently than told to by your doctor or pharmacist, you should call your doctor or pharmacist and tell him/her that you have taken more. Always take the outer carton of this medicine with you, even if it is empty. If you forget to use SOLYMBIC If you forget to give yourself an injection, you should inject it as soon as you remember. Then take your next dose as you would have on your originally scheduled day, had you not forgotten a dose. If you stop using SOLYMBIC The decision to stop using SOLYMBIC should be discussed with your doctor. Your symptoms may return upon discontinuation. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects are mild to moderate. However, some may be serious and require treatment. Side effects may occur at least up to 4 months after the last SOLYMBIC injection. Tell your doctor immediately if you notice any of the following: • severe rash, hives or other signs of allergic reaction; • swollen face, hands, feet; • trouble breathing, swallowing; • shortness of breath with exertion or upon lying down or swelling of the feet. Tell your doctor as soon as possible if you notice any of the following: • signs of infection such as fever, feeling sick, wounds, dental problems, burning on urination; • feeling weak or tired; • coughing; • tingling; • numbness; • double vision; • arm or leg weakness; • a bump or open sore that doesn't heal; • signs and symptoms suggestive of blood disorders such as persistent fever, bruising, bleeding, paleness. The symptoms described above can be signs of the below listed side effects, which have been observed with adalimumab: Very common side effects (may affect more than 1 in 10 people): • injection site reactions (including pain, swelling, redness or itching); • respiratory tract infections (including cold, runny nose, sinus infection, pneumonia); • headache; • abdominal pain; • nausea and vomiting; • rash; • musculoskeletal pain. Me dic ina l p rod uc t n o l on ge r a uth ori se d 89 Common side effects (may affect up to 1 in 10 people): • serious infections (including blood poisoning and influenza); • skin infections (including cellulitis and shingles); • ear infections; • oral infections (including tooth infections and cold sores); • reproductive tract infections; • urinary tract infection; • fungal infections; • joint infections; • benign tumours; • skin cancer; • allergic reactions (including seasonal allergy); • dehydration; • mood swings (including depression); • anxiety; • difficulty sleeping; • sensation disorders such as tingling, prickling or numbness; • migraine; • nerve root compression (including low back pain and leg pain); • vision disturbances; • eye inflammation; • inflammation of the eye lid and eye swelling; • vertigo; • sensation of heart beating rapidly; • high blood pressure; • flushing; • haematoma; • cough; • asthma; • shortness of breath; • gastrointestinal bleeding; • dyspepsia (indigestion, bloating, heart burn); • acid reflux disease; • sicca syndrome (including dry eyes and dry mouth); • itching; • itchy rash; • bruising; • inflammation of the skin (such as eczema); • breaking of finger nails and toe nails; • increased sweating; • hair loss; • new onset or worsening of psoriasis; • muscle spasms; • blood in urine; • kidney problems; • chest pain; • oedema; • fever; • reduction in blood platelets which increases risk of bleeding or bruising; • impaired healing. Uncommon side effects (may affect up to 1 in 100 people): • opportunistic infections (which include tuberculosis and other infections that occur when resistance to disease is lowered); • neurological infections (including viral meningitis); • eye infections; Me dic ina l p rod uc t n o l on ge r a uth ori se d 90 • bacterial infections; • diverticulitis (inflammation and infection of the large intestine); • cancer; • cancer that affects the lymph system; • melanoma; • immune disorders that could affect the lungs, skin and lymph nodes (most commonly presenting as sarcoidosis); • vasculitis (inflammation of blood vessels); • tremor; • neuropathy; • stroke; • double vision; • hearing loss, buzzing; • sensation of heart beating irregularly such as skipped beats; • heart problems that can cause shortness of breath or ankle swelling; • heart attack; • a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; • lung diseases causing shortness of breath (including inflammation); • pulmonary embolism (blockage in an artery of the lung); • pleural effusion (abnormal collection of fluid in the pleural space); • inflammation of the pancreas which causes severe pain in the abdomen and back; • difficulty in swallowing; • facial oedema; • gallbladder inflammation, gallbladder stones; • fatty liver; • night sweats; • scar; • abnormal muscle breakdown; • systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other organ systems); • sleep interruptions; • impotence; • inflammations. Rare side effects (may affect up to 1 in 1,000 people): • leukaemia (cancer affecting the blood and bone marrow); • severe allergic reaction with shock; • multiple sclerosis; • nerve disorders (such as eye nerve inflammation and Guillain-Barré syndrome that may cause muscle weakness, abnormal sensations, tingling in the arms and upper body); • heart stops pumping; • pulmonary fibrosis (scarring of the lung); • intestinal perforation; • hepatitis; • reactivation of hepatitis B; • autoimmune hepatitis (inflammation of the liver caused by the body's own immune system); • cutaneous vasculitis (inflammation of blood vessels in the skin); • Stevens-Johnson syndrome (early symptoms include malaise, fever, headache and rash); • facial oedema associated with allergic reactions; • erythema multiforme (inflammatory skin rash); • lupus-like syndrome. Not known (frequency cannot be estimated from available data): • hepatosplenic T-cell lymphoma (a rare blood cancer that is often fatal); • Merkel cell carcinoma (a type of skin cancer); • liver failure; Me dic ina l p rod uc t n o l on ge r a uth ori se d 91 • worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle weakness). Some side effects observed with adalimumab may not have symptoms and may only be discovered through blood tests. These include: Very common side effects (may affect more than 1 in 10 people): • low blood measurements for white blood cells; • low blood measurements for red blood cells; • increased lipids in the blood; • elevated liver enzymes. Common side effects (may affect up to 1 in 10 people): • high blood measurements for white blood cells; • low blood measurements for platelets; • increased uric acid in the blood; • abnormal blood measurements for sodium; • low blood measurements for calcium; • low blood measurements for phosphate; • high blood sugar; • high blood measurements for lactate dehydrogenase; • autoantibodies present in the blood. Rare side effects (may affect up to 1 in 1,000 people): • low blood measurements for white blood cells, red blood cells and platelet count. Not known (frequency cannot be estimated from available data): • liver failure. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store SOLYMBIC Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2C – 8C). Do not freeze. Store in the original carton in order to protect from light. A single SOLYMBIC pre-filled pen may be stored at temperatures up to a maximum of 25°C for a period of up to 14 days. The pre-filled pen must be protected from light, and discarded if not used within the 14-day period. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 92 6. Contents of the pack and other information What SOLYMBIC contains - The active substance is adalimumab. Each pre-filled pen contains 40 mg of adalimumab in 0.8 mL of solution. - The other ingredients are glacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. What SOLYMBIC looks like and contents of the pack SOLYMBIC is a clear and colourless to slightly yellow solution. Each pack contains 1, 2, 4, or 6 single use SureClick pre-filled pens. Marketing Authorisation Holder and Manufacturer Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda The Netherlands Marketing Authorisation Holder Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda The Netherlands Manufacturer Amgen Technology Ireland UC Pottery Road Dun Laoghaire Co Dublin Ireland Manufacturer Amgen NV Telecomlaan 5-7 1831 Diegem Belgium For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien s.a. Amgen n.v. Tel/Tél: +32 (0)2 7752711 Lietuva Amgen Switzerland AG Vilniaus filialas Tel: +370 5 219 7474 България Амджен България ЕООД Тел.: +359 (0)2 424 7440 Luxembourg/Luxemburg s.a. Amgen Belgique/Belgien Tel/Tél: +32 (0)2 7752711 Me dic ina l p rod uc t n o l on ge r a uth ori se d 93 Česká republika Amgen s.r.o. Tel: +420 221 773 500 Magyarország Amgen Kft. Tel.: +36 1 35 44 700 Danmark Amgen, filial af Amgen AB, Sverige Tlf: +45 39617500 Malta Amgen B.V. The Netherlands Tel: +31 (0)76 5732500 Deutschland AMGEN GmbH Tel.: +49 89 1490960 Nederland Amgen B.V. Tel: +31 (0)76 5732500 Eesti Amgen Switzerland AG Vilniaus filialas Tel: +372 586 09553 Norge Amgen AB Tel: +47 23308000 Ελλάδα Amgen Ελλάς Φαρμακευτικά Ε.Π.Ε. Τηλ.: +30 210 3447000 Österreich Amgen GmbH Tel: +43 (0)1 50 217 España Amgen S.A. Tel: +34 93 600 18 60 Polska Amgen Biotechnologia Sp. z o.o. Tel.: +48 22 581 3000 France Amgen S.A.S. Tél: +33 (0)9 69 363 363 Portugal Amgen Biofarmacêutica, Lda. Tel: +351 21 4220550 Hrvatska Amgen d.o.o. Tel: +385 (0)1 562 57 20 România Amgen România SRL Tel: +4021 527 3000 Ireland Amgen Limited United Kingdom Tel: +44 (0)1223 420305 Slovenija AMGEN zdravila d.o.o. Tel: +386 (0)1 585 1767 Ísland Vistor hf. Sími: +354 535 7000 Slovenská republika Amgen Slovakia s.r.o. Tel: +421 2 321 114 49 Italia Amgen S.r.l. Tel: +39 02 6241121 Suomi/Finland Amgen AB, sivuliike Suomessa/Amgen AB, filial i Finland Puh/Tel: +358 (0)9 54900500 Kύπρος C.A. Papaellinas Ltd Τηλ.: +357 22741 741 Sverige Amgen AB Tel: +46 (0)8 6951100 Latvija Amgen Switzerland AG Rīgas filiāle Tel: +371 257 25888 United Kingdom Amgen Limited Tel: +44 (0)1223 420305 This leaflet was last revised in Me dic ina l p rod uc t n o l on ge r a uth ori se d 94 Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. --------------------------------------------------------------------------------------------------------------------------- Instructions for use: SOLYMBIC single use SureClick pre-filled pen For subcutaneous use Guide to parts Before use After use Blue start button Expiration date Window Medicine Yellow cap on Expiration date Yellow window (injection complete) Yellow safety guard Yellow cap off Important: Needle is inside Me dic ina l p rod uc t n o l on ge r a uth ori se d http://www.ema.europa.eu/ 95 Important Before you use a SOLYMBIC pre-filled pen, read this important information: Using your SOLYMBIC pre-filled pen ● It is important that you do not try to give the injection unless you or your caregiver has received training. ● Do not use a SOLYMBIC pre-filled pen if it has been dropped on a hard surface. Part of the SOLYMBIC pre-filled pen may be broken even if you cannot see the break. Use a new SOLYMBIC pre-filled pen. ● The needle cover of the SOLYMBIC pre-filled pen is made from dry natural rubber, which contains latex. Tell your healthcare provider if you are allergic to latex. Step 1: Prepare A. Remove one SOLYMBIC pre-filled pen from the package. Carefully lift the pre-filled pen straight up out of the box. Put the original package with any unused pre-filled pens back in the refrigerator. For a more comfortable injection, leave the pre-filled pen at room temperature for 15 to 30 minutes before injecting. ● Do not put the pre-filled pen back in the refrigerator once it has reached room temperature. ● Do not try to warm the pre-filled pen by using a heat source such as hot water or microwave. ● Do not shake the pre-filled pen. ● Do not remove the yellow cap from the pre-filled pen yet. B. Inspect the SOLYMBIC pre-filled pen. Yellow cap on Window Medicine Make sure the medicine in the window is clear and colourless to slightly yellow. ● Do not use the pre-filled pen if: - The medicine is cloudy or discoloured, or contains flakes or particles. - Any part appears cracked or broken. - The pre-filled pen has been dropped on a hard surface. - The yellow cap is missing or not securely attached. - The expiration date printed on the label has passed. In all cases, use a new pre-filled pen. Me dic ina l p rod uc t n o l on ge r a uth ori se d 96 C. Gather all materials needed for your injection. Wash your hands thoroughly with soap and water. On a clean, well-lit work surface, place a new, pre-filled pen. You will also need these additional items, as they are not included in the carton: ● Alcohol wipes ● Cotton ball or gauze pad ● Plaster ● Sharps disposal container D. Prepare and clean your injection site. Belly Thigh You can use: ● Your thigh ● Belly, except for a 2-inch (5 centimetre) area right around your belly button Clean your injection site with an alcohol wipe. Let your skin dry. ● Do not touch this area again before injecting. ● If you want to use the same injection site, make sure it is not the same spot on the injection site you used for a previous injection. - Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. ● If you have psoriasis, you should avoid injecting directly into raised, thick, red, or scaly skin patch or lesion. Me dic ina l p rod uc t n o l on ge r a uth ori se d 97 Step 2: Get ready E. Pull the yellow cap straight off when you are ready to inject. It is normal to see a drop of liquid at the end of the needle or yellow safety guard. ● Do not twist or bend the yellow cap. ● Do not put the yellow cap back onto the pre-filled pen. ● Do not remove the yellow cap from the pre-filled pen until you are ready to inject. F. Stretch or pinch your injection site to create a firm surface. Stretch method Stretch the skin firmly by moving your thumb and fingers in opposite directions, creating an area about 2 inches (5 centimetres) wide. OR Pinch method Pinch the skin firmly between your thumb and fingers, creating an area about 2 inches (5 centimetres) wide. Important: Keep the skin stretched or pinched while injecting. Step 3: Inject Me dic ina l p rod uc t n o l on ge r a uth ori se d 98 G. Hold the stretch or pinch. With the yellow cap off, place the pre-filled pen on your skin at 90 degrees. Important: Do not touch the blue start button yet. H. Firmly push the pre-filled pen down onto the skin until it stops moving. Important: You must push all the way down but do not touch the blue start button until you are ready to inject. I. When you are ready to inject, press the blue start button. “Click” Me dic ina l p rod uc t n o l on ge r a uth ori se d 99 J. Keep pushing down on your skin. Your injection could take about 10 seconds. ~10s The window turns yellow When the injection is done Note: After you remove the pre-filled pen from your skin, the needle will be automatically covered. Important: When you remove the pre-filled pen, if the window has not turned yellow, or if it looks like the medicine is still injecting, this means you have not received a full dose. Call your doctor immediately. “Click” Me dic ina l p rod uc t n o l on ge r a uth ori se d 100 Step 4: Finish K. Discard the used pre-filled pen and the yellow cap. ● Put the used pre-filled pen in a sharps disposal container immediately after use. Do not throw away (dispose of) the pre-filled pen in your household waste. ● Talk with your doctor or pharmacist about proper disposal. There may be local guidelines for disposal. ● Do not reuse the pre-filled pen. ● Do not recycle the pre-filled pen or sharps disposal container or throw them into the household waste. Important: Always keep the sharps disposal container out of the sight and reach of children. L. Examine the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply a plaster if needed. Me dic ina l p rod uc t n o l on ge r a uth ori se d SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '2. what you need to know before you use solymbic', 'Section_Content': 'do not use solymbic: - if you are allergic to adalimumab or any of the other ingredients of this medicine (listed in section 6). - if you have a severe infection, including active tuberculosis (see "warnings and precautions"). it is important that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, feeling tired, dental problems. - if you have moderate or severe heart failure. it is important to tell your doctor if you have had or have a serious heart condition (see "warnings and precautions"). warnings and precautions talk to your doctor or pharmacist before using solymbic: - if you experience allergic reactions with symptoms such as chest tightness, wheezing, dizziness, swelling or rash do not inject more solymbic and contact your doctor immediately since, in rare cases, these reactions can be life threatening. - if you have an infection, including long-term or localised infection (for example, leg ulcer) consult your doctor before starting solymbic. if you are unsure, please contact your doctor. - you might get infections more easily while you are receiving solymbic treatment. this risk may increase if your lung function is impaired. these infections may be serious and include tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other opportunistic infections and sepsis that may, in rare cases, be life-threatening. it is important to tell your 65 doctor if you get symptoms such as fever, wounds, feeling tired or dental problems. your doctor may recommend temporary discontinuation of solymbic. - as cases of tuberculosis have been reported in patients treated with adalimumab, your doctor will check you for signs and symptoms of tuberculosis before starting solymbic. this will include a thorough medical evaluation including your medical history and appropriate screening tests (for example chest x-ray and a tuberculin test). the conduct and results of these tests should be recorded on your patient alert card. it is very important that you tell your doctor if you have ever had tuberculosis, or if you have been in close contact with someone who has had tuberculosis. tuberculosis can develop during therapy even if you have received preventative treatment for tuberculosis. if symptoms of tuberculosis (persistent cough, weight loss, listlessness, mild fever), or any other infection appear during or after therapy, tell your doctor immediately. - advise your doctor if you reside or travel in regions where fungal infections such as histoplasmosis coccidioidomycosis or blastomycosis are endemic. - advise your doctor if you have a history of recurrent infections or other conditions that increase the risk of infections. - advise your doctor if you are a carrier of the hepatitis b virus (hbv), if you have active hbv or if you think you might be at risk of contracting hbv. your doctor should test you for hbv. solymbic can cause reactivation of hbv in people who carry this virus. in some rare cases, especially if you are taking other medicines that suppress the immune system, reactivation of hbv can be life-threatening. - if you are over 65 years you may be more susceptible to infections while taking solymbic. you and your doctor should pay special attention to signs of infection while you are being treated with solymbic. it is important to tell your doctor if you get symptoms of infections, such as fever, wounds, feeling tired or dental problems. - if you are about to undergo surgery or dental procedures please inform your doctor that you are taking solymbic. your doctor may recommend temporary discontinuation of solymbic. - if you have or develop demyelinating disease such as multiple sclerosis, your doctor will decide if you should receive or continue to receive solymbic. tell your doctor immediately if you experience symptoms like changes in your vision, weakness in your arms or legs or numbness or tingling in any part of your body. - certain vaccines may cause infections and should not be given while receiving solymbic. please check with your doctor before you receive any vaccines. it is recommended that children, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating solymbic therapy. if you received solymbic while you were pregnant, your baby may be at higher risk for getting such an infection for up to approximately five months after the last dose you received during pregnancy. it is important that you tell your baby\'s doctors and other health care professionals about your solymbic use during your pregnancy so they can decide when your baby should receive any vaccine. - if you have mild heart failure and you are being treated with solymbic, your heart failure status must be closely monitored by your doctor. it is important to tell your doctor if you have had or have a serious heart condition. if you develop new or worsening symptoms of heart failure (e.g. shortness of breath, or swelling of your feet), you must contact your doctor immediately. - in some patients the body may fail to produce enough of the blood cells that help your body fight infections or help you to stop bleeding. if you develop a fever that does not go away, 66 bruise or bleed very easily or look very pale, call your doctor right away. your doctor may decide to stop treatment. - there have been very rare cases of certain kinds of cancer in children and adult patients taking adalimumab or other tnf blockers. people with more serious rheumatoid arthritis that have had the disease for a long time may have a higher than average risk of getting lymphoma (a type of cancer that affects the lymph system), and leukaemia (a type of cancer that affects the blood and bone marrow). if you take solymbic the risk of getting lymphoma, leukaemia, or other cancers may increase. on rare occasions, a specific and severe type of lymphoma has been observed in some patients taking adalimumab. some of those patients were also treated with azathioprine or 6-mercaptopurine. tell your doctor if you are taking azathioprine or 6-mercaptopurine with solymbic. in addition, cases of non-melanoma skin cancer have been observed in patients taking adalimumab. if new skin lesions appear during or after therapy or if existing lesions change appearance, tell your doctor. - there have been cases of cancers other than lymphoma in patients with a specific type of lung disease called chronic obstructive pulmonary disease (copd) treated with another tnf blocker. if you have copd, or are a heavy smoker, you should discuss with your doctor whether treatment with a tnf blocker is appropriate for you. the needle cover of the pre-filled syringe is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. in order to improve the traceability of this medicine, your doctor or pharmacist should record the tradename and the lot number of the product you have been given in your patient file. you may also wish to make a note of these details in case you are asked for this information in the future. children and adolescents - vaccinations: if possible children should be up to date with all vaccinations before using solymbic. - do not use the 20 mg or 40 mg pre-filled syringe if doses other than 20 mg or 40 mg are recommended. other medicines and solymbic tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. solymbic can be taken together with methotrexate or certain disease-modifying anti-rheumatic agents (sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), steroids or pain medications including non-steroidal anti-inflammatory drugs (nsaids). you should not take solymbic with medicines containing the active substance, anakinra or abatacept. if you have questions, please ask your doctor. pregnancy and breast-feeding the effects of solymbic in pregnant women are not known and so the use of solymbic in pregnant women is not recommended. you are advised to avoid becoming pregnant and must use adequate contraception while using solymbic and for at least 5 months after the last solymbic treatment. if you become pregnant, you should consult your doctor. it is not known whether solymbic passes into breast milk. if you are a breast-feeding mother, you should stop breast-feeding during solymbic treatment and for at least 5 months after the last solymbic treatment. if you received solymbic during your 67 pregnancy, your baby may have a higher risk for getting an infection. it is important that you tell your baby\'s doctors and other health care professionals about your solymbic use during your pregnancy before the baby receives any vaccine (for more information see section on vaccination). if you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. driving and using machines solymbic may have a minor influence on your ability to drive, cycle or use machines. room spinning sensation and vision disturbances may occur after taking solymbic. solymbic contains sodium this medicine contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, i.e. essentially \'sodium- free\'.', 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 34, 'EndOffset': 42}, {'Id': 6, 'BeginOffset': 46, 'EndOffset': 56, 'Score': 0.9796355962753296, 'Text': 'adalimumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 92, 'EndOffset': 105}, {'Text': 'a severe infection', 'Type': 'PROBLEM', 'BeginOffset': 143, 'EndOffset': 161}, {'Text': 'active tuberculosis', 'Type': 'PROBLEM', 'BeginOffset': 173, 'EndOffset': 192}, {'Text': 'symptoms', 'Type': 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{'Title': '3. how to use solymbic', 'Section_Content': "always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis without radiographic evidence of ankylosing spondylitis solymbic is injected under the skin (subcutaneous use). the usual dose for adults with rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, and for patients with psoriatic arthritis is 40 mg given every other week as a single dose. in rheumatoid arthritis, methotrexate is continued while using solymbic. if your doctor determines that methotrexate is inappropriate, solymbic can be given alone. if you have rheumatoid arthritis and you do not receive methotrexate with your solymbic therapy, your doctor may decide to give 40 mg every week. children with enthesitis-related arthritis the recommended dose of solymbic for patients with enthesitis-related arthritis, aged 6 to 17 years depends on the height and weight of the child. your child's doctor will tell you the correct dose to use. adults with psoriasis the usual dose for adults with psoriasis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. you should continue to inject solymbic for as long as your doctor has told you. depending on your response, your doctor may increase the dose frequency to 40 mg every week. children or adolescents with plaque psoriasis the recommended dose of solymbic for patients aged 4 to 17 years with plaque psoriasis depends on the weight of your child. solymbic should only be used in patients weighing either 23 to 28 kg or 47 kg and greater. your child's doctor will tell you the correct dose to use. adults with hidradenitis suppurativa 68 the usual dose regimen for hidradenitis suppurativa is an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by an 80 mg dose (as two 40 mg injections on the same day) two weeks later. after two further weeks, continue with a dose of 40 mg every week. it is recommended that you use an antiseptic wash daily on the affected areas. adults with crohn's disease the usual dose regimen for crohn's disease is 80 mg initially followed by 40 mg every other week two weeks later. if a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later, and thereafter as 40 mg every other week. depending on your response, your doctor may increase the dose frequency to 40 mg every week. children or adolescents with crohn's disease children or adolescents weighing less than 40 kg: the usual dose regimen is 40 mg initially followed by 20 mg two weeks later. if a faster response is required, your doctor may prescribe an initial dose of 80 mg (as two 40 mg injections in 1 day) followed by 40 mg two weeks later. thereafter, the usual dose is 20 mg every other week. depending on your response, your doctor may increase the dose frequency to 20 mg every week. children or adolescents weighing 40 kg or more: the usual dose regimen is 80 mg initially followed by 40 mg two weeks later. if a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in 1 day or as two 40 mg injections per day for 2 consecutive days) followed by 80 mg two weeks later. thereafter, the usual dose is 40 mg every other week. depending on your response, your doctor may increase the dose frequency to 40 mg every week. adults with ulcerative colitis the usual solymbic dose for adults with ulcerative colitis is 160 mg initially (dose can be administered as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days) followed by 80 mg two weeks later, then 40 mg every other week. depending on your response, your doctor may increase the dose to 40 mg every week. adults with non-infectious uveitis the usual dose for adults with non-infectious uveitis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. you should continue to inject solymbic for as long as your doctor has told you. in non-infectious uveitis, corticosteroids or other medicines that influence the immune system may be continued while using solymbic. solymbic can also be given alone. method and route of administration solymbic is administered by injection under the skin (subcutaneous injection). if you use more solymbic than you should 69 if you accidentally inject solymbic more frequently than told to by your doctor or pharmacist, you should call your doctor or pharmacist and tell him/her that you have taken more. always take the outer carton of this medicine with you, even if it is empty. if you forget to use solymbic if you forget to give yourself an injection, you should inject it as soon as you remember. then take your next dose as you would have on your originally scheduled day, had you not forgotten a dose. if you stop using solymbic the decision to stop using solymbic should be discussed with your doctor. your symptoms may return upon discontinuation. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.", 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Id': 26, 'BeginOffset': 146, 'EndOffset': 166, 'Score': 0.88294917345047, 'Text': 'rheumatoid arthritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9669777154922485}]}, {'Id': 27, 'BeginOffset': 168, 'EndOffset': 187, 'Score': 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. most side effects are mild to moderate. however, some may be serious and require treatment. side effects may occur at least up to 4 months after the last solymbic injection. tell your doctor immediately if you notice any of the following: severe rash, hives or other signs of allergic reaction; swollen face, hands, feet; trouble breathing, swallowing; shortness of breath with exertion or upon lying down or swelling of the feet. tell your doctor as soon as possible if you notice any of the following: signs of infection such as fever, feeling sick, wounds, dental problems, burning on urination; feeling weak or tired; coughing; tingling; numbness; double vision; arm or leg weakness; a bump or open sore that doesn't heal; signs and symptoms suggestive of blood disorders such as persistent fever, bruising, bleeding, paleness. the symptoms described above can be signs of the below listed side effects, which have been observed with adalimumab: very common side effects (may affect more than 1 in 10 people): injection site reactions (including pain, swelling, redness or itching); respiratory tract infections (including cold, runny nose, sinus infection, pneumonia); headache; abdominal pain; nausea and vomiting; rash; musculoskeletal pain. common side effects (may affect up to 1 in 10 people): serious infections (including blood poisoning and influenza); skin infections (including cellulitis and shingles); 70 ear infections; oral infections (including tooth infections and cold sores); reproductive tract infections; urinary tract infection; fungal infections; joint infections; benign tumours; skin cancer; allergic reactions (including seasonal allergy); dehydration; mood swings (including depression); anxiety; difficulty sleeping; sensation disorders such as tingling, prickling or numbness; migraine; nerve root compression (including low back pain and leg pain); vision disturbances; eye inflammation; inflammation of the eye lid and eye swelling; vertigo; sensation of heart beating rapidly; high blood pressure; flushing; haematoma; cough; asthma; shortness of breath; gastrointestinal bleeding; dyspepsia (indigestion, bloating, heart burn); acid reflux disease; sicca syndrome (including dry eyes and dry mouth); itching; itchy rash; bruising; inflammation of the skin (such as eczema); breaking of finger nails and toe nails; increased sweating; hair loss; new onset or worsening of psoriasis; muscle spasms; blood in urine; kidney problems; chest pain; oedema; fever; reduction in blood platelets which increases risk of bleeding or bruising; impaired healing. uncommon side effects (may affect up to 1 in 100 people): opportunistic infections (which include tuberculosis and other infections that occur when resistance to disease is lowered); neurological infections (including viral meningitis); eye infections; bacterial infections; diverticulitis (inflammation and infection of the large intestine); cancer; 71 cancer that affects the lymph system; melanoma; immune disorders that could affect the lungs, skin and lymph nodes (most commonly presenting as sarcoidosis); vasculitis (inflammation of blood vessels); tremor; neuropathy; stroke; double vision; hearing loss, buzzing; sensation of heart beating irregularly such as skipped beats; heart problems that can cause shortness of breath or ankle swelling; heart attack; a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; lung diseases causing shortness of breath (including inflammation); pulmonary embolism (blockage in an artery of the lung); pleural effusion (abnormal collection of fluid in the pleural space); inflammation of the pancreas which causes severe pain in the abdomen and back; difficulty in swallowing; facial oedema; gallbladder inflammation, gallbladder stones; fatty liver; night sweats; scar; abnormal muscle breakdown; systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other organ systems); sleep interruptions; impotence; inflammations. rare side effects (may affect up to 1 in 1,000 people): leukaemia (cancer affecting the blood and bone marrow); severe allergic reaction with shock; multiple sclerosis; nerve disorders (such as eye nerve inflammation and guillain-barré syndrome that may cause muscle weakness, abnormal sensations, tingling in the arms and upper body); heart stops pumping; pulmonary fibrosis (scarring of the lung); intestinal perforation; hepatitis; reactivation of hepatitis b; autoimmune hepatitis (inflammation of the liver caused by the body's own immune system); cutaneous vasculitis (inflammation of blood vessels in the skin); stevens-johnson syndrome (early symptoms include malaise, fever, headache and rash); facial oedema associated with allergic reactions; erythema multiforme (inflammatory skin rash); lupus-like syndrome. not known (frequency cannot be estimated from available data): hepatosplenic t-cell lymphoma (a rare blood cancer that is often fatal); merkel cell carcinoma (a type of skin cancer); liver failure; worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle weakness). some side effects observed with adalimumab may not have symptoms and may only be discovered through blood tests. these include: very common side effects (may affect more than 1 in 10 people): low blood measurements for white blood cells; low blood measurements for red blood cells; increased lipids in the blood; elevated liver enzymes. common side effects (may affect up to 1 in 10 people): high blood measurements for white blood cells; low blood measurements for platelets; increased uric acid in the blood; abnormal blood measurements for sodium; low blood measurements for calcium; low blood measurements for phosphate; high blood sugar; high blood measurements for lactate dehydrogenase; autoantibodies present in the blood. rare side effects (may affect up to 1 in 1,000 people): low blood measurements for white blood cells, red blood cells and platelet count. not known (frequency cannot be estimated from available data): liver failure. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 23, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9641301035881042, 'Text': 'side effects', 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'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.7396762371063232, 'RelationshipScore': 0.9716028571128845, 'RelationshipType': 'TEST_VALUE', 'Id': 313, 'BeginOffset': 5430, 'EndOffset': 5433, 'Text': 'low', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'low blood measurements', 'Type': 'PROBLEM', 'BeginOffset': 5476, 'EndOffset': 5498}, {'Id': 318, 'BeginOffset': 5503, 'EndOffset': 5518, 'Score': 0.6171738505363464, 'Text': 'red blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.9885690212249756, 'RelationshipScore': 0.9999873638153076, 'RelationshipType': 'TEST_VALUE', 'Id': 316, 'BeginOffset': 5476, 'EndOffset': 5479, 'Text': 'low', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'increased lipids in the blood', 'Type': 'PROBLEM', 'BeginOffset': 5520, 'EndOffset': 5549}, {'Text': 'elevated liver enzymes', 'Type': 'PROBLEM', 'BeginOffset': 5551, 'EndOffset': 5573}, {'Text': 'common side effects', 'Type': 'PROBLEM', 'BeginOffset': 5575, 'EndOffset': 5594}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 5613, 'EndOffset': 5614}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 5618, 'EndOffset': 5620}, {'Id': 324, 'BeginOffset': 5635, 'EndOffset': 5653, 'Score': 0.9957589507102966, 'Text': 'blood measurements', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.5580159425735474, 'RelationshipScore': 0.9999254941940308, 'RelationshipType': 'TEST_VALUE', 'Id': 323, 'BeginOffset': 5630, 'EndOffset': 5634, 'Text': 'high', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 325, 'BeginOffset': 5658, 'EndOffset': 5675, 'Score': 0.9568458199501038, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'low blood measurements', 'Type': 'PROBLEM', 'BeginOffset': 5677, 'EndOffset': 5699}, {'Id': 328, 'BeginOffset': 5704, 'EndOffset': 5713, 'Score': 0.9093987941741943, 'Text': 'platelets', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.9936157464981079, 'RelationshipScore': 0.9955239295959473, 'RelationshipType': 'TEST_VALUE', 'Id': 326, 'BeginOffset': 5677, 'EndOffset': 5680, 'Text': 'low', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'increased uric acid in the blood', 'Type': 'PROBLEM', 'BeginOffset': 5715, 'EndOffset': 5747}, {'Text': 'abnormal blood measurements', 'Type': 'PROBLEM', 'BeginOffset': 5749, 'EndOffset': 5776}, {'Id': 333, 'BeginOffset': 5781, 'EndOffset': 5787, 'Score': 0.8658434152603149, 'Text': 'sodium', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.9923917651176453, 'RelationshipScore': 0.6930268406867981, 'RelationshipType': 'TEST_VALUE', 'Id': 331, 'BeginOffset': 5749, 'EndOffset': 5757, 'Text': 'abnormal', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 335, 'BeginOffset': 5793, 'EndOffset': 5811, 'Score': 0.9929584264755249, 'Text': 'blood measurements', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.9931409955024719, 'RelationshipScore': 0.9996064305305481, 'RelationshipType': 'TEST_VALUE', 'Id': 334, 'BeginOffset': 5789, 'EndOffset': 5792, 'Text': 'low', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 336, 'BeginOffset': 5816, 'EndOffset': 5823, 'Score': 0.8540021777153015, 'Text': 'calcium', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 338, 'BeginOffset': 5829, 'EndOffset': 5847, 'Score': 0.9926179051399231, 'Text': 'blood measurements', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.9927536845207214, 'RelationshipScore': 0.9999960660934448, 'RelationshipType': 'TEST_VALUE', 'Id': 337, 'BeginOffset': 5825, 'EndOffset': 5828, 'Text': 'low', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 339, 'BeginOffset': 5852, 'EndOffset': 5861, 'Score': 0.8993991017341614, 'Text': 'phosphate', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'high blood sugar', 'Type': 'PROBLEM', 'BeginOffset': 5863, 'EndOffset': 5879}, {'Text': 'high blood measurements', 'Type': 'TEST', 'BeginOffset': 5881, 'EndOffset': 5904}, {'Text': 'lactate dehydrogenase', 'Type': 'PROBLEM', 'BeginOffset': 5909, 'EndOffset': 5930}, {'Id': 346, 'BeginOffset': 5932, 'EndOffset': 5946, 'Score': 0.3874019682407379, 'Text': 'autoantibodies', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'rare side effects', 'Type': 'PROBLEM', 'BeginOffset': 5969, 'EndOffset': 5986}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 6005, 'EndOffset': 6006}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 6010, 'EndOffset': 6015}, {'Text': 'low blood measurements', 'Type': 'PROBLEM', 'BeginOffset': 6025, 'EndOffset': 6047}, {'Id': 349, 'BeginOffset': 6052, 'EndOffset': 6069, 'Score': 0.8136500716209412, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 350, 'BeginOffset': 6071, 'EndOffset': 6086, 'Score': 0.5232493877410889, 'Text': 'red blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 360, 'BeginOffset': 6091, 'EndOffset': 6105, 'Score': 0.8647813200950623, 'Text': 'platelet count', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 353, 'BeginOffset': 6170, 'EndOffset': 6183, 'Score': 0.9017720222473145, 'Text': 'liver failure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9341897368431091}]}, {'Id': 354, 'BeginOffset': 6198, 'EndOffset': 6210, 'Score': 0.9486430883407593, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6704307794570923}]}, {'Id': 355, 'BeginOffset': 6226, 'EndOffset': 6238, 'Score': 0.91483074426651, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7164624929428101}]}, {'Id': 356, 'BeginOffset': 6302, 'EndOffset': 6314, 'Score': 0.9510350823402405, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6249579191207886}]}, {'Id': 357, 'BeginOffset': 6363, 'EndOffset': 6375, 'Score': 0.8542649149894714, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6871013641357422}]}, {'Id': 358, 'BeginOffset': 6429, 'EndOffset': 6440, 'Score': 0.36577558517456055, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5964338183403015}]}, {'Id': 359, 'BeginOffset': 6454, 'EndOffset': 6466, 'Score': 0.8547968864440918, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7281083464622498}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 6522, 'EndOffset': 6535}]}

{'Title': '5. how to store solymbic', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2c 8c). do not freeze. store in the original carton in order to protect from light. a single solymbic pre-filled syringe may be stored at temperatures up to a maximum of 25 for a period of up to 14 days. the pre-filled syringe must be protected from light, and discarded if not used within the 14-day period. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'a single solymbic pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 320, 'EndOffset': 356}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 406, 'EndOffset': 408}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 431, 'EndOffset': 433}, {'Text': 'the pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 440, 'EndOffset': 462}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 530, 'EndOffset': 532}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what solymbic contains - the active substance is adalimumab. each pre-filled syringe contains 20 mg of adalimumab in 0.4 ml of solution or 40 mg of adalimumab in 0.8 ml of solution. - the other ingredients are glacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. what solymbic looks like and contents of the pack solymbic is a clear and colourless to slightly yellow solution. each pack contains 1 single-use 20 mg pre-filled syringe (with yellow plunger rod). each pack contains 1, 2, 4 or 6 single-use 40 mg pre-filled syringes (with blue plunger rod).', 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 49, 'EndOffset': 59, 'Score': 0.9894786477088928, 'Text': 'adalimumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.4237994849681854, 'RelationshipScore': 0.9951267242431641, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 66, 'EndOffset': 93, 'Text': 'pre-filled syringe contains', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 61, 'EndOffset': 84}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 94, 'EndOffset': 96}, {'Id': 3, 'BeginOffset': 103, 'EndOffset': 113, 'Score': 0.9870290756225586, 'Text': 'adalimumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.4237994849681854, 'RelationshipScore': 0.9778947234153748, 'RelationshipType': 'FORM', 'Id': 1, 'BeginOffset': 66, 'EndOffset': 93, 'Text': 'pre-filled syringe contains', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9673892855644226, 'RelationshipScore': 0.9999908208847046, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 94, 'EndOffset': 99, 'Text': '20 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8351287841796875, 'RelationshipScore': 0.9255297183990479, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 117, 'EndOffset': 123, 'Text': '0.4 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.984997034072876, 'RelationshipScore': 0.9538276791572571, 'RelationshipType': 'FORM', 'Id': 5, 'BeginOffset': 127, 'EndOffset': 135, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '0.4', 'Type': 'NUMBER', 'BeginOffset': 117, 'EndOffset': 120}, {'Text': '40', 'Type': 'NUMBER', 'BeginOffset': 139, 'EndOffset': 141}, {'Id': 7, 'BeginOffset': 148, 'EndOffset': 158, 'Score': 0.9887070655822754, 'Text': 'adalimumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8351287841796875, 'RelationshipScore': 0.92750084400177, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 117, 'EndOffset': 123, 'Text': '0.4 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.984997034072876, 'RelationshipScore': 0.9781227707862854, 'RelationshipType': 'FORM', 'Id': 5, 'BeginOffset': 127, 'EndOffset': 135, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9071652889251709, 'RelationshipScore': 0.9999338388442993, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 139, 'EndOffset': 144, 'Text': '40 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.893244743347168, 'RelationshipScore': 0.8321431875228882, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 162, 'EndOffset': 168, 'Text': '0.8 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9109216928482056, 'RelationshipScore': 0.934687077999115, 'RelationshipType': 'FORM', 'Id': 9, 'BeginOffset': 172, 'EndOffset': 180, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '0.8', 'Type': 'NUMBER', 'BeginOffset': 162, 'EndOffset': 165}, {'Id': 10, 'BeginOffset': 210, 'EndOffset': 229, 'Score': 0.9232679009437561, 'Text': 'glacial acetic acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9071652889251709, 'RelationshipScore': 0.5939413905143738, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 139, 'EndOffset': 144, 'Text': '40 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.36842086911201477, 'RelationshipScore': 0.760423481464386, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 287, 'EndOffset': 296, 'Text': 'injection', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 11, 'BeginOffset': 231, 'EndOffset': 238, 'Score': 0.7375661730766296, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 240, 'EndOffset': 254, 'Score': 0.7120705842971802, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.36842086911201477, 'RelationshipScore': 0.8194689750671387, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 287, 'EndOffset': 296, 'Text': 'injection', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 13, 'BeginOffset': 256, 'EndOffset': 272, 'Score': 0.9985477328300476, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.36842086911201477, 'RelationshipScore': 0.9999340772628784, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 287, 'EndOffset': 296, 'Text': 'injection', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injection', 'Type': 'TREATMENT', 'BeginOffset': 287, 'EndOffset': 296}, {'Text': 'slightly yellow solution', 'Type': 'PROBLEM', 'BeginOffset': 386, 'EndOffset': 410}, {'Text': 'each pack', 'Type': 'TREATMENT', 'BeginOffset': 412, 'EndOffset': 421}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 431, 'EndOffset': 432}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 444, 'EndOffset': 446}, {'Text': 'yellow plunger rod', 'Type': 'TREATMENT', 'BeginOffset': 475, 'EndOffset': 493}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 515, 'EndOffset': 516}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 518, 'EndOffset': 519}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 521, 'EndOffset': 522}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 526, 'EndOffset': 527}, {'Text': '40', 'Type': 'NUMBER', 'BeginOffset': 539, 'EndOffset': 541}, {'Text': 'blue plunger rod', 'Type': 'TREATMENT', 'BeginOffset': 571, 'EndOffset': 587}]}

CD78CA4FC3E4B0ECA814EEE4FA81E8D3

https://www.ema.europa.eu/documents/product-information/clopidogrel-teva-pharma-epar-product-information_en.pdf

Clopidogrel Teva Pharma

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 Me dic ina l p ro du ct no lo ng er au th or ise d 1. NAME OF THE MEDICINAL PRODUCT Clopidogrel Teva Pharma 75 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride). Excipient with known effect: Each film-coated tablet contains 13 mg of hydrogenated castor oil. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Pink, round and slightly convex film-coated tablets. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prevention of atherothrombotic events Clopidogrel is indicated in:  Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.  Adult patients suffering from acute coronary syndrome: - Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). - ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy. Prevention of atherothrombotic and thromboembolic events in atrial fibrillation In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke. For further information please refer to section 5.1. 4.2 Posology and method of administration Posology  Adults and elderly Clopidogrel should be given as a single daily dose of 75 mg. In patients suffering from acute coronary syndrome: 2 Me dic ina l p ro du ct no lo ng er au th or ise d  Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300-mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months (see section 5.1). - ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300-mg loading dose in combination with ASA and with or without thrombolytics. For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination of clopidogrel with ASA beyond four weeks has not been studied in this setting (see section 5.1). In patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg. ASA (75-100 mg daily) should be initiated and continued in combination with clopidogrel (see section 5.1). If a dose is missed:  Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.  For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.  Paediatric population Clopidogrel should not be used in children because of efficacy concerns (see section 5.1).  Renal impairment Therapeutic experience is limited in patients with renal impairment (see section 4.4).  Hepatic impairment Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses (see section 4.4). Method of administration For oral use It may be given with or without food. 4.3 Contraindications  Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Severe hepatic impairment.  Active pathological bleeding such as peptic ulcer or intracranial haemorrhage. 4.4 Special warnings and precautions for use Bleeding and haematological disorders Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or other medicinal products associated with bleeding risk such as pentoxifylline (see section 4.5). Patients should be followed 3 Me dic ina l p ro du ct no lo ng er au th or ise d carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.5). If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician. Thrombotic Thrombocytopenic Purpura (TTP) Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. Acquired haemophilia Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued. Recent ischaemic stroke In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke. Cytochrome P450 2C19 (CYP2C19) Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Tests are available to identify a patient's CYP2C19 genotype. Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2). CYP2C8 substrates Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinal products (see section 4.5). Cross-reactions among thienopyridines Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see section 4.8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous monitored allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised. Renal impairment 4 Me dic ina l p ro du ct no lo ng er au th or ise d Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients (see section 4.2). Hepatic impairment Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population (see section 4.2). Excipients This medicinal product contains hydrogenated castor oil which may cause stomach upset and diarrhoea. 4.5 Interaction with other medicinal products and other forms of interaction Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicinal products associated with bleeding risk should be undertaken with caution (see section 4.4). Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.4). Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4). Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). However, clopidogrel and ASA have been administered together for up to one year (see section 5.1). Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA (see section 4.8). NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution (see section 4.4). SSRIs: since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution. 5 Me dic ina l p ro du ct no lo ng er au th or ise d Other concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4 and 5.2). Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz. Proton Pump Inhibitors (PPI): Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours between the administrations of the two drugs decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel. Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be discouraged (see section 4.4). Less pronounced reductions of metabolite exposure has been observed with pantoprazole or lansoprazole. The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole. There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers or antacids interfere with antiplatelet activity of clopidogrel. Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of phenobarbital or oestrogen. The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption. Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely co-administered with clopidogrel. CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see section 4.4). Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents 6 Me dic ina l p ro du ct no lo ng er au th or ise d (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions. 4.6 Fertility, pregnancy and lactation Pregnancy As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Breast-feeding It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during treatment with Clopidogrel Teva Pharma. Fertility Clopidogrel was not shown to alter fertility in animal studies. 4.7 Effects on ability to drive and use machines Clopidogrel has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Clopidogrel has been evaluated for safety in more than 44,000 patients, who have participated in clinical studies, including over 12,000 patients treated for 1 year or more. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactions have been spontaneously reported. Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the first month of treatment. In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA. In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA. In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the placebo plus ASA group. The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy. In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups. In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo +ASA group), mainly from the 7 Me dic ina l p ro du ct no lo ng er au th or ise d gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA group and 0.7% in the placebo +ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups. Tabulated list of adverse reactions Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: common ( 1/100 to <1/10); uncommon ( 1/1,000 to < 1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness. 8 Me dic ina l p ro du ct no lo ng er au th or ise d System Organ Class Common Uncommon Rare Very rare, not known* Blood and the lymphatic system disorders Thrombocytopenia, leucopenia, eosinophilia Neutropenia, including severe neutropenia Thrombotic thrombocytopenic purpura (TTP) (see section 4.4), aplastic anaemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired haemophilia A, granulocytopenia, anaemia Immune system disorders Serum sickness, anaphylactoid reactions, cross-reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel) (see section 4.4)* Psychiatric disorders Hallucinations, confusion Nervous system disorders Intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizziness Taste disturbances Eye disorders Eye bleeding (conjunctival, ocular, retinal) Ear and labyrinth disorders Vertigo Vascular disorders Haematoma Serious haemorrhage, haemorrhage of operative wound, vasculitis, hypotension Respiratory, thoracic and mediastinal disorders Epistaxis Respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia 9 Me dic ina l p ro du ct no lo ng er au th or ise d System Organ Class Common Uncommon Rare Very rare, not known* Gastrointestinal disorders Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia Gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence Retroperitoneal haemorrhage Gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis Hepato-biliary disorders Acute liver failure, hepatitis, abnormal liver function test Skin and subcutaneous tissue disorders Bruising Rash, pruritus, skin bleeding (purpura) Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme, acute generalised exanthematous pustulosis (AGEP)), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), rash erythematous or exfoliative, urticaria, eczema, lichen planus Reproductive systems and breast disorders Gynaecomastia Musculoskeletal, connective tissue and bone disorders Musculo-skeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgia Renal and urinary disorders Haematuria Glomerulonephritis, blood creatinine increased General disorders and administration site conditions Bleeding at puncture site Fever Investigations Bleeding time prolonged, neutrophil count decreased, platelet count decreased * Information related to clopidogrel with frequency “not known”. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 10 Me dic ina l p ro du ct no lo ng er au th or ise d professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excl. heparin, ATC Code: B01AC-04. Mechanism of action Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition. Pharmacodynamic effects Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued. Clinical efficacy and safety The safety and efficacy of clopidogrel have been evaluated in 5 double-blind studies involving over 88,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY, COMMIT and ACTIVE-A studies comparing clopidogrel to placebo, both medicinal products given in combination with ASA and other standard therapy. Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of the patients received ASA for the first few days following the acute myocardial infarction. 11 Me dic ina l p ro du ct no lo ng er au th or ise d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA (relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every 1000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6.0%). In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the benefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = - 4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients over 75 years was less than that observed in patients ≤75 years. Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real, or a result of chance. Acute coronary syndrome The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA (75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in more than 90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy. The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)). New cardiovascular events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage persisted (see section 4.4). The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy (RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%, 28.3%). The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated group]. There was no observed effect on the rate of rehospitalisation for unstable angina. 12 Me dic ina l p ro du ct no lo ng er au th or ise d The results obtained in populations with different characteristics (e.g. unstable angina or non-Q-wave MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with the results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the total CURE population) who underwent stent placement (Stent-CURE), the data showed that clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the second co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this subset are in line with the overall trial results. The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of ASA (75-325 mg once daily). In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT. The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population included 19.7% women and 29.2% patients ≥ 65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7% ACE inhibitors and 63% statins. Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36 % odds reduction in favor of clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients’ age and gender, infarct location, and type of fibrinolytic or heparin used. The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The population included 27.8% women, 58.4% patients ≥ 60 years (26% ≥ 70 years) and 54.5% patients who received fibrinolytics. Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours. Atrial fibrillation The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (such as warfarin). The ACTIVE-A study included patients who could not receive VKA therapy because they were unable or unwilling to receive the treatment. 13 Me dic ina l p ro du ct no lo ng er au th or ise d The ACTIVE-W study demonstrated that anticoagulant treatment with vitamin K antagonists was more effective than with clopidogrel and ASA. The ACTIVE-A study (N=7,554) was a multicenter, randomized, double-blind, placebo-controlled study which compared clopidogrel 75 mg/day + ASA (N=3,772) to placebo + ASA (N=3,782). The recommended dose for ASA was 75 to 100 mg/day. Patients were treated for up to 5 years. Patients randomized in the ACTIVE program were those presenting with documented AF, i.e., either permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of the following risk factors: age 75 years or age 55 to 74 years and either diabetes mellitus requiring drug therapy, or documented previous MI or documented coronary artery disease; treated for systemic hypertension; prior stroke, transient ischaemic attack (TIA), or non-CNS systemic embolus; left ventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheral vascular disease. The mean CHADS2 score was 2.0 (range 0-6). The major exclusion criteria for patients were documented peptic ulcer disease within the previous 6 months; prior intracerebral hemorrhage; significant thrombocytopenia (platelet count < 50 x 109/l); requirement for clopidogrel or oral anticoagulants (OAC); or intolerance to any of the two compounds. Seventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA due to physician assessment, inability to comply with INR (international normalised ratio) monitoring, predisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the physician’s decision was based on the patient’s unwillingness to take VKA. The patient population included 41.8 % women. The mean age was 71 years, 41.6% of patients were ≥75 years. A total of 23.0% of patients received anti-arrhythmics, 52.1% beta-blockers, 54.6% ACE inhibitors, and 25.4% statins. The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%; 95% CI of 2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving placebo + ASA (relative risk reduction, 28.4%; 95% CI, 16.8% to 38.3%; p=0.00001). Paediatric population In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis (PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and infants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition of 49.3% (5 µM ADP-induced platelet aggregation) which was comparable to that of adults taking Clopidogrel 75 mg/day. In a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with concomitant background therapy up to the time of second stage surgery. The mean time between shunt palliation and first administration of study medicinal product was 20 days. Approximately 88% of patients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference between groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related intervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%] for the clopidogrel group and 90 [20.5%] for the placebo group) (see section 4.2). Bleeding was the most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was no significant difference in the bleeding rate between groups. In the long-term safety follow-up of this study, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 months of age. No new safety concerns were noted during this long-term follow-up. 14 Me dic ina l p ro du ct no lo ng er au th or ise d The CLARINET and the PICOLO trials were conducted using a constituted solution of clopidogrel. In a relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent and slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the authorised tablet. 5.2 Pharmacokinetic properties Absorption After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Distribution Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98 % and 94 % respectively). The binding is non-saturable in vitro over a wide concentration range. Biotransformation Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation. The Cmax of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose as it is after four days of 75-mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. Elimination Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination halflife of the main circulating (inactive) metabolite was 8 hours after single and repeated administration. Pharmacogenetics CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, *6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as defined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient’s CYP2C19 genotype. A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg 15 Me dic ina l p ro du ct no lo ng er au th or ise d followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of 39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials. Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers. The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomised, controlled trials. There have been a number of retrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), TRITON-TIMI 38 (n=1477), and ACTIVE-A (n=601), as well as a number of published cohort studies. In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers. In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers. In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status. None of these analyses were adequately sized to detect differences in outcome in poor metabolisers. Special populations The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations. Renal impairment After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients. Hepatic impairment After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups. Race 16 Me dic ina l p ro du ct no lo ng er au th or ise d The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events. 5.3 Preclinical safety data During non clinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the therapeutic dose. At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of clopidogrel was also reported in rat and baboon. There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day). Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no genotoxic activity. Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be excluded. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Cellulose, microcrystalline Colloidal anhydrous silica Crospovidone (type A) Macrogol 6000 Hydrogenated castor oil Film coating: Polyvinyl alcohol Titanium dioxide (E171) Red iron oxide (E172) Yellow iron oxide (E172) Talc Macrogol 3000 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 17 Me dic ina l p ro du ct no lo ng er au th or ise d 6.4 Special precautions for storage Store in the original package in order to protect from moisture and light. 6.5 Nature and contents of container Blister of OPA/Al/PVC-Al containing 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in the box. Perforated unit dose blister of OPA/Al/PVC-Al containing 28x1 and 50x1 film-coated tablets in the box. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Teva B.V. Swensweg 5 2031GA Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/09/561/001 Cartons of 7 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/002 Cartons of 14 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/003 Cartons of 28 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/004 Cartons of 30 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/005 Cartons of 50 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/006 Cartons of 56 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/007 Cartons of 84 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/008 Cartons of 90 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/009 Cartons of 100 film-coated tablets in OPA/Al/PVC - Al blisters EU/1/09/561/010 Cartons of 28x1 film-coated tablets in OPA/Al/PVC - Al perforated unit-dose blisters EU/1/09/561/011 Cartons of 50x1 film-coated tablets in OPA/Al/PVC - Al perforated unit-dose blisters 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 21 September 2009 Date of latest renewal: 8 May 2014 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. 18 Me dic ina l p ro du ct no lo ng er au th or ise d http://www.emea.europa.eu/ 19 Me dic ina l p ro du ct no lo ng er au th or ise d ANNEX II A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 20 Me dic ina l p ro du ct no lo ng er au th or ise d A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release KRKA, d.d., Novo mesto Šmarješka cesta 6 8501 Novo mesto Slovenia TAD Pharma GmbH Heinz-Lohmann-Straße 5 27472 Cuxhaven Germany Pharmachemie B.V. Swensweg 5, 2031 GA Haarlem The Netherlands The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic Safety Update Reports The PSUR submission schedule for Clopidogrel Teva Pharma film coated tablets should follow PSURs submission schedule for the reference medicinal product.  Pharmacovigilance system The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1 of the Marketing Authorisation, is in place and functioning before and whilst the product is on the market. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk Management Plan (RMP) Risk Management Plan was not submitted. The application is based on a reference medicinal product for which no safety concerns requiring additional risk minimization activities have been identified. 21 Me dic ina l p ro du ct no lo ng er au th or ise d ANNEX III LABELLING AND PACKAGE LEAFLET 22 Me dic ina l p ro du ct no lo ng er au th or ise d A. LABELLING 23 Me dic ina l p ro du ct no lo ng er au th or ise d PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Clopidogrel Teva Pharma 75 mg film-coated tablets Clopidogrel 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride). 3. LIST OF EXCIPIENTS It also contains hydrogenated castor oil. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 7 film-coated tablets 14 film-coated tablets 28 film-coated tablets 30 film-coated tablets 50 film-coated tablets 56 film-coated tablets 84 film-coated tablets 90 film-coated tablets 100 film-coated tablets 28x1 film-coated tablets 50x1 film-coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 24 Me dic ina l p ro du ct no lo ng er au th or ise d 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in the original package in order to protect from moisture and light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Teva B.V. Swensweg 5 2031GA Haarlem The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/09/561/001 7 film-coated tablets EU/1/09/561/002 14 film-coated tablets EU/1/09/561/003 28 film-coated tablets EU/1/09/561/004 30 film-coated tablets EU/1/09/561/005 50 film-coated tablets EU/1/09/561/006 56 film-coated tablets EU/1/09/561/007 84 film-coated tablets EU/1/09/561/008 90 film-coated tablets EU/1/09/561/009 100 film-coated tablets EU/1/09/561/010 28x1 film-coated tablets EU/1/09/561/011 50x1 film-coated tablets 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Clopidogrel Teva Pharma 75 mg 25 Me dic ina l p ro du ct no lo ng er au th or ise d MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER (7, 14, 28, 30, 50, 56, 84, 90, 100, 50x1 film-coated tablets) 1. NAME OF THE MEDICINAL PRODUCT Clopidogrel Teva Pharma 75 mg film-coated tablets Clopidogrel 2. NAME OF THE MARKETING AUTHORISATION HOLDER Teva B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER Batch 5. OTHER 26 Me dic ina l p ro du ct no lo ng er au th or ise d MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER (28x1 film-coated tablets) 1. NAME OF THE MEDICINAL PRODUCT Clopidogrel Teva Pharma 75 mg film-coated tablets Clopidogrel 2. NAME OF THE MARKETING AUTHORISATION HOLDER Teva B.V. 3. EXPIRY DATE EXP 4. BATCH NUMBER Batch 5. OTHER Calendar days Mon Tue Wed Thu Fri Sat Sun 27 Me dic ina l p ro du ct no lo ng er au th or ise d B. PACKAGE LEAFLET 28 Me dic ina l p ro du ct no lo ng er au th or ise d Package leaflet: Information for the user Clopidogrel Teva Pharma 75 mg film-coated tablets Clopidogrel Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you have any of the side effects, including any side effects not listed in this leaflet, talk to your doctor or pharmacist. See section 4. What is in this leaflet: 1. What Clopidogrel Teva Pharma is and what it is used for 2. What you need to know before you take Clopidogrel Teva Pharma 3. How to take Clopidogrel Teva Pharma 4. Possible side effects 5. How to store Clopidogrel Teva Pharma 6. Contents of the pack and other information 1. What Clopidogrel Teva Pharma is and what it is used for Clopidogrel Teva Pharma contains clopidogrel and belongs to a group of medicines called antiplatelet medicinal products. Platelets are very small structures in the blood, which clump together during blood clotting. By preventing this clumping, antiplatelet medicinal products reduce the chances of blood clots forming (a process called thrombosis). Clopidogrel Teva Pharma is taken by adults to prevent blood clots (thrombi) forming in hardened blood vessels (arteries), a process known as atherothrombosis, which can lead to atherothrombotic events (such as stroke, heart attack, or death). You have been prescribed Clopidogrel Teva Pharma to help prevent blood clots and reduce the risk of these severe events because: - You have a condition of hardening of arteries (also known as atherosclerosis), and - You have previously experienced a heart attack, stroke or have a condition known as peripheral arterial disease, or - You have experienced a severe type of chest pain known as ‘unstable angina’ or ‘myocardial infarction’ (heart attack). For the treatment of this condition your doctor may have placed a stent in the blocked or narrowed artery to restore effective blood flow. You should also be given acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever as well as to prevent blood clotting) by your doctor. - You have an irregular heartbeat, a condition called ‘atrial fibrillation’, and you cannot take medicines known as ‘oral anticoagulants’ (vitamin K antagonists) which prevent new clots from forming and prevent existing clots from growing. You should have been told that ‘oral anticoagulants’ are more effective than acetylsalicylic acid or the combined use of Clopidogrel Teva Pharma and acetylsalicylic acid for this condition. Your doctor should have prescribed Clopidogrel Teva Pharma plus acetylsalicylic acid if you cannot take ‘oral anticoagulants’ and you do not have a risk of major bleeding 2. What you need to know before you take Clopidogrel Teva Pharma 29 Me dic ina l p ro du ct no lo ng er au th or ise d Do not take Clopidogrel Teva Pharma  If you are allergic to clopidogrel or any of the other ingredients of this medicine (listed in section 6).  If you have a medical condition that is currently causing bleeding such as a stomach ulcer or bleeding within the brain.  If you suffer from severe liver disease. If you think any of these apply to you, or if you are in any doubt at all, consult your doctor before taking Clopidogrel Teva Pharma. Warnings and precautions If any of the situations mentioned below apply to you, you should tell your doctor before taking Clopidogrel Teva Pharma:  if you have a risk of bleeding such as - a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer) - a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, organs or joints of your body). - a recent serious injury. - a recent surgery (including dental). - a planned surgery (including dental) in the next seven days.  if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the last seven days.  if you have kidney or liver disease.  if you have had an allergy or reaction to any medicine used to treat your disease. While you are taking Clopidogrel Teva Pharma:  You should tell your doctor if a surgery (including dental) is planned.  You should also tell your doctor immediately if you develop a medical condition (also known as Thrombotic Thrombocytopenic Purpura or TTP) that includes fever and bruising under the skin that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice) (see section 4 ‘Possible side effects’).  If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to the way your medicine works as it prevents the ability of blood clots to form. For minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 4 ‘Possible side effects’).  Your doctor may order blood tests. Children and adolescents Do not give this medicine to children because it does not work. Other medicines and Clopidogrel Teva Pharma Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription. Some other medicines may influence the use of Clopidogrel Teva Pharma or vice versa. You should specifically tell your doctor if you take - medicines that may increase your risk of bleeding such as: o oral anticoagulants, medicines used to reduce blood clotting, o a non-steroidal anti-inflammatory medicine, usually used to treat painful and/or inflammatory conditions of muscle or joints, o heparin or any other injectable medicine used to reduce blood clotting, o ticlopidine, other antiplatelet agent, o a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or fluvoxamine), medicines usually used to treat depression, - omeprazole or esomeprazole, medicines to treat upset stomach, 30 Me dic ina l p ro du ct no lo ng er au th or ise d - fluconazole or voriconazole, medicines to treat fungal infections, - efavirenz, a medicine to treat HIV (human immunodeficiency virus) infections, - carbamazepine, a medicine to treat some forms of epilepsy, - moclobemide, medicine to treat depression, - repaglinide, medicine to treat diabetes, - paclitaxel, medicine to treat cancer. If you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed Clopidogrel Teva Pharma in combination with acetylsalicylic acid, a substance present in many medicines used to relieve pain and lower fever. An occasional use of acetylsalicylic acid (no more than 1,000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other circumstances should be discussed with your doctor. Pregnancy and breast-feeding It is preferable not to take this medicine during pregnancy. If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist before taking Clopidogrel Teva Pharma. If you become pregnant while taking Clopidogrel Teva Pharma, consult your doctor immediately as it is recommended not to take clopidogrel while you are pregnant. You should not breast-feed while taking this medicine. If you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Clopidogrel Teva Pharma is unlikely to affect your ability to drive or to use machines. Clopidogrel Teva Pharma contains hydrogenated castor oil This may cause stomach upset or diarrhoea. 3. How to take Clopidogrel Teva Pharma Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The recommended dose, including for patients with a condition called ‘atrial fibrillation’ (an irregular heartbeat), is one 75 mg tablet of Clopidogrel Teva Pharma per day to be taken orally with or without food, and at the same time each day. If you have experienced severe chest pain (unstable angina or heart attack), your doctor may give you 300 mg of Clopidogrel Teva Pharma (4 tablets of 75 mg) once at the start of treatment. Then, the recommended dose is one 75 mg tablet of Clopidogrel Teva Pharma per day as described above. You should take Clopidogrel Teva Pharma for as long as your doctor continues to prescribe it. If you take more Clopidogrel Teva Pharma than you should Contact your doctor or the nearest hospital emergency department because of the increased risk of bleeding. If you forget to take Clopidogrel Teva Pharma If you forget to take a dose of Clopidogrel Teva Pharma, but remember within 12 hours of your usual time, take your tablet straightaway and then take your next tablet at the usual time. 31 Me dic ina l p ro du ct no lo ng er au th or ise d If you forget for more than 12 hours, simply take the next single dose at the usual time. Do not take a double dose to make up for a forgotten tablet. For the 28x1 tablets pack size, you can check the day on which you last took the tablet by referring to the calendar printed on the blister. If you stop taking Clopidogrel Teva Pharma Do not stop the treatment unless your doctor tells you so. Contact your doctor or pharmacist before stopping. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Contact your doctor immediately if you experience: - fever, signs of infection or extreme tiredness. These may be due to rare decrease of some blood cells. - signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not associated with bleeding which appears under the skin as red pinpoint dots and/or confusion (see section 2 ‘Warnings and precautions’). - swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. These may be the signs of an allergic reaction. The most common side effect reported with Clopidogrel Teva Pharma is bleeding. Bleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or bruising under the skin), nose bleed, blood in the urine. In a small number of cases, bleeding in the eye, inside the head, the lung or the joints has also been reported. If you experience prolonged bleeding when taking Clopidogrel Teva Pharma If you cut or injure yourself, it may take slightly longer than usual for bleeding to stop. This is linked to the way your medicine works as it prevents the ability of blood clots to form. For minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 2 ‘Warnings and precautions’). Other side effects include: Common side effects (may affect up to 1 in 10 people): Diarrhoea, abdominal pain, indigestion or heartburn. Uncommon side effects (may affect up to 1 in 100 people): Headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of tingling and numbness. Rare side effect (may affect up to 1 in 1000 people): Vertigo, enlarged breasts in males. Very rare side effects (may affect up to 1 in 10,000 people): Jaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes associated with cough; generalised allergic reactions (for example, overall sensation of heat with sudden general discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy; sore mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; changes in taste of food. 32 Me dic ina l p ro du ct no lo ng er au th or ise d In addition, your doctor may identify changes in your blood or urine test results. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Clopidogrel Teva Pharma Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and on the blister, after EXP. The expiry date refers to the last day of that month. Store in the original package in order to protect from moisture and light. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment. 6. Contents of the pack and other information What Clopidogrel Teva Pharma contains The active substance is clopidogrel. Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride). The other ingredients are (see section 2 ‘Clopidogrel Teva Pharma contains hydrogenated castor oil’):  Tablet core: microcrystalline cellulose, colloidal anhydrous silica, crospovidone (type A), macrogol 6000 and hydrogenated castor oil  Tablet coating: Polyvinyl alcohol, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172), talc and macrogol 3000. What Clopidogrel Teva Pharma looks like and contents of the pack The film-coated tablets are pink, round and slightly convex. Boxes of 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in blisters or boxes of 28x1 and 50x1 film-coated tablets in perforated unit dose blisters are available. Not all pack sizes may be marketed. Marketing Authorisation Holder Teva B.V. Swensweg 5 2031GA Haarlem The Netherlands Manufacturers KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany Pharmachemie B.V., Swensweg 5, 2031 GA Haarlem, The Netherlands For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder 33 Me dic ina l p ro du ct no lo ng er au th or ise d http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 34 België/Belgique/Belgien Teva Pharma Belgium N.V./S.A. /AG Tel/Tél: +32 3 820 73 73 Lietuva UAB “Sicor Biotech” Tel: +370 5 266 02 03 България Тева Фармасютикълс България ЕООД Teл: +359 2 489 95 82 Luxembourg/Luxemburg ratiopharm GmbH Allemagne/Deutschland Tél/Tel: +49 731 402 02 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251 007 111 Magyarország Teva Gyógyszergyár Zrt. Tel.: +36 1 288 64 00 Danmark Teva Denmark A/S Tlf: +45 44 98 55 11 Malta Teva Pharmaceuticals Ireland L-Irlanda Tel: +353 51 321740 Deutschland TEVA GmbH Tel: (+49) 731 402 08 Nederland Teva Nederland B.V. Tel: +31 (0) 800 0228400 Eesti Teva Eesti esindus UAB Sicor Biotech Eesti filiaal Tel: +372 6610801 Norge Teva Norway AS Tlf: 47 66 77 55 90 Ελλάδα Teva Ελλάς Α.Ε. Τηλ: +30 210 72 79 099 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43/1/97007-0 España TEVA PHARMA, S.L.U Tel: +(34) 91 387 32 80 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel.: +(48) 22 345 93 00 France Teva Santé Tél: +(33) 1 55 91 7800 Portugal Teva Pharma - Produtos Farmacêuticos Lda Tel: +351 21 476 75 50 Hrvatska Pliva Hrvatska d.o.o. Tel:+ 385 1 37 20 000 România Teva Pharmaceuticals S.R.L Tel: +4021 230 65 24 Ireland Teva Pharmaceuticals Ireland Tel: +353 (0)51 321 740 Slovenija Pliva Ljubljana d.o.o. Tel: +386 1 58 90 390 Ísland ratiopharm Oy Finnland Sími: +358 20 180 5900 Slovenská republika Teva Pharmaceuticals Slovakia s.r.o. Tel: +(421) 2 5726 7911 Italia Teva Italia S.r.l Tel: +(39) 028917981 Suomi/Finland ratiopharm Oy Puh/Tel: +358 20 180 5900 Me dic ina l p ro du ct no lo ng er au th or ise d 35 Κύπρος Teva Ελλάς Α.Ε. Ελλάδα Τηλ: +30 210 72 79 099 Sverige Teva Sweden AB Tel: +(46) 42 12 11 00 Latvija UAB Sicor Biotech filiāle Latvijā Tel: +371 67 323 666 United Kingdom Teva UK Limited Tel: +44(0) 1977 628500 This leaflet was last revised in. Detailed information is available on the European Medicines Agency website: http://www.ema.europa.eu. Me dic ina l p ro du ct no lo ng er au th or ise d SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

{'Title': '1. what clopidogrel teva pharma is and what it is used for', 'Section_Content': "clopidogrel teva pharma contains clopidogrel and belongs to a group of medicines called antiplatelet medicinal products. platelets are very small structures in the blood, which clump together during blood clotting. by preventing this clumping, antiplatelet medicinal products reduce the chances of blood clots forming (a process called thrombosis). clopidogrel teva pharma is taken by adults to prevent blood clots (thrombi) forming in hardened blood vessels (arteries), a process known as atherothrombosis, which can lead to atherothrombotic events (such as stroke, heart attack, or death). you have been prescribed clopidogrel teva pharma to help prevent blood clots and reduce the risk of these severe events because: - you have a condition of hardening of arteries (also known as atherosclerosis), and - you have previously experienced a heart attack, stroke or have a condition known as peripheral arterial disease, or - you have experienced a severe type of chest pain known as 'unstable angina' or 'myocardial infarction' (heart attack). for the treatment of this condition your doctor may have placed a stent in the blocked or narrowed artery to restore effective blood flow. you should also be given acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever as well as to prevent blood clotting) by your doctor. - you have an irregular heartbeat, a condition called 'atrial fibrillation', and you cannot take medicines known as 'oral anticoagulants' (vitamin k antagonists) which prevent new clots from forming and prevent existing clots from growing. you should have been told that 'oral anticoagulants' are more effective than acetylsalicylic acid or the combined use of clopidogrel teva pharma and acetylsalicylic acid for this condition. your doctor should have prescribed clopidogrel teva pharma plus acetylsalicylic acid if you cannot take 'oral anticoagulants' and you do not have a risk of major bleeding", 'Entity_Recognition': [{'Text': 'clopidogrel teva pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 23}, {'Id': 12, 'BeginOffset': 33, 'EndOffset': 44, 'Score': 0.9981221556663513, 'Text': 'clopidogrel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a group of medicines', 'Type': 'TREATMENT', 'BeginOffset': 60, 'EndOffset': 80}, {'Text': 'antiplatelet medicinal products', 'Type': 'TREATMENT', 'BeginOffset': 88, 'EndOffset': 119}, {'Id': 57, 'BeginOffset': 121, 'EndOffset': 130, 'Score': 0.20370370149612427, 'Text': 'platelets', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.3164716064929962, 'RelationshipScore': 0.9999996423721313, 'RelationshipType': 'TEST_VALUE', 'Id': 58, 'BeginOffset': 135, 'EndOffset': 169, 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{'Title': '2. what you need to know before you take clopidogrel teva pharma', 'Section_Content': "do not take clopidogrel teva pharma if you are allergic to clopidogrel or any of the other ingredients of this medicine (listed in section 6). if you have a medical condition that is currently causing bleeding such as a stomach ulcer or bleeding within the brain. if you suffer from severe liver disease. if you think any of these apply to you, or if you are in any doubt at all, consult your doctor before taking clopidogrel teva pharma. warnings and precautions if any of the situations mentioned below apply to you, you should tell your doctor before taking clopidogrel teva pharma: if you have a risk of bleeding such as - a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer) - a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, organs or joints of your body). - a recent serious injury. - a recent surgery (including dental). - a planned surgery (including dental) in the next seven days. if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the last seven days. if you have kidney or liver disease. if you have had an allergy or reaction to any medicine used to treat your disease. while you are taking clopidogrel teva pharma: you should tell your doctor if a surgery (including dental) is planned. you should also tell your doctor immediately if you develop a medical condition (also known as thrombotic thrombocytopenic purpura or ttp) that includes fever and bruising under the skin that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice) (see section 4 'possible side effects'). if you cut or injure yourself, it may take longer than usual for bleeding to stop. this is linked to the way your medicine works as it prevents the ability of blood clots to form. for minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. however, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 4 'possible side effects'). your doctor may order blood tests. children and adolescents do not give this medicine to children because it does not work. other medicines and clopidogrel teva pharma tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription. some other medicines may influence the use of clopidogrel teva pharma or vice versa. you should specifically tell your doctor if you take - medicines that may increase your risk of bleeding such as: o oral anticoagulants, medicines used to reduce blood clotting, o a non-steroidal anti-inflammatory medicine, usually used to treat painful and/or inflammatory conditions of muscle or joints, o heparin or any other injectable medicine used to reduce blood clotting, o ticlopidine, other antiplatelet agent, o a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or fluvoxamine), medicines usually used to treat depression, - omeprazole or esomeprazole, medicines to treat upset stomach, 30 - fluconazole or voriconazole, medicines to treat fungal infections, - efavirenz, a medicine to treat hiv (human immunodeficiency virus) infections, - carbamazepine, a medicine to treat some forms of epilepsy, - moclobemide, medicine to treat depression, - repaglinide, medicine to treat diabetes, - paclitaxel, medicine to treat cancer. if you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed clopidogrel teva pharma in combination with acetylsalicylic acid, a substance present in many medicines used to relieve pain and lower fever. an occasional use of acetylsalicylic acid (no more than 1,000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other circumstances should be discussed with your doctor. pregnancy and breast-feeding it is preferable not to take this medicine during pregnancy. if you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist before taking clopidogrel teva pharma. if you become pregnant while taking clopidogrel teva pharma, consult your doctor immediately as it is recommended not to take clopidogrel while you are pregnant. you should not breast-feed while taking this medicine. if you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. ask your doctor or pharmacist for advice before taking any medicine. driving and using machines clopidogrel teva pharma is unlikely to affect your ability to drive or to use machines. clopidogrel teva pharma contains hydrogenated castor oil this may cause stomach upset or diarrhoea.", 'Entity_Recognition': [{'Text': 'clopidogrel teva pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 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{'Title': '3. how to take clopidogrel teva pharma', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose, including for patients with a condition called 'atrial fibrillation' (an irregular heartbeat), is one 75 mg tablet of clopidogrel teva pharma per day to be taken orally with or without food, and at the same time each day. if you have experienced severe chest pain (unstable angina or heart attack), your doctor may give you 300 mg of clopidogrel teva pharma (4 tablets of 75 mg) once at the start of treatment. then, the recommended dose is one 75 mg tablet of clopidogrel teva pharma per day as described above. you should take clopidogrel teva pharma for as long as your doctor continues to prescribe it. if you take more clopidogrel teva pharma than you should contact your doctor or the nearest hospital emergency department because of the increased risk of bleeding. if you forget to take clopidogrel teva pharma if you forget to take a dose of clopidogrel teva pharma, but remember within 12 hours of your usual time, take your tablet straightaway and then take your next tablet at the usual time. if you forget for more than 12 hours, simply take the next single dose at the usual time. do not take a double dose to make up for a forgotten tablet. for the 28x1 tablets pack size, you can check the day on which you last took the tablet by referring to the calendar printed on the blister. if you stop taking clopidogrel teva pharma do not stop the treatment unless your doctor tells you so. contact your doctor or pharmacist before stopping. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.", 'Entity_Recognition': [{'Text': 'clopidogrel teva pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 'a condition', 'Type': 'PROBLEM', 'BeginOffset': 185, 'EndOffset': 196}, {'Text': "'atrial fibrillation", 'Type': 'PROBLEM', 'BeginOffset': 204, 'EndOffset': 224}, {'Text': 'an irregular heartbeat', 'Type': 'PROBLEM', 'BeginOffset': 227, 'EndOffset': 249}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 259, 'EndOffset': 261}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 275, 'EndOffset': 298}, {'Text': 'severe chest pain', 'Type': 'PROBLEM', 'BeginOffset': 403, 'EndOffset': 420}, {'Id': 29, 'BeginOffset': 422, 'EndOffset': 437, 'Score': 0.8165594935417175, 'Text': 'unstable angina', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8158350586891174}]}, {'Id': 30, 'BeginOffset': 441, 'EndOffset': 453, 'Score': 0.9776108860969543, 'Text': 'heart attack', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8991856575012207}]}, {'Text': '300', 'Type': 'NUMBER', 'BeginOffset': 481, 'EndOffset': 484}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 491, 'EndOffset': 514}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 529, 'EndOffset': 531}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 557, 'EndOffset': 566}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 602, 'EndOffset': 604}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 618, 'EndOffset': 641}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 686, 'EndOffset': 709}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 781, 'EndOffset': 804}, {'Id': 32, 'BeginOffset': 865, 'EndOffset': 885, 'Score': 0.9763028621673584, 'Text': 'emergency department', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'ADDRESS', 'Traits': []}, {'Id': 31, 'BeginOffset': 919, 'EndOffset': 927, 'Score': 0.9876846075057983, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6078229546546936}]}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 951, 'EndOffset': 974}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 1007, 'EndOffset': 1030}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 1052, 'EndOffset': 1054}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 1189, 'EndOffset': 1191}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 1263, 'EndOffset': 1276}, {'Text': 'the 28x1 tablets pack size', 'Type': 'TREATMENT', 'BeginOffset': 1316, 'EndOffset': 1342}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 1472, 'EndOffset': 1495}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1654, 'EndOffset': 1667}]}

{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. contact your doctor immediately if you experience: - fever, signs of infection or extreme tiredness. these may be due to rare decrease of some blood cells. - signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not associated with bleeding which appears under the skin as red pinpoint dots and/or confusion (see section 2 'warnings and precautions'). - swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. these may be the signs of an allergic reaction. the most common side effect reported with clopidogrel teva pharma is bleeding. bleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or bruising under the skin), nose bleed, blood in the urine. in a small number of cases, bleeding in the eye, inside the head, the lung or the joints has also been reported. if you experience prolonged bleeding when taking clopidogrel teva pharma if you cut or injure yourself, it may take slightly longer than usual for bleeding to stop. this is linked to the way your medicine works as it prevents the ability of blood clots to form. for minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. however, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 2 'warnings and precautions'). other side effects include: common side effects (may affect up to 1 in 10 people): diarrhoea, abdominal pain, indigestion or heartburn. uncommon side effects (may affect up to 1 in 100 people): headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of tingling and numbness. rare side effect (may affect up to 1 in 1000 people): vertigo, enlarged breasts in males. very rare side effects (may affect up to 1 in 10,000 people): jaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes associated with cough; generalised allergic reactions (for example, overall sensation of heat with sudden general discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy; sore mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; changes in taste of food. in addition, your doctor may identify changes in your blood or urine test results. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'clopidogrel teva pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 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[{'Name': 'SYMPTOM', 'Score': 0.6429743766784668}]}, {'Text': 'severe abdominal pain', 'Type': 'PROBLEM', 'BeginOffset': 1978, 'EndOffset': 1999}, {'Id': 92, 'BeginOffset': 2016, 'EndOffset': 2025, 'Score': 0.9372137784957886, 'Text': 'back pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.933485209941864}, {'Name': 'NEGATION', 'Score': 0.720675528049469}]}, {'Id': 93, 'BeginOffset': 2027, 'EndOffset': 2032, 'Score': 0.991847038269043, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9345110058784485}, {'Name': 'NEGATION', 'Score': 0.4244747757911682}]}, {'Id': 94, 'BeginOffset': 2034, 'EndOffset': 2056, 'Score': 0.9774678945541382, 'Text': 'breathing difficulties', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9381107687950134}, {'Name': 'NEGATION', 'Score': 0.5180843472480774}]}, {'Id': 95, 'BeginOffset': 2083, 'EndOffset': 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'BeginOffset': 2209, 'EndOffset': 2230}, {'Text': 'blisters of the skin', 'Type': 'PROBLEM', 'BeginOffset': 2232, 'EndOffset': 2252}, {'Id': 102, 'BeginOffset': 2254, 'EndOffset': 2266, 'Score': 0.5108931064605713, 'Text': 'skin allergy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9343803524971008}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9981551766395569, 'RelationshipScore': 0.964052677154541, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 84, 'BeginOffset': 2248, 'EndOffset': 2252, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'sore mouth (stomatitis', 'Type': 'PROBLEM', 'BeginOffset': 2268, 'EndOffset': 2290}, {'Id': 105, 'BeginOffset': 2293, 'EndOffset': 2319, 'Score': 0.3891910910606384, 'Text': 'decrease in blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9159213900566101}]}, {'Id': 106, 'BeginOffset': 2321, 'EndOffset': 2330, 'Score': 0.9937570095062256, 'Text': 'confusion', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9676558971405029}]}, {'Id': 107, 'BeginOffset': 2332, 'EndOffset': 2346, 'Score': 0.9962705373764038, 'Text': 'hallucinations', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9539763927459717}]}, {'Id': 108, 'BeginOffset': 2348, 'EndOffset': 2358, 'Score': 0.9051169157028198, 'Text': 'joint pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.936259388923645}]}, {'Id': 109, 'BeginOffset': 2360, 'EndOffset': 2373, 'Score': 0.9646674394607544, 'Text': 'muscular pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9092928171157837}]}, {'Id': 110, 'BeginOffset': 2375, 'EndOffset': 2399, 'Score': 0.9377449750900269, 'Text': 'changes in taste of food', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7322067022323608}]}, {'Text': 'your blood', 'Type': 'TEST', 'BeginOffset': 2450, 'EndOffset': 2460}, {'Id': 117, 'BeginOffset': 2464, 'EndOffset': 2474, 'Score': 0.6691615581512451, 'Text': 'urine test', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 111, 'BeginOffset': 2497, 'EndOffset': 2509, 'Score': 0.9298073053359985, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7695973515510559}]}, {'Id': 112, 'BeginOffset': 2525, 'EndOffset': 2537, 'Score': 0.9229269623756409, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7549090385437012}]}, {'Id': 113, 'BeginOffset': 2601, 'EndOffset': 2613, 'Score': 0.9541658163070679, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6725427508354187}]}, {'Id': 114, 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{'Title': '5. how to store clopidogrel teva pharma', 'Section_Content': None, 'Entity_Recognition': None}

{'Title': '6. contents of the pack and other information', 'Section_Content': "what clopidogrel teva pharma contains the active substance is clopidogrel. each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride). the other ingredients are (see section 2 'clopidogrel teva pharma contains hydrogenated castor oil'): tablet core: microcrystalline cellulose, colloidal anhydrous silica, crospovidone (type a), macrogol 6000 and hydrogenated castor oil tablet coating: polyvinyl alcohol, titanium dioxide (e171), red iron oxide (e172), yellow iron oxide (e172), talc and macrogol 3000. what clopidogrel teva pharma looks like and contents of the pack the film-coated tablets are pink, round and slightly convex. boxes of 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in blisters or boxes of 28x1 and 50x1 film-coated tablets in perforated unit dose blisters are available. not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'clopidogrel teva pharma', 'Type': 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C9E8D7498E39356E239560CC21BAE76F

https://www.ema.europa.eu/documents/product-information/potactasol-epar-product-information_en.pdf

Potactasol

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Potactasol 1 mg powder for concentrate for solution for infusion Potactasol 4 mg powder for concentrate for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Potactasol 1 mg powder for concentrate for solution for infusion Each vial contains 1 mg topotecan (as hydrochloride). After reconstitution, 1 ml concentrate contains 1 mg topotecan. Excipient with known effect Each vial contains 0.52 mg (0.0225 mmol) sodium. Potactasol 4 mg powder for concentrate for solution for infusion Each vial contains 4 mg topotecan (as hydrochloride). After reconstitution, 1 ml concentrate contains 1 mg topotecan. Excipient with known effect Each vial contains 2.07 mg (0.09 mmol) sodium. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for concentrate for solution for infusion. Yellow lyophilisate. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Topotecan monotherapy is indicated for the treatment of: - patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy - patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate (see section 5.1). Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination (see section 5.1). 4.2 Posology and method of administration The use of topotecan should be confined to units specialised in the administration of cytotoxic chemotherapy. Topotecan should only be administered under the supervision of a physician experienced in the use of chemotherapy (see section 6.6). Posology When topotecan is used in combination with cisplatin, the full prescribing information for cisplatin should be consulted. 3 Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of ≥ 1.5 x 109/l, a platelet count of ≥ 100 x 109/l and a haemoglobin level of ≥ 9 g/dl (after transfusion if necessary). Ovarian and small cell lung carcinoma Initial dose The recommended dose of topotecan is 1.5 mg/m2 body surface area per day administered by intravenous infusion over 30 minutes daily for five consecutive days with a three week interval between the start of each course. If well tolerated, treatment may continue until disease progression (see sections 4.8 and 5.1). Subsequent doses Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/l, the platelet count is ≥ 100 x 109/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary). Standard oncology practice for the management of neutropenia is either to administer topotecan with other medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts. If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/l) for seven days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.25 mg/m2/day to 1.25 mg/m2/day (or subsequently down to 1.0 mg/m2/day if necessary). Doses should be similarly reduced if the platelet count falls below 25 x 109/l. In clinical studies, topotecan was discontinued if the dose had been reduced to 1.0 mg/m2/day and a further dose reduction was required to manage adverse effects. Cervical carcinoma Initial dose The recommended dose of topotecan is 0.75 mg/m2/day administered as a 30-minute intravenous infusion on days 1, 2 and 3. Cisplatin is administered as an intravenous infusion on day 1 at a dose of 50 mg/m2/day and following the topotecan dose. This treatment schedule is repeated every 21 days for six courses or until progressive disease. Subsequent doses Topotecan should not be re-administered unless the neutrophil count is ≥ 1.5 x 109/l, the platelet count is ≥ 100 x 109/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary). Standard oncology practice for the management of neutropenia is either to administer topotecan with other medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts. If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/l) for seven days or more, or severe neutropenia associated with fever or infection or who have had treatment delayed due to neutropenia, the dose should be reduced by 20 % to 0.60 mg/m2/day for subsequent courses (or subsequently down to 0.45 mg/m2/day if necessary). Doses should be similarly reduced if the platelet count falls below 25 x 109/l. Special populations Patients with renal impairment Monotherapy (ovarian and small cell lung carcinoma) There is insufficient experience with the use of topotecan in patients with severely impaired renal function (creatinine clearance <20 ml/min). Use of topotecan in this group of patients is not recommended (see section 4.4). 4 Limited data indicate that the dose should be reduced in patients with moderate renal impairment. The recommended monotherapy dose of topotecan in patients with ovarian or small cell lung carcinoma and a creatinine clearance between 20 and 39 ml/min is 0.75 mg/m2/day for five consecutive days. Combination therapy (cervical carcinoma) In clinical studies with topotecan in combination with cisplatin for the treatment of cervical cancer, therapy was only initiated in patients with serum creatinine less than or equal to 1.5 mg/dl. If, during topotecan/cisplatin combination therapy serum creatinine exceeds 1.5 mg/dl, it is recommended that the full prescribing information be consulted for any advice on cisplatin dose reduction/continuation. If cisplatin is discontinued, there are insufficient data regarding continuing monotherapy with topotecan in patients with cervical cancer. Patients with hepatic impairment A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m2/day for five days every three weeks. A reduction in topotecan clearance was observed. However, there are insufficient data available to make a dose recommendation for this patient group (see section 4.4). There is insufficient experience with the use of topotecan in patients with severely impaired hepatic function (serum bilirubin ≥ 10 mg/dl) due to cirrhosis. Topotecan is not recommended to be used in this patient group (see section 4.4). Paediatric population Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made. Method of administration Potactasol is for intravenous infusion after reconstitution and dilution. It must be reconstituted and further diluted before use (see section 6.6). Precautions to be taken before handling or administering the medicinal product Reconstitution and dilution of the medicinal product must be performed by trained personnel. The preparation should be performed in a designated area under aseptic conditions. Adequate protective disposable gloves, goggles, gown and mask should be worn. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water. Then seek medical evaluation by a physician. In case of skin contact, thoroughly wash the affected area with large amount of water. Always wash hands after removing gloves. See section 6.6. Pregnant staff should not handle the cytotoxic preparation. 4.3 Contraindications - Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1 - Breast-feeding (see section 4.6) - Severe bone marrow depression prior to starting first course, as evidenced by baseline neutrophils < 1.5 x 109/l and/or a platelet count of < 100 x 109/l. 4.4 Special warnings and precautions for use Haematological toxicity is dose-related and full blood count including platelets should be determined regularly (see section 4.2). As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression. Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.8). 5 Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical studies with topotecan. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered. Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic substances and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed. Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia. This should be taken into account, when prescribing topotecan, e.g. if patients at increased risk of tumour bleeds are considered for therapy. As would be expected, patients with poor performance status (PS > 1) have a lower response rate and an increased incidence of complications such as fever, infection and sepsis (see section 4.8). Accurate assessment of performance status at the time therapy is given is important, to ensure that patients have not deteriorated to PS 3. There is insufficient experience of the use of topotecan in patients with severely impaired renal function (creatinine clearance < 20 ml/min) or severely impaired hepatic function (serum bilirubin ≥ 10 mg/dl) due to cirrhosis. Use of topotecan in these patient groups is not recommended (see section 4.2). A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m2/day for five days every three weeks. A reduction in topotecan clearance was observed. However, there are insufficient data available to make a dose recommendation for this patient group (see section 4.2). This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium- free’. 4.5 Interaction with other medicinal products and other forms of interaction No in vivo human pharmacokinetic interaction studies have been performed. Topotecan does not inhibit human P450 enzymes (see section 5.2). In a population study using the intravenous route, the co-administration of granisetron, ondansetron, morphine or corticosteroids did not appear to have a significant effect on the pharmacokinetics of total topotecan (active and inactive form). When combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal product may be required to improve tolerability. However, when combining with platinum agents, there is a distinct sequence-dependent interaction depending on whether the platinum agent is given on day 1 or 5 of the topotecan dosing. If either cisplatin or carboplatin is given on day 1 of the topotecan dosing, a lower dose of each agent must be given to improve tolerability compared to the dose of each agent which can be given if the platinum agent is given on day 5 of the topotecan dosing. When topotecan (0.75 mg/m2/day for 5 consecutive days) and cisplatin (60 mg/m2/day on day 1) were administered in 13 patients with ovarian cancer, a slight increase in AUC (12 %, n = 9) and Cmax (23 %, n = 11) was noted on day 5. This increase is considered unlikely to be of clinical relevance. 4.6 Fertility, pregnancy and lactation Women of childbearing potential / Contraception in males and females 6 Topotecan has been shown to cause embryo-foetal lethality and malformations in preclinical studies (see section 5.3). As with other cytotoxic medicinal products, topotecan may cause foetal harm and therefore women of childbearing potential should be advised to avoid becoming pregnant during therapy with topotecan. As with all cytotoxic chemotherapy, patients being treated with topotecan must be advised that they or their partner must use an effective method of contraception. Pregnancy If topotecan is used during pregnancy, or if the patient becomes pregnant during therapy with topotecan, the patient must be warned of the potential hazards to the foetus. Breast-feeding Topotecan is contraindicated during breast-feeding (see section 4.3). Although it is not known whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at the start of therapy. Fertility No effects on male or female fertility have been observed in reproductive toxicity studies in rats (see section 5.3). However, as with other cytotoxic medicinal products topotecan is genotoxic and effects on fertility, including male fertility, cannot be excluded. 4.7 Effects on ability to drive and use machines No studies of the effects on the ability to drive and use machines have been performed. However, caution should be observed when driving or operating machines if fatigue and asthenia persist. 4.8 Undesirable effects In dose-finding studies involving 523 patients with relapsed ovarian cancer and 631 patients with relapsed small cell lung cancer, the dose limiting toxicity of topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible. There were no signs of cumulative haematological or non-haematological toxicity. The safety profile of topotecan when given in combination with cisplatin in the cervical cancer clinical studies is consistent with that seen with topotecan monotherapy. The overall haematological toxicity is lower in patients treated with topotecan in combination with cisplatin compared to topotecan monotherapy, but higher than with cisplatin alone. Additional adverse events were seen when topotecan was given in combination with cisplatin, however, these events were seen with cisplatin monotherapy and were not attributable to topotecan. The prescribing information for cisplatin should be consulted for a full list of adverse events associated with cisplatin use. The integrated safety data for topotecan monotherapy are presented below. Adverse reactions are listed below, by system organ class and absolute frequency (all reported events). Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 7 Infections and infestations Very common: infection Common: sepsis1 Blood and lymphatic system disorders Very common: febrile neutropenia neutropenia (see Gastrointestinal disorders below) thrombocytopenia anaemia leucopenia Common: pancytopenia Not known: severe bleeding (associated with thrombocytopenia) Immune system disorders Common: hypersensitivity reaction including rash Rare: anaphylactic reaction angioedema urticaria Metabolism and nutrition disorders Very common: anorexia (which may be severe) Respiratory, thoracic and mediastinal disorders Rare: interstitial lung disease (some cases have been fatal) Gastrointestinal disorders Very common: nausea, vomiting and diarrhoea (all of which may be severe) constipation abdominal pain2 mucositis Not known: gastrointestinal perforation Hepatobiliary disorders Common: hyperbilirubinaemia Skin and subcutaneous tissue disorders Very common: alopecia Common: pruritus General disorders and administration site conditions Very common: pyrexia asthenia fatigue Common: malaise Very rare: extravasation3 Not known: mucosal inflammation 1 Fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.4) 2 Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia (see section 4.4). 3 Reactions have been mild and have not generally required specific therapy. The adverse events listed above have the potential to occur with a higher frequency in patients who have a poor performance status (see section 4.4). The frequencies associated with the haematological and non-haematological adverse events listed below represent the adverse event reports considered to be related/possibly related to topotecan therapy. Haematological Neutropenia: Severe (neutrophil count < 0.5 x 109/l) during course 1 in 55 % of patients, with duration ≥ seven days in 20 % and overall in 77 % of patients (39 % of courses). In association with severe neutropenia, fever or infection occurred in 16 % of patients during course 1 and overall in 23 % 8 of patients (6 % of courses). Median time to onset of severe neutropenia was nine days and the median duration was seven days. Severe neutropenia lasted beyond seven days in 11 % of courses overall. Among all patients treated in clinical studies (including both those with severe neutropenia and those who did not develop severe neutropenia), 11 % (4 % of courses) developed fever and 26 % (9 % of courses) developed infection. In addition, 5 % of all patients treated (1 % of courses) developed sepsis (see section 4.4). Thrombocytopenia: Severe (platelets < 25 x 109/l) in 25 % of patients (8 % of courses); moderate (platelets between 25.0 and 50.0 x 109/l) in 25 % of patients (15 % of courses). Median time to onset of severe thrombocytopenia was day 15 and the median duration was five days. Platelet transfusions were given in 4 % of courses. Reports of significant sequelae associated with thrombocytopenia including fatalities due to tumour bleeds have been infrequent. Anaemia: Moderate to severe (Hb ≤ 8.0 g/dl) in 37 % of patients (14 % of courses). Red cell transfusions were given in 52 % of patients (21 % of courses). Non-haematological Frequently reported non-haematological effects were gastrointestinal such as nausea (52 %), vomiting (32 %), diarrhoea (18 %), constipation (9 %) and mucositis (14 %). The incidence of severe (Grade 3 or 4) nausea, vomiting, diarrhoea and mucositis was 4, 3, 2 and 1 % respectively. Mild abdominal pain was reported in 4 % of patients. Fatigue was observed in approximately 25 % and asthenia in 16 % of patients receiving topotecan. Severe (Grade 3 or 4) fatigue and asthenia both occurred with an incidence of 3 %. Total or pronounced alopecia was observed in 30 % of patients and partial alopecia in 15 % of patients. Other severe events that were recorded as related or possibly related to topotecan treatment were anorexia (12 %), malaise (3 %) and hyperbilirubinaemia (1 %). Hypersensitivity reactions including rash, urticaria, angioedema and anaphylactic reactions have been reported rarely. In clinical studies, rash was reported in 4 % of patients and pruritus in 1.5 % of patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Overdoses have been reported in patients being treated with intravenous topotecan (up to 10 fold of the recommended dose) and topotecan capsules (up to 5 fold of the recommended dose). The signs and symptoms observed following overdose were consistent with the known undesirable events associated with topotecan (see section 4.8). The primary complications of overdose are bone marrow suppression and mucositis. In addition, elevated hepatic enzymes have been reported with intravenous topotecan overdose. There is no known antidote for topotecan overdose. Further management should be as clinically indicated or as recommended by the national poisons centre, where available. 5. PHARMACOLOGICAL PROPERTIES http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 9 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XX17. Mechanism of action The anti-tumour activity of topotecan involves the inhibition of topoisomerase-I, an enzyme intimately involved in DNA replication as it relieves the torsional strain introduced ahead of the moving replication fork. Topotecan inhibits topoisomerase-I by stabilising the covalent complex of enzyme and strand-cleaved DNA which is an intermediate of the catalytic mechanism. The cellular sequela of inhibition of topoisomerase-I by topotecan is the induction of protein-associated DNA single-strand breaks. Clinical efficacy and safety Relapsed ovarian cancer In a comparative study of topotecan and paclitaxel in patients previously treated for ovarian carcinoma with platinum based chemotherapy (n = 112 and 114, respectively), the response rate (95 % CI) was 20.5 % (13 %, 28 %) versus 14 % (8 %, 20 %) and median time to progression 19 weeks versus 15 weeks (hazard ratio 0.7 [0.6, 1.0]), for topotecan and paclitaxel, respectively. Median overall survival was 62 weeks for topotecan versus 53 weeks for paclitaxel (hazard ratio 0.9 [0.6, 1.3]). The response rate in the whole ovarian carcinoma programme (n = 392, all previously treated with cisplatin or cisplatin and paclitaxel) was 16 %. The median time to response in clinical studies was 7.6-11.6 weeks. In patients refractory to, or relapsing within 3 months after cisplatin therapy (n = 186), the response rate was 10 %. These data should be evaluated in the context of the overall safety profile of the medicinal product, in particular of the significant haematological toxicity (see section 4.8). A supplementary retrospective analysis was conducted on data from 523 patients with relapsed ovarian cancer. Overall, 87 complete and partial responses were observed, with 13 of these occurring during cycles 5 and 6 and 3 occurring thereafter. Of the patients who received more than 6 cycles of therapy, 91 % completed the study as planned or were treated until disease progression with only 3 % withdrawn for adverse events. Relapsed SCLC A Phase III study (Study 478) compared oral topotecan plus best supportive care (BSC) (n = 71) with BSC alone (n = 70) in patients who had relapsed following first line therapy (median time to progression [TTP] from first-line therapy: 84 days for oral topotecan plus BSC, 90 days for BSC alone) and for whom re-treatment with intravenous chemotherapy was not considered appropriate. In the oral topotecan plus BSC group there was a statistically significant improvement in overall survival compared with the BSC alone group (Log-rank p = 0.0104). The unadjusted hazard ratio for the oral topotecan plus BSC group relative to the BSC alone group was 0.64 (95 % CI: 0.45, 0.90). Median survival in patients treated with oral topotecan plus BSC was 25.9 weeks (95 % CI 18.3, 31.6) compared to 13.9 weeks (95 % CI 11.1, 18.6) for patients receiving BSC alone (p = 0.0104). Patient self-reports of symptoms using an unblinded assessment showed a consistent trend for symptom benefit for oral topotecan plus BSC. One Phase II study (Study 065) and one Phase III study (Study 396) were conducted to evaluate the efficacy of oral topotecan versus intravenous topotecan in patients who had relapsed ≥ 90 days after completion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were associated with similar symptom palliation in patients with relapsed sensitive SCLC in patient self- reports on an unblinded symptom scale assessment in each of these two studies. 10 Table 1. Summary of survival, response rate, and time to progression in SCLC patients treated with oral or intravenous topotecan Study 065 Study 396 Oral topotecan Intravenous topotecan Oral topotecan Intravenous topotecan (N = 52) (N = 54) (N = 153) (N = 151) Median survival (weeks) 32.3 25.1 33.0 35.0 (95 % CI) (26.3, 40.9) (21.1, 33.0) (29.1, 42.4) (31.0, 37.1) Hazard ratio (95 % CI) 0.88 (0.59, 1.31) 0.88 (0.7, 1.11) Response rate (%) 23.1 14.8 18.3 21.9 (95 % CI) (11.6, 34.5) (5.3, 24.3) (12.2, 24.4) (15.3, 28.5) Difference in response rate (95 % CI) 8.3 (-6.6, 23.1) -3.6 (-12.6, 5.5) Median time to progression (weeks) 14.9 13.1 11.9 14.6 (95 % CI) (8.3, 21.3) (11.6, 18.3) (9.7, 14.1) (13.3, 18.9) Hazard ratio (95 % CI) 0.90 (0.60, 1.35) 1.21 (0.96, 1.53) N = total number of patients treated. CI = confidence interval. In another randomised Phase III study which compared intravenous (IV) topotecan to cyclophosphamide, doxorubicin and vincristine (CAV) in patients with relapsed, sensitive SCLC, the overall response rate was 24.3 % for topotecan compared to 18.3 % for the CAV group. Median time to progression was similar in the two groups (13.3 weeks and 12.3 weeks, respectively). Median survivals for the two groups were 25.0 and 24.7 weeks respectively. The hazard ratio for survival with IV topotecan relative to CAV was 1.04 (95 %, CI 0.78 -1.40). The response rate to topotecan in the combined small cell lung cancer programme (n = 480) for patients with relapsed disease sensitive to first-line therapy, was 20.2 %. Median survival was 30.3 weeks (95 % CI: 27.6, 33.4). In a population of patients with refractory SCLC (those not responding to first-line therapy), the response rate to topotecan was 4.0 %. Cervical carcinoma In a randomised, comparative Phase III study conducted by the Gynecologic Oncology Group (GOG 0179), topotecan plus cisplatin (n = 147) was compared with cisplatin alone (n = 146) for the treatment of histologically confirmed persistent, recurrent or Stage IVB carcinoma of the cervix where curative treatment with surgery and/or radiation was not considered appropriate. Topotecan plus cisplatin had a statistically significant benefit in overall survival relative to cisplatin monotherapy after adjusting for interim analyses (Log-rank p = 0.033). Table 2. Study results Study GOG-0179 ITT population Cisplatin 50 mg/m2 on day 1, every 21 days Cisplatin 50 mg/m2 on day 1, + Topotecan 0,75 mg/m2 on days 1–3, every 21 days Survival (months) (n = 146) (n = 147) Median (95 % CI) 6.5 (5.8, 8.8) 9.4 (7.9, 11.9) Hazard ratio (95 % CI) 0.76 (0.59, 0.98) Log rank p-value 0.033 Patients without prior cisplatin chemoradiotherapy Cisplatin Topotecan/Cisplatin 11 Survival (months) (n = 46) (n = 44) Median (95 % CI) 8.8 (6.4, 11.5) 15.7 (11.9, 17.7) Hazard ratio (95 % CI) 0.51 (0.31, 0.82) Patients with prior cisplatin chemoradiotherapy Cisplatin Topotecan/Cisplatin Survival (months) (n = 72) (n = 69) Median (95 % CI) 5.9 (4.7, 8.8) 7.9 (5.5, 10.9) Hazard ratio (95 % CI) 0.85 (0.59, 1.21) In patients (n = 39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the median survival in the topotecan plus cisplatin arm was 4.6 months (95 % CI: 2.6, 6.1) versus 4.5 months (95 % CI: 2.9, 9.6) for the cisplatin arm with a hazard ratio of 1.15 (0.59, 2.23). In those patients (n = 102) with recurrence after 180 days, median survival in the topotecan plus cisplatin arm was 9.9 months (95 % CI: 7, 12.6) versus 6.3 months (95 % CI: 4.9, 9.5) for the cisplatin arm with a hazard ratio of 0.75 (0.49, 1.16). Paediatric population Topotecan was also evaluated in the paediatric population; however, only limited data on efficacy and safety are available. In an open-label study involving children (n = 108, age range: infant to 16 years) with recurrent or progressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m2 given as a 30 minute infusion for 5 days repeated every 3 weeks for up to one year depending on response to therapy. Tumour types included were Ewing's sarcoma/primitive neuroectodermal tumour, neuroblastoma, osteoblastoma, and rhabdomyosarcoma. Anti-tumour activity was demonstrated primarily in patients with neuroblastoma. Toxicities of topotecan in paediatric patients with recurrent and refractory solid tumours were similar to those historically seen in adult patients. In this study, forty-six (43 %) patients received G-CSF over 192 (42.1 %) courses; sixty-five (60 %) received transfusions of packed red blood cells and fifty (46 %) of platelets over 139 and 159 courses (30.5 % and 34.9 %), respectively. Based on the dose-limiting toxicity of myelosuppression, the maximum tolerated dose (MTD) was established at 2.0 mg/m2/day with G-CSF and 1.4 mg/m2/day without G-CSF in a pharmacokinetic study in paediatric patients with refractory solid tumours (see section 5.2). 5.2 Pharmacokinetic properties Distribution Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m2 as a 30 minute infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22), corresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume of distribution, about 132 l, (SD 57), and a relatively short half-life of 2-3 hours. Comparison of pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of dosing. Area under the curve increased approximately in proportion to the increase in dose. There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in the pharmacokinetics after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low (35 %) and distribution between blood cells and plasma was fairly homogeneous. Biotransformation The elimination of topotecan has only been partly investigated in man. A major route of clearance of topotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate. Metabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite, which was shown to have similar or less activity than the parent in a cell-based assay, was found in urine, plasma, and faeces. The mean metabolite:parent AUC ratio was < 10 % for both total topotecan and 12 topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine. Elimination Overall recovery of topotecan-related material following five daily doses of topotecan was 71 to 76 % of the administered IV dose. Approximately 51 % was excreted as total topotecan and 3 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl metabolite contributed a mean of less than 7 % (range 4-9 %) of the total topotecan-related material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide in the urine were less than 2.0 %. In vitro data using human liver microsomes indicate the formation of small amounts of N-demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A or CYP4A nor did it inhibit the human cytosolic enzymes dihydropyrimidine or xanthine oxidase. When given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance of topotecan was reduced on day 5 compared to day 1 (19.1 l/h/m2 compared to 21.3 l/h/m2 [n = 9]) (see section 4.5). Special populations Hepatic impairment Plasma clearance in patients with hepatic impairment (serum bilirubin between 1.5 and 10 mg/dl) decreased to about 67 % when compared with a control group of patients. Topotecan half-life was increased by about 30 % but no clear change in volume of distribution was observed. Plasma clearance of total topotecan (active and inactive form) in patients with hepatic impairment only decreased by about 10 % compared with the control group of patients. Renal impairment Plasma clearance in patients with renal impairment (creatinine clearance 41-60 ml/min.) decreased to about 67 % compared with control patients. Volume of distribution was slightly decreased and thus half-life only increased by 14 %. In patients with moderate renal impairment topotecan plasma clearance was reduced to 34 % of the value in control patients. Mean half-life increased from 1.9 hours to 4.9 hours. Age/weight In a population study, a number of factors including age, weight and ascites had no significant effect on clearance of total topotecan (active and inactive form). Paediatric population The pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in two studies. One study included a dose range of 1.4 to 2.4 mg/m2 in children (aged 2 up to 12 years, n = 18), adolescents (aged 12 up to 16 years, n = 9) and young adults (aged 16 to 21 years, n = 9) with refractory solid tumours. The second study included a dose range of 2.0 to 5.2 mg/m2 in children (n = 8), adolescents (n = 3) and young adults (n = 3) with leukaemia. In these studies, there were no apparent differences in the pharmacokinetics of topotecan among children, adolescents, and young adult patients with solid tumours or leukaemia, but data are too limited to draw definite conclusions. 5.3 Preclinical safety data Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and mouse bone marrow cells in vivo. Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits. 13 In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; however, in females super-ovulation and slightly increased pre-implantation loss were observed. The carcinogenic potential of topotecan has not been studied. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Mannitol (E421) Tartaric acid (E334) Sodium hydroxide Hydrochloric acid (E507) 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Vials 4 years. Reconstituted and diluted solution Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C in normal light conditions, and for 24 hours at 2°C to 8°C when protected from light. Chemical and physical stability of the solution obtained after dilution of the concentrate in sodium chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has been demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions. The concentrates tested were stored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, and then diluted. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. 6.4 Special precautions for storage Keep the vial in the outer carton in order to protect from light. For storage conditions of the reconstituted and diluted medicinal product, see section 6.3. 6.5 Nature and contents of container Potactasol 1 mg powder for concentrate for solution for infusion Type I colourless glass vial (5 ml) with grey bromobutylic stopper and aluminium seal with plastic flip-off cap containing 1 mg topotecan. Potactasol 4 mg powder for concentrate for solution for infusion Type I colourless glass vial (8 ml), with grey bromobutylic stopper and aluminium seal with plastic flip-off cap containing 4 mg topotecan. Vials may or may not be sheathed in a protective sleeve. 14 Potactasol is available in cartons containing 1 vial. 6.6 Special precautions for disposal and other handling Potactasol 1 mg powder for concentrate for solution for infusion Potactasol 1 mg vials must be reconstituted with 1.1 ml water for injections. The clear concentrate is pale yellow in colour and provides 1 mg per ml of topotecan, as Potactasol 1 mg contains a 10 % overage of fill. Further dilution of the appropriate volume of the reconstituted solution with either sodium chloride 9 mg/ml (0.9 %) or 5 % w/v glucose is required to give a final concentration of between 25 and 50 microgram/ml. Potactasol 4 mg powder for concentrate for solution for infusion Potactasol 4 mg vials must be reconstituted with 4 ml water for injections. The clear concentrate is pale yellow in colour and provides 1 mg per ml of topotecan. Further dilution of the appropriate volume of the reconstituted solution with either sodium chloride 9 mg/ml (0.9 %) or 5 % w/v glucose is required to give a final concentration of between 25 and 50 microgram/ml. The normal procedures for proper handling and disposal of anticancer medicinal products should be adopted, namely: − Personnel should be trained to reconstitute and dilute the the medicinal product. − Pregnant staff should be excluded from working with this medicinal product. − Personnel handling this medicinal product during reconstitution and dilution should wear protective clothing including mask, goggles and gloves. − Accidental contact with the skin or eyes should be treated immediately with copious amounts of water. − All items for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high-temperature incineration. 7. MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. Reykjavíkurvegi 76-78 IS-220 Hafnarfjörður Iceland 8. MARKETING AUTHORISATION NUMBER(S) Potactasol 1 mg powder for concentrate for solution for infusion EU/1/10/660/001 Potactasol 4 mg powder for concentrate for solution for infusion EU/1/10/660/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 6 January 2011 Date of latest renewal: 5 October 2015 10. DATE OF REVISION OF THE TEXT 15 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. http://www.ema.europa.eu/ 16 ANNEX II A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 17 A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer responsible for batch release S.C. Sindan-Pharma S.R.L. 11 Ion Mihalache Blvd. 011171 Bucharest Romania B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic Safety Update Reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP) Not applicable. 18 ANNEX III LABELLING AND PACKAGE LEAFLET 19 A. LABELLING 20 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Outer Carton 1. NAME OF THE MEDICINAL PRODUCT Potactasol 1 mg powder for concentrate for solution for infusion topotecan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 1 mg topotecan (as hydrochloride). After reconstitution, 1 ml concentrate contains 1 mg topotecan. 3. LIST OF EXCIPIENTS Contains mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium hydroxide. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for concentrate for solution for infusion. 1 x 1 mg vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For intravenous use as infusion, after reconstitution and dilution. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic, special handling instructions (see package leaflet). Cytotoxic 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Keep the vial in the outer carton in order to protect from light. 21 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/660/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 22 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Potactasol 1 mg powder for concentrate for solution for infusion topotecan IV 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 mg 6. OTHER Cytotoxic 23 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Outer Carton 1. NAME OF THE MEDICINAL PRODUCT Potactasol 4 mg powder for concentrate for solution for infusion topotecan 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 4 mg topotecan (as hydrochloride). After reconstitution, 1 ml concentrate contains 1 mg topotecan. 3. LIST OF EXCIPIENTS Contains mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium hydroxide. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for concentrate for solution for infusion. 1 x 4 mg vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For intravenous use as infusion, after reconstitution and dilution. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Cytotoxic, special handling instructions (see package leaflet). Cytotoxic 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Keep the vial in the outer carton in order to protect from light. 24 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. 220 Hafnarfjörður Iceland 12. MARKETING AUTHORISATION NUMBER(S) EU/1/10/660/002 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA PC: SN: NN: 25 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Vial 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Potactasol 4 mg powder for concentrate for solution for infusion topotecan IV 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 4 mg 6. OTHER Cytotoxic 26 B. PACKAGE LEAFLET 27 Package leaflet: Information for the user Potactasol 1 mg powder for concentrate for solution for infusion Potactasol 4 mg powder for concentrate for solution for infusion topotecan Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or nurse. - If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Potactasol is and what it is used for 2. What you need to know before you use Potactasol 3. How to use Potactasol 4. Possible side effects 5. How to store Potactasol 6. Contents of the pack and other information 1. What Potactasol is and what it is used for Potactasol contains the active substance topotecan which helps to kill tumour cells. Potactasol is used to treat: - ovarian cancer or small cell lung cancer that has come back after chemotherapy - advanced cervical cancer if surgery or radiotherapy is not possible. In this case Potactasol treatment is combined with medicines containing cisplatin. 2. What you need to know before you use Potactasol Do not use Potactasol - if you are allergic to topotecan or any of the other ingredients of this medicine (listed in section 6); - if you are breast-feeding.; - if your blood cell counts are too low. Your doctor will tell you whether this is the case, based on the results of your last blood test. Tell you doctor if you think any of these could apply to you. Warnings and precautions Talk to your doctor before using Potactasol: - if you have any kidney problems. Your dose of Potactasol may need to be adjusted. Potactasol is not recommended in case of severe kidney impairment; - if you have liver problems. Potactasol is not recommended in case of severe liver impairment; - if you suffer from lung inflammation with signs such as cough, fever and difficulties in breathing, see also section 4 “Possible side effects”. Potactasol may cause a decrease in the number of blood clotting cells (platelets). This can lead to severe bleeding from relatively small injuries such as a small cut. Rarely, it can lead to more severe bleeding (haemorrhage). Talk to your doctor for advice on how to minimize the risk of bleeding. The incidence of side effects is more frequent in patients who are in poor general health. The doctor will evaluate your general health during the treatment and you should tell him/her in case you have fever, infection or are in some ways feeling unwell. 28 Use in children and adolescents The experience in children and adolescents is limited and treatment is therefore not recommended. Other medicines and Potactasol Tell your doctor if you are taking, have recently taken or might take any other medicines. Pregnancy and breast-feeding Potactasol should not be used in pregnant women, unless clearly necessary. If you are or think you might be pregnant, tell your doctor immediately. Effective contraception methods should be used to avoid becoming pregnant or fathering a child while on treatment with Potactasol. Ask your doctor for advice. Patients who are concerned about their fertility should ask their doctor for counselling on fertility and family planning options prior to starting treatment. You must not breast-feed while on treatment with Potactasol. Driving and using machines Potactasol can make you feel tired or weak. If you experience this, do not drive or use machines. Potactasol contains sodium This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’. 3. How to use Potactasol Your dose of Potactasol will depend on: - the disease being treated, - your body surface area (m2), - the results of blood tests carried out before and during treatment, - how well you tolerate treatment. Adults Ovarian cancer and small cell lung cancer The usual dose is 1.5 mg per m2 of body surface area once daily for 5 days. This treatment cycle will normally be repeated every three weeks. Cervical cancer The usual dose is 0.75 mg per m2 of body surface area once daily for 3 days. This treatment cycle will normally be repeated every three weeks. For cervical cancer, it will be used together with another anticancer medicines containing cisplatin. For more information about cisplatin, please refer to the corresponding package leaflet. Patients with impaired kidney function Your doctor might need to reduce your dose based on your kidney function. How Potactasol is prepared Topotecan is supplied as a powder for concentrate for solution for infusion. The powder must be dissolved, and the resulting concentrate further diluted before administration. How Potactasol is given A doctor or nurse will give you the reconstituted and diluted Potactasol solution as an infusion (drip), usually into your arm, over about 30 minutes. If you are given too much Potactasol 29 As this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much. In the unlikely event of an overdose, your doctor will monitor you for side effects. Tell your doctor or nurse if you have any concerns about the amount of medicine that you receive. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious side effects You must tell your doctor immediately if you experience any of the following serious side effects. They may require hospitalisation and could even be life-threatening. - Infections (very common; may affect more than 1 in 10 people), with signs such as: - fever - serious decline of your general condition - local symptoms, such as sore throat or burning sensation when urinating - severe stomach pain, fever and possibly diarrhoea (rarely with blood) can be signs of bowel inflammation (neutropenic colitis) Potactasol may reduce your ability to fight infections. - Lung inflammation (rare; may affect up to 1 in 1,000 people), with signs such as: - difficulty breathing - cough - fever The risk of developing this severe condition (interstitial lung disease) is higher if you currently have lung problems, or if you have received previous radiation treatment or medicines that affected your lungs, see also section 2 “Warnings and precautions”. This condition can be fatal. - Severe allergic (anaphylactic) reactions (rare; may affect up to 1 in 1,000 people), with signs such as: - swelling of the face, lips, tongue or throat, difficulty breathing, low blood pressure, dizziness and itchy rash. Other side effects with Potactasol include: Very common side effects (may affect more than 1 in 10 people) - Feeling generally weak and tired, which can be symptoms of a decrease in the number of red blood cells (anaemia). In some cases you may need a blood transfusion. - Decrese in number of circulating white blood cells (leucotyes) in the blood. Abnormal low number of neutrophil granulocytes (a type of white blood cell) in the blood, with or without fever. - Unusual bruising or bleeding, sometimes severe, caused by a decrease in the number of blood clotting cells (platelets). - Weight loss and loss of appetite (anorexia); tiredness; weakness. - Feeling sick (nausea), vomiting; diarrhoea; stomach pain; constipation. - Inflammation of the lining of the mouth and digestive tract. - Fever. - Hair loss. Common side effects (may affect up to 1 in 10 people) - Allergic (hypersensitivity) reactions (including rash). - Abnormal high level of bilirubin, a waste product produced by the liver during breakdown of red blood cells. Symptoms may include yellow skin (jaundice). - Decrease in the number of all blood cells (pancytopenia). - Feeling unwell. - Serious blood infection, which can be fatal. 30 - Itching (pruritus). Rare side effects (may affect up to 1 in 1,000 people) - Swelling caused by fluid build-up (angioedema) e.g. around the eyes and lips as well as hands, feet and throat. If severe it may cause breathing difficulties. - Itchy rash (or hives). Very rare side effects (may affect up to 1 in 10,000 people) - Mild pain and inflammation at the site of injection due to accidental administration of the medicinal product into the surrounding tissue (extravasation) e.g. by leakage. Not known (frequency cannot be estimated from the available data) - Severe stomach pain, nausea, vomiting of blood, black or bloody stools (possible symptoms of gastrointestinal perforation). - Mouth sores, difficulty swallowing, abdominal pain, nausea, vomiting, diarrhoea, bloody stools (possible signs and symptoms of inflammation of the inner lining of the mouth, stomach and/or gut [mucosal inflammation]). If you are being treated for cervical cancer, you may get side effects from the other medicine (cisplatin) that you will be given along with Potactasol. Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Potactasol Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the vial and carton after EXP. The expiry date refers to the last day of that month. Keep the vial in the outer carton in order to protect from light. Storage after reconstitution and dilution Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in normal light conditions and 24 hours at 2°C to 8°C, protected from light. The physico-chemical stability of the medicinal product solution obtained after dilution in solutions for infusion (NaCl 0.9 % and Glucose 5 %) has been demonstrated for 4 hours at room temperature, in normal lighting conditions, on samples reconstituted and stored for 12 hours and respectively 24 hours at 25oC ± 2oC and then diluted. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic material. 6. Contents of the pack and other information http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc 31 What Potactasol contains - The active substance is topotecan. Each vial contains 1 mg or 4 mg topotecan (as hydrochloride). After reconstitution 1 ml concentrate contains 1 mg topotecan. - The other ingredients are: mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium hydroxide (see section 2). What Potactasol looks like and contents of the pack Potactasol is supplied in type I colourless glass vials with grey bromobutylic stopper and aluminium seals with plastic flip-off caps. Vials may or may not be sheathed in a protective sleeve. Vials contain either 1 mg or 4 mg of topotecan. Each pack contains one vial. Marketing Authorisation Holder Actavis Group PTC ehf. Reykjavíkurvegi 76-78 220 Hafnarfjörður Iceland Manufacturer S.C. Sindan-Pharma S.R.L. 11 Ion Mihalache Blvd Bucharest Romania For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Actavis Group PTC ehf. IJsland/Islande/Island Tél/Tel: +354 5503300 Lietuva UAB Teva Baltics Tel: +370 52660203 България Тева Фарма ЕАД Teл: +359 24899585 Luxembourg/Luxemburg Actavis Group PTC ehf. Islande/Island Tél/Tel: +354 5503300 Česká republika Teva Pharmaceuticals CR, s.r.o. Tel: +420 251007111 Magyarország Teva Gyógyszergyár Zrt. Tel: +36 12886400 Danmark Teva Denmark A/S Tlf: +45 44985511 Malta Actavis Ltd. Tel: +356 21693533 Deutschland PUREN Pharma GmbH & Co. KG Tel: +49 895589090 Nederland Actavis Group PTC ehf. IJsland Tel: +354 5503300 Eesti UAB Teva Baltics Eesti filiaal Tel: +372 6610801 Norge Teva Norway AS Tlf: +47 66775590 32 Ελλάδα Specifar A.B.E.E. Τηλ: +30 2118805000 Österreich ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1970070 España Actavis Group PTC ehf. Islandia Tel: +354 5503300 Polska Teva Pharmaceuticals Polska Sp. z o.o. Tel: +48 223459300 France Actavis Group PTC ehf. Islande Tél: +354 5503300 Portugal Teva Pharma - Produtos Farmacêuticos, Lda. Tel: +351 214767550 Hrvatska Pliva Hrvatska d.o.o. Tel: +385 13720000 România Teva Pharmaceuticals S.R.L. Tel: +40 212306524 Ireland Teva Pharmaceuticals Ireland Tel: +353 19127700 Slovenija Pliva Ljubljana d.o.o. Tel: +386 15890390 Ísland Teva Pharma Iceland ehf. Sími: +354 5503300 Slovenská republika TEVA Pharmaceuticals Slovakia s.r.o. Tel: +421 257267911 Italia Teva Italia S.r.l. Tel: +39 028917981 Suomi/Finland Teva Finland Oy Puh/Tel: +358 201805900 Κύπρος Specifar A.B.E.E. Ελλάδα Τηλ: +30 2118805000 Sverige Teva Sweden AB Tel: +46 42121100 Latvija UAB Teva Baltics filiāle Latvijā Tel: +371 67323666 United Kingdom Actavis UK Limited Tel: +44 1271385257 This leaflet was last revised in {MM/YYYY}. Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. -------------------------------------------------------------------------------------------------------------------------- The following information is intended for healthcare professionals only: Potactasol INSTRUCTIONS ON USE Reconstitution and dilution prior to administration http://www.ema.europa.eu/ 33 Before infusion, Potactasol powder for concentrate for solution for infusion must be reconstituted with an appropriate volume of water for injections, as follows: - Potactasol 1 mg with 1.1 ml water for injections (as it contains 10 % overage of fill) - Potactasol 4 mg with 4 ml water for injections Reconstitution will result in a concentrate containing 1 mg topotecan per ml. This concentrate (1 mg/ml) must be diluted prior to administration. The volume of reconstituted concentrate corresponding to the calculated individual dose should be further diluted with either sodium chloride 9 mg/ml (0.9 %) or 5 % w/v glucose, to give a final concentration of between 25 and 50 microgram per ml in the solution for infusion, for example: Volume for 25 microgram/ml solution Volume for 50 microgram/ml solution 1 ml of 1 mg/ml topotecan solution Add 39 ml to give 40 ml Add 19 ml to give 20 ml 4 ml of 1 mg/ml topotecan solution Add 156 ml to give 160 ml Add 76 ml to give 80 ml Storage after reconstitution and dilution Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C in normal light conditions, and for 24 hours at 2°C to 8°C when protected from light. Chemical and physical stability of the solution obtained after dilution of the concentrate in sodium chloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has been demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions .The concentrates tested were reconstituted and stored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, and then diluted. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. Handling and disposal The normal procedures for proper handling and disposal of anti-tumour medicinal products should be adopted: − Staff should be trained to reconstitute and dilute the the medicinal product. − Pregnant staff should be excluded from working with this medicinal product. − Staff handling this medicinal product during reconstitution and dilution should wear protective clothing including mask, goggles and gloves. − Accidental contact with the skin or eyes should be treated immediately with copious amounts of water. − All items for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high-temperature incineration. SUMMARY OF PRODUCT CHARACTERISTICS A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT A. LABELLING B. PACKAGE LEAFLET

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{'Title': '3. how to use potactasol', 'Section_Content': 'your dose of potactasol will depend on: - the disease being treated, - your body surface area (m2), - the results of blood tests carried out before and during treatment, - how well you tolerate treatment. adults ovarian cancer and small cell lung cancer the usual dose is 1.5 mg per m2 of body surface area once daily for 5 days. this treatment cycle will normally be repeated every three weeks. cervical cancer the usual dose is 0.75 mg per m2 of body surface area once daily for 3 days. this treatment cycle will normally be repeated every three weeks. for cervical cancer, it will be used together with another anticancer medicines containing cisplatin. for more information about cisplatin, please refer to the corresponding package leaflet. patients with impaired kidney function your doctor might need to reduce your dose based on your kidney function. how potactasol is prepared topotecan is supplied as a powder for concentrate for solution for infusion. the powder must be dissolved, and the resulting concentrate further diluted before administration. how potactasol is given a doctor or nurse will give you the reconstituted and diluted potactasol solution as an infusion (drip), usually into your arm, over about 30 minutes. if you are given too much potactasol 29 as this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much. in the unlikely event of an overdose, your doctor will monitor you for side effects. tell your doctor or nurse if you have any concerns about the amount of medicine that you receive.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 13, 'EndOffset': 23, 'Score': 0.7917085886001587, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the disease', 'Type': 'PROBLEM', 'BeginOffset': 42, 'EndOffset': 53}, {'Id': 25, 'BeginOffset': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects you must tell your doctor immediately if you experience any of the following serious side effects. they may require hospitalisation and could even be life-threatening. - infections (very common; may affect more than 1 in 10 people), with signs such as: - fever - serious decline of your general condition - local symptoms, such as sore throat or burning sensation when urinating - severe stomach pain, fever and possibly diarrhoea (rarely with blood) can be signs of bowel inflammation (neutropenic colitis) potactasol may reduce your ability to fight infections. - lung inflammation (rare; may affect up to 1 in 1,000 people), with signs such as: - difficulty breathing - cough - fever the risk of developing this severe condition (interstitial lung disease) is higher if you currently have lung problems, or if you have received previous radiation treatment or medicines that affected your lungs, see also section 2 "warnings and precautions". this condition can be fatal. - severe allergic (anaphylactic) reactions (rare; may affect up to 1 in 1,000 people), with signs such as: - swelling of the face, lips, tongue or throat, difficulty breathing, low blood pressure, dizziness and itchy rash. other side effects with potactasol include: very common side effects (may affect more than 1 in 10 people) - feeling generally weak and tired, which can be symptoms of a decrease in the number of red blood cells (anaemia). in some cases you may need a blood transfusion. - decrese in number of circulating white blood cells (leucotyes) in the blood. abnormal low number of neutrophil granulocytes (a type of white blood cell) in the blood, with or without fever. - unusual bruising or bleeding, sometimes severe, caused by a decrease in the number of blood clotting cells (platelets). - weight loss and loss of appetite (anorexia); tiredness; weakness. - feeling sick (nausea), vomiting; diarrhoea; stomach pain; constipation. - inflammation of the lining of the mouth and digestive tract. - fever. - hair loss. common side effects (may affect up to 1 in 10 people) - allergic (hypersensitivity) reactions (including rash). - abnormal high level of bilirubin, a waste product produced by the liver during breakdown of red blood cells. symptoms may include yellow skin (jaundice). - decrease in the number of all blood cells (pancytopenia). - feeling unwell. - serious blood infection, which can be fatal. - itching (pruritus). rare side effects (may affect up to 1 in 1,000 people) - swelling caused by fluid build-up (angioedema) e.g. around the eyes and lips as well as hands, feet and throat. if severe it may cause breathing difficulties. - itchy rash (or hives). very rare side effects (may affect up to 1 in 10,000 people) - mild pain and inflammation at the site of injection due to accidental administration of the medicinal product into the surrounding tissue (extravasation) e.g. by leakage. not known (frequency cannot be estimated from the available data) - severe stomach pain, nausea, vomiting of blood, black or bloody stools (possible symptoms of gastrointestinal perforation). - mouth sores, difficulty swallowing, abdominal pain, nausea, vomiting, diarrhoea, bloody stools (possible signs and symptoms of inflammation of the inner lining of the mouth, stomach and/or gut [mucosal inflammation]). if you are being treated for cervical cancer, you may get side effects from the other medicine (cisplatin) that you will be given along with potactasol. reporting of side effects if you get any side effects, talk to your doctor or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 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'EndOffset': 3388, 'Text': 'stomach', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9907638430595398, 'RelationshipScore': 0.6822801828384399, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 84, 'BeginOffset': 3396, 'EndOffset': 3399, 'Text': 'gut', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 136, 'BeginOffset': 3454, 'EndOffset': 3469, 'Score': 0.9533217549324036, 'Text': 'cervical cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9636351466178894}]}, {'Id': 137, 'BeginOffset': 3483, 'EndOffset': 3495, 'Score': 0.9125102162361145, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6527734994888306}]}, {'Text': 'the other medicine (cisplatin)', 'Type': 'TREATMENT', 'BeginOffset': 3501, 'EndOffset': 3531}, {'Id': 87, 'BeginOffset': 3566, 'EndOffset': 3576, 'Score': 0.9569910168647766, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 138, 'BeginOffset': 3591, 'EndOffset': 3603, 'Score': 0.9454371929168701, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7773797512054443}]}, {'Id': 139, 'BeginOffset': 3619, 'EndOffset': 3631, 'Score': 0.92707759141922, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7638394832611084}]}, {'Id': 140, 'BeginOffset': 3690, 'EndOffset': 3702, 'Score': 0.959625780582428, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6577098965644836}]}, {'Id': 141, 'BeginOffset': 3751, 'EndOffset': 3763, 'Score': 0.8630843758583069, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7130597829818726}]}, {'Id': 142, 'BeginOffset': 3817, 'EndOffset': 3828, 'Score': 0.3529776334762573, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7306555509567261}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 3910, 'EndOffset': 3923}]}

{'Title': '5. how to store potactasol', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the vial and carton after exp. the expiry date refers to the last day of that month. keep the vial in the outer carton in order to protect from light. storage after reconstitution and dilution chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2, in normal light conditions and 24 hours at 2 to 8, protected from light. the physico-chemical stability of the medicinal product solution obtained after dilution in solutions for infusion (nacl 0.9 % and glucose 5 %) has been demonstrated for 4 hours at room temperature, in normal lighting conditions, on samples reconstituted and stored for 12 hours and respectively 24 hours at 25oc ± 2oc and then diluted. from a microbiological point of view, the product should be used immediately. if not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic material.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 227, 'EndOffset': 243}, {'Text': 'reconstitution', 'Type': 'TREATMENT', 'BeginOffset': 290, 'EndOffset': 304}, {'Text': 'dilution chemical', 'Type': 'TREATMENT', 'BeginOffset': 309, 'EndOffset': 326}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 395, 'EndOffset': 397}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 407, 'EndOffset': 409}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 412, 'EndOffset': 413}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 446, 'EndOffset': 448}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 458, 'EndOffset': 459}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 463, 'EndOffset': 464}, {'Text': 'the medicinal product solution', 'Type': 'TREATMENT', 'BeginOffset': 522, 'EndOffset': 552}, {'Text': 'dilution in solutions', 'Type': 'TREATMENT', 'BeginOffset': 568, 'EndOffset': 589}, {'Text': 'infusion (nacl', 'Type': 'TREATMENT', 'BeginOffset': 594, 'EndOffset': 608}, {'Text': '0.9', 'Type': 'NUMBER', 'BeginOffset': 609, 'EndOffset': 612}, {'Text': 'glucose', 'Type': 'TREATMENT', 'BeginOffset': 619, 'EndOffset': 626}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 627, 'EndOffset': 628}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 658, 'EndOffset': 659}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 758, 'EndOffset': 760}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 784, 'EndOffset': 786}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 1050, 'EndOffset': 1052}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 1062, 'EndOffset': 1063}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 1067, 'EndOffset': 1068}, {'Text': 'reconstitution/dilution', 'Type': 'TREATMENT', 'BeginOffset': 1077, 'EndOffset': 1100}, {'Text': 'any unused product or waste material', 'Type': 'PROBLEM', 'BeginOffset': 1165, 'EndOffset': 1201}, {'Text': 'cytotoxic material', 'Type': 'TREATMENT', 'BeginOffset': 1266, 'EndOffset': 1284}]}

{'Title': '6. contents of the pack and other information', 'Section_Content': 'what potactasol contains - the active substance is topotecan. each vial contains 1 mg or 4 mg topotecan (as hydrochloride). after reconstitution 1 ml concentrate contains 1 mg topotecan. - the other ingredients are: mannitol (e421), tartaric acid (e334), hydrochloric acid (e507) and sodium hydroxide (see section 2). what potactasol looks like and contents of the pack potactasol is supplied in type i colourless glass vials with grey bromobutylic stopper and aluminium seals with plastic flip-off caps. vials may or may not be sheathed in a protective sleeve. vials contain either 1 mg or 4 mg of topotecan. each pack contains one vial.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 15, 'Score': 0.37037527561187744, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 51, 'EndOffset': 60, 'Score': 0.9918953776359558, 'Text': 'topotecan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9419365525245667, 'RelationshipScore': 0.99893718957901, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 81, 'EndOffset': 85, 'Text': '1 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 81, 'EndOffset': 82}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 89, 'EndOffset': 90}, {'Id': 4, 'BeginOffset': 94, 'EndOffset': 103, 'Score': 0.9961233735084534, 'Text': 'topotecan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8393182158470154, 'RelationshipScore': 0.9994053840637207, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 89, 'EndOffset': 93, 'Text': '4 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9895880222320557, 'RelationshipScore': 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'MEDICATION', 'Traits': []}]}, {'Text': 'plastic flip', 'Type': 'TREATMENT', 'BeginOffset': 482, 'EndOffset': 494}, {'Text': 'a protective sleeve', 'Type': 'TREATMENT', 'BeginOffset': 541, 'EndOffset': 560}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 583, 'EndOffset': 584}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 591, 'EndOffset': 592}, {'Id': 19, 'BeginOffset': 599, 'EndOffset': 608, 'Score': 0.994967520236969, 'Text': 'topotecan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8967345952987671, 'RelationshipScore': 0.9359602928161621, 'RelationshipType': 'DOSAGE', 'Id': 17, 'BeginOffset': 583, 'EndOffset': 587, 'Text': '1 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8192265629768372, 'RelationshipScore': 0.999971866607666, 'RelationshipType': 'DOSAGE', 'Id': 18, 'BeginOffset': 591, 'EndOffset': 595, 'Text': '4 mg', 'Category': 'MEDICATION', 'Traits': []}]}]}